A Phase 1/2, Randomized, Dose-finding/Dose-confirmation Study to Evaluate the Reactogenicity, Safety and Immunogenicity of mRNA-based Multivalent Seasonal Influenza Vaccine Candidates Administered in Healthy Younger and Older Adults
Phase: PHASE1
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
1 
CLINICAL STUDY PROTOCOL 
Primary study Intervention(s) 
BIO FLU SV MRNA (GSK4382276A) 
Other study intervention(s) 
Study Identifier 
217884 (FLU SV MRNA-002) 
EU CT Number 
2022-502308-66-00 
IND number 
29301 
Approval Date 
28 Aug 2023 
Title 
A Phase 1/2, randomized, dose-finding/dose-
confirmation study to evaluate the reactogenicity, 
safety and immunogenicity of mRNA-based 
multivalent seasonal influenza vaccine candidates 
administered in healthy younger and older adults 
Brief title 
A study to find and confirm the dose and assess the 
safety, reactogenicity and immune response of a 
vaccine against influenza in healthy younger and 
older adults. 
Sponsor 
GlaxoSmithKline Biologicals S.A. 
Rue De L'Institut 89 
1330 Rixensart 
Belgium 
Sponsor signatory 
Pascal Peeters, MD 
Senior Director, Clinical Project Lead 
Medical monitor name and contact information will be provided in the local study 
contact information document. 
©2023 GSK group of companies or its licensor. 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
2 
PROTOCOL AMENDMENT 2 INVESTIGATOR AGREEMENT 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, 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 GCP and all applicable regulatory 
requirements. 
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study intervention and other study-related duties and functions as described 
in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site are qualified to perform those study-related 
duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained on-site or 
elsewhere without the approval of GSK and the express physical informed consent of 
the participant and/or the participant’s LAR. 
• 
To perform no biological assays on the clinical samples other than those described in 
the protocol or its amendment(s). 
• 
To co-operate with representative(s) of GSK in the monitoring and data management 
processes of the study with respect to data entry and resolution of queries about the 
data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator(s)’ ownership interest 
in the sponsor or the study 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. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
3 
Hence, I: 
• 
Agree to supply GSK with any necessary information regarding ownership interest 
and financial ties (including those of my spouse and dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other documents 
required by regulatory agencies for this study. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
4 
Study identifier 
217884 (FLU SV MRNA-002) 
EU CT Number 
2022-502308-66-00 
IND number 
29301 
Approval date 
28 Aug 2023 
Title 
A Phase 1/2, randomized, dose-finding/dose-
confirmation study to evaluate the reactogenicity, 
safety and immunogenicity of mRNA-based 
multivalent seasonal influenza vaccine candidates 
administered in healthy younger and older adults 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
5 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2 
28 Aug 2023 
Amendment 1 
07 April 2023 
Protocol 
02 February 2023 
Amendment 2 (28 Aug 2023) 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because it significantly impacts the safety of participants. 
Overall rationale for the current amendment: 
Following the first scheduled interim analysis (on reactogenicity, safety and 
immunogenicity data from Phase 1, up to Day 29 post-dosing), the protocol has been 
amended to include the doses selected for Phase 2, by the internal data review committee, 
as well as justification of dose selection. 
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: 
Section # and title 
Description of change 
Brief rationale 
1.2. Schema; Figure 2. Study 
design overview. Phase 2 
Figure updated according to sample 
size for Phase 2, and with Phase 2 
interim analysis at Day 29. 
Sample size was adjusted for 
Phase 2, and information for interim 
analysis at Day 29 was added. 
2.3.3. Overall benefit-risk 
conclusion 
Updated to include the safety, 
reactogenicity and immunogenicity 
conclusions from the Phase 1 part. 
The benefit-risk profile was updated 
to include the conclusion from the 
first scheduled interim analysis of 
Phase 1 data. 
4.1 Overall design 
Added that participants completing 
the Phase 2 part will be offered the 
opportunity to participate in the 
extension study. 
Participants completing the Phase 2 
part of this study will be offered the 
opportunity to participate in the 
extension study. 
4.1. Overall design; Table 7. List of 
study interventions for Phase 2 
4.3. Justification of dose 
4.3.2. Dose selection for Phase 2 
6.1 Study interventions 
administered; Table 9. Study 
interventions administered. Phase 2 
Selected dose levels (and study 
interventions) and study groups are 
now described 
Rationale for dose levels and study 
groups is provided in Section 4.3 
Justification for dose. 
4.1. Overall design 
6.3. Assignment to study 
intervention 
8.2.3. Immunological read-outs 
Updated according to the sample 
size proposed in Phase 2. 
The initial sample size for Phase 2 
was based on a conservative value 
of 0.55 standard deviation. The 
Phase 1 part indicated that 0.5 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
6 
Section # and title 
Description of change 
Brief rationale 
9.5.2. Sample size determination 
for Phase 2 
could be used and the sample size 
was adjusted accordingly. 
5.2.1. Medical conditions 
10.6.1. Specific requirements for 
South Africa 
Information regarding HIV testing of 
participants from South Africa 
before enrollment was added. 
To align with South African Health 
Products Regulatory Authority 
request. 
8.3.4. Myocarditis and pericarditis 
assessment and definitions 
Further details added from the 
already referenced Brighton 
Collaboration guidance on 
myocarditis/pericarditis 
investigation (SPEAC, 2022) to 
clarify the specific clinical data 
needed in the diagnostic 
procedures of 
myocarditis/pericarditis 
To further clarity the diagnostic 
procedures of 
myocarditis/pericarditis in Phase 2. 
8.3.7.2. Study holding rules; 
Table 13. Study holing rules for 
Phase 1, Table 14. Study holding 
rules for Phase 2 
Holding rule 2a for Phase 2 revised 
to include “same solicited AE 
lasting 2 consecutive days (48 
hours) or more as Grade 3.” 
Holding rule 2a and 2b for Phase 2 
thresholds changed from ≥2 to 
≥5% (and ≥2). 
To accommodate these changes 
the holding rule table was split in 
two. 
During Phase 1 it was observed 
that the endpoint for holding rule 2a 
was related to transient self-limiting 
events not considered relevant for 
justifying a study hold and the 
endpoint was therefore revised to 
events lasting 2 consecutive days 
or more. 
Thresholds changed to account for 
group size difference between 
Phase 1 (n=24 per group) and 
Phase 2 (n=120 per group).  
8.4.1. Time period and frequency 
for collecting AE, SAE, and other 
safety information 
Clarification of the role of the 
investigator in notifying the sponsor 
regarding AEs or SAEs after 
conclusion of study participation. 
Updated to clarify the role of the 
investigator in notifying the sponsor 
regarding AEs or SAEs after 
conclusion of study participation. 
9.4.1. Sequence of interim and 
other planned analyses 
Updated language regarding 
access to group data during Phase 
2 interim analysis. 
To provide further clarity on 
blinding. 
10.3.3. Solicited events 
10.3.4 Unsolicited AE 
Added language regarding eDiary 
process 
To comply with CBER’s non-hold 
recommendations  
 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
7 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 5 
List of main changes in the protocol and their rationale: ........................................... 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 14 
1. 
PROTOCOL SUMMARY ........................................................................................ 20 
1.1. 
Synopsis ..................................................................................................... 20 
1.2. 
Schema ...................................................................................................... 20 
1.3. 
Schedule of activities (SoA) ........................................................................ 22 
2. 
INTRODUCTION .................................................................................................... 30 
2.1. 
Study rationale ............................................................................................ 30 
2.2. 
Background ................................................................................................ 31 
2.3. 
Benefit/risk assessment .............................................................................. 31 
2.3.1. 
Risk assessment .......................................................................... 32 
2.3.2. 
Benefit assessment ..................................................................... 37 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 37 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 37 
4. 
STUDY DESIGN .................................................................................................... 40 
4.1. 
Overall design ............................................................................................. 40 
4.2. 
Scientific rationale for study design ............................................................. 45 
4.2.1. 
Rationale for study design of Phase 1 .......................................... 45 
4.2.2. 
Rationale for study design of Phase 2 .......................................... 46 
4.2.3. 
Rationale for choice of study population and choice of 
comparator .................................................................................. 47 
4.3. 
Justification for dose ................................................................................... 47 
4.3.1. 
Dose selection for Phase 1 .......................................................... 48 
4.3.2. 
Dose selection for Phase 2 .......................................................... 48 
4.4. 
End of study definition................................................................................. 50 
5. 
STUDY POPULATION ........................................................................................... 50 
5.1. 
Inclusion criteria .......................................................................................... 50 
5.2. 
Exclusion criteria ......................................................................................... 51 
5.2.1. 
Medical conditions ....................................................................... 51 
5.2.2. 
Prior/Concomitant therapy ........................................................... 52 
5.2.3. 
Other exclusions .......................................................................... 53 
5.3. 
Lifestyle considerations ............................................................................... 53 
5.4. 
Screen failures ............................................................................................ 53 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study intervention .................... 54 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 54 
6.1. 
Study intervention(s) administered .............................................................. 54 
6.1.1. 
Medical devices ........................................................................... 68 
6.2. 
Preparation, handling, storage, and accountability ...................................... 68 
6.3. 
Assignment to study intervention ................................................................ 68 
6.4. 
Blinding ....................................................................................................... 69 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
8 
6.4.1. 
Emergency unblinding ................................................................. 70 
6.5. 
Study intervention compliance .................................................................... 70 
6.6. 
Dose modification ....................................................................................... 70 
6.7. 
Continued access to study intervention after the end of the study ............... 70 
6.8. 
Treatment of overdose and management of anaphylaxis ............................ 70 
6.9. 
Prior and concomitant therapy .................................................................... 71 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 72 
7.1. 
Discontinuation of study intervention ........................................................... 72 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 72 
7.3. 
Lost to follow up .......................................................................................... 73 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 73 
8.1. 
Administrative baseline procedures ............................................................ 74 
8.1.1. 
Collection of demographic data .................................................... 74 
8.1.2. 
Medical/vaccination history .......................................................... 74 
8.1.3. 
Provision of eDiary device or installing of eDiary 
application on participant’s personal device ................................. 74 
8.2. 
Immunogenicity assessments ..................................................................... 75 
8.2.1. 
Biological samples ....................................................................... 75 
8.2.2. 
Laboratory assays ....................................................................... 76 
8.2.3. 
Immunological read-outs .............................................................. 78 
8.2.4. 
Immunological correlates of protection ......................................... 79 
8.3. 
Safety assessments .................................................................................... 79 
8.3.1. 
Physical examination ................................................................... 79 
8.3.2. 
Pre-dosing body temperature ....................................................... 80 
8.3.3. 
Warnings and precautions to administration of study 
intervention .................................................................................. 80 
8.3.4. 
Myocarditis and pericarditis assessment and definitions .............. 80 
8.3.5. 
Clinical safety laboratory tests ..................................................... 81 
8.3.6. 
Pregnancy testing ........................................................................ 82 
8.3.7. 
Study holding rules, safety monitoring committee ........................ 82 
8.3.7.1. 
Safety monitoring ....................................................... 82 
8.3.7.1.1. 
Phase 1 .................................................. 83 
8.3.7.1.2. 
Phase 2 (YA groups) .............................. 84 
8.3.7.1.3. 
Phase 2 (OA groups) .............................. 84 
8.3.7.2. 
Study holding rules ..................................................... 85 
8.4. 
Adverse events (AEs) serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 87 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 87 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 89 
8.4.3. 
Follow up of AEs and SAEs ......................................................... 89 
8.4.4. 
AEs of special interest ................................................................. 90 
8.4.4.1. 
Potential immune-mediated diseases ......................... 90 
8.4.4.2. 
Other AEs of special interest ...................................... 94 
8.4.5. 
Regulatory reporting requirements for SAEs/AESI ....................... 95 
8.4.6. 
Pregnancy ................................................................................... 95 
8.4.7. 
Contact information for reporting SAEs, AESIs, 
pregnancies and study holding rules ............................................ 96 
8.4.8. 
Participant card ............................................................................ 96 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
9 
8.4.9. 
Medical device deficiencies ......................................................... 97 
8.4.9.1. 
Time period for detecting medical device 
deficiencies ................................................................ 97 
8.4.9.2. 
Follow up of medical device deficiencies .................... 97 
8.4.9.3. 
Prompt reporting of device deficiencies to the 
sponsor ...................................................................... 97 
8.4.9.4. 
Regulatory reporting requirements for device 
deficiencies ................................................................ 98 
8.5. 
Pharmacokinetics ....................................................................................... 98 
8.6. 
Pharmacodynamics .................................................................................... 98 
8.7. 
Genetics ..................................................................................................... 98 
8.8. 
Biomarkers ................................................................................................. 98 
8.9. 
Immunogenicity assessments ..................................................................... 98 
8.10. 
Health economics ....................................................................................... 98 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 99 
9.1. 
Statistical hypotheses ................................................................................. 99 
9.2. 
Analysis sets ............................................................................................... 99 
9.3. 
Statistical analyses ..................................................................................... 99 
9.3.1. 
Co-primary reactogenicity and safety endpoints......................... 100 
9.3.1.1. 
Analysis of reactogenicity: Bayesian Logistic 
Regression Model (BLRM) ....................................... 100 
9.3.2. 
Co-primary and secondary immunogenicity endpoints ............... 101 
9.4. 
Interim analyses ........................................................................................ 102 
9.4.1. 
Sequence of interim and other planned analyses ....................... 102 
9.4.2. 
Statistical considerations associated with the interim 
analyses .................................................................................... 102 
9.5. 
Sample size determination ........................................................................ 102 
9.5.1. 
Sample size determination for Phase 1 ...................................... 103 
9.5.2. 
Sample size determination for Phase 2 ...................................... 103 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 104 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations ........ 104 
10.1.1. 
Regulatory and ethical considerations ....................................... 104 
10.1.2. 
Financial disclosure ................................................................... 105 
10.1.3. 
Informed consent process .......................................................... 105 
10.1.4. 
Recruitment strategy .................................................................. 106 
10.1.5. 
Data protection .......................................................................... 106 
10.1.6. 
Committees structure ................................................................. 107 
10.1.7. 
Dissemination of clinical study data ........................................... 107 
10.1.8. 
Data quality assurance .............................................................. 108 
10.1.9. 
Source documents ..................................................................... 108 
10.1.10. Study and site start and closure ................................................. 109 
10.1.11. Publication policy ....................................................................... 110 
10.2. 
Appendix 2: Clinical laboratory tests ......................................................... 110 
10.2.1. 
Protocol-required safety laboratory assessments ....................... 110 
10.2.2. 
FDA Guidance for industry: Toxicity grading scale for 
healthy adult and adolescent volunteers enrolled in 
preventive vaccine clinical trials (September 2007) .................... 111 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow up, and reporting .......................................... 112 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
10 
10.3.1. 
Definition of AE .......................................................................... 112 
10.3.2. 
Definition of SAE ........................................................................ 114 
10.3.3. 
Solicited events.......................................................................... 115 
10.3.4. 
Unsolicited AE ........................................................................... 116 
10.3.5. 
Recording, assessment and follow up of AE, SAE, AESIs 
and pregnancies ........................................................................ 116 
10.3.5.1. AE and SAE recording .............................................. 116 
10.3.5.2. Time period for collecting and recording AEs, 
SAEs, AESIs and pregnancies ................................. 117 
10.3.5.3. Assessment of intensity ............................................ 118 
10.3.5.4. Assessment of causality ........................................... 119 
10.3.5.5. Assessment of outcomes.......................................... 120 
10.3.5.6. Follow up of AEs, SAEs, AESIs, pregnancies 
or any other events of interest .................................. 120 
10.3.5.7. Updating of SAE, AESI and pregnancy 
information after removal of write access to the 
participant’s eCRF .................................................... 121 
10.3.6. 
Reporting of SAEs, AESIs and pregnancies .............................. 121 
10.4. 
Appendix 4: Contraceptive and barrier guidance ....................................... 122 
10.4.1. 
Definitions .................................................................................. 122 
10.4.1.1. Woman of childbearing potential (WOCBP) .............. 122 
10.4.1.2. Woman of non-childbearing potential 
(WONCBP) ............................................................... 122 
10.4.2. 
Contraception guidance ............................................................. 123 
10.5. 
Appendix 5: Medical device AEs, ADEs, SAEs, sADEs, USADEs 
and device deficiencies: Definitions and procedures for recording, 
evaluating, follow up, and reporting in medical device studies .................. 124 
10.5.1. 
Definition of medical device AE and ADE................................... 124 
10.5.2. 
Definition of medical device SAE, SADE and USADE ................ 125 
10.5.3. 
Definition of device deficiency .................................................... 125 
10.5.4. 
Recording and follow up of medical device AE and/or SAE 
and device deficiencies .............................................................. 126 
10.5.4.1. Medical device AE, SAE, and device deficiency 
recording .................................................................. 126 
10.5.4.2. Assessment of intensity ............................................ 126 
10.5.4.3. Assessment of causality ........................................... 126 
10.5.4.4. Follow-up of medical device AE/SAE and 
device deficiency ...................................................... 127 
10.5.5. 
Reporting of medical device SAEs ............................................. 127 
10.5.6. 
Reporting of SADEs ................................................................... 128 
10.5.7. 
Reporting of medical device deficiencies for associated 
person ....................................................................................... 128 
10.6. 
Appendix 6: Country-specific requirements ............................................... 129 
10.6.1. 
Specific requirements for South Africa ....................................... 129 
10.7. 
Appendix 7 Statistics: BLRM Model specification and data scenarios ....... 129 
10.8. 
Appendix 8: Protocol amendment history .................................................. 130 
11. REFERENCES ..................................................................................................... 133 
 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
11 
LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities (SoA). Phase 1 ..................................................... 22 
Table 2 
Schedule of activities (SoA). Phase 2 ..................................................... 25 
Table 3 
Intervals between study visits. Phase 1 .................................................. 29 
Table 4 
Intervals between study visits. Phase 2 .................................................. 29 
Table 5 
Objectives and endpoints ....................................................................... 37 
Table 6 
Potential study interventions composition (Phase 1) .............................. 42 
Table 7 
List of study interventions for Phase 2 .................................................... 44 
Table 8 
Study intervention(s) administered. Phase 1 - (Table spreading 
through multiple pages) .......................................................................... 55 
Table 9 
Study intervention(s) administered. Phase 2 .......................................... 63 
Table 10 
Approximate volume of blood collected at each time point and 
during the whole study ........................................................................... 76 
Table 11 
Laboratory assays .................................................................................. 76 
Table 12 
Immunological read-outs ........................................................................ 78 
Table 13 
Study holding rules for Phase 1 .............................................................. 85 
Table 14 
Study holding rules for Phase 2 .............................................................. 86 
Table 15 
Collection and reporting of safety information ......................................... 88 
Table 16 
List of potential immune-mediated diseases (pIMDs) ............................. 90 
Table 17 
Timeframes for submitting SAE, pregnancy and other events 
reports to GSK ....................................................................................... 95 
Table 18 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules ................................................................................. 96 
Table 19 
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 .................. 103 
Table 20 
Half-width of 95% CI for the group difference in seroconversion 
rates by to control and strain (Evaluable N per group = 108) ................ 104 
Table 21 
Protocol-required safety laboratory tests (Phase 1 only) ...................... 111 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
12 
Table 22 
Toxicity grading scales for biochemistry parameters evaluated in 
the current study (adapted from FDA Guidance for industry) ................ 111 
Table 23 
Toxicity grading scales for hematology parameters evaluated in 
the current study (adapted from FDA Guidance for industry) ................ 112 
Table 24 
Solicited administration site events....................................................... 115 
Table 25 
Solicited systemic events ..................................................................... 115 
Table 26 
Intensity scales for solicited events in participants of 6 years of 
age or more .......................................................................................... 118 
Table 27 
Highly effective contraceptive methods ................................................ 123 
Table 28 
Hypothetical data scenarios for assessment of reactogenicity 
using BLRM in YAs .............................................................................. 130 
 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
13 
LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview. Phase 1 ............................................................ 20 
Figure 2 
Study design overview. Phase 2 ............................................................ 21 
 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
Ab 
Antibody 
ADE 
Adverse device effect 
AE 
Adverse event 
AESI 
Adverse events of special interest 
BLRM 
Bayesian Logistic Regression Model 
BMI 
Body mass index 
CI 
Confidence interval 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EoS 
End of study 
ES 
Exposed set 
FDA 
Food and Drug Administration, United States of 
America 
FSFV 
First subject first visit 
FTiH 
First-time in human 
GCP 
Good clinical practices 
GMI 
Geometric mean increase 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
15 
Abbreviation 
Definition 
GMT 
Geometric mean titers 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ICSR 
Individual case safety reports 
iDRC 
Internal Data Review Committee 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
iSRC 
Internal Safety Review Committee 
LLOQ 
Lower level of quantification 
LSLV 
Last Subject Last Visit 
MAE 
Medically attended event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
Microneutralization 
OA 
Older adult 
PI 
Prescribing Information 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
16 
Abbreviation 
Definition 
pIMD 
Potential immune-mediated disease 
PPS 
Per Protocol set 
PRO 
Patient-related outcomes 
PT 
Preferred term 
QTL 
Quality tolerance limit 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SBIR 
Source data Base for Internet Randomization  
SCR 
Seroconversion rate 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SPR 
Seroprotection rate 
SRT 
Safety Review Team 
USADE 
Unanticipated serious adverse device effect 
VAERS 
Vaccine adverse event reporting system 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of non-childbearing potential 
YA 
Younger adult 
 
