Clinical trial NCT05972993
Conditions: COVID-19
Keywords: COVID-19 SARS-CoV-2 Master Protocol Omicron mRNA
Sponsor: GlaxoSmithKline
Start date: 2023-08-07; Completion date: 2024-10-14
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety, reactogenicity and immune responses of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA-CR-04 vaccine construct when administered in healthy adults previously vaccinated with SARS-CoV-2 mRNA vaccines.

Detailed description:
There will be dose-escalation in part A of the study with sentinel dosing strategy implemented in each of 3 dosing levels (Group 1; 2; 3). At start, enrollment in Group 1 and 2 will occur simultaneously with the enrolment of 1st participant in Group 1. Each group will consist of 8 sentinel participants, with 6 receiving the mRNA-CR-04 vaccine and 2 receiving a placebo. The safety data from the sentinel participants in both groups, up to Day 8 post-vaccination, will be reviewed by the Internal Safety Review Committee (iSRC).

If no safety signal is observed, vaccination of the non-sentinel participants in that group will continue. If there are no safety signals observed from the sentinel participants in Group 1 and Group 2, the enrollment and vaccination of the sentinel participants in Group 3 will begin.

Part B of the study will commence only after all Part A participants have completed their Day 15 study visits and the Day 15 interim analysis is completed. In Part B, 2 doses of the mRNA-CR-04 vaccine will be evaluated.

Arms: arm 1: Participants received mRNA 10 micrograms (µg) administered on Day 1. arm 2: Participants received placebo dose administered on Day 1. arm 3: Participants received placebo dose administered on Day 1. arm 4: Participants received placebo dose administered on Day 1. arm 5: Participants received mRNA 100 µg administered on Day 1 arm 6: Participants received placebo dose administered on Day 1. arm 7: Participants received mRNA 3 µg administered on Day 1. arm 8: Participants received mRNA 10 µg administered on Day 1. arm 9: Participants received placebo dose administered on Day 1.
Interventions: intervention 1: mRNA-CR-04 vaccine 10μg intervention 2: mRNA-CR-04 vaccine 30μg intervention 3: mRNA-CR-04 vaccine 100μg intervention 4: Placebo intervention 5: mRNA-CR-04 vaccine 3μg
Intervention descriptions: intervention 1: mRNA CR-04 vaccine, 10 µg, is administered intramuscularly into the deltoid muscle of the non-dominant arm on day 1. intervention 2: mRNA CR-04 vaccine, 30 µg, is administered intramuscularly into the deltoid muscle of the non-dominant arm on day 1. intervention 3: mRNA CR-04 vaccine, 100 µg, is administered intramuscularly into the deltoid muscle of the non-dominant arm on day 1. intervention 4: Placebo is administered intramuscularly into the deltoid muscle of the non-dominant arm on day 1. intervention 5: mRNA CR-04 vaccine, 3 µg, is administered intramuscularly into the deltoid muscle of the non-dominant arm on day 1.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
219112 (MRNA CLINRES-001) 
Protocol Amendment 3 Final 
07 Feb 2024  
1 
 
CLINICAL STUDY PROTOCOL 
SPONSOR: 
GlaxoSmithKline Biologicals SA (GSK) 
Primary study intervention 
GSK’s mRNA Clinical Research CR-04 
Other study intervention 
Placebo (normal saline) 
Study identifier 
219112 (MRNA CLINRES-001) 
NCT identifier number 
NCT05972993 
IND number 
29606 
Date of protocol 
Final: 11 May 2023  
Date of protocol amendment 
Amendment 3 Final: 07 Feb 2024 
Title 
Exploratory, FTIH, observer-blind, randomized, 
controlled study to evaluate safety, reactogenicity 
and immunogenicity of various doses of GSK’s 
investigational mRNA-CR-04 vaccine when 
administered intramuscularly in healthy adults 18 to 
49 years of age 
Brief title 
A safety and immune response study to evaluate 
varying doses of an mRNA vaccine against COVID-
19 in healthy adults 
Sponsor signatory 
Pavitra Keshavan, Sr. Director, Clinical Project 
Lead, Vaccines Clinical Sciences  
Based on GSK Protocol WS v17.3 
©2024 GSK group of companies or its licensor. 


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219112 (MRNA CLINRES-001) 
Protocol Amendment 3 Final 
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PROTOCOL AMENDMENT 3 INVESTIGATOR AGREEMENT 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GSK and/or CRO. 
• 
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 onsite or 
elsewhere without the approval of GSK and the express written informed consent of 
the participant. 
• 
To perform no biological assays on the clinical samples other than those described in 
the protocol or its amendment(s). 
• 
To co-operate with representative(s) of GSK in the monitoring process of the study 
and in resolution of queries about the data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator(s)’ ownership interest 
in the sponsor or the investigational intervention(s), and more generally about their 
financial ties with the sponsor. GSK will use and disclose the information solely for 
the purpose of complying with regulatory requirements. 


CONFIDENTIAL 
219112 (MRNA CLINRES-001) 
Protocol Amendment 3 Final 
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Hence, I: 
• 
Agree to supply GSK with any necessary information regarding ownership interest 
and financial ties (including those of my spouse and dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other documents 
required by regulatory agencies for this study. 


CONFIDENTIAL 
219112 (MRNA CLINRES-001) 
Protocol Amendment 3 Final 
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eTrack study number and 
abbreviated title 
219112 (MRNA CLINRES-001) 
NCT identifier number 
NCT05972993 
IND number 
29606 
Date of protocol 
Final: 11 May 2023  
Date of protocol amendment 
Amendment 3 Final: 07 Feb 2024 
Title 
Exploratory, FTIH, observer-blind, randomized, 
controlled study to evaluate safety, reactogenicity 
and immunogenicity of various doses of GSK’s 
investigational mRNA-CR-04 vaccine when 
administered intramuscularly in healthy adults 18 to 
49 years of age 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 


CONFIDENTIAL 
219112 (MRNA CLINRES-001) 
Protocol Amendment 3 Final 
07 Feb 2024  
5 
SPONSOR INFORMATION 
1. Sponsor 
GSK (Rixensart) 
2. Sponsor medical expert for the study 
Refer to the local study contact information document. 
3. Sponsor study monitor 
Refer to the local study contact information document. 
4. Sponsor study contact for reporting of SAEs 
Back up study contact for reporting SAEs: refer to Section 8.4.7. 
Study contact for reporting SAEs: refer to the local study contact information 
document. 
5. Emergency unblinding 
Refer to Section 6.3.4. 