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
17 
Term 
Definition 
Adverse event of special 
interest 
An adverse event of special interest (serious or non-
serious) is one of scientific and medical concern specific 
to the sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the investigator 
to the sponsor may be appropriate. Such events may 
require further investigation in order to characterize and 
understand them. Depending on the nature of the event, 
rapid communication by the trial sponsor to other parties 
may also be needed (e.g., regulators) [CIOMS, 2021]. 
Blinding 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a SAE. 
In 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.  
Caregiver 
A ‘caregiver’ is someone who 
• 
lives in the close surroundings of a participant and 
has a continuous caring role or 
• 
has substantial periods of contact with a participant 
and is engaged in their daily health care (e.g., a 
relative of the participant, a nurse who helps with 
daily activities in case of residence in a nursing 
home). 
In the context of a clinical study, a caregiver could 
include an individual appointed to oversee and support 
the participant's compliance with protocol-specified 
procedures. 
Certified copy 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e., by a dated 
signature or by generation through a validated process) 
to have the same information, including data that 
describe the context, content, and structure, as the 
original. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
18 
Term 
Definition 
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. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced. 
Immunological correlate of 
protection 
A correlate of risk that has been validated to predict a 
certain level of protection from the targeted endpoint. 
Intercurrent medical 
conditions 
Intercurrent medical conditions are defined as medical 
conditions that occur after vaccine administration and 
either preclude observation of the outcome of interest 
(immunogenicity/efficacy endpoint) or affect its 
interpretation (by altering the immune response to 
vaccination or altering the initial immune status of the 
participant). 
Intervention number 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational 
medicinal/vaccine product 
An IMP is a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a 
clinical study, including products already with a 
marketing authorization but used or assembled 
(formulated or packaged) in a way different from the 
authorized form, or when used for an unauthorized 
indication, or when used to gain further information 
about the authorized form. Medicinal products with a 
marketing authorization are IMPs when they are to be 
used as the test substance, reference substance, or 
comparator in a clinical study, provided the 
requirement(s) in the definition is/are met. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
19 
Term 
Definition 
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. 
Medically attended event 
An AE that results in an unscheduled visit to a medical 
professional (e.g., physician’s office visits, emergency 
room visits or hospitalization). 
Participant 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject. 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Self-contained study 
Study with objectives not linked to the data of another 
study. 
Source data 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 
Study 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. 
Study monitor 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
Subset 
A group of participants for whom specific study 
procedures are planned as compared to other 
participants or a group of participants who share a 
common characteristic (e.g., ages, vaccination schedule, 
etc.) at the time of enrollment. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
20 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol title: 
A Phase 1/2, randomized, dose-finding/dose-confirmation study to evaluate the 
reactogenicity, safety and immunogenicity of mRNA-based multivalent seasonal 
influenza vaccine candidates administered in healthy younger and older adults. 
Brief title: 
A Phase 1/2, randomized, dose-finding/dose-confirmation study to evaluate how healthy 
younger and older adults respond to mRNA-based seasonal influenza vaccine candidates. 
Rationale: Refer to Section 2.1. 
Objectives, Endpoints and Estimands: Refer to Section 3. 
Overall Design: Refer to Section 4.1. 
Number of Participants: Refer to Section 9.5. 
Data Monitoring/Other Committee: Refer to Section 10.1.6. 
1.2. 
Schema 
Figure 1 
Study design overview. Phase 1  
 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
21 
D: day; SRT: safety review team; iDRC: internal data review committee; N: number of participants 
Control: licensed influenza vaccine. Refer to Section 4.1 for more information. 
* Safety review of 7-days post-dosing (Day 8) data of sentinel participants by SRT. Refer to Section 8.3.7.1 for details. 
** Selection of doses/formulations for Phase 2 by the iDRC. Refer to Section 4.3 for more information. 
*** Contact 1 will only be applicable for the first 5 participants per group. Remaining Phase 1 participants will not have 
any contact at Day 2. 
**** Visit 4 and 5 will be replaced by a Contact if participant has received the standard of care vaccination against 
seasonal flu after Day 29 and prior to this visit and did not report any adverse events that would require physical 
examination on site. 
Figure 2 
Study design overview. Phase 2 
 
D: day; EoS: end of study; SRT: safety review team; iSRC: internal safety review committee; N: number of participants. 
Control: licensed influenza vaccine. Refer to Section 4.1 for more information. 
* Safety review of 7-days post-dosing (Day 8) data of sentinel OA participants by SRT/iSRC. Refer to Section 8.3.7.1 
for details. 
** Contact 1 will only be applicable for the first 5 participants in OA groups. Visit 2 (Day 2) will only be applicable for 
participants in the exploratory immunogenicity subset in Phase 2. Remaining Phase 2 participants will not have any 
contact or visit at Day 2. 
*** Visit 3 (Day 8) will be replaced by a Contact for all non-subset participants in Phase 2. 
† Visit 5 and 6 will be replaced by a Contact if participant has received the standard of care vaccination against 
seasonal flu after Day 29 prior to this visit and did not report any adverse events that would require physical 
examination on site. 
 ‡ Additional blood samples will be collected for a subset of participants in Phase 2. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
22 
1.3. 
Schedule of activities (SoA)  
Table 1 
Schedule of activities (SoA). Phase 1 
Type Of Contact 
Screening 
Visit 
Visit 1 
Contact 1* Contact 2 Visit 2 
Visit 3 
Visit 4‡ 
Visit 5‡ 
Notes 
Timepoints 
Day -28 to 
Day 1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 29 
Day 92  Day 183 
Informed consent 
●a 
 
 
 
 
 
 
 
See Section 10.1.3 for details  
Inclusion and 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 8.1.1 for details 
Medical and vaccination history  
● 
○ a 
 
 
 
 
 
 
See Section 8.1.2 for details 
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 8.3.1 for details 
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 8.3.6 for details 
Randomization  
 
○ a 
 
 
 
 
 
 
Country, study, center and flu vaccination history in 
the past 2 years will be used as minimization factor. 
Sentinel status will be a stratification factor. 
See Section 6.3 for details. 
Check contraindications, warnings, 
and precautions to vaccination 
 
○a 
 
 
 
 
 
 
See Section 8.3.3 for details 
Check criteria for temporary delay 
for enrollment and/or study 
intervention administration  
 
○a 
 
 
 
 
 
 
See Section 5.5 for details 
Study group and intervention 
number allocation 
 
●a 
 
 
 
 
 
 
See Section 6.3 for details 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
23 
Type Of Contact 
Screening 
Visit 
Visit 1 
Contact 1* Contact 2 Visit 2 
Visit 3 
Visit 4‡ 
Visit 5‡ 
Notes 
Timepoints 
Day -28 to 
Day 1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 29 
Day 92  Day 183 
Body temperature before study 
intervention administration 
 
●a 
 
 
 
 
 
 
Fever is defined as a temperature ≥38.0°C/100.4°F 
regardless the location of measurement. 
The preferred location for measuring temperature will 
be axillary. 
See Section 8.3.2 for details 
Administration of study intervention 
 
● 
 
 
 
 
 
 
See Section 6.1 for details 
Recording of administered study 
intervention number 
 
● 
 
 
 
 
 
 
 
Post-dose observation period 
 
○ 
 
 
 
 
 
 
See Section 6.1 for details 
Distribution of participant card 
 
○ 
 
 
 
 
 
 
See Section 8.4.8 for details 
Check participant’s device 
compatibility for eDiary data 
collection 
○ 
○ 
 
 
 
 
 
 
See Section 8.1.3 for details 
Training and installing/assigning 
eDiary 
 
○ 
 
 
 
 
 
 
See Section 8.1.3 for details 
Review of eDiary data 
 
 
○ 
○ 
○ 
○ 
 
 
Reporting 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 Sections 8.10 and 8.4.1 for details 
Return/uninstalling of eDiary 
 
 
 
 
 
○ 
 
 
See Section 10.3.5.1 for details 
Laboratory assessment  
Urine sampling for routine safety 
panel 
All participants 
● 
 
 
 
 
 
 
 
Volume of urine sample will be defined as per local 
practice. 
See Section 8.2.1 for details 
Blood sampling for antibody 
determination (~30 mL) 
 
○ a 
 
 
 
○ 
○** 
○** 
For this assessment, serum has to be isolated from 
blood. 
See Section 8.2.1 for details 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
24 
Type Of Contact 
Screening 
Visit 
Visit 1 
Contact 1* Contact 2 Visit 2 
Visit 3 
Visit 4‡ 
Visit 5‡ 
Notes 
Timepoints 
Day -28 to 
Day 1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 29 
Day 92  Day 183 
Blood sampling for routine safety 
panel (~10 mL) 
● 
●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 8.2.1 for details 
Safety assessments 
Record any concomitant 
vaccinations 
 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 6.9 for details 
Recording of SAEs related to study 
participation, or to a concurrent 
GSK medication/vaccine 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 8.4.1 for details 
Record AEs leading to withdrawal 
from study  
 
● 
● 
● 
● 
● 
● 
● 
See Section 8.4.1 for details 
Recording of non-serious adverse 
events 
 
● 
● 
● 
● 
● 
 
 
See Section 8.4.1 for details 
Recording of MAEs, SAEs, AESIs 
and pregnancies  
 
● 
● 
● 
● 
● 
● 
● 
See Section 8.4.1 for details 
Record any concomitant 
medications 
 
● 
● 
● 
● 
● 
● 
● 
See Section 6.9 for details 
Record any intercurrent medical 
conditions 
 
● 
● 
● 
● 
● 
● 
● 
See Section 9.2 for details 
Study conclusion 
 
 
 
 
 
 
 
● 
See Section 10.1.10 for details 
● Is used to indicate a study procedure that requires documentation in the individual eCRF 
○ Is used to indicate a study procedure that does not require documentation in the individual eCRF 
a 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. 
* Contact 1 (Day 2) will only be applicable for the sentinel participants in Phase 1. Remaining Phase 1 participants will not have a visit or contact at Day 2. 
** Blood samples should only be collected for participants who did not receive a standard of care vaccination against seasonal flu since their enrollment into the study. 
‡ Visit 4 and 5 will be replaced by a Contact if participant has received the standard of care vaccination against seasonal flu after Day 29 and prior to this visit and did not report any 
adverse events that would require physical examination on site. 
Contact may be via telephone, SMS, email, video-telephone/telemedicine or other means, depending on local best practice. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
25 
Table 2 
Schedule of activities (SoA). Phase 2  
Type Of Contact 
Visit 1 
Visit 2*  Contact 1** Contact 2 
Visit 3† 
Visit 4 
Visit 5‡ Visit 6‡ 
Notes 
Timepoints 
Day 1 
Day 2 
Day 2 
Day 3 
Day 8 
Day 29 
Day 92  Day 183 
Informed consent 
●a 
 
 
 
 
 
 
 
See Section 10.1.3 for details 
Inclusion and 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 8.1.1 for details 
Medical and vaccination history  
● a 
 
 
 
 
 
 
 
See Section 8.1.2 for details 
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 8.3.1 for details 
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 8.3.6 for details 
Randomization  
○ a 
 
 
 
 
 
 
 
Country, study, center and flu vaccination history in 
the past 2 years will be used as minimization factor. 
Age group and sentinel status will be stratification 
factors. 
See Section 6.3 for details. 
Check contraindications, warnings, 
and precautions to vaccination 
○a 
 
 
 
 
 
 
 
See Section 8.3.3 for details 
Check criteria for temporary delay 
for enrollment and/or study 
intervention administration  
○a 
 
 
 
 
 
 
 
See Section 5.5 for details 
Study group and intervention 
number allocation 
●a 
 
 
 
 
 
 
 
See Section 6.3 for details 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
26 
Type Of Contact 
Visit 1 
Visit 2*  Contact 1** Contact 2 
Visit 3† 
Visit 4 
Visit 5‡ Visit 6‡ 
Notes 
Timepoints 
Day 1 
Day 2 
Day 2 
Day 3 
Day 8 
Day 29 
Day 92  Day 183 
Body temperature before study 
intervention administration 
●a 
 
 
 
 
 
 
 
Fever is defined as a temperature 
≥38.0°C/100.4°F regardless the location of 
measurement. 
The preferred location for measuring temperature 
will be axillary. 
See Section 8.3.2 for details 
Administration of study intervention 
● 
 
 
 
 
 
 
 
See Section 6.1 for details 
Recording of administered study 
intervention number 
● 
 
 
 
 
 
 
 
 
Post-dose observation period 
○ 
 
 
 
 
 
 
 
See Section 6.1 for details 
Distribution of participant card 
○ 
 
 
 
 
 
 
 
See Section 8.4.8 for details 
Check participant’s device 
compatibility for eDiary data 
collection 
○ 
 
 
 
 
 
 
 
See Section 8.1.3 for details 
Training and installing/assigning 
eDiary 
○ 
 
 
 
 
 
 
 
See Section 8.1.3 for details 
Review of eDiary data 
 
○ 
○ 
○ 
○ 
○ 
 
 
Reporting 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 Sections 8.10 and 8.4.1 for details 
Return/uninstalling of eDiary 
 
 
 
 
 
○ 
 
 
See Section 10.3.5.1 for details 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
27 
Type Of Contact 
Visit 1 
Visit 2*  Contact 1** Contact 2 
Visit 3† 
Visit 4 
Visit 5‡ Visit 6‡ 
Notes 
Timepoints 
Day 1 
Day 2 
Day 2 
Day 3 
Day 8 
Day 29 
Day 92  Day 183 
Laboratory assessment  
Blood sampling for antibody 
determination 
○ a 
 
 
 
 
○ 
○*** 
○*** 
For this assessment, serum has to be isolated from 
blood. 
See Section 8.2.1 for details 
For YA non-subset participants in Phase 2, the 
individual volume per visit will be 30 mL 
For OA non-subset participants in Phase 2, the 
individual volume per visit will be 10 mL. 
For YA and OA subset participants in Phase 2 the 
individual volume per visit will be 10 mL. 
Blood sampling for CMI response 
(PBMC) 
Subset of Phase 2 participants 
○a 
 
 
 
○ 
 
 
○*** 
Volume to be collected: 
Visit 1 and Visit 6: ~40 mL per visit 
Visit 3: ~60 mL 
See Section 8.2.1 for details 
Blood sampling for cell-produced 
cytokine response (whole blood, 
 tubes) (~4 mL) 
Subset of Phase 2 participants 
○a 
 
 
 
○ 
 
 
 
For 
 sample collection will be limited to 
selected sites. 
See Section 8.2.1 for details 
Blood sampling for innate response 
(~5 mL) 
Subset of Phase 2 participants 
○a 
○ 
 
 
○ 
 
 
 
For this assessment, plasma should be isolated 
from blood. 
See Section 8.2.1 for details 
Blood sampling for humoral 
immunity for circulating drift variants 
of the vaccine subtypes not used in 
the vaccine, for MN and potential 
additional exploratory assays 
(~20 mL) 
Subset of Phase 2 participants 
○a 
 
 
 
 
○ 
 
○*** 
For this assessment, serum should be isolated 
from blood. 
See Section 8.2.1 for details 
Safety assessments 
Record any concomitant 
vaccinations 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 6.9 for details 
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
28 
Type Of Contact 
Visit 1 
Visit 2*  Contact 1** Contact 2 
Visit 3† 
Visit 4 
Visit 5‡ Visit 6‡ 
Notes 
Timepoints 
Day 1 
Day 2 
Day 2 
Day 3 
Day 8 
Day 29 
Day 92  Day 183 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 8.4.1 for details 
Record AEs leading to withdrawal 
from study  
● 
● 
● 
● 
● 
● 
● 
● 
See Section 8.4.1 for details 
Recording of non-serious adverse 
events  
● 
● 
● 
● 
● 
● 
 
 
See Section 8.4.1 for details 
Recording of MAEs, SAEs, AESIs 
and pregnancies  
● 
● 
● 
● 
● 
● 
● 
● 
See Section 8.4.1 for details 
Record any concomitant 
medications 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 6.9 for details 
Record any intercurrent medical 
conditions 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 9.2 for details 
Study conclusion 
 
 
 
 
 
 
 
● 
See Section 10.1.10 for details 
● Is used to indicate a study procedure that requires documentation in the individual CRF/eCRF 
○ Is used to indicate a study procedure that does not require documentation in the individual CRF/eCRF 
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. 
* Visit 2 (Day 2) will only be applicable for participants in the exploratory immunogenicity subset in Phase 2. Remaining Phase 2 participants will not have a visit at Day 2. 
** Contact 1 (Day 2) will only be applicable for the sentinel OA participants in Phase 2. Remaining Phase 2 participants will not have a contact at Day 2. 
*** Blood samples should only be collected for participants who did not receive a standard of care vaccination against seasonal flu since their enrollment into the study. 
† Visit 3 (Day 8) will be replaced by a Contact for all non-subset participants in Phase 2 and if participant did not report any adverse events that would require physical examination on 
site. 
‡ Visit 5 and 6 will be replaced by a Contact if participant has received the standard of care vaccination against seasonal flu after Day 29 and prior to this visit and did not report any 
adverse events that would require physical examination on site. 
Contact may be via telephone, SMS, email, video-telephone/telemedicine or other means, depending on local best practice. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
29 
Table 3 
Intervals between study visits. Phase 1 
Interval* 
Planned visit interval  
Allowed interval range 
Screening Visit** → Visit 1 
1-28 days 
1 – 28 days 
Visit 1 → Contact 1*** 
1 day 
1 day 
Visit 1 → Contact 2 
2 days 
2-3 days 
Visit 1 → Visit 2 
7 days 
6-8 days 
Visit 1 → Visit 3 
28 days 
28-35 days 
Visit 1 → Visit 4‡  
91 days 
84-98 days 
Visit 1 → Visit 5‡ 
182 days 
180-210 days 
* Interval is computed as the difference between 2 dates 
** Screening Visit is planned for participants enrolled in Phase 1 and needs to be performed within 28 days before 
Visit 1, with sufficient time to receive/review the hematology, biochemistry, HbA1c 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. In this 
case, all screening procedures must be completed within 28 days before Visit 1 (Day 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 only be applicable for the sentinel participants in Phase 1. Remaining Phase 1 participants 
will not have a visit or contact at Day 2. 
‡ Visit 4 and 5 will be replaced by a Contact if participant has received the standard of care vaccination against 
seasonal flu after Day 29 and prior to this visit and did not report any adverse events that would require physical 
examination on site. 
Table 4 
Intervals between study visits. Phase 2 
Interval* 
Planned visit interval  
Allowed interval range 
Visit 1 → Visit 2** 
1 day 
1 day 
Visit 1 → Contact 1*** 
1 day 
1 day 
Visit 1 → Contact 2 
2 days 
2-3 days 
Visit 1 → Visit 3† 
7 days 
6-8 days 
Visit 1 → Visit 4 
28 days 
28-35 days 
Visit 1 → Visit 5‡  
91 days 
84-98 days 
Visit 1 → Visit 6‡ 
182 days 
180-210 days 
* Interval is computed as the difference between 2 dates 
** Visit 2 (Day 2) will only be applicable for participants in the exploratory immunogenicity subset in Phase 2. 
Remaining Phase 2 participants will not have a visit at Day 2. 
*** Contact 1 (Day 2) will only be applicable for the sentinel OA participants in Phase 2. Remaining Phase 2 
participants will not have a contact at Day 2. 
† Visit 3 (Day 8) will be replaced by a Contact for all non-subset participants in Phase 2 and if participant did not report 
any adverse events that would require physical examination on site. 
‡ Visit 5 and 6 will be replaced by a Contact if participant has received the standard of care vaccination against 
seasonal flu after Day 29 and prior to this visit and did not report any adverse events that would require physical 
examination on site. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
30 
2. 
INTRODUCTION 
2.1. 
Study rationale 
Annual influenza vaccination is currently the most effective mean of controlling 
influenza and preventing its complications and mortality [WHO, 2018]. 
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]. 
GSK and CureVac are developing a quadrivalent seasonal influenza vaccine based on 
mRNAs encoding the genetic sequences of 4 
 
, encapsulated in lipid nanoparticles. The vaccine is based 
on CureVac’s second-generation mRNA backbone and modified nucleotides (i.e., N1-
methyl-pseudouridine [N1mΨ]) which together are expected to have increased 
immunogenicity and lower reactogenicity [Stuart, 2021] compared to the mRNA 
platform used in the CVnCoV study [Kremsner, 2021]. Three clinical studies using the 
second-generation mRNA backbone (2 of them using modified nucleotides) have 
provided reactogenicity, safety and immunogenicity data to support the design of the 
current Phase 1/2 study: 
• 
 was a CureVac-sponsored dose-escalation Phase 1 study in healthy 
younger adults (YAs) and older adults (OAs). The study evaluated a multivalent 
seasonal influenza mRNA investigational vaccine based on unmodified nucleotides. 
Safety and reactogenicity data showed the vaccine candidate to be generally well 
tolerated with no safety concerns observed across all tested dose levels 
 
 Refer to IB for more information. 
• 
FLU SV MRNA-003 is an ongoing GSK-sponsored dose-escalation Phase 1 study in 
healthy YAs and OAs. The study is evaluating a monovalent influenza mRNA 
investigational vaccine based on modified nucleotides. Safety and reactogenicity 
data show the investigational vaccine to be generally well tolerated with no safety 
concerns observed across all tested dose levels 
 Refer to IB for more 
information. 
• 
CV2 SARS-COV2-012 BST is a GSK-sponsored dose-escalation Phase 1 study in 
healthy YAs and OAs. The study is evaluating a COVID-19 investigational vaccine 
based on modified nucleotides. Safety and reactogenicity data show the 
investigational vaccine to be generally well tolerated with no safety concerns 
observed across all tested dose levels 
). Refer to IB for more 
information. 
In the current Phase 1/2 study, the safety, reactogenicity and immunogenicity of 
quadrivalent seasonal influenza investigational study interventions will be evaluated. The 
study consists of an exploratory dose-finding part (Phase 1) and dose-confirmation part 
(Phase 2). All study interventions will be based on the second-generation mRNA 
backbone and modified nucleotides. The data generated in Phase 1 (Refer to the IB for 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
31 
more information) will be used to determine the study interventions in Phase 2. The 
investigational study interventions in Phase 1 and Phase 2 will be compared to licensed 
influenza vaccines. 
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 world’s 
population is typically infected, resulting in 3-5 million cases of severe illness. Moreover, 
up to 650 000 deaths annually are associated with seasonal influenza [WHO, 2017]. 
Please refer to the current Investigator’s Brochure (IB) for information regarding pre-
clinical and clinical studies of Flu Seasonal mRNA. 
2.3. 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of Flu Seasonal mRNA may be found in the 
IB. 
Detailed information about the known and expected benefits and risks and expected AEs 
related to the licensed influenza vaccines used as active controls can be found in the 
respective Summary of Product Characteristics (SmPC) or Prescribing Information (PI). 
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. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
32 
2.3.1. 
Risk assessment  
Potential risk 
Summary of data/rationale for risk 
Mitigation strategy 
All study vaccines  
Hypersensitivity reactions, including anaphylaxis Hypersensitivity reactions following vaccinations 
are not uncommon but are mostly non-serious. 
Serious allergic reactions, including 
anaphylaxis, are usually very rare [McNeil, 
2019]. The US Vaccine Safety Datalink found 
that most cases of anaphylaxis occurred shortly 
after vaccination [Law, 2021]. In general, the 
symptoms can be treated successfully if the 
treatment is started quickly. There is currently 
limited data on the risk of hypersensitivity 
reactions following mRNA flu vaccines. 
Severe hypersensitivity events occurring within 
24 hours of dosing will be collected as AESIs. 
Participants with a history of hypersensitivity to 
any previous vaccine or any component of the 
study intervention (including latex, polyethylene 
glycol, egg protein and aminoglycoside 
antibiotics) will be excluded from study 
participation. 
All participants will be observed for a specified 
period following dosing (60 minutes for Phase 1; 
30 minutes for YA and 60 minutes for OA 
participants in Phase 2). Appropriate 
resuscitation equipment, medication and trained 
staff will be available at the vaccination site. 
Participants will be instructed to contact the 
study site immediately for occurrence of any 
possible hypersensitivity reaction within 1 day 
following study intervention administration. 
Bell’s Palsy 
Previous studies have shown controversial 
results on the risk of Bell’s palsy after influenza 
vaccination [Ozonoff, 2021; Bardage, 2011; 
Huang, 2012; Wijnans, 2017; Baxter, 2017; 
Mutsch, 2004]. A review of vaccine adverse 
event reporting system (VAERS) data found 
Participants with a history of, or uncontrolled, 
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. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
33 
Potential risk 
Summary of data/rationale for risk 
Mitigation strategy 
increased reporting of facial paralysis following 
any influenza vaccination seems to be higher 
compared with that following the administration 
of other vaccines. However, the authors 
cautioned that the findings need to be 
interpreted in light of the limitations of data 
generated from VAERS, which is exploratory 
rather than confirmatory [Kamath, 2020]. A 
recent review of vaccines, including influenza 
vaccines and mRNA-based Covid-19 vaccines, 
and Bell’s palsy found insufficient evidence to 
confirm an excess risk of Bell’s palsy following 
vaccination, with the exception of an intranasally 
administered influenza vaccine adjuvanted with 
E.coli heat-labile toxin. In the case of the 
intranasal influenza vaccine, the adjuvant was 
the suggested cause [Bertin, 2022]. 
Literature is sparse regarding the potential 
mechanism that may be involved. Of note, Bell’s 
palsy has also been reported to occur following 
influenza infection. Bell’s palsy is included in the 
product information (under Post-Marketing 
Data) of some influenza vaccines (e.g., Fluzone 
Quadrivalent, Fluzone High-Dose Quadrivalent). 
Given the association between influenza 
infection and the incidence of facial palsy and 
due to the earlier associations with influenza 
vaccination and that the potential mechanism is 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
34 
Potential risk 
Summary of data/rationale for risk 
Mitigation strategy 
still not completely understood, Bell’s palsy is 
proposed as an important potential risk for this 
candidate vaccine. 
Guillain-Barré Syndrome (GBS) 
The risk window of GBS is in the first 6 weeks 
post-vaccination. The estimated risk of GBS is 1 
-to 2 cases per million vaccinations. One of the 
biological mechanisms for GBS following 
influenza vaccine may involve the synergistic 
effects of endotoxins and vaccine-induced 
autoimmunity. Of note, influenza infection has 
also been associated with GBS. The estimated 
risk of GBS after influenza has been reported to 
be 17.2 cases per 1 million patients hospitalized 
with influenza. Furthermore, a study in Norway 
during the 2009 pandemic (H1N1) influenza 
found that the risk of GBS after influenza 
infection was higher than the relative risk for 
pH1N1 vaccination [Babazadeh, 2019]. 
Despite the small observed increased risk of 
GBS after influenza vaccination, evidence is 
growing in support of an apparent larger benefit 
of vaccination in the context of population health 
[Vellozzi, 2014]. 
GBS has been included in the product 
information (under Warnings and Precautions 
and/or Post-Marketing Data) of some influenza 
vaccines (e.g., Fluarix Quadrivalent, Fluad 
Participants with a history of, or uncontrolled, 
neurological disorders or seizures, including 
GBS, will be excluded from the study 
enrollment. Moreover, pIMDs including GBS will 
be collected as AESIs 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
35 
Potential risk 
Summary of data/rationale for risk 
Mitigation strategy 
Tetra, Fluzone Quadrivalent, Fluzone High-
Dose Quadrivalent). 
Given the association between influenza 
infection and GBS and due to the earlier 
associations with influenza vaccination this 
potential risk needs to be evaluated for any 
possible association with the Flu Seasonal 
mRNA vaccine. 
Study procedures 
Pain and bruising 
Pain or bruising at the site where blood is 
drawn. 
A topical analgesic may be applied to the site 
where blood will be taken. 
Syncope and vasovagal reactions to study 
intervention administration 
Syncope (fainting) and other anxiety related 
reactions can occur as a psychogenic response 
to the needle injection following or before blood 
draw or dosing.  
To minimize the risk of injury associated with 
syncope before/after dosing or blood draw, all 
participants will be seated or lying down during 
study intervention administration/blood draw 
and will remain under observation after the 
procedure. 
The decision to dose the participant will be 
dependent on the clinical judgment of the 
investigator. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
36 
Potential risk 
Summary of data/rationale for risk 
Mitigation strategy 
Bleeding following intramuscular injection 
As with other intramuscular injections, study 
intervention should be given with caution in 
individuals with bleeding disorders, such as 
hemophilia or on anticoagulant therapy, to avoid 
the risk of hematoma following the injection. 
To minimize the risk of bleeding, study 
intervention should be given with caution in 
individuals with thrombocytopenia or any 
coagulation disorder. 
Participants with any medical condition that in 
the judgment of the investigator would make 
intramuscular injection unsafe will be excluded 
from study enrollment. 
Note: Myocarditis and pericarditis are currently not considered as important potential risks for this vaccine candidate as review of 
published literature has not identified evidence to consider myocarditis/pericarditis as an mRNA vaccine class-effect and the patho-
mechanism is still unknown. However, these are considered as AESIs to further characterize the safety profile of the vaccine. In line with 
this, measures described in Section 8.3.4 have been included in the study protocol to closely monitor potential cases. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
37 
2.3.2. 
Benefit assessment 
The participants receiving the Flu Seasonal mRNA investigational study intervention 
may not directly benefit from this vaccination because vaccine efficacy has not been 
assessed. 
Participants may gain information and medical advice about their general health status 
through medical evaluations/assessments associated with this study (i.e., physical 
examinations). 
2.3.3. 
Overall benefit-risk conclusion  
The Flu Seasonal mRNA investigational study intervention is currently in an early stage 
of clinical development. Considering the measures to minimize the risk to participants in 
this Phase 1/2 clinical study and given the accumulation of favorable 
safety/immunogenicity data from the FLU SV MRNA-003 (217895), safety data from 
CV2 SARS-COV2-012 BST (218595) studies, as well as the data presented as interim 
analysis up to Day 29 post-dosing (on reactogenicity, safety and immunogenicity of the 
vaccine candidates from Phase 1) for this study, the anticipated benefit-risk profile for 
the seasonal mRNA investigational vaccine candidates remain positive to proceed with 
the Phase 2 part of the study. Refer to the IB for more information. 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Table 5 
Objectives and endpoints  
Objectives 
Endpoints (population summary) 
Co-primary 
To evaluate the safety and reactogenicity profile 
of the investigational study intervention 
Solicited events*: 
• 
Occurrence of solicited administration site and systemic 
events within 7 days (i.e., from Day 1 to Day 7 included) 
of study intervention administration (percentage of 
participants). 
Unsolicited AEs*: 
• 
Occurrence of unsolicited AEs within 28 days (i.e., from 
Day 1 to Day 28 included) after study intervention 
administration (percentage of participants). 
SAEs*, AESI* and MAEs: 
• 
Occurrence of SAEs within 6 months (i.e., from Day 1 to 
Day 183) after study intervention administration 
(percentage of participants) 
• 
Occurrence of AESIs within 6 months (i.e., from Day 1 to 
Day 183) after study intervention administration 
(percentage of participants) 
• 
Occurrence of MAEs within 6 months (i.e., from Day 1 to 
Day 183) after study intervention administration 
(percentage of participants). 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
38 
Objectives 
Endpoints (population summary) 
For participants in Phase 1: 
Safety laboratory: 
• 
Shift from a non-clinically significant laboratory value on 
Day 1 (pre-dose) to a clinically significant abnormal 
laboratory value on Day 8 (post-dose) and/or Day 29 
(post-dose) for hematology and clinical chemistry 
(percentage of participants). 
To evaluate the humoral immune response 
induced by the investigational study intervention  
• 
antibody titer at Day 29 (GMT) 
• 
Fold increase in
antibody titer from Day 1 to Day 29 
(GMI) 
• 
seroconversion from Day 1 to Day 29 (SCR) 
• 
seroprotection at Day 1 and Day 29 (SPR) 
• 
antibody titer at Day 29 (GMT) 
• 
Fold increase in
antibody titer from Day 1 to Day 29 
(GMI) 
• 
seroconversion from Day 1 to Day 29 (SCR†) 
Secondary 
To evaluate the humoral immune response 
induced by the investigational study intervention 
• 
antibody titer at Day 92 and Day 183 (GMT) 
• 
Fold increase in
antibody titer from Day 1 to Day 92 
(GMI) 
• 
Fold increase in
antibody titer from Day 1 to Day 183 
(GMI) 
• 
seroprotection at Day 183 (SPR†) 
• 
antibody titer at Day 92 and Day 183 (GMT) 
• 
Fold increase in
antibody titer from Day 1 to Day 92 
(GMI) 
• 
Fold increase in
antibody titer from Day 1 to Day 183 
(GMI) 
Tertiary 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
39 
Objectives 
Endpoints (population summary) 
Endpoints are designed for all the participants, unless indicated otherwise in the table. 
AE: adverse event; SAE: serious adverse event; AESI: adverse events of special interest; MAE: medically attended 
event; SCR: seroconversion rate; SPR: seroprotection rate; 
 
 GMI: geometric mean increase; 
GMT: geometric mean titers; MN: microneutralization; 
; 
 
* Refer to Section 8.4.1 for the list of safety events and timeframe for collection. 
† Refer to Section 9.3.2 for definition of SCR and SPR. 
Details related to attributes of estimand covering intercurrent events, population and 
treatment definition are provided in the Section 9. 
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
40 
4. 
STUDY DESIGN 
4.1. 
Overall design  
Refer to Figure 1 and Figure 2 (Section 1.2) for the overview of study design. 
• 
Multi-country, multi-center. 
• 
Self-contained. 
• 
All study interventions are administered as single-dose intramuscularly (IM). 
• 
Active control: 
• 
Intended duration of the study per participant: Up to 7 months for participants 
enrolled in Phase 1 (screening period included) and 6 months for participants 
enrolled in Phase 2 of the study. 
• 
Aspects of data collection: blood samples, safety events, 
 
. 
• 
Method of data collection: 
− 
Standardized electronic Case Report Form (eCRF) 
− 
Solicited AEs, the occurrence of unsolicited AEs and responses to 
 will be 
collected using an electronic Diary (eDiary); participants, with support from the 
site, may install the eDiary application on their own personal, handheld device 
(e.g., mobile phone, tablet) or the site may provide a device that is pre-
programmed with the eDiary. 
• 
Safety monitoring: the review of safety data will be performed by an internal Safety 
Review Team (SRT) and internal Safety Review Committee (iSRC). Refer to 
Section 8.3.7.1 for more information on safety monitoring strategy applicable to this 
study and Section 10.1.6 for SRT and iSRC composition and role. 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
41 
• 
Dose selection for Phase 2: refer to Section 4.3.2 for detailed information on dose 
selection by an internal Data Review Committee (iDRC) and Section 10.1.6 for 
iDRC composition and role. 
Phase 1: 
• 
Participants aged 18-50 years. 
• 
13 groups enrolled in parallel (12 mRNA groups and 1 control group), detailed in 
Table 6. 
• 
Approximate number of participants: 312 (24 participants per group). 
• 
Blinding: single-blind. Refer to Section 6.4 for more information on blinding. 
• 
Study interventions administered in Phase 1 will be manufactured as separate 
components and mixed at site by the site staff/pharmacist based on the scheme 
provided in the Table 6, before dosing each participant. This approach will only be 
applicable in the Phase 1 part. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
42 
Table 6 
Potential study interventions composition (Phase 1) 
Study groups 
Study 
interventions* 
Flu mRNA_1_1  
F2C22C/DL001Z 
Flu mRNA_1_2 
F2B22A/DL001Z 
Flu mRNA_1_3 
F2B22B/DL001Z  
Flu mRNA_1_4 
F2B22C/DL001Z 
Flu mRNA_1_5 
F2B22D/DL001Z  
Flu mRNA_1_6 
F2B22E/DL001Z 
Flu mRNA_1_7  
F2F22A/DL001Z 
Flu mRNA_1_8  
F2F22B/DL001Z  
Flu mRNA_1_9  
F2F22C/DL001Z  
Flu mRNA_1_10 
F2F22D/DL001Z 
Flu mRNA_1_11 
F2F22E/DL001Z 
Flu mRNA_1_12  
F2F22F/DL001Z 
Control 
 
 
 
* Strains used to design study interventions are based on WHO recommendation for influenza virus vaccine composition for the 2022-2023 NH season. 
** 
 GSKVx000000034792; 
: GSKVx000000040033; 
: 
GSKVx000000034794; 
: GSKVx000000034795; 
: GSKVx000000034796; 
: GSKVx000000034797; 
: GSKVx000000034798; 
: 
GSKVx000000039711. Refer to Section 4.3 for information on selection of doses and combinations and Section 6.1 for details on study interventions. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
43 
Phase 2: 
• 
Participants aged 18-64 and 65-85 years. 
• 
8 groups enrolled in parallel (3 mRNA groups and 1 control group for each age 
range), Table 7. 
• 
Approximate number of participants: 960 (120 participants per group).  
• 
Blinding: observer-blind. Refer to Section 6.4 for more information on blinding. 
• 
 
 
 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
44 
Table 7 
List of study interventions for Phase 2  
Study groups 
Study interventions* 
Flu mRNA_Ph2_1_YA 
F2F23D/DL001Z-NH 
Flu mRNA_Ph2_2_YA 
F2F23A/DL001Z-NH 
Flu mRNA_Ph2_3_YA 
F2F23B/DL001Z-NH 
Control_Ph2_YA 
 
Refer to Table 9 for details 
Flu mRNA_Ph2_1_OA 
F2F23A/DL001Z-NH 
Flu mRNA_Ph2_2_OA 
F2F23B/DL001Z-NH 
Flu mRNA_Ph2_3_OA 
F2F23C/DL001Z-NH 
Control_Ph2_OA 
 
Refer to Table 9 for details 
 
 
YA: younger adult; OA: older adult. 
* Strains used to design study interventions are based on WHO recommendation for influenza virus vaccine composition for the 2023-2024 NH season. 
** 
: GSKVx000000048110; 
: GSKVx000000040033; 
 
GSKVx000000034794; 
: GSKVx000000034795; 
 GSKVx000000048111; 
: GSKVx000000034797; 
: GSKVx000000034798; 
 
GSKVx000000039711. Refer to Section 4.3.2 for additional information and Section 6.1 for details on study interventions. 
Note: 
 
. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
45 
• 
Study interventions in Phase 2 will be provided to the site staff/pharmacist in vials 
containing the 
, that will be reconstituted with diluent 
according to the instructions detailed in Pharmacy Manual, prior to dosing the 
participants. 
Study extension 
Participants who complete the Phase 2 part of the study will be offered an opportunity 
to participate in the extension study (FLU SV MRNA-019). 
4.2. 
Scientific rationale for study design 
The study objective is to generate Phase 1/2 reactogenicity, safety, immunogenicity, and 
dose-finding/dose-confirming data of an mRNA-based 
 
seasonal influenza vaccine candidate in healthy YA and OAs 
 
 
4.2.1. 
Rationale for study design of Phase 1  
Phase 1 will assess the reactogenicity, safety and immunogenicity of 12 different 
formulations and 1 active control to 
 
 
 
 
 
 
 
 
The specific aims for Phase 1 (in YAs only) are: 
To minimize the number of study groups and number of healthy participants exposed to 
suboptimal investigational study intervention formulations, the aims of Phase 1 will be 
investigated using both 
 
 
 In addition to addressing the specific aims above, this design will 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
46 
 
The Phase 1 part will be conducted in YAs only as the pattern (in contrast to the 
magnitude) of immune responses against subtype A and B lineage strains observed in 
 was comparable between YAs and OAs (refer to IB for details). The 
findings in Phase 1 for YAs will therefore be applied to both YA and OA groups in Phase 
2. 
In Phase 1, all study groups will be enrolled in parallel. Given the careful dose escalation 
conducted in the FLU SV MRNA-003 (217895) and CV2 SARS-COV2-012 BST 
(218595) studies and the total dose in all study groups will remain below the maximum 
tolerated dose identified in these studies (refer to Section 4.3.1 for details on dose 
justification in Phase 1), employing parallel enrolment is considered appropriate. 
Comprehensive safety monitoring will be carried out to ensure the safety and wellbeing 
of the participants (refer to Section 8.3.7 for details). The safety monitoring in Phase 1 
includes, but not limited to (1) screening visit, (2) safety laboratory assessment at 
screening, Day 1, Day 8 and Day 29, (3) inclusion of sentinel participants and review of 
safety data prior to dosing non-sentinel participants, (4) per site, an interval of at least 60 
minutes between dosing of sentinel participants, (5) all participants will be observed on 
site for a minimum of 60 minutes after dosing, (6) study holding rules, (7) per site, 
limitation of maximum number of participants dosed per day, (8) across sites, limitation 
of maximum number of sentinel participants dosed per day and (9) unblinded review of 
safety data by SRT. 
4.2.2. 
Rationale for study design of Phase 2  
Phase 2 will assess the reactogenicity, safety and immunogenicity of 3 different 
 