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219112 (MRNA CLINRES-001) 
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PROTOCOL AMENDMENT 3 SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Substantial 
Region 
Amendment 3 
07 Feb 2024 
Yes 
United States (US) 
Amendment 2 
15 Nov 2023 
Yes 
United States (US) 
Amendment 1 
03 Oct 2023 
Yes 
United States (US) 
Original Protocol 
11 May 2023 
- 
- 
Overall Rationale for the Amendment: 
The Protocol Amendment 3 has been amended to allow for additional Day 31 interim 
analyses and to add a Part B to the study following the Day 15 interim analysis, during 
which a lower dose (3 µg) of the mRNA-CR-04 vaccine will be evaluated and sponsor 
personnel will be unblinded. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 (Synopsis), Section 1.2 
(Schema), Section 4.1 (Overall 
design), Section 4.2 (Scientific 
rationale for study design), Section 
4.3 (Justification for dose), and 
Section 6.3.3 (Intervention allocation 
to the participant).  
This study is divided into two parts 
(Parts A and B). Part B will 
commence only after all Part A 
participants have completed their 
Day 15 study visits and the Day 15 
interim analysis is completed. In 
Part B, 42 more participants will be 
enrolled in parallel and randomly 
assigned in a 3:3:1 ratio to receive: 
(a) 3 µg mRNA-CR-04 vaccine, or 
(b) 10 µg mRNA-CR-04 vaccine, or 
(c) saline placebo. 
To explore a wider range of 
vaccine doses and to repeat the 10 
µg dose vaccine group, which may 
assist in standardizing the Part B to 
Part A study groups. 
Section 1.1 (Synopsis), Section 1.2 
(Schema), Section 4.1 (Overall 
design), Section 6.3.4 (Blinding and 
unblinding), Section 8.3.7.1 
(Staggered administration of study 
intervention), Section 8.3.7.4 (SRT 
and iSRC evaluation), and Section 
8.4.4.2.1 (Myocarditis and 
pericarditis: definitions and 
assessment). 
Text modified to allow unblinding of 
sponsor personnel (including the 
SRT) to individual level treatment 
assignments following the Part A 
Day 15 interim analysis. The 
observer-blind will be maintained at 
the site level. 
Practical consideration to allow all 
sponsor personnel to use 
unblinded data analyses from this 
initial phase 1 trial to plan further 
clinical development of the 
investigational vaccine platform. 
The SRT will no longer need to rely 
on the iSRC as the sole reviewer of 
unblinded safety data. 
Section 2.2 (Background) and 
Section 4.3 (Justification for dose). 
FDA authorization of monovalent 
COVID-19 vaccine boosters 
encoding XBB.1.5 since 11 
September 2023 added to text. 
Since the prior protocol 
amendment, the FDA has 
approved and authorized new 
monovalent COVID-19 vaccines 
encoding this variant for 
administration as booster doses. 
Section 6.1 (Study interventions 
administered). 
Added a new table to specify the 
study interventions to be 
administered to Part B study 
participants. 
To align with the new interventions 
planned for Part B of the study. 
Section 8.2.3 (Immunological read-
outs). 
Revised the number of participants 
column to add the planned 42 Part 
B study participants. 
To align with the planned additional 
study participants in Part B of the 
study. 
Section 9.3 (Analysis sets). 
Modified the per protocol analysis 
set definition to clarify the 
immunogenicity endpoint of interest 
To align the per protocol set 
definition immunogenicity endpoint 
of interest with the endpoint 


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Section # and Name 
Description of Change 
Brief Rationale 
being the neutralizing antibody titer 
against pseudovirus bearing S 
protein and removed the overall 
safety analysis set. 
specified in the statistical analysis 
plan and to remove the redundant 
overall safety analysis set. 
Section 9.4.1 (Primary endpoint), 
Section 9.4.2.1 (Safety endpoints), 
Section 9.4.2.2 (Immunogenicity 
endpoints), and Section 9.4.3 
(Analyses of exploratory 
immunogenicity endpoints). 
Clarified that these statistical 
analyses will be performed 
descriptively and separately for 
study Part A and Part B participants 
and will be pooled for model based 
analyses. 
To align with the additional 
analyses required with the addition 
of the study Part B participants. 
Section 9.5.1 (Sequence of 
analyses). 
Added text to perform a Day 31 
interim analysis on Part A 
participants and to allow for 
potential Day 15 and Day 31 interim 
analyses for Part B participants. 
To explicitly note the known and 
potential additional interim 
analyses currently planned for this 
study. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore not summarized. 
 