. Given the 
high unmet need for an improved vaccine in OAs, the Phase 2 part will be conducted in 
both YAs and OAs to confirm that the selected formulation(s) induces an appropriate 
immune response in both age groups. 
All YA and OA study groups are planned to be enrolled in parallel. Given the 
a. 
Safety and reactogenicity data from YAs in the Phase 1 part 
 
, and 
b. Safety and reactogenicity data in YA and OA from the FLU SV MRNA-003 
(217895) and (CV2 SARS-COV2-012 BST [218595]) studies, and 
c. 
Total dose in all study groups will remain below the maximum dose evaluated in 
Phase 1 
), and 
d. mRNA-based vaccines are less reactogenic in OAs than in YAs supported by both 
internal (FLU SV MRNA-003 [217895] and CV2 SARS-COV2-012 BST [218595]) 
and external studies for COVID-19 [Baden, 2021; Polack, 2020] and influenza 
[Moderna, 2021], employing parallel enrollment and including OAs are considered 
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
47 
appropriate. Refer to IB for details for the safety and reactogenicity data and the 
maximum tolerated dose. 
To ensure the safety and wellbeing of the participants, comprehensive safety monitoring 
will be carried out (refer to Section 8.3.7 for details). The safety monitoring includes, but 
not limited to (1) all participants will be observed on site after dosing (for a minimum of 
60 minutes for OAs and 30 minutes for YAs), (2) inclusion of sentinel participants in OA 
groups and review of safety data prior to dosing non-sentinel participants, (3) study 
holding rules, (4) per site, limitation of maximum number of participants dosed per day in 
OA groups, (5) across sites, limitation of maximum number of sentinel participants dosed 
per day in OA groups and (6) review of safety data by SRT (blinded) and iSRC 
(unblinded). 
Screening visit and safety laboratory assessment will not be included in the Phase 2 part 
given the accumulation of safety data from the Phase 1 part of the study (312 participants 
planned to be enrolled) and from the FLU SV MRNA-003 (217895) and CV2 SARS-
COV2-012 BST (218595) studies. 
4.2.3. 
Rationale for choice of study population and choice of 
comparator 
In this study, participants will be enrolled according to the following age categories: 
• 
Phase 1: 18 to 50 years of age (YAs) 
• 
Phase 2: 18-64 (YA) and 65-85 years of age (OA). 
In Phase 1, the target population in the YA groups will be limited to 18 to 50 years of 
age. In Phase 2, the target population in the YA groups will be 18 to 64 years of age and 
65 to 85 years of age in the OA groups. This design will facilitate the generation of 
additional safety data of the platform 
 in a 
restricted age range prior to expansion to the full target age range for the vaccine 
candidate. The division of YAs and OAs at 65 years of age is in alignment with the 
definitions from WHO and CDC [WHO, 2018; CDC, 2022] and several licensed 
influenza vaccines. 
The comparator in Phase 1 is a licensed influenza vaccine approved for use in persons 18 
years of age or older. 
 
 
 
. Refer to Section 6.1 for the details on comparator. 
4.3. 
Justification for dose  
For all dose levels in Phase 1, the total dose will remain below the maximum tolerated 
dose identified
 based on the results of the FLU SV MRNA-003 
 
 and CV2 SARS-COV2-012 BST 
 
studies using the same mRNA backbone and modified nucleotides (Refer to Section 2.1 
and IB for details). 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
48 
For all dose levels in Phase 2, the total dose will remain below the maximum dose 
evaluated in YAs in the Phase 1 part 
 
(Refer to IB for details). 
4.3.1. 
Dose selection for Phase 1  
The individual dose level of the mRNAs encoding 
 
 is based primarily on the 
immunogenicity data from the FLU SV MRNA-003 (217895) study and secondarily on 
the 
 study. 
Specifically, 
 was selected for comparison based on the findings in FLU SV 
MRNA-003 (217895) where this dose level induced a superior immune response 
compared to the active control. 
The dose range 
 was selected based on the findings in FLU SV MRNA-003 
(217895) and 
 
 
 
 
 
For mRNAs encoding 
 only data 
from 
 is available which indicated that NA antigens may need relatively 
. However, as the relevance of data generated with 
 is not 
completely clear a 
 was selected to provide a sufficiently 
broad dose range for these antigens. 
Refer to Section 2.1 and IB for details on the FLU SV MRNA-003 (217895) and 
 studies. 
4.3.2. 
Dose selection for Phase 2  
The individual dose level of the mRNAs encoding 
 
 are 
based primarily on the immunogenicity and safety data from the Phase 1 part of this 
study and secondarily on the FLU SV MRNA-003 (217895) study. 
YA dose selection: 
The lowest total dose level evaluated in 
 
) was 
selected as the maximum dose level for the Phase 2 part in YAs as: 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
49 
Considering that a 
 
 as compared to the active control, 
 
 for the Phase 2 part. The 
 
 were selected as: 
OA dose selection: 
The 
 was selected as the highest dose 
level for the Phase 2 part in OAs as:  
• 
mRNA-based vaccines are less immunogenic and reactogenic in OAs than in YAs, 
as supported by both internal (FLU SV MRNA-003 [217895] and CV2 SARS-
COV2-012 BST [218595]) and external studies for COVID-19 [Baden, 2021; 
Polack, 2020] and influenza [Moderna, 2021], and 
• 
No safety signal has been observed in (i) the Phase 1 part of this study 
 
 
 
 and 
• 
A dose level 
 
 
 
• 
Dose levels in the Phase 1 part of this study in YA 
 
 
 
 immune 
responses in OAs. 
The YA dose levels 
 
 with an optimal 
immunogenicity/reactogenicity profile in OAs. Further, the lowest dose selected in OAs 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
50 
Refer to the IB for details on the results from the Phase 1 part of this study as well as 
from the FLU SV MRNA-003 (217895) and CV2 SARS-COV2-012 BST (218595) 
studies. 
4.4. 
End of study definition 
A participant is considered to have completed the study if the participant has completed 
all periods of the study including the last visit or the last scheduled procedure shown in 
the SoA. 
End of Study (EoS) is defined as: LSLV (Visit 6 in Phase 2 part) or Date of the last 
testing/reading released of the Human Biological Samples, related to primary and 
secondary endpoints, whichever occurs later. EoS must be achieved no later than 8 
months after LSLV. EoS cannot be before LSLV. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
1. A male or female between and including 18 and 50 years of age in Phase 1 and 
between and including 18 and 85 years of age (YA: 18-64; OA: 65-85) in Phase 2 at 
the time of the study intervention administration. 
2. Healthy participants or medically stable patients as established by medical history, 
clinical examination and safety laboratory assessments. Participants with chronic 
medical conditions with or without specific treatment (e.g., chronic metabolic, 
cardiac, pulmonary, renal, hepatic, neurologic, and hematologic diseases) are 
allowed to participate in this study if considered by the investigator as medically 
stable. A stable medical condition is defined as disease not requiring significant 
change in therapy or hospitalization for worsening disease during 3 months before 
enrollment. 
3. Body mass index (BMI) ≥18 kg/m² and ≤35kg/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 10.4.1.2 for the definition of women of non-childbearing potential. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
51 
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 for the definition of women of 
childbearing potential and adequate contraception. 
5.2. 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Medical conditions  
1. Only in Phase 1: Any clinically significant* hematological, biochemical, urinalysis 
or HbA1c laboratory abnormality. 
*The investigator should use his/her clinical judgment to decide which abnormalities 
are clinically significant. 
2. Participant tested positive for influenza by local health authority-approved testing 
methods within 180 days prior to Day 1. 
3. Current or past malignancy, unless completely resolved without clinically significant 
sequelae (e.g., scars following surgical resection for treatment of basal cell 
carcinoma cases are allowed) 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). However, in Phase 2, HIV-infected individuals may be 
enrolled if they have been stable on antiretroviral therapy for the past 6 consecutive 
months, i.e., their treatment has not been modified, their CD4 cell count is ≥200/mm³ 
and their viral load has been undetectable (i.e., HIV-RNA <50 copies/mL) (based on 
medical records, no laboratory testing required). For country specific instruction 
please refer to Section 10.6. 
5. History of myocarditis or pericarditis less than or equal to 10 years prior to vaccine 
administration, including a history of myocarditis or pericarditis following 
vaccination with an mRNA COVID-19 vaccine. 
6. Participants with history of hypersensitivity or severe allergic reaction to any 
previous vaccine or hypersensitivity likely to be exacerbated by any component of 
the study intervention (including latex, polyethylene glycol, egg protein and 
aminoglycoside antibiotics). 
7. History of, or uncontrolled neurological disorders or seizures, including Guillain-
Barré syndrome and Bell’s palsy, with the exception of febrile seizures during 
childhood. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
52 
8. Any history of dementia or any medical condition that moderately or severely 
impairs cognition. 
9. Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe. 
10. Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the participant due to participation in the study. 
5.2.2. 
Prior/Concomitant therapy  
11. Administration of an influenza vaccine (including any of the study investigational 
vaccines) within 180 days before enrollment or planned administration within 28 
days (Day 29) after the study intervention administration. 
12. Phase 1: Administration of a vaccine not foreseen by the study protocol in the period 
starting 28 days (Day -28) before the study intervention administration, or planned 
administration within 28 days (Day 29) after the study intervention administration*. 
Phase 2: Administration of a vaccine not foreseen by the study protocol in the 
period starting 15 days (Day -15) before the study intervention administration, or 
planned administration within 28 days (Day 29) after the study intervention 
administration*. 
*In case emergency mass vaccination for an unforeseen public health threat (e.g., a 
pandemic) is recommended and/or organized by public health authorities outside the 
routine immunization program, the time period described above can be reduced to 7 
days if, necessary for that vaccine, provided it is used according to the local 
governmental recommendations and that the Sponsor is notified accordingly. 
13. 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. 
14. 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). 
15. 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 Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2), for treatment of COVID-19 disease is 
allowed. 
16. 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. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
53 
5.2.3. 
Other exclusions 
17. Concurrently participating in another clinical study, at any time during the study 
period, in which the participant has been or will be exposed to an investigational or a 
non-investigational intervention (drug/invasive medical device). 
18. Pregnant or lactating female. 
19. Bedridden participants. 
20. Female planning to become pregnant or planning to discontinue contraceptive 
precautions within the 1-month post-dosing period. 
21. Alcoholism or substance use disorder within the past 24 months based on the 
presence of 2 or more of the following abuse criteria: hazardous use, 
social/interpersonal problems related to use, neglect of major roles to use, 
withdrawal, tolerance, use of larger amounts or longer, repeated attempts to quit or 
control use, much time spent using, physical or psychological problems related to 
use, activities given up to use, craving. 
22. Any study personnel or their immediate dependents, family, or household members. 
23. Participants with extensive tattoos covering deltoid region on both arms that would 
preclude the assessment of local reactogenicity. 
5.3. 
Lifestyle considerations 
No lifestyle restrictions are required for this study. 
5.4. 
Screen failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently assigned/randomized to study intervention/entered in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes informed consent date, demography, screen 
failure details and eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants should be assigned the same participant 
number if they are rescreened within the screening period (Day -28 Day -1). 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
54 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study 
intervention 
Study intervention administration may be postponed within the permitted time interval 
(Table 3) until transient conditions cited below are resolved: 
• 
Acute disease and/or fever at the time of randomization and/or study intervention 
administration. Fever is defined as a temperature ≥38.0°C/100.4°F by any route. The 
route for measuring temperature can be oral, axillary or tympanic. 
• 
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. 
• 
Close contact in the past 14 days prior to Visit 1 (Day 1) with at least 1 person 
diagnosed with SARS-COV-2 (laboratory-confirmed or a clinical diagnosis). Close 
contact is defined as standing less than 2 meters or 6 feet away from an infected 
person for a cumulative total of 15 minutes or more over a 24-hour period. Dosing 
will be delayed until 14 days after the last contact, unless the participant has tested 
negative for SARS-COV-2 in the meantime. 
• 
Close contact with persons with influenza (clinical diagnosis) in the past 14 days 
prior to Visit 1. Close contact is defined as standing less than 2 meters or 6 feet away 
from an infected person for a cumulative total of 15 minutes or more over a 24-hour 
period. Dosing will be delayed until 14 days after the last contact, unless the 
participant has tested negative for flu in the meantime. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definitions. 
6.1. 
Study intervention(s) administered 
Study interventions in Phase 1 listed in Table 8 will be manufactured as separate 
components (investigational medicinal products [IMPs]) that will be provided to the site 
staff/pharmacist, who will be responsible to combine them at according to the scheme 
provided in the Table 6 before dosing each participant. 
Study interventions in Phase 2 will be provided to the site staff/pharmacist in vials 
containing 
, that will be reconstituted with diluent 
according to the instructions detailed in Pharmacy Manual, prior to dosing the 
participants. 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
55 
Table 8 
Study intervention(s) administered. Phase 1 - (Table spreading through multiple pages)  
Study 
intervention 
name: 
Flu Seasonal mRNA * 
Study 
intervention 
formulation: 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
56 
Study 
intervention 
name: 
Flu Seasonal mRNA * 
Presentation: 
Manufacturer: 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
Type: 
Investigational 
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 Pharmacy Manual 
Packaging and 
labeling: 
Refer to the Pharmacy Manual for more details 
 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
57 
Study intervention 
name: 
Flu Seasonal mRNA*  
Study intervention 
formulation: 
Presentation: 
Manufacturer: 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
Type: 
Investigational 
Product category: 
Biologic 
Volume to be 
administered by 
dose: 
Refer to the Pharmacy Manual  
Route of 
administration:  
IM 
Location 
Deltoid 
Directionality  
Upper 
Laterality *** 
Non-Dominant 
Packaging and 
labeling: 
Refer to the Pharmacy Manual for more details 
 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
58 
Study 
intervention 
name: 
Flu Seasonal mRNA * 
Study 
intervention 
formulation: 
Excipients; Water for 
injections 
Excipients; Water 
for injections 
Excipients; Water 
for injections 
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
59 
Study 
intervention 
name: 
Flu Seasonal mRNA * 
Presentation: 
Manufacturer: 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
Type: 
Investigational 
Product 
category: 
Biologic 
Number of 
doses to be 
administered: 
Volume to be 
administered 
by dose: 
Refer to the Pharmacy Manual 
Route of 
administration:  
IM 
Location 
Deltoid 
Directionality  
Upper 
Laterality *** 
Non-Dominant 
Packaging and 
labeling: 
Refer to the Pharmacy Manual for more details 
 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
60 
Study 
intervention 
name: 
Flu Seasonal mRNA * 
 
Study 
intervention 
formulation: 
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
61 
Study 
intervention 
name: 
Flu Seasonal mRNA * 
 
Presentation: 
Manufacturer: 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
Type: 
Investigational 
Active control 
Product 
category: 
Biologic 
Number of 
doses to be 
administered: 
Volume to be 
administered 
by dose: 
Refer to the Pharmacy Manual 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
62 
Study 
intervention 
name: 
Flu Seasonal mRNA * 
 
 
Route of 
administration:  
IM 
Location 
Deltoid 
Directionality  
Upper 
Laterality *** 
Non-Dominant 
Packaging and 
labeling: 
Refer to the Pharmacy Manual for more details 
* Strains used to design study interventions are based on WHO recommendation for influenza virus vaccine composition 
. 
** Another manufacturer might be used depending on study site. 
*** 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. 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
63 
Table 9 
Study intervention(s) administered. Phase 2  
Study 
intervention 
name: 
Younger adults 
Flu Seasonal mRNA* 
 
Study 
intervention 
formulation: 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
64 
Study 
intervention 
name: 
Younger adults 
Flu Seasonal mRNA* 
 
Presentation: 
Manufacturer: 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
Type: 
Investigational  
Active control 
Product 
category: 
Biologic 
Volume to be 
administered 
by dose: 
Refer to the Pharmacy Manual 
Route of 
administration:  
IM 
Location 
Deltoid 
Directionality  
Upper 
Laterality *** 
Non-Dominant 
Number of 
doses to be 
administered: 
Packaging and 
labeling: 
Refer to the Pharmacy Manual for more details 
 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
65 
Study 
intervention 
name: 
Older adults 
Flu Seasonal mRNA* 
 
 
Study 
intervention 
formulation: 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
66 
Study 
intervention 
name: 
Older adults 
Flu Seasonal mRNA* 
 
 
Presentation: 
Manufacturer: 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
GSK Biologicals 
BBRAUN** 
Sanofi Pasteur 
Type: 
Investigational 
Active control 
Product 
category: 
Biologic 
Combination product  
Volume to be 
administered 
by dose: 
Refer to the Pharmacy Manual 
0.7 mL 
Route of 
administration:  
IM 
Location 
Deltoid 
Directionality  
Upper 
Laterality *** 
Non-Dominant 
Number of 
doses to be 
administered: 
Packaging and 
labeling: 
Refer to the Pharmacy Manual for more details 
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
67 
. 
* Strains used to design study interventions will be based on WHO recommendation for influenza virus vaccine composition 
. 
** Another manufacturer might be used depending on study site. 
*** 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. 
 
. 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
68 
All the participants in Phase 1, must be observed closely for at least 60 minutes after the 
administration of the study intervention. All OA participants in Phase 2 will be observed 
on site for a minimum of 60 minutes after dosing. All YA participants in Phase 2 must be 
observed closely for at least 30 minutes after dosing for detection of immediate allergic 
reactions [Shimabukuro, 2021]. 
Appropriate resuscitation equipment, medical treatment and trained staff must be readily 
available during the observation period in case of anaphylaxis, syncope. 
6.1.1. 
Medical devices 
• 
Licensed vaccines used as active controls in this study are provided as a single-dose 
pre-filled syringe (i.e., considered as combination product). 
• 
Other medical devices (e.g., syringes, thermometers) may be provided for use in this 
study. Refer to the study Pharmacy Manual for instructions on use of medical 
devices. 
• 
All device deficiencies (including malfunction, use error and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical 
investigation (see Sections 8.4.7 and 10.5) and appropriately managed by GSK. 
6.2. 
Preparation, handling, storage, and accountability 
• 
Instructions for the preparation of study interventions are provided in Pharmacy 
Manual. 
• 
The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study intervention received, and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply, prepare, or administer study intervention. 
• 
All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
• 
The investigator or authorized site staff is responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
• 
Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual. 
6.3. 
Assignment to study intervention 
All participants will be centrally assigned to randomized study intervention using an 
automated Internet-based system, Source data Base for Internet Randomization (e.g., 
SBIR). Before the study is initiated, the log-in information and directions for SBIR will 
be provided to each site. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
69 
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. Additionally, a QR code will be 
generated for each participant to allow faster identification and management of biological 
samples. This QR code will be linked to participant’s identification number and will not 
contain any other participant-related information. 
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 for specific instructions. 
In Phase 1 of the study, the randomization algorithm will use a minimization procedure 
accounting for sentinel status as a stratification factor, and study, country, center, and flu 
vaccination history during past 2 years as minimization factors. 
For Phase 2, the randomization algorithm will use a minimization procedure accounting 
for age group and sentinel status as a stratification factors, and study, country, center, and 
flu vaccination history during past 2 years as minimization factors. In addition, an 
exploratory immunogenicity subset consisting of approximately 50 participants in each 
group will be defined 
 
 
. This subset will be enrolled in dedicated centers. 
The randomization of supplies within blocks will be performed at GSK, using MATerial 
Excellence (MatEx), a program developed for use in Statistical Analysis System (SAS) 
(Cary, NC, US) by GSK. Entire blocks will be shipped to the study centers/warehouse(s). 
To allow GSK to take advantage of greater rates of recruitment 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. 
6.4. 
Blinding 
This study will be single-blind for Phase 1 and observer-blind for Phase 2. Refer to 
Definitions Of Terms for definition of single-blind and observer-blind. 
The laboratory in charge of sample testing will be blinded to the study intervention 
assignment. Codes will be used to link the participant and study to each sample. There 
will be no link between the study intervention groups and the identity of the participant. 
For Phase 1, to limit the testing of samples to relevant assays, the laboratory may be 
provided with list of participant codes to be considered 
 
 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded. 
GSK’s Global Safety staff may unblind the intervention assignment for any participant 
with an SAE. If the SAE requires that an expedited regulatory report be sent to one or 
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
70 
more regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy. 
6.4.1. 
Emergency unblinding 
SBIR will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participants’ 
intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator may, at the investigator’s discretion, contact GSK to discuss 
the situation prior to unblinding a participant’s intervention assignment unless this could 
delay emergency treatment for the participant. If a participant’s intervention assignment 
is unblinded, GSK must be notified within 24 hours of this occurrence. The date and 
reason for the unblinding must be recorded. 
If the investigator is unable to access SBIR, they can contact the GSK helpdesk based on 
the information provided in the Pharmacy Manual. 
A physician other than the investigator (e.g., an emergency room physician) or 
participant/participant’s caregiver or family member may also request emergency access 
to the participant’s study intervention information as per participant card. 
6.5. 
Study intervention compliance 
When participants are dosed at the site, they will receive study intervention directly from 
the investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. 
6.6. 
Dose modification 
This Section is not applicable. 
6.7. 
Continued access to study intervention after the end of the 
study 
This Section is not applicable. 
6.8. 
Treatment of overdose and management of anaphylaxis 
An overdose is any dose of study intervention given to a participant that exceeds the 
planned, randomized dose for an individual within a given dose group. 
GSK does not recommend specific treatment for an overdose. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
71 
The appropriate medical treatment to be administered for any episode 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. 
6.9. 
Prior and concomitant therapy 
At each study visit/contact, the investigator or their delegate should question the 
participant about all medications/products taken, and vaccinations received by the 
participant. 
The following prior and concomitant medication(s)/product(s)/vaccine(s) must be 
recorded in the eCRF: 
• 
All concomitant medications, except vitamins and dietary supplements, administered 
after the study intervention administration (Day 1) until Day 28. 
• 
All concomitant medication leading to withdrawal from Day1 to Day 183. Refer to 
Section 5.2.2 for more information. 
• 
Any concomitant vaccination administered in the period starting 28 days before 
study intervention administration (Day -28) until Day 28. 
• 
Administration of any influenza vaccine 2 years prior to dosing and up to Day 183. 
• 
All concomitant medication which may explain/cause/be used to treat an SAE/AESI 
including vaccines/products, as defined in Sections 8.4.1 and 10.3.5. These must also 
be recorded in the Expedited Adverse Event report. 
• 
All concomitant medications associated with medically attended events (MAEs), 
including vaccines/products, except vitamins and dietary supplements, administered 
after the study intervention administration (Day 1) until the last visit (Day 183). 
• 
Prophylactic medication (i.e., medication administered in the absence of any 
symptom and in anticipation of a reaction to the vaccination). 
Any medication or vaccine (including over-the-counter or prescription medicines) that 
the participant is receiving at the time of enrollment or receives during the study must be 
recorded along with: 
1. Reason for use 
2. Dates of administration including start and end dates 
3. Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Refer to Section 5.2.2 for the details on exclusionary concomitant medication for this 
study. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
72 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
This 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. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow up. 
The participant will be permanently discontinued from the study intervention and the 
study at that time. 
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. If the participant withdraws 
consent for disclosure of future information, the sponsor may retain and continue to use 
any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
The primary reason for participant discontinuation/ withdrawal from the study will be 
documented in the eCRF based on the list below: 
• 
AE requiring reporting to GSK 
• 
Unsolicited non-serious AE 
• 
Solicited AE 
• 
Lost to follow up 
• 
Physician decision 
• 
Site terminated by Sponsor 
• 
Study terminated by Sponsor 
• 
Withdrawal by participant 
• 
Other (specify). 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
73 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.5.6). 
7.3. 
Lost to follow up 
A participant will be considered lost to follow up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
1. The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
2. Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls, and if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
3. Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
1. Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
2. Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
3. All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Participants who have signed informed 
consent but are not eligible to proceed should be recorded in the eCRF with a status 
of ‘screen failure’. 
4. In the event of a significant study-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, study intervention distribution 
and monitoring may be implemented by the sponsor or the investigator, as per local 
health authority/ethics requirements. 
5. Laboratory results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded. 
Study participants may decide to assign a caregiver to help them complete the study 
procedures. Please refer to the Definitions Of Terms for the definition of a caregiver. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
74 
A caregiver can be appointed by the participant at any time during the study, when the 
participant feels it is necessary. Caregiver should receive the caregiver information letter 
before providing support to the study participant. Ideally, a single caregiver should be 
appointed by the participant but, in some situations, it may happen that several caregivers 
will support a study participant throughout the conduct of the study. This should be 
recorded in the source documents. However, every effort should be done to ensure that 
only 1 caregiver enters the data into eDiary to allow for timely completion. 
Caregivers may help the study participants with performing some practical study 
procedures such as receiving or making phone calls to site staff, planning study visits, 
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. At the first study visit (screening 
visit in Phase 1 part or Visit 1 in Phase 2 part) the site staff should inform the participant 
of the possibility to appoint a caregiver. Then at subsequent study visit(s), the site staff 
should check again with the participants if they wish to appoint a caregiver or if there 
were or will be changes of caregiver. 
8.1. 
Administrative baseline procedures 
8.1.1. 
Collection of demographic data 
Record demographic data such as year of birth, sex, race, and ethnicity in the 
participant’s eCRF. 
Collection of sex, race and ethnicity data is necessary to assess and monitor the diversity 
of the trial participants, and to determine if the trial participants are truly representative of 
the impacted population. 
8.1.2. 
Medical/vaccination history 
Obtain the participant’s medical/vaccination history by interviewing the participant 
and/or review of the participant’s medical records. Record any pre-existing conditions, 
signs and/or symptoms present prior to the study intervention administration and flu 
vaccination history for the past 2 years in the eCRF. 
8.1.3. 
Provision of eDiary device or installing of eDiary application on 
participant’s personal device 
Participants will be encouraged to bring their own personal electronic devices (e.g., smart 
phone or tablet) to the screening visit (in Phase 1 only) or to Visit 1 (Day 1 in Phase 1 
and Phase 2). The study staff will check the compatibility of the participant’s device with 
respect to the eDiary application. 
At Visit 1 (Day 1), with support from the study staff, the participant will download the 
eDiary application on his/her own electronic device. For participants who do not wish to 
use their own device for study purposes or whose device is incompatible with the eDiary 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
75 
application, will be provided an electronic device by the study staff. The provisioned 
devices will have the study eDiary application already installed. 
The eDiary application will be used by the participant to self-report information related to 
his/her health post-dosing (e.g., solicited events, responses to the 
 The study staff 
will train the participant on the use of the eDiary and emphasize the importance of 
completing the eDiary throughout the eDiary data collection period. 
The study staff will train the participant and/or his/her caregiver (if identified by the 
study participant) on the use of the eDiary. 
Refer to Section 8.4.1 for details of collection of safety information and Section 10.3.5 
for guidelines. 
8.2. 
Immunogenicity assessments 
Planned timepoints for all immunogenicity assessments are provided in the SoA. 
Biological samples will be used for research planned in the protocol and for purposes 
related to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. 
Findings in this or future studies may make it desirable to use samples acquired in this 
study 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. 
8.2.1. 
Biological samples 
Approximate amount of blood collected from each participant, over the duration of the 
study, is summarized in the SoA (Section 1.3) and Table 10. 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
76 
Table 10 
Approximate volume of blood collected at each time point and 
during the whole study 
 
Sample 
type 
Day -
28 to 
Day 1 
Day 1 
Day 2 
Day 8 
Day 
29 
Day 92 
Day 183 
Total 
Phase 1 
Blood 
10 mL 
40 mL 
- 
10 mL 
40 mL 
30 mL* 
30 mL* 
160 mL 
Phase 1 
Urine** 
As per 
local 
practice 
 
 
 
 
 
 
 
Phase 2 (YA 
and OA 
subset 
participants***) 
Blood 
- 
79 mL 
5 mL 
69 mL 
30 mL 
10 mL* 
70 mL* 
263 mL 
Phase 2 (non-
subset YA 
participants) 
Blood 
- 
30 mL† 
- 
- 
30 mL† 
30 mL*, † 
30 mL *, † 
120 mL 
Phase 2 (non-
subset OA 
participants) 
Blood 
- 
10 mL 
- 
- 
10 mL 
10 mL* 
10 mL* 
40 mL 
* Blood samples should only be collected for participants who did not receive a standard of care vaccination against 
seasonal flu since their enrollment into the study. 
** Urine sample will only be taken for screening purposes in Phase 1. 
*** Refer to Section 6.3 for subset description. 
† Part of the blood samples might be used for assay development and validation. 
8.2.2. 
Laboratory assays 
Table 11 
Laboratory assays  
Test 
classification 
System 
Component 
Challenge 
Method 
Laboratory* 
Humoral 
immunity 
(Antibody 
determination) 
Serum 
 
GSK or GSK 
designated lab 
Serum 
GSK or GSK 
designated lab 
Serum 
GSK or GSK 
designated lab 
Serum 
GSK or GSK 
designated lab 
Serum 
GSK or GSK 
designated lab 
Serum 
GSK or GSK 
designated lab 
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
77 
Test 
classification 
System 
Component 
Challenge 
Method 
Laboratory* 
Serum 
GSK or GSK 
designated lab 
Serum 
GSK or GSK 
designated lab 
Serum 
GSK or GSK 
designated lab 
GSK or GSK 
designated lab 
GSK or GSK 
designated lab 
Whole blood 
(
  
GSK or GSK 
designated lab  
Innate 
immunity 
Plasma 
N/A 
GSK or GSK 
designated lab 
Ab: antibody; 
 
; MN: microneutralization
; N/A: not applicable; 
. 
* Refer to the list of clinical laboratories for details. 
** 
 
† Only when possible. 
Clinical testing with assays supporting tertiary endpoints where analyses might be 
deemed futile due to the other study results might not be performed. 
Additional testing on collected samples (such as, but not limited to, 
 
 might be done during or after the 
study if deemed necessary to gain a better understanding of the vaccine(s), of the clinical 
study data and/or of the disease. These additional assays may not be represented in the 
objectives/endpoints of the study protocol. 
The addresses of clinical laboratories used for sample analysis are provided in a separate 
document accompanying this study protocol. 
GSK clinical laboratories have established a Quality System supported by procedures. 
The activities of GSK clinical laboratories are audited regularly for quality assessment by 
an internal (sponsor-dependent) but laboratory-independent Quality Department. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
78 
8.2.3. 
Immunological read-outs 
Table 12 
Immunological read-outs  
Blood sampling timepoint 
Subset name 
Approximate 
No. of 
participants 
Component 
Type of contact and 
timepoint 
Sampling 
timepoint 
Day 1 
Pre-dose 
All enrolled 
participants (Phase 
1 and Phase 2) 
1272 
Participants in 
exploratory 
immunogenicity 
subset (Phase 2) 
400 
For 
 
sample 
collection will 
be limited to 
selected sites. 
 
400 
400 
400 
400 
Day 2 
Post-dose 
Participants in 
exploratory 
immunogenicity 
subset (Phase 2) 
400 
Day 8 
Post-dose 
Participants in 
exploratory 
immunogenicity 
subset (Phase 2) 
400 
For 
 
sample 
collection will 
be limited to 
selected sites. 
 
400 
400 
Day 29 
Post-dose 
All enrolled 
participants (Phase 
1 and Phase 2) 
1272 
Participants in 
exploratory 
immunogenicity 
subset (Phase 2) 
400 
400 
Day 92 
Post-dose 
All enrolled 
participants (Phase 
1 and Phase 2) 
1272‡ 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
79 
Blood sampling timepoint 
Subset name 
Approximate 
No. of 
participants 
Component 
Type of contact and 
timepoint 
Sampling 
timepoint 
Day 183 
Post-dose 
All participants 
enrolled (Phase 1 
and Phase 2) 
1272‡ 
Participants in 
exploratory 
immunogenicity 
subset (Phase 2) 
400‡ 
400‡ 
400‡ 
400‡ 
Ab: antibody; 
 
* Strains used to design the study intervention 
** 
 
‡ Given that samples will only be collected from participants who did not receive a standard of care vaccination against 
seasonal flu, this number represents the maximum number of participants who will have a sample collected for the 
Visit. 
8.2.4. 
Immunological correlates of protection 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
8.3.1. 
Physical examination 
1. During the screening visit (in Phase 1 only) and prior to dosing at Visit 1 (Day 1), 
the investigator will perform physical examination of the participant including 
assessment of resting vital signs: systolic/diastolic blood pressure, heart rate and 
respiratory rate after at least 10 minutes of rest, body weight and height. Vital signs 
are to be taken before blood collection for laboratory tests. 
2. If the investigator determines that the participant’s health on the day of study 
intervention administration temporarily precludes dosing, the visit will be 
rescheduled. Refer to the Section 5.5 for the list of criteria for temporary delay of 
study intervention administration. 
3. 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. 
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
80 
4. 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. 
5. 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. 
8.3.2. 
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. 
8.3.3. 
Warnings and precautions to administration of study intervention 
Warnings and precautions to administration of study intervention must be checked at 
Visit 1 (Day 1) prior to dosing, as specified in SoA (Section 1.3). 
Refer to the approved product label/package insert. 
8.3.4. 
Myocarditis and pericarditis assessment and definitions  
All potential cases of myocarditis or pericarditis will undergo diagnostic work-up and be 
clinically evaluated. 
To detect asymptomatic participants, cardiac troponin (Troponin I and/or Troponin T) 
testing will be performed for all study participants on Day 1, Day 8 and Day 29 in 
Phase 1 of the study. An abnormal cardiac troponin test on Day 8 or Day 29 will be 
repeated for confirmation. 
Cardiac symptoms of myocarditis and/or pericarditis include the following: acute chest 
pain or pressure; palpitations; dyspnea after exercise, at rest or lying down; and 
diaphoresis. Non-specific symptoms may include fatigue, abdominal pain, dizziness or 
syncope, edema, cough, cyanosis, weakness, shoulder and/or upper back pain, nausea, 
vomiting, diarrhea, altered mental status and low-grade intermittent fever [SPEAC, 
2022].  
Phase 1: The following cases will be referred to a cardiologist or emergency room (as 
appropriate) for further evaluation and management following current practice guidelines 
(e.g., American Heart Association or local standard of care): 
• 
Asymptomatic participants with elevated cardiac troponin values on Day 8 or Day 29 
(confirmed on repeat testing) following a normal cardiac troponin value at baseline 
(Day 1), with no other identifiable cause of the finding. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
81 
• 
Symptomatic participants with ≥1 new or worsening cardiac symptom or ≥2 new or 
worsening non-specific symptoms within 4 weeks after dosing, with no potential 
alternative etiology, as assessed by the investigator [SPEAC, 2022]. 
Phase 2: Monitoring for asymptomatic participants by routine screening for elevated 
cardiac troponin will not be included in the Phase 2 part of the study. However, an 
expanded focus on symptom identification (including participant specific educational 
material), unscheduled study site visits for further evaluation, and an extended 
monitoring time period will be implemented as outlined below. 
• 
Participants will be provided with educational materials, as part of the consent 
process, describing the signs and symptoms of myocarditis and pericarditis as well 
as guidance on how and when to seek medical care and contacting study personal. 
• 
If the participant develops ≥1 new or worsening cardiac symptoms, and/or ≥2 new 
or worsening non-specific symptoms within 6 weeks after dosing with no potential 
alternative etiology, as assessed by the Investigator, an unscheduled study site visit 
will take place immediately (or an emergency room visit as per clinical judgment 
by the investigator) where a full physical examination, an ECG (if a study site does 
not have the capability to conduct an ECG, an alternative medical facility/ 
qualified vendor can be used), screening of a cardiac biomarker (Troponin I 
and/or Troponin T), and screening of an inflammatory marker (CRP, erythrocyte 
sedimentation rate or D-dimer) will be done. 
• 
If the ECG, the cardiac biomarker and/or the inflammatory marker results are 
abnormal with no potential alternative etiology, as assessed by the investigator, the 
participant will be referred to a cardiologist immediately (or an emergency room 
visit as per clinical judgment by the investigator) for further evaluation and 
management following current practice guidelines (e.g., American Heart 
Association or local standard of care). 
Definitive, probable and possible cases of myocarditis/pericarditis (per Brighton case 
definitions [SPEAC, 2022]) will be determined by the cardiologist and reported as an 
AESI. Participants will be followed-up until cardiac evaluation is completed, and/or 
symptoms have resolved, whichever comes later. 
Definitive, probable and possible cases of myocarditis or pericarditis occurring in 
temporal association with vaccination of study participants will be submitted as expedited 
reports following suspected unexpected serious adverse reaction (SUSAR) reporting 
timelines. 
8.3.5. 
Clinical safety laboratory tests 
• 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3). 
• 
The investigator must review the laboratory results, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
82 
• 
Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or 
medical monitor. 
− 
In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results the investigator considers clinically significant will be recorded 
as an AE or SAE, if they meet the definition of an AE or SAE (refer to Sections 
10.3.1 and 10.3.2). 
− 
If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
the sponsor notified. 
− 
If laboratory values from non-protocol-specified laboratory tests performed at 
the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE), then 
the results must be recorded. 
8.3.6. 
Pregnancy testing 
• 
For women of childbearing potential: only women with negative pregnancy test 
result at the screening visit (in Phase 1) and at Visit 1 (in Phase 1 and Phase 2) 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, both in Phase 1 and 2). Refer to 
Section 10.4.1.1 for definition of women of childbearing potential. 
• 
Female participants of childbearing potential must perform a urine pregnancy test 
before the administration of any dose of 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 8.4.6 for the information on study continuation for participants who 
become pregnant during the study. 
8.3.7. 
Study holding rules, safety monitoring committee 
8.3.7.1. 
Safety monitoring  
Participant safety will be continuously monitored by the medical monitor, designated 
Safety Lead (or delegate) and SRT, throughout the study. Pertinent findings and 
conclusions are shared with the product’s SRT for review of the overall benefit-risk 
profile of the product. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
83 
The SRT will oversee the unblinded safety monitoring in Phase 1 and blinded safety 
monitoring in Phase 2 whereas the iSRC will oversee the unblinded safety monitoring in 
Phase 2. Refer to Section 10.1.6 for the SRT and iSRC composition and role. 
Safety monitoring for Phase 1 and Phase 2 participants is specified in SoA (Section 1.3), 
Figure 1 and Figure 2, and the safety endpoints are presented in Section 3. 
Safety assessments for Phase 1 and Phase 2 participants are listed in Section 8.3. Study 
holding rules are listed in Section 8.3.7.1.2. Additional safety assessments for Phase 1 
participants are listed in Section 10.2. 
8.3.7.1.1. Phase 1  
Early participants in each group in Phase 1 will be referred to as ‘sentinel participants’. 
Enrollment and dosing of sentinel and non-sentinel participants will be managed as 
described below. 
• 
Sentinel participants will be the first 5 participants to be enrolled and dosed in each 
group. 
• 
On a per site level, sentinel participants will be dosed with an interval of at least 60 
minutes between them. On a per site level, a maximum of 7 sentinel participants will 
be dosed per day and across sites, a maximum of 20 sentinel participants will be 
dosed per day. All sentinel participants will be observed on site for a minimum of 60 
minutes after dosing. 
• 
A safety follow up contact (Contact 1) for all sentinel participants will be performed 
approximately 20 hours post-dosing. 
• 
After at least 7 days (Day 8) of follow up of sentinel participants, a SRT meeting will 
occur where all available safety data will be reviewed. The SRT will decide for each 
group whether to allow the dosing of non-sentinel participants. The investigator is 
not permitted to start dosing the non-sentinel participants prior to receipt of the SRT 
meeting outcome. However, screening procedures for non-sentinel participants may 
be performed prior to receipt of the SRT meeting outcome. 
• 
For groups obtaining a favorable decision from the SRT, non-sentinel participants 
can be dosed (unless a holding rule is met). All participants will be observed on site 
for a minimum of 60 minutes after dosing. 
• 
On a per site level, a maximum of 15 participants will be dosed per day. 
• 
After at least 28 days (Day 29) of follow up of all participants, a SRT meeting will 
occur where all available safety data will be reviewed. The SRT will evaluate the 
overall safety profile for each group and provide a summary to the iDRC (refer to 
Section 4.3.2 for dose selection for Phase 2). 
• 
In addition to the scheduled meetings above, the SRT will periodically evaluate the 
safety data as it becomes available, during the enrollment and follow up period. 
• 
If any safety concerns are identified outside of scheduled SRT meetings, an ad-hoc 
SRT meeting will occur, during the enrollment and follow up periods. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
84 
Refer to Section 8.3.7.1.2 for Phase 1 holding rules. 
8.3.7.1.2. Phase 2 (YA groups)  
In Phase 2, enrollment and dosing of YA participants will be performed as described 
below. 
• 
Participants in all groups can be enrolled and dosed without restrictions (unless a 
holding rule is met). All participants will be observed on site for a minimum of 30 
minutes after dosing. 
• 
The SRT and iSRC will periodically evaluate the safety data as it becomes available, 
during enrollment and follow up. 
• 
If any safety concerns are identified outside of scheduled SRT and iSRC meetings, 
ad-hoc meetings will occur, during the enrollment and follow up periods. 
Refer to Section 8.3.7.2 for Phase 2 holding rules. 
8.3.7.1.3. Phase 2 (OA groups)  
In Phase 2, enrollment and dosing of OA participants will be performed as described 
below. Early participants in each group will be referred to as ‘sentinel participants’. 
• 
Sentinel participants will be the first 5 participants to be enrolled and dosed in each 
group. 
• 
On a per site level, sentinel participants will be dosed with an interval of at least 60 
minutes between them. On a per site level, a maximum of 7 sentinel participants will 
be dosed per day and across sites, a maximum of 20 sentinel participants will be 
dosed per day. All sentinel participants will be observed on site for a minimum of 60 
minutes after dosing. 
• 
A safety follow up contact (Contact 1) for all sentinel participants will be performed 
approximately 20 hours post-dosing. 
• 
After at least 7 days (Day 8) of follow up of sentinel participants, a iSRC meeting 
will occur where all available safety data will be reviewed. The iSRC will decide for 
each group whether to allow the dosing of non-sentinel participants. The investigator 
is not permitted to start dosing the non-sentinel participants prior to receipt of the 
iSRC meeting outcome. 
• 
For groups obtaining a favorable decision from the iSRC, non-sentinel participants 
can be dosed (unless a holding rule is met). All non-sentinel participants will be 
observed on site for a minimum of 60 minutes after dosing. 
• 
On a per site level, a maximum of 15 participants will be dosed per day. 
• 
In addition to the scheduled meeting above, the iSRC will periodically evaluate the 
safety data as it becomes available, during the enrollment and follow up period. 
• 
If any safety concerns are identified outside of scheduled iSRC meetings, an ad-hoc 
iSRC meeting will occur, during the enrollment and follow up periods. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
85 
Refer to Section 8.3.7.2 for Phase 2 holding rules. 
8.3.7.2. 
Study holding rules  
The safety holding rules for Phase 1 and Phase 2, are defined in the Table 13 and Table 
14, respectively. Holding rules 1a-f will be assessed by the investigator on a continuous 
basis. Holding rules 2a and 2b will be assessed by the SRT in Phase 1 and iSRC in Phase 
2 during the safety evaluations of the data. 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, for all the study groups. 
Of note, no formal holding rules will be applied for other reactogenicity and safety data, 
such as missed visits due to study intervention-related AEs, Grade 1 and Grade 2 
solicited 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/iSRC to allow an overall 
assessment of the benefit/risk ratio of study intervention administration, for each group. 
Table 13 
Study holding rules for Phase 1  
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 
Necrosis at the injection site 
≥1 
1e 
Confirmed myocarditis or pericarditis events not clearly 
attributable to any cause other than study vaccine 
≥1 
1f 
Laryngospasm, bronchospasm, or anaphylaxis within 24 hours 
after administration of study intervention 
≥1 
2a 
Maximum number of participants with the same Grade 3 
solicited local or systemic AE in an investigational vaccine 
group, with onset within the 7-day (Day 1-7) post-dosing period 
≥2 
2b 
Maximum number of participants with the same or similar 
Grade 3 related unsolicited AE in an investigational vaccine 
group, including events with an identical MedDRA High 
Level Term and events assessed as clinically similar. Includes 
any Grade 3 or above laboratory abnormalities* of clinical 
relevance, symptomatic or not, as determined by the investigator 
≥2 
* 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”. N/A: not applicable 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
86 
Table 14 
Study holding rules for Phase 2  
Holding rule 
Events, per dose and per individual study group 
Number of participants to 
pause dosing in all groups, 
pending further evaluation 
by the iSRC 
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 
Necrosis at the injection site 
≥1 
1d 
Confirmed myocarditis or pericarditis events not clearly 
attributable to any cause other than study vaccine 
≥1 
1e 
Laryngospasm, bronchospasm, or anaphylaxis within 24 
hours after administration of study intervention 
≥1 
2a 
Maximum number of participants with the same Grade 3 
solicited local or systemic AE (same solicited AE lasting 2 
consecutive days [48 hours] or more as grade 3)* in an 
investigational vaccine group, with onset within the 7-day 
(Day 1-7) post-dosing period 
≥5% (and ≥2) 
2b 
Maximum number of participants with the same or similar 
Grade 3 related unsolicited AE in an investigational vaccine 
group, including events with an identical MedDRA High 
Level Term and events assessed as clinically similar. 
Includes any Grade 3  
≥5% (and ≥2) 
* E.g., 2 cases of grade 3 fever occurring 2 consecutive days in 2 participants in the same group 
Refer to Section 4.3 for details on selection of doses for further assessment for the next 
phase of the study. 
If a holding rule is met, the investigator must suspend administration of the study 
intervention and inform GSK immediately (e.g., holding rules 1a-f). Refer to Table 18 for 
contact information. 
The following communication sequence must be followed: 
• 
The concerned site staff has to put study intervention administration on hold. 
• 
The concerned site staff must immediately inform their local GSK contact defined in 
the Table 18. 
• 
GSKs local medical contact will inform the other sites of their country and the study 
Clinical Lead. GSK will put the randomization in SBIR on hold. 
• 
The study Clinical Lead will ensure that all local medical contacts in all study 
countries are notified. 
• 
All informed site staff will confirm to their local contact that action has been taken 
providing appropriate documentation to GSK. 
• 
GSK will further evaluate the case with the SRT and GSK Global Safety Board and 
will take the decision to stop or to restart the study intervention administration. All 
site staff will be informed about that final decision by their local GSK contact. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
87 
GSK will inform the investigator if holding rules 2a or b are met or if a safety signal is 
observed during the safety evaluation by the SRT/iSRC. 
• 
GSK will put the randomization in SBIR on hold. 
• 
The study Clinical Lead will ensure that all local medical contacts in all study 
countries are notified upon meeting holding rules 2a-2b. 
• 
Local medical 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 will further evaluate the case with the SRT, iSRC and GSK Global Safety 
Board and will take the decision to stop or to restart the study intervention 
administration. All site staff will be informed about that final decision by their local 
GSK contact. 
• 
In case of favorable outcome of the safety evaluations, randomization in SBIR will 
be re-launched allowing the investigators to restart enrollment and dosing of the 
remaining participants in the study. 
Refer to SRT framework, iSRC charter or relevant procedure for details on 
communication regarding holding rules. 
8.4. 
Adverse events (AEs) serious adverse events (SAEs), and 
other safety reporting 
For definitions relating to safety information see Section 10.3. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and other safety 
information and remain responsible for following up AEs that are serious, considered 
related to the study intervention or study procedures, or that caused the participant to 
discontinue the study (see Section 7). This includes events reported by the participant (or, 
when appropriate, by a caregiver). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 
and/or Section 10.5. 
8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information  
All SAEs will be collected from the day of study intervention administration (Day 1) 
until LSLV (Day 183) at the time points specified in the SoA. SAEs assessed as related to 
study participation (e.g., study intervention, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a GSK product (non-IMP) will be 
recorded from the time a participant consents to participate in the study. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
88 
All AEs will be collected from the start of study intervention until Day 7 (for solicited 
events) or Day 28 (for unsolicited events) at the timepoints specified in the SoA. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as medical history/current medical conditions, not as 
AEs. 
Complete list of safety events to be collected in this study and the timeframes for their 
collection and reporting are provided in Table 15. 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, after a participant has been discharged from the study, the 
investigator must record it in the medical records. If the investigator considers the 
event to be reasonably related to the study intervention or study participation, the 
investigator must promptly notify the sponsor. 
Table 15 
Collection and reporting of safety information 
Event 
Pre-Dose* 
D-28 to D-1 
Dose 
 
 
 
 
D1 
 
D7 
 
D28 
D183 
SAEs assessed as related 
to study participation** or 
concurrent GSK 
medication/ vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration site 
solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Systemic solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs leading to withdrawal 
from study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent medical 
conditions*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
89 
Event 
Pre-Dose* 
D-28 to D-1 
Dose 
 
 
 
 
D1 
 
D7 
 
D28 
D183 
MAEs**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D: Day 
* i.e., informed 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. 
*** Intercurrent medical conditions are defined as medical conditions that occur after vaccine administration and either 
preclude observation of the outcome of interest (immunogenicity/efficacy endpoint) or affect its interpretation (by 
altering the immune response to vaccination or altering the initial immune status of the participant). 
**** An AE that results in an unscheduled visit to a medical professional (e.g., physician’s office visits, emergency room 
visits or hospitalization). 
The shaded region in the table indicates time period of data collection. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Section 10.3 and Section 
10.5. The investigator will submit any updated SAE data to the sponsor within 24 hours 
of it being available. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 15. 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
the investigator considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
8.4.2. 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AEs of special interest (as defined 
in Section 8.4.4) will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow up (as defined in Section 7.3). Further 
information on follow up procedures is provided in Sections 10.3.5.6 and 10.5.4.4. 
The investigator should follow up on influenza-like illness (ILI) cases occurring during 
the study and aim to confirm the diagnosis by local health authority-approved testing 
methods for flu detection. These cases will be considered as intercurrent medical 
conditions and will be managed as described in Sections 8.4.1 and 9.2. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
90 
8.4.4. 
AEs of special interest 
8.4.4.1. 
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 the Table 16. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the below 
diagnoses will be available to investigators at study start. 
The investigator(s) must exercise their medical/scientific judgment to determine whether 
other diseases have an autoimmune origin (i.e., pathophysiology involving systemic or 
organ-specific pathogenic autoantibodies) and should also be recorded as a pIMD. In 
addition, the investigator should categorize each pIMD either as a new onset condition (if 
it started following vaccination) or as an exacerbation of a pre-existing chronic condition 
(if it exacerbated following vaccination) in the eCRF. 
Table 16 
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) 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
91 
Medical Concept 
Additional Notes 
Pulmonary alveolar proteinosis 
(PAP) 
• 
Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-mediated 
thyroiditis  
Including but not limited to: 
• 
Hashimoto thyroiditis (autoimmune hypothyroidism, lymphocytic 
thyroiditis) 
• 
Atrophic thyroiditis 
• 
Silent thyroiditis 
• 
Thyrotoxicosis 
Autoimmune diseases of the testis 
and ovary 
• 
Includes autoimmune oophoritis, autoimmune ovarian failure and 
autoimmune orchitis 
Autoimmune hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s disease 
• 
Includes Marine Lenhart syndrome and Graves' ophthalmopathy, also 
known as thyroid eye disease (TED) or endocrine ophthalmopathy 
Insulin autoimmune syndrome 
 
Polyglandular autoimmune 
syndrome 
• 
Includes Polyglandular autoimmune syndrome type I, II and III 
Eye disorders 
Ocular Autoimmune / Immune-
mediated disorders 
Including but not limited to: 
• 
Acute macular neuroretinopathy (also known as acute macular outer 
retinopathy) 
• 
Autoimmune / Immune-mediated retinopathy 
• 
Autoimmune / Immune-mediated uveitis, including idiopathic uveitis 
and sympathetic ophthalmia 
• 
Cogan's syndrome: an oculo-audiovestibular disease 
• 
Ocular pemphigoid 
• 
Ulcerative keratitis 
• 
Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-mediated 
pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel disease  
Including but not limited to: 
• 
Crohn’s disease 
• 
Microscopic colitis 
• 
Terminal ileitis 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Musculoskeletal and connective tissue disorders  
Gout 
• 
Includes gouty arthritis 
Idiopathic inflammatory myopathies 
Including but not limited to: 
• 
Dermatomyositis 
• 
Inclusion body myositis 
• 
Immune-mediated necrotizing myopathy 
• 
Polymyositis 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
92 
Medical Concept 
Additional Notes 
Mixed connective tissue disorder 
 
Polymyalgia rheumatica (PMR) 
 
Psoriatic arthritis (PsA) 
 
Relapsing polychondritis 
 
Rheumatoid arthritis  
Including but not limited to: 
• 
Rheumatoid arthritis associated conditions 
• 
Juvenile idiopathic arthritis 
• 
Palindromic rheumatism 
• 
Still's disease 
• 
Felty’s syndrome 
Sjögren’s syndrome 
 
Spondyloarthritis 
Including but not limited to: 
• 
Ankylosing spondylitis 
• 
Juvenile spondyloarthritis 
• 
Keratoderma blenorrhagica 
• 
Psoriatic spondylitis 
• 
Reactive Arthritis (Reiter's Syndrome) 
• 
Undifferentiated spondyloarthritis 
Systemic lupus Erythematosus  
• 
Includes Lupus associated conditions (e.g., Cutaneous lupus 
erythematosus, Lupus nephritis, etc.) or complications such as 
shrinking lung syndrome (SLS) 
Systemic Scleroderma (systemic 
sclerosis) 
• 
Includes Reynolds syndrome (RS), systemic sclerosis with diffuse 
scleroderma and systemic sclerosis with limited scleroderma (also 
known as CREST syndrome) 
Neuroinflammatory/neuromuscular disorders 
Acute disseminated 
encephalomyelitis (ADEM) and 
other inflammatory demyelinating 
variants  
Includes the following: 
• 
Acute necrotizing myelitis 
• 
Bickerstaff's brainstem encephalitis 
• 
Disseminated necrotizing leukoencephalopathy (also known as 
Weston-Hurst syndrome, acute hemorrhagic leuko-encephalitis, or 
acute necrotizing hemorrhagic encephalomyelitis) 
• 
Myelin oligodendrocyte glycoprotein antibody-associated disease 
• 
Neuromyelitis optica (also known as Devic’s disease) 
• 
Noninfective encephalitis / encephalomyelitis / myelitis 
• 
Postimmunization encephalomyelitis  
Guillain-Barré syndrome (GBS) 
• 
Includes variants such as Miller Fisher syndrome and the acute motor 
and sensory axonal neuropathy (AMSAN) 
Idiopathic cranial nerve 
palsies/paresis and inflammations 
(neuritis) 
Including but not limited to: 
• 
Cranial nerve neuritis (e.g., Optic neuritis) 
• 
Idiopathic nerve palsies/paresis (e.g., Bell’s palsy) 
• 
Melkersson-Rosenthal syndrome 
• 
Multiple cranial nerve palsies/paresis  
Multiple sclerosis (MS) 
Includes the following: 
• 
Clinically isolated syndrome (CIS) 
• 
Malignant MS (the Marburg type of MS) 
• 
Primary-progressive MS (PPMS) 
• 
Radiologically isolated syndrome (RIS) 
• 
Relapsing-remitting MS (RRMS) 
• 
Secondary-progressive MS (SPMS) 
• 
Uhthoff's phenomenon  
Myasthenia gravis 
• 
Includes ocular myasthenia and Lambert-Eaton myasthenic syndrome 
Narcolepsy 
• 
Includes narcolepsy with or without presence of unambiguous 
cataplexy 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
93 
Medical Concept 
Additional Notes 
Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies 
Including but not limited to: 
• 
Acute Brachial Radiculitis (also known as Parsonage-Turner 
Syndrome or neuralgic amyotrophy) 
• 
Antibody-mediated demyelinating neuropathy 
• 
Chronic idiopathic axonal polyneuropathy (CIAP) 
• 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), 
including atypical CIDP variants (e.g., multifocal acquired 
demyelinating sensory and motor neuropathy also known as Lewis-
Sumner syndrome) 
• 
Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
• 
Includes acute partial transverse myelitis (APTM) and acute complete 
transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / immune-mediated 
glomerulonephritis  
Including but not limited to: 
• 
IgA nephropathy 
• 
IgM nephropathy 
• 
C1q nephropathy 
• 
Fibrillary glomerulonephritis 
• 
Glomerulonephritis rapidly progressive 
• 
Membranoproliferative glomerulonephritis 
• 
Membranous glomerulonephritis 
• 
Mesangioproliferative glomerulonephritis 
• 
Tubulointerstitial nephritis and uveitis syndrome 
Skin and subcutaneous tissue disorders 
Alopecia areata 
 
Autoimmune / immune-mediated 
blistering dermatoses  
Including but not limited to: 
• 
Bullous Dermatitis 
• 
Bullous Pemphigoid 
• 
Dermatitis herpetiformis 
• 
Epidermolysis bullosa acquisita (EBA) 
• 
Linear IgA-mediated bullous dermatosis (LABD), also known as Linear 
IgA disease 
• 
Pemphigus  
Erythema multiforme 
 
Erythema nodosum 
 
Reactive granulomatous dermatitis  
Including but not limited to 
• 
Interstitial granulomatous dermatitis 
• 
Palisaded neutrophilic granulomatous dermatitis 
Lichen planus 
• 
Includes liquen planopilaris 
Localized Scleroderma (Morphoea) 
• 
Includes Eosinophilic fasciitis (also called Shulman syndrome) 
Psoriasis 
 
Pyoderma gangrenosum 
 
Stevens-Johnson syndrome (SJS) 
Including but not limited to: 
• 
Toxic Epidermal Necrolysis (TEN) 
• 
SJS-TEN overlap 
Sweet’s syndrome 
• 
Includes Acute febrile neutrophilic dermatosis 
Vitiligo 
 
Vasculitis 
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  

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
94 
Medical Concept 
Additional Notes 
Medium sized and/or small vessels 
vasculitis  
Including but not limited to: 
• 
Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type 
unspecified) 
• 
Behcet's syndrome 
• 
Buerger’s disease (thromboangiitis obliterans) 
• 
Churg–Strauss syndrome (allergic granulomatous angiitis) 
• 
Erythema induratum (also known as nodular vasculitis) 
• 
Henoch-Schonlein purpura (also known as IgA vasculitis) 
• 
Microscopic polyangiitis 
• 
Necrotizing vasculitis 
• 
Polyarteritis nodosa 
• 
Single organ cutaneous vasculitis, including leukocytoclastic vasculitis, 
hypersensitivity vasculitis and acute hemorrhagic edema of infancy 
(AHEI) 
• 
Wegener's granulomatosis  
Other (including multisystemic) 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
• 
Frequently used related terms include: “systemic capillary leak 
syndrome (SCLS)” or “Clarkson's Syndrome” 
Goodpasture syndrome 
• 
Frequently used related terms include: “pulmonary renal syndrome” 
and “anti-Glomerular Basement Membrane disease (anti-GBM 
disease)” 
Immune-mediated enhancement of 
disease 
• 
Includes vaccine associated enhanced disease (VAED and VAERD). 
Frequently used related terms include ‘vaccine-mediated enhanced 
disease (VMED)’, ‘enhanced respiratory disease (ERD)’, ‘vaccine-
induced enhancement of infection’, ‘disease enhancement’, ‘immune 
enhancement’, and ‘antibody-dependent enhancement (ADE)’ 
Immunoglobulin G4 related disease 
 
Langerhans' cell histiocytosis 
 
Multisystem inflammatory 
syndromes 
Including but not limited to: 
• 
Kawasaki’s disease 
• 
Multisystem inflammatory syndrome in adults (MIS-A) 
• 
Multisystem inflammatory syndrome in children (MIS-C)  
Overlap syndrome 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
• 
Includes Loefgren syndrome 
Susac's syndrome 
 
8.4.4.2. 
Other AEs of special interest 
The following events are also considered as AESIs in this study. 
• 
Severe hypersensitivity reactions within 24 hours after study intervention 
administration 
• 
Myocarditis/Pericarditis. Refer to Section 8.3.4 for myocarditis/pericarditis 
assessment and definitions. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as AESI. Symptoms, signs or conditions which might (or might not) lead to one 
of the above diagnoses, should be recorded and reported as AEs but not as AESI until the 
final or definitive diagnosis has been made, and alternative diagnoses eliminated or 
shown to be less likely. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
95 
8.4.5. 
Regulatory reporting requirements for SAEs/AESI 
• 
Prompt notification by the investigator to the sponsor of an SAE/AESI is essential so 
that legal obligations and ethical responsibilities toward the safety of participants and 
the safety of a study intervention under clinical investigation are met. See 
Section 8.4.1 for reporting timeframes. 
• 
For SAEs/AESIs, the investigator must always provide an assessment of causality at 
the time of the initial report, as defined in the Section 10.3.5.7 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 
Table 17 
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 Adverse 
Events Report 
24 hours* 
paper/electronic 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 Adverse 
Events Report 
24 hours* 
paper/electronic 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 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. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
8.4.6. 
Pregnancy 
Female participants who become pregnant after administration of the study intervention 
may continue the study at the discretion of the investigator. 
• 
Details of all pregnancies in female participants will be collected after the start of 
study intervention and until the last visit (Day 183). 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant pregnancy. 
• 
Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
96 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on the participant and the neonate and 
the information will be forwarded to the sponsor. See Table 17 for reporting 
timeframes. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• 
Any female participant who becomes pregnant post-dosing while participating in the 
study will be allowed to continue the study until the end unless she withdraws 
consent or the investigator decides that it is in the participant’s best interest to be 
discontinued from the study. 
8.4.7. 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules 
Table 18 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules 
Study contact for questions regarding 
SAEs, AESIs, pregnancies and SAEs 
linked to device deficiencies 
 
Study contact for reporting of study 
holding/stopping rules  
Contact GSK’s local and/or medical 
contacts 
If a holding/stopping rule is met, the 
investigator must immediately inform the 
GSKs Local and/or Medical contacts. 
Contacts for reporting SAEs, AESIs, 
pregnancies and SAEs linked to device 
deficiencies 
Available 24/24 hours and 7/7 days 
ogm28723@gsk.com 
Fax: +32 2 656 8009 
Back up study contact for escalation of 
holding/stopping rules 
Refer to the local study contact 
information document. 
8.4.8. 
Participant card 
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in their possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending 
physician/caregiver/family member that the participant is in a clinical study and that 
relevant information may be obtained by contacting the investigator(s) or their back up. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
97 
8.4.9. 
Medical device deficiencies 
Medical devices are being provided for use in this study as part of the study intervention. 
To fulfill regulatory reporting obligations worldwide, the investigator is responsible for 
the detection and documentation of events meeting the definitions of device deficiency 
that occur during the study with such devices. 
The definition of a medical device deficiency can be found in Section 10.5. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes 
outlined in Section 10.5 of the protocol. 
8.4.9.1. 
Time period for detecting medical device deficiencies 
• 
Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. 
• 
If the investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency is considered reasonably 
related to a medical device provided for the study, the investigator will promptly 
notify the sponsor. 
The method of documenting medical device deficiencies is provided in Section 10.5. 
8.4.9.2. 
Follow up of medical device deficiencies 
• 
Follow up applies to all participants, including those who discontinue study 
intervention. 
• 
The investigator is responsible for ensuring that follow up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• 
New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 
8.4.9.3. 
Prompt reporting of device deficiencies to the sponsor 
• 
Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical 
device deficiency. 
• 
The medical device deficiency report form will be sent to the sponsor by email. If 
email is unavailable, then fax should be utilized. 
• 
The sponsor will be the contact for the receipt of device deficiency reports. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
98 
8.4.9.4. 
Regulatory reporting requirements for device deficiencies 
• 
The investigator will promptly report all device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the 
legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical 
studies. 
• 
The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
8.5. 
Pharmacokinetics 
PK is not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamics is not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Section is not applicable. 
8.9. 
Immunogenicity assessments 
Immunogenicity is described in Section 8.2 
8.10. 
Health economics 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
28 Aug 2023 
99 
9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan will be finalized prior to the first subject first visit and it will 
include a more technical and detailed description of the statistical analyses including 
demography, tertiary endpoint analyses and supporting analyses, if applicable. This 
Section is a summary of the planned statistical analyses of the most important endpoints, 
i.e., the primary endpoints. 
9.1. 
Statistical hypotheses 
There is no formal hypothesis testing in this study; where statistical methods are applied, 
the emphasis will be on estimation with 95% CIs. 
9.2. 
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 the dose of study intervention as per protocol, 
had immunogenicity results pre- and Day 29 post-dosing, without intercurrent 
conditions (influenza disease) that may interfere with immunogenicity and without 
prohibited concomitant medication/vaccination before Day 29. 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 3 and 
Table 4) as well as results obtained after intercurrent conditions (influenza 
disease, new malignancy and immunocompromised condition) that may 
interfere with immunogenicity or after prohibited concomitant 
medication/vaccination during this period will be excluded from the PPS. 
9.3. 
Statistical analyses 
The co-primary and secondary endpoints are described in Section 3. The primary 
analyses of immunogenicity endpoints will be based on the PPS. The analysis of 
reactogenicity and safety endpoints will be based on the ES. All analyses will be done 
separately for OAs and YAs according to study phase, unless specified otherwise. 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
100 
9.3.1. 
Co-primary reactogenicity and 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-dosing) 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 PT. The percentage of participants with any 
unsolicited AEs within the 28-day follow up period (i.e., Day 1-Day 28 post-dosing) 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, with at least 1 report of 
MAE 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-dosing) will be summarized by group. 
9.3.1.1. 
Analysis of reactogenicity: Bayesian Logistic Regression Model 
(BLRM)  
An adaptive BLRM will be used to inform on the posterior probability of the true Grade 3 
solicited event rate for all dose levels used in Phase 1 study groups. 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. [Rogatko, 2007] and is one of the key elements of the FDA’s Critical Path 
Initiative. 
The 2-parameter BLRM described by Neuenschwander et al., 2008 [Neuenschwander, 
2008] will be used to assess reactogenicity and recommend the mRNA doses to proceed 
to Phase 2 of the study. 
Standardized dose level will be used such that one 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 1 mRNA 
vaccine dose range [Walsh, 2020; Kremsner, 2021]. 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 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
101 
• 
≥18% to 100%: intolerance. 
The principle of the BLRM 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 10.7 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/iSRC or iDRC (Refer to Section 
10.1.6 for the SRT, iSRC and iDRC roles) will be used to select the investigational study 
intervention for Phase 2. The frequency of each safety event associated to holding rules 
(see Table 13) will be tabulated by study group (i.e., by dose level and formulation). 
Individual data will also be available. 
9.3.2. 
Co-primary and secondary immunogenicity endpoints 
At each phase, the group difference between the investigational study intervention 
formulation, and dose level and the control group will be assessed separately as follows 
for 
: 
• 
At each post-dosing timepoint separately, the 2-sided CI for group GMT ratio 
between investigational study intervention dose and (over) the control group will be 
derived from an ANCOVA model on log10 transformed concentration. The 
ANCOVA model will include group (i.e., each of the investigational study 
intervention and the control group), actual age of participants, country, flu 
vaccination history and log10-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 lower level of quantification (LLOQ) will be replaced by half the assay LLOQ. 
• 
For a given age group, the 2-sided 95% CI on group difference in SCR between an 
investigational study intervention and (minus) the control group will be computed at 
Day 29 based on the method of Miettinen and Nurminen [Miettinen, 1985]. 
• 
For
only: the percentage of participants achieving seroprotection, defined as 
having post-dosing 
 will be summarized by age group with associated 
exact 95% CI. 
All analyses will be performed separately for each age group, where applicable. 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
102 
Abbreviation/term 
Definition 
GMI 
The geometric mean of the ratios of the post-dosing titer over the Day 1 titer. 
The percentage of dosed participants who have either a
pre-dose 
 and 
a post-dosing 
 or a pre-dose 
 and at least a 4-fold 
increase in post-dosing 
. 
The percentage of dosed participants who have either a
pre-dose 
 
and a post-dosing 
 or a pre-dose 
 and at least a 4-
fold increase in post-dosing NI titer. 
SPR (seroprotection rate)* 
The percentage of dosed participants with a 
. 
S+ (seropositive)  
Titer ≥LLOQ 
 
9.4. 
Interim analyses 
9.4.1. 
Sequence of interim and other planned analyses  
In addition to the analyses detailed below, additional analyses e.g., safety analyses, may 
be conducted to support the SRT, iSRC and iDRC decisions, as described in Section 
8.3.7.1. Refer to Section 10.1.6 for the SRT, iSRC and iDRC roles. 
Two interim analyses are foreseen and will be conducted upon availability of all primary 
endpoints up to Day 29 for participants in Phase 1 and Phase 2, respectively. 
 
. For the 
observer-blinded Phase 2 interim analyses, a restricted study team will be unblinded to 
individual participant data and all efforts will be made to ensure the participants, 
investigators and monitoring staff blinding is maintained up to study end. The rest of 
the study team will have access to group data but will remain blinded to individual 
participant data and treatment assignment until the end of the study. It is possible, 
however, due to the limited sample size, that unblinding occurs for a few participants 
having a specific AE or SAE (e.g., an AE/SAE occurring only in a single participant). 
Therefore, anyone having access to the results could become unblinded regarding 
those few specific cases. 
An analysis with all primary and secondary endpoints obtained until the last visit 
(Day 183) will be performed and made available to the investigators and submitted to 
regulatory authorities, as appropriate. This may be performed separately for each phase. 
Analysis of tertiary endpoints may be performed at a later stage. Tertiary analyses 
deemed futile due to the other study results will not be analyzed nor reported. 
9.4.2. 
Statistical considerations associated with the interim analyses 
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. 
All interim analyses will be based on the ES. 
9.5. 
Sample size determination 
Enrolled participants who withdraw from the study will not be replaced. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
103 
9.5.1. 
Sample size determination for Phase 1  
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 vaccine. 
For each investigational study intervention group, it is expected that 24 participants will 
be enrolled. 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 19 provides the 
estimate and 95% credibility interval for a given observed number of participants for a 
sample size of 24 participants per study group (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 19 
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 10.7. 
9.5.2. 
Sample size determination for Phase 2  
The primary objective is to explore how the different formulation(s) or dose level(s) of 
mRNA-based vaccine compare to licensed control group(s). 
The sample size of 108 evaluable participants in each dose level cohort and age group, is 
expected to provide a 95% CI for group difference in SCR with a lower half-width below 
12% for difference in seroconversion rates for the different strains (Table 20) and a 95% 
CI with an expected half-width of 1.36 fold for the group geometric mean concentration 
ratio considering a population standard deviation of 0.5 in log10 transformation 
concentration post-dosing and 5% of unevaluable participants per group. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
104 
Table 20 
Half-width of 95% CI for the group difference in seroconversion 
rates by to control and strain (Evaluable N per group = 108) 
Control  
Strain 
Proportion (%)* 
95% CI of Proportion (%) 
Lower Half-width of  
95 CI (%) 
*Obtained from meta-analysis of historical data from 
 
 
 
. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (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 and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• 
As per local regulations, amendments to the protocol may require IRB/IEC approval 
before implementation of changes made to the study design. Changes necessary to 
eliminate an immediate hazard to study participants may be implemented prior to 
IRB/IEC approval. 
• 
Protocols and substantial amendments to the protocol may require health authority 
approval prior to initiation and/or implementation as per local regulations. Changes 
necessary to eliminate an immediate hazard to study participants may be 
implemented prior to health authorities approval. 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
105 
• 
The investigator will be responsible for the following, as applicable: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
− 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, 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 new information on financial interests during 
the course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed consent process 
• 
The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants and answer all questions 
regarding the study. 
• 
Potential participants must be informed that their participation is voluntary. They 
will be required to physically sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
• 
The medical record must include a statement that physical informed consent was 
obtained before the participant was enrolled in the study and the date the physical 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
• 
A physical copy of the ICF(s) must be provided to the participant. 
• 
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. 
The ICF will contain a separate Section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
106 
explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period. 
In case of unexpected pregnancy, participant must be informed that personal information 
such as date of birth, sex of the baby will be collected as part of safety follow up. Consent 
for the baby may be obtained from the participant and/or their partner as per local 
regulations. 
10.1.4. 
Recruitment strategy 
Printed and digitalized advertising and recruitment materials may be used to support 
recruitment. 
All advertisement and participant’s facing materials will be approved as per local 
regulations before their use. 
Refer to Section 8.3.7.1 for details on enrollment strategy for Phase 1 (including 
enrollment of sentinel and non-sentinel participants) and Phase 2. 
10.1.5. 
Data protection 
• 
Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• 
Validated electronic application will be used by sites to track collection of laboratory 
samples. Participant’s identification number and individual QR code will be used to 
identify blood samples at the time of sample collection/processing. However, no 
personal information or lab data will be captured in this application. 
• 
GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• 
The participant must be informed that their personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant. Their data to be used as described in the 
informed consent. 
• 
The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• 
The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
107 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure 
or access. 
10.1.6. 
Committees structure  
The internal SRT is a cross-functional team including safety, clinical, and statistics 
experts from both GSK and CureVac. The SRT includes study/project team members. 
The SRT is responsible for the ongoing assessment of benefit-risk for the investigational 
study intervention. The role of the SRT is to oversee the safety of participants and study 
conduct in both Phase 1 (unblinded) and Phase 2 (blinded). 
The iSRC is a cross-functional team including safety, clinical, and statistics experts from 
GSK. The iSRC members are independent of the study/project team. The role of the 
iSRC is to oversee the safety of participants and study conduct in Phase 2 (unblinded). 
The iDRC is a multidisciplinary committee including immunogenicity, safety, clinical, 
and statistics experts from GSK. The iDRC members are from the sponsor therapeutic-
area leadership. The role of the iDRC is to oversee interim analyses in both Phase 1 and 
Phase 2, and to determine the composition of the investigational study intervention 
formulations to be assessed Phase 2. Refer to Section 4.3 for detailed information. 
For more details, refer to iDRC and iSRC charters, SRT framework or relevant 
procedure. 
10.1.7. 
Dissemination of clinical study data 
• 
The key design elements of this protocol and results summaries will be posted on EU 
clinical trials Register, 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 or allow for delaying disclosure, GSK will follow those 
timelines. 
• 
Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• 
Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities.  
• 
GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
108 
• 
GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by study participants are used to maximum effect in the creation of 
knowledge and understanding. 
10.1.8. 
Data quality assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRFs 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 CRF. 
• 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• 
QTLs will be predefined in the QTL Report to identify systematic issues that can 
impact participant safety and/or reliability of study results. These predefined 
parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarized in the CSR. 
• 
Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the monitoring plan. 
• 
The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final CSR/ 
equivalent summary unless local regulations or institutional policies require a 
different 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. 
10.1.9. 
Source documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the eCRF/eDiaries or entered in the eCRF/eDiaries that are 
transcribed from source documents must be consistent with the source documents or 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
109 
the discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
• 
Definition of what constitutes source data and its origin can be found in Definitions 
Of Terms 
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• 
The sponsor or designee will perform monitoring to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and 
that the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
10.1.10. 
Study and site start and closure 
First act of recruitment 
The start of study and the first act of recruitment are defined as FSFV (first ICF signature 
date) at a country-level. 
Study/Site termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• 
Discontinuation of further study intervention development 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• 
Total number of participants included earlier than expected 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
110 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow up. 
10.1.11. 
Publication policy 
The results of this study may be published in peer reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with ICMJE authorship requirements. 
10.2. 
Appendix 2: Clinical laboratory tests 
10.2.1. 
Protocol-required safety laboratory assessments 
• 
The tests detailed in Table 21 will be performed by the local laboratory using local 
standards, and the results will be encoded by the investigator into the eCRF. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• 
Investigators must document their review of each laboratory safety report. 
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. 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. Refer to 
Section 10.2.2 for more information on toxicity grading scales to be considered in this 
study. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
111 
Table 21 
Protocol-required safety laboratory tests (Phase 1 only) 
Assay type 
System 
Component 
Method 
Hematology 
Whole Blood  
White Blood Cells count and differentials 
As per local laboratory 
procedures 
Whole Blood  
Erythrocytes 
Whole Blood  
Hemoglobin 
Whole Blood  
Glycated hemoglobin (Hba1c) * 
Whole Blood   
Platelets  
Biochemistry 
Serum 
Blood urea nitrogen/Urea 
Creatinine 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Troponin (Troponin I and/or Troponin T) 
Urinalysis*, ** 
Urine 
Leukocytes, Blood, Proteins, Glucose, 
Ketones, Bilirubin, Urobilinogen, Nitrite, 
Specific gravity, pH 
* Only applicable for screening visit in Phase 1. 
** Urinalysis will be done by dipstick. 
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 22 
Toxicity grading scales for biochemistry parameters evaluated in the 
current study (adapted from FDA Guidance for industry)  
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. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
112 
Table 23 
Toxicity grading scales for hematology parameters evaluated in the 
current study (adapted from FDA Guidance for industry)  
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. 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow up, and reporting 
10.3.1. 
Definition of AE 
AE definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events meeting the AE definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
113 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
Significant failure of an expected pharmacologic or biological action. 
• 
Events that occur as a result of protocol-mandated procedures (i.e., invasive 
procedures, modification of participant’s previous therapeutic regimen). 
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. "Lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or 
SAE. 
Events NOT meeting the AE definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, admission for routine examination.). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. Pre-existing 
diseases will be recorded in the medical history Section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
114 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death. 
b. Is life-threatening. 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
− 
In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency 
ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
− 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
− 
The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
− 
This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant. 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
g. Is a suspected transmission of any infectious agent via an authorized medicinal 
product. 
h. Other situations: 
− 
Possible Hy’s Law case: ALT ≥3x ULN AND total bilirubin ≥2x ULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
− 
Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
115 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
− 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.3.3. 
Solicited events  
Definition of solicited event 
• 
Solicited events are predefined events administration site events and systemic 
events for which the participant is specifically questioned, and which are noted by 
the participant in their eDiary.  
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 24 
Solicited administration site events 
Pain at administration site 
Redness at administration site 
Swelling at administration site 
Lymphadenopathy*  
* Defined as localized axillary, cervical or supraclavicular swelling or tenderness ipsilateral to the injection arm 
b. Solicited systemic events 
The following systemic events will be solicited: 
Table 25 
Solicited systemic events 
Fever 
Headache 
Myalgia (muscle pain) 
Arthralgia (joint pain) 
Fatigue (tiredness) 
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. 
Site staff should monitor participants compliance to completion of eDiary on ongoing 
basis based on eDiary web-reporting portal and/or automated alerts sent by e-mail.  
During solicited reporting period, if eDiary was not submitted by a participant for a 
day, site should attempt to contact the participant as quickly as possible, ideally the 
following day, to retrain on importance of eDiary compliance and collect missing 
information, the data for the missed eDiary for that day will be documented in the 
participant’s records and entered into eCRF. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
116 
10.3.4. 
Unsolicited AE  
Definition of unsolicited AE 
• 
An unsolicited AE is an AE that was either not included in the list of solicited 
events or could be included in the list of solicited events but with an onset outside 
the specified period of follow up for solicited events. Unsolicited AEs must have 
been communicated by participants who has signed the informed consent or 
through his/her caregiver. Unsolicited AEs include both serious and non-serious 
AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). 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 as soon as possible. Detailed information about reported 
unsolicited AEs will be collected by qualified site personnel and documented in 
the participant’s records and entered into eCRF. 
• 
Unsolicited AEs that are not medically attended nor 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 visit/contact and documented in the 
participant’s records and entered into eCRF. 
• 
Site staff should monitor participants compliance to completion of eDiary on 
ongoing basis based on eDiary web-reporting portal and/or automated alerts 
sent by e-mail. During unsolicited reporting period, if eDiary was not submitted 
by a participant for a day, site should attempt to contact the participant in timely 
manner to re-train on importance of eDiary compliance and to collect 
information about AEs, if any. 
10.3.5. 
Recording, assessment and follow up of AE, SAE, AESIs and 
pregnancies 
10.3.5.1. 
AE and SAE recording  
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the paper Expedited Adverse Events 
Report/eCRF. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
117 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
An eDiary (provided by Signant Health) 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. 
Anyone who measures administration site or systemic events and who will record the 
event in the eDiary should be trained on using the eDiary. This training must be 
documented in the participant’s source record. 
For each solicited and unsolicited AE the participant experiences, the participant will be 
asked if they received medical attention (defined as unscheduled visit to or from medical 
personnel for any reason, including emergency room visits). This information will be 
recorded in the participant’s eDiary and in the participant’s eCRF as part of normal AE 
reporting (for unsolicited AEs). If the collection of solicited AEs was not possible for any 
reasons via the eDiary and solicited AEs were reported to the investigator by the 
participant/caregiver, then it would be possible for it to be reported directly to the site 
staff and submitted (e.g., via the eCRF). Medical attention received for SAEs/AESIs will 
have to be reported using the normal AE reporting process in the eCRF. 
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 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. 
10.3.5.2. 
Time period for collecting and recording AEs, SAEs, AESIs and 
pregnancies 
Occurrence of unsolicited events will be recorded in to eDiary within 28 days after 
administration of the study intervention (Day 1 to Day 28). An automatic reminder to 
complete the eDiary will be sent to the participants/caregivers during this timeframe. 
Unsolicited AE information 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. 
All solicited events that occur during 7 days following administration of the dose of study 
intervention (Day 1 to Day 7 included) must be recorded into the eDiary, irrespective of 
intensity. Solicited events ongoing after Day 7 will continue to be recorded into the 
eDiary from Day 8 to Day 28 and followed-up until the event has resolved, subsided, 
stabilized, disappeared, or until the event is otherwise explained, the participant is lost to 
follow up, or study is completed. 
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. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
118 
Refer to Section 8.4.1 for more information on collection and reporting of safety 
information in this study. 
10.3.5.3. 
Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
Table 26 
Intensity scales for solicited events in participants of 6 years of age 
or more 
Event 
Intensity grade 
Parameter 
Pain at administration site 
0 
None 
 
1 
Mild: Any pain neither interfering with nor preventing 
normal everyday activities 
 
2 
Moderate: Painful when limb is moved and interferes with 
everyday activities 
 
3 
Severe: Significant pain at rest. Prevents normal everyday 
activities 
Redness at administration site* 
0 
< 25 mm 
 
1 
≥ 25 - ≤ 50 mm 
 
2 
≥ 51 - ≤ 100 mm 
 
3 
> 100 mm 
Swelling at administration site* 
0 
< 25 mm 
 
1 
≥ 25 - ≤ 50 mm 
 
2 
≥ 51 - ≤ 100 mm 
 
3 
> 100 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*** 
0 
< 38.0°C (100.4°F) 
 
1 
≥ 38.0°C (100.4°F) - ≤ 38.4°C (101.1°F) 
 
2 
≥ 38.5°C (101.2°F) - ≤ 38.9°C (102.0°F) 
 
3 
≥ 39.0°C (102.1°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 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
119 
Event 
Intensity grade 
Parameter 
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 
* Greatest surface diameter in mm 
** 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. 
The investigator will make an assessment of intensity for each AE, AESI, SAE and 
device deficiency reported during the study and assign it to one of the following 
categories: 
• 
Mild: 
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
• 
Moderate:  
A type of adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• 
Severe:  
A type of adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
10.3.5.4. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency. The investigator will use 
clinical judgment to determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes There may be situations in which an 
SAE has occurred and the investigator has minimal information to include in the 
initial report to GSK. However, it is very important that the investigator always make 
an assessment of causality for every event before the initial transmission of the SAE 
data to GSK. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
120 
• 
The investigator may change their opinion of causality in light of follow up 
information and send an SAE follow up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.5.5. 
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). 
10.3.5.6. 
Follow up of AEs, SAEs, AESIs, pregnancies or any other events of 
interest 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
After the initial AE/SAE/AESI/pregnancy or any other event of interest, the investigator 
is required to proactively follow each participant at subsequent visits/contacts. All SAEs, 
and non-serious AESI (as defined in the Section 8.4.4), will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow up. 
Other non-serious AEs must be followed for 6 months (until Day 183) or until the 
participant is lost to follow up. 
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 (Day 183) or the participant is lost to follow up. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
121 
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. 
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 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 10.3.6. 
10.3.5.7. 
Updating of SAE, AESI and pregnancy information after removal of 
write access to the participant’s eCRF 
When additional SAE, AESI or pregnancy information is received after write access to 
the participant’s eCRF is removed, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be sent to the study contact for reporting SAEs (refer to Section 
8.4.3). 
10.3.6. 
Reporting of SAEs, AESIs and pregnancies 
SAE reporting to GSK via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next Section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
Section) or to the medical monitor by telephone. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
122 
• 
If the site during the course of the study becomes aware of any serious, non-serious 
AEs, pregnancy exposure, related to any GSK non-IMP they will report these events 
to GSK or to the concerned competent authority via the national spontaneous 
reporting system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
SAE reporting to GSK via paper data collection tool 
• 
Email/facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
Woman of childbearing potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective 
of the occurrence of menarche or following menarche. 
2. From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below). 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development and 
pubic hair growth. 
10.4.1.2. 
Woman of non-childbearing potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenarchal: Tanner stage 1 (prepubertal) 
2. Permanently sterile due to one of the following procedures: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
123 
For permanently sterile individuals due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. If reproductive 
status is questionable, additional evaluation should be considered. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
3. 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, confirmation with more than 1 FSH measurement is required. 
• 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception guidance 
• 
Female participants of childbearing potential are eligible to participate if they agree 
to use a highly effective contraceptive method consistently and correctly according 
to the methods listed in GSK’s list of highly effective contraceptive methods (Table 
27). 
Table 27 
Highly effective contraceptive methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
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.)  

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
124 
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.)  
a`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 
10.5. 
Appendix 5: Medical device AEs, ADEs, SAEs, sADEs, 
USADEs and device deficiencies: Definitions and 
procedures for recording, evaluating, follow up, and 
reporting in medical device studies 
• 
Both the investigator and the sponsor will comply with all local reporting 
requirements for medical devices. 
• 
The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list 
of sponsor medical devices. 
10.5.1. 
Definition of medical device AE and ADE 
Medical device AE and ADE definition  
• 
A medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether or not considered related to the investigational medical 
device. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of an investigational medical device. This 
definition includes events related to the investigational medical device or 
comparator and events related to the procedures involved except for events in 
users or other persons, which only include events related to investigational 
devices. 
• 
An ADE is defined as an AE related to the use of an investigational medical 
device. This definition includes any AE resulting from insufficient or inadequate 
instructions for use or any malfunction of the investigational medical device as 
well as any event resulting from use error or from intentional misuse of the 
investigational medical device. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
125 
10.5.2. 
Definition of medical device SAE, SADE and USADE 
A Medical Device SAE is any serious adverse event that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
− 
A life-threatening illness or injury. The term ‘life-threatening' in the definition 
of ‘serious' refers to an event in which the participant was at risk of death at 
the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
− 
A permanent impairment of a body structure or a body function. 
− 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
− 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
− 
Chronic disease (MDR 2017/745). 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. Is a suspected transmission of any infectious agent via a medicinal product 
SADE definition 
• 
A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of an SAE. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less 
fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is 
defined as a serious adverse device effect that by its nature, incidence, severity or 
outcome has not been identified in the current version of the IB (see Section 2.3). 
10.5.3. 
Definition of device deficiency 
Device deficiency definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequacy of the information supplied by 
the manufacturer. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
126 
10.5.4. 
Recording and follow up of medical device AE and/or SAE and 
device deficiencies 
10.5.4.1. 
Medical device AE, SAE, and device deficiency recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice and on the appropriate form. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE/device deficiency 
form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
− 
A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence. 
• 
If the site during the course of the study becomes aware of any serious, non-serious 
incident (including device deficiencies and malfunctions) related to any GSK non-
IMP product they will report these events to GSK or to the concerned competent 
authority via the national spontaneous reporting system.  These will be classified as 
spontaneous ICSRs. 
10.5.4.2. 
Assessment of intensity 
Refer to Section 10.3.5.3 
10.5.4.3. 
Assessment of causality 
Refer to Section 10.3.5.4 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
127 
10.5.4.4. 
Follow-up of medical device AE/SAE and device deficiency 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow 
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally completed form. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.5.5. 
Reporting of medical device SAEs 
Medical device SAE reporting to GSK via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next Section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
table) or to the medical monitor by telephone. 
• 
If the site during the course of the study or post-study becomes aware of any serious, 
non-serious AEs, pregnancy exposure, related to any GSK device they will report 
these events to GSK or to the concerned competent authority via the national 
spontaneous reporting system.  These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
Medical device SAE reporting to GSK via paper data collection tool 
• 
Email/Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE paper data collection tool sent by 
overnight mail or courier service. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
128 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated reporting 
time frames. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.5.6. 
Reporting of SADEs 
SADE reporting to GSK 
NOTE: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
• 
Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency. 
• 
The sponsor will review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national 
regulations. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.5.7. 
Reporting of medical device deficiencies for associated person 
• 
Reporting to GSK  
If an associated person (e.g., spouse, caregiver, site staff) experiences a device 
deficiency, the medical device deficiency information, and any associated AE/SAE 
information will be reported to GSK. The associated person will be provided with the 
authorization to contact physician letter. 
If follow up information is required, authorization to contact physician (or other 
licensed medical practitioner) must be signed to obtain consent. 
• 
Medical device deficiencies that are not related to an AE or SAE should be 
reported via email to gsk-rd.complaints@gsk.com, using the medical device 
deficiency report form. 
• 
If the medical device deficiency is related to a non-serious AE and not linked to an 
SAE, please send the medical device deficiency report form with details of the 
associated AE via email to gsk-rd.complaints@gsk.com only. 
• 
If the device incident is linked to an SAE, please email the medical device 
deficiency report form, within 24 hours. Refer to section 8.4.7 for reporting. 
• 
GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
129 
10.6. 
Appendix 6: Country-specific requirements 
10.6.1. 
Specific requirements for South Africa 
As per regulatory requirement and due to high prevalence of HIV infection, all 
participants from South Africa with unknown HIV status (unknown or previously 
tested negative) will be counselled and tested for HIV infection, using the South 
African Health Products Regulatory Authority (SAHPRA) approved test kits prior to 
enrolment. If HIV result is positive, these participants will be excluded as per Section 
5.2.1 Medical Conditions exclusion criterion 2. 
Participants from South Africa with known HIV status (previously tested positive) may 
be enrolled if they have been stable on antiretroviral therapy for the past 6 consecutive 
months, i.e., their treatment has not been modified, their CD4 cell count is ≥200/mm³ 
and their viral load has been undetectable (i.e., HIV-RNA <50 copies/mL). The 
evaluation will be made based on medical records, and no additional laboratory testing 
is required for known HIV positive participants. 
10.7. 
Appendix 7 Statistics: BLRM Model specification and data 
scenarios 
An adaptive BLRM will be used to inform on the posterior probability of the true Grade 3 
solicited event rate for all mRNA dose levels used in Phase 1 study in order to 
recommend the mRNA doses to proceed to Phase 2 of the study: 
logit(p(d)) = log(α) + β1*log(d/d*) 
where 
• 
p(d) = percentage of participants with Grade 3 solicited event at mRNA dose level d 
• 
logit(p) = log(p/(1-p)) 
• 
d* = 50µg is the reference dose representing the total mRNA dose 
• 
α is the intercept parameter 
• 
β1 is a dose effect 
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: 
• 
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. 
• 
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. 
A zero covariance between priors is assumed. 
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
130 
A greater than 50% posterior probability that the Grade 3 solicited event rate ≥18% at a 
given mRNA dose will indicate that the dose may not be tolerable. 
Hypothetical scenarios illustrating the posterior probability are presented in Table 28. 
Table 28 
Hypothetical data scenarios for assessment of reactogenicity using 
BLRM in YAs 
Scenario 
Age group 
mRNA Dose 
#Events 
#Participants 
CD – P(TD) 
CD – P(OD) 
1 
YA 
0 
24 
0.995 
0.005 
0 
24 
1 
0 
0 
24 
1 
0 
0 
24 
1 
0 
0 
24 
1 
0 
2 
YA 
0 
24 
0.995 
0.005 
1 
24 
0.997 
0.003 
1 
24 
0.998 
0.002 
3 
24 
0.961 
0.039 
5 
24 
0.758 
0.242 
3 
YA 
0 
24 
0.995 
0.005 
0 
24 
1 
0 
2 
24 
0.994 
0.006 
4 
24 
0.834 
0.166 
6 
24 
0.404 
0.596* 
* Unacceptable reactogenicity, i.e., CD – P(OD) >0.5 
CD = Current dose; P(TD) = Probability of tolerable dose; and P(OD) = Probability of overdose; YA: younger adult. 
10.8. 
Appendix 8: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the TOC. 
Amendment 1 (07 April 2023) 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because it significantly impacts the safety of participants. 
Overall rationale for Amendment 1: 
Following the feedback received from the Belgian and US Competent Authorities after 
the CTA and IND submission of the Flu SV MRNA-002 study, the protocol has been 
amended to accommodate requested clarifications. 
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
131 
Summary of changes table of previous amendments: 
Section # and title 
Description of change 
Brief rationale 
LIST OF ABBREVIATIONS AND 
DEFINITIONS OF TERMS 
Definition of adverse event of special 
interest (AESI) was added. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
1.2. Schema 
8.3.7.1.1. Phase 1 
8.3.7.1.3. Phase 2 (OA groups) 
Follow up period for sentinel participants 
was extended to 7 days after dosing (i.e., 
Day 1 to Day 8 post-dosing). 
To comply with the 
recommendation from the US 
Competent Authorities. 
1.3. Schedule of activities (SoA) 
(Table 2) 
Table 5 
Objectives and endpoints 
8.2.2. Laboratory assays 
Table 11 
 Laboratory assays 
Wording related to the generation of 
monoclonal antibodies was removed. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
2.3.1. Risk assessment 
Footnote related to 
myocarditis/pericarditis surveillance was 
added. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
4.1. Overall design 
Table 8 
Study intervention(s) 
administered. Phase 1 
9.5.1. Sample size determination for 
Phase 1 
Wording related to the number of groups 
in Phase 1 and approximate number of 
participants in both phases was updated.  
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
4.2.1. Rationale for study design of 
Phase 1 
4.2.2. Rationale for study design of 
Phase 2 
Mention of maximum number of sentinel 
participants across sites was added. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
4.2.1. Rationale for study design of 
Phase 1 
4.3.1. Dose selection for Phase 1 
Wording for justification of dose selection 
of individual antigens was updated. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
5.2.1. Medical conditions 
Exclusion criterion N°8 was updated to 
clarify that participants with conditions 
that moderately or severely impair 
cognition will be excluded from the study, 
not only conditions that may interfere with 
the completing of study tasks. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
8.2.3. Immunological read-outs 
Table 12 
 Immunological read-outs 
Footnote related to the number of 
participants was updated. 
To align with 
recommendations from 
Belgian Competent 
Authorities.  
8.3.4. Myocarditis and pericarditis 
assessment and definitions 
Bullet point classifying asymptomatic 
participants as suspected cases was 
removed.  
The definition of a suspected 
case of 
myocarditis/pericarditis has 
been updated to align with 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
132 
Section # and title 
Description of change 
Brief rationale 
the definition of a probable 
case by the Brighton 
Collaboration (SPEAC, 2022) 
and the CDC (CDC, 2021).  
8.3.7.1.1. Phase 1 
8.3.7.1.3. Phase 2 (OA groups) 
Maximum number of sentinel participants 
to be dosed per day was specified. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
Table 13 Study holding rules 
Study holding rule 1f has been updated. 
Holding rules 2a and 2b were made 
applicable for Phase 2 participants. 
To comply with the 
recommendation from the US 
Competent Authorities. 
9.5.1. Sample size determination for 
Phase 1 
Number of participants per group was 
further clarified. 
To comply with the 
recommendation from the 
Belgian Competent 
Authorities. 
10.2.2. 
FDA Guidance for 
industry: Toxicity grading scale for 
healthy adult and adolescent 
volunteers enrolled in preventive 
vaccine clinical trials (September 
2007) 
Tables 21 and 22 were updated to 
remove the values corresponding to SI 
units.  
To align with original FDA 
definitions.  
10.3.5.1. AE and SAE recording 
Name of the third-party provider for the 
eDiary was added. 
To address EMA inspection 
finding in another study 
conducted by GSK.  
Details of substantial changes made to the study protocol since the previous submitted 
version are provided in the Protocol Amendment Substantial Change Table 
accompanying this protocol amendment. 

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
133 
11. 
REFERENCES  
Babazadeh A, Mohseni Afshar Z, Javanian M, Mohammadnia-Afrouzi M, Karkhah A, 
Masrour-Roudsari J, Sabbagh P, Koppolu V, Vasigala VK, Ebrahimpour S. Influenza 
Vaccination and Guillain-Barré Syndrome: Reality or Fear. J Transl Int Med. 2019 Dec 
31;7(4):137-142. doi: 10.2478/jtim-2019-0028. PMID: 32010599; PMCID: 
PMC6985921. 
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Stat Med. 1998 May 30;17(10):1103-20. 
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and 
Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 2021;384(5):403-416 
Bardage C, Persson I, Ortqvist A, Bergman U, Ludvigsson JF, Granath F. Neurological 
and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a 
monovalent adjuvanted vaccine: Population based cohort study in Stockholm, Sweden. 
BMJ. 2011; 343:d5956 Epub 2011/10/14. 10.1136/bmj.d5956. 
Baxter R, Abigail Eaton, John Hansen, Laurie Aukes, Herve Caspard, Christopher S. 
Ambrose. Safety of quadrivalent live attenuated influenza vaccine in subjects aged 2–49 
years. Vaccine 2017 Mar 1;35(9):1254-1258. 
Bertin B, Grenet G, Pizzoglio-Billaudaz V, Lepelley M, Atzenhoffer M, Vial T. Vaccines 
and Bell's palsy: A narrative review. Therapie. 2022 Aug 1:S0040-5957(22)00137-8. doi: 
10.1016/j.therap.2022.07.009. Epub ahead of print. PMID: 36038397; PMCID: 
PMC9341208. 
 
 
Centers for Disease Control and Prevention [CDC] (August, 2022). Prevention and 
Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory 
Committee on Immunization Practices - United States, 2022–23 Influenza Season. 
Available at: https://www.cdc.gov/mmwr/volumes/71/rr/rr7101a1.htm. [Accessed on 05 
December, 2022] 
 
 
. 
CIOMS Cumulative Pharmacovigilance Glossary, Geneva, Switzerland: Council for 
International Organizations of Medical Sciences (CIOMS), 2021. 
 
 
 
 
 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
134 
 
 
 
 
 
European Medicines Agency (EMA). Guideline on clinical trials in small populations. 
2006. Ref. CHMP/EWP/83561/2005. 
Huang WT, Huang WI, Huang YW, Hsu CW, Chuang JH. The reporting completeness of 
a passive safety surveillance system for pandemic (H1N1) 2009 vaccines: a capture-
recapture analysis. Vaccine. 2012;30(12):2168–72. 10.1016/j.vaccine.2012.01.013. 
Kamath A, Maity N, Nayak MA. Facial Paralysis Following Influenza Vaccination: A 
Disproportionality Analysis Using the Vaccine Adverse Event Reporting System 
Database. Clin Drug Investig. 2020 Sep;40(9):883-889. 
 
 
Law B. AESI Case Definition Companion Guide for 1st Tier AESI: Anaphylaxis v1.0. 
Safety Platform for Emergency vACcines. 2021 February 05. 
McNeil MM. Vaccine-Associated Anaphylaxis. Curr Treat Options Allergy. 2019 
Sep;6(3):297-308. doi: 10.1007/s40521-019-00215-0. Epub 2019 Jul 16. PMID: 
31815089; PMCID: PMC6896995. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-
26. 
Moderna Announces Positive Interim Phase 1 Data for mRNA Flu Vaccine and Provides 
Program Update. Available at: https://investors.modernatx.com/news/news-
details/2021/Moderna-Announces-Positive-Interim-Phase-1-Data-for-mRNA-Flu-
Vaccine-and-Provides-Program-Update/default.aspx. Accessed on: 15 March 2022 
Mutsch M, Zhou W, Rhodes P, et al. Use of the inactivated intranasal influenza vaccine 
and the risk of Bell's palsy in Switzerland. N Engl J Med 2004; 350:896-903. 
CCI
CCI
CCI

CONFIDENTIAL 
217884 (FLU SV MRNA-002) 
Protocol Amendment 2 Final 
28 Aug 2023 
135 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Statist. Med. 2008; 27:2420–2439. 
Ozonoff Al, Etsuro Nanishi, Ofer Levy. Bell’s palsy and SARS-CoV-2 vaccines. 
VOLUME 21, ISSUE 4, P450-452, APRIL 01, 2021. 
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and 
Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020;383(27):2603-
15. 
Rogatko A, Schoeneck D, Jonas W, et al. Translation of innovative designs into phase I 
trials. J Clin Oncol. 2007 Nov 1;25(31):4982-6. 
Safety Platform for Emergency vACcines (SPEAC) SPEAC_D2.5.2.2_Myocarditis-
companion-guide_codes-updated_BL_2022_May12.pdf (brightoncollaboration.us). 
[Accessed 04 August 2022]. 
Shimabukuro TT, Cole M, Su JR. Reports of Anaphylaxis After Receipt of mRNA 
COVID-19 Vaccines in the US-December 14, 2020-January 18, 2021. JAMA. 2021 Mar 
16;325(11):1101-1102. 
 
Vellozzi C, Iqbal S, Broder K. Guillain-Barre syndrome, influenza, and influenza 
vaccination: the epidemiologic evidence. Clin Infect Dis. 2014;58(8):1149-55 
Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and Immunogenicity of Two RNA-
Based Covid-19 Vaccine Candidates. N Engl J Med 2020; 383:2439-2450. DOI: 
10.1056/NEJMoa2027906 
Wijnans L, Dodd CN, Weibel D, Sturkenboom M. Bell’s palsy and 
influenza(H1N1)pdm09 containing vaccines: A self-controlled case series. PLoS One; 
12(5); 2017. 
World Health Organization (WHO) (13 December 2017). News release. Available at: 
https://www.who.int/news/item/13-12-2017-up-to-650-000-people-die-of-respiratory-
diseases-linked-to-seasonal-flu-each-year [Accessed on 17 December 2020]. 
World Health Organization (WHO). Influenza (seasonal) factsheet. 2018. Available at: 
http://www.who.int/mediacentre/factsheets/fs211/en/ [Accessed 14 July 2021]. 
World Health Organization (WHO) (26 February 2021). Recommended composition of 
influenza virus vaccines for use in the 2020-2021 northern hemisphere influenza season 
202102_recommendation.pdf (who.int) [Accessed 14 July 2021]. 
CCI

Signature Page for  217884 TMF-16305293 v1.0
Signature Page for TMF-16305293 v1.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 28-Aug-2023 10:44:40 GMT+0000
PPD