CONFIDENTIAL 
219112 (MRNA CLINRES-001) 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT 3 INVESTIGATOR AGREEMENT ....................................... 2 
SPONSOR INFORMATION ............................................................................................ 5 
PROTOCOL AMENDMENT 3 SUMMARY OF CHANGES TABLE .................................. 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 15 
1. 
PROTOCOL SUMMARY ........................................................................................ 24 
1.1. 
Synopsis ..................................................................................................... 24 
1.2. 
Schema ...................................................................................................... 25 
1.3. 
Schedule of Activities (SoA) ........................................................................ 28 
2. 
INTRODUCTION .................................................................................................... 31 
2.1. 
Study rationale ............................................................................................ 31 
2.2. 
Background ................................................................................................ 31 
2.3. 
Benefit/risk assessment .............................................................................. 32 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ................................................... 34 
4. 
STUDY DESIGN .................................................................................................... 35 
4.1. 
Overall design ............................................................................................. 35 
4.2. 
Scientific rationale for study design ............................................................. 37 
4.3. 
Justification for dose ................................................................................... 38 
4.4. 
End-of-study definition ................................................................................ 38 
5. 
STUDY POPULATION ........................................................................................... 38 
5.1. 
Inclusion criteria .......................................................................................... 39 
5.2. 
Exclusion criteria ......................................................................................... 39 
5.2.1. 
Medical conditions ....................................................................... 39 
5.2.2. 
Prior/concomitant therapy ............................................................ 41 
5.2.3. 
Other exclusions .......................................................................... 41 
5.3. 
Screen failures ............................................................................................ 41 
5.4. 
Criteria for temporarily delaying enrollment, randomization and 
study intervention administration ................................................................. 42 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 42 
6.1. 
Study interventions administered ................................................................ 42 
6.2. 
Preparation, handling, storage, and accountability ...................................... 45 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 45 
6.3.1. 
Participant identification ............................................................... 45 
6.3.2. 
Randomization to study intervention ............................................ 45 
6.3.3. 
Intervention allocation to the participant ....................................... 45 
6.3.4. 
Blinding and unblinding ................................................................ 45 
6.4. 
Study intervention compliance .................................................................... 46 
6.5. 
Dose modification ....................................................................................... 46 
6.6. 
Continued access to study intervention after the end of the study ............... 46 
6.7. 
Treatment of overdose ................................................................................ 47 
6.8. 
Concomitant therapy ................................................................................... 47 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 48 
7.1. 
Discontinuation of study intervention ........................................................... 48 
7.1.1. 
Contraindications to subsequent study interventions 
administration .............................................................................. 48 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 48 
7.3. 
Lost to follow-up.......................................................................................... 49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 49 
8.1. 
Administrative procedures .......................................................................... 50 
8.1.1. 
Collection of demographic data .................................................... 50 
8.1.2. 
Medical/vaccination history .......................................................... 50 
8.1.3. 
Distribution of eDiary or installing the application for 
devices ........................................................................................ 50 
8.2. 
Immunogenicity assessments ..................................................................... 51 
8.2.1. 
Biological samples ....................................................................... 52 
8.2.2. 
Laboratory assays ....................................................................... 52 
8.2.3. 
Immunological read-outs .............................................................. 54 
8.2.4. 
Cytology ...................................................................................... 54 
8.2.5. 
Immunological correlates of protection ......................................... 54 
8.3. 
Safety assessments .................................................................................... 54 
8.3.1. 
Physical examination ................................................................... 54 
8.3.2. 
Pre-dosing body temperature ....................................................... 55 
8.3.3. 
Pregnancy test ............................................................................. 55 
8.3.4. 
EKGs ........................................................................................... 55 
8.3.5. 
Warnings and precautions to administration of study 
intervention .................................................................................. 56 
8.3.6. 
Clinical safety laboratory tests ..................................................... 56 
8.3.7. 
Study holding rules and safety monitoring.................................... 57 
8.3.7.1. 
Staggered administration of study intervention ........... 57 
8.3.7.2. 
Outcome of safety evaluation ..................................... 58 
8.3.7.3. 
Study holding rules ..................................................... 58 
8.3.7.4. 
SRT and iSRC evaluation ........................................... 62 
8.3.8. 
Cardiac adjudication .................................................................... 62 
8.4. 
AEs, SAEs, and other safety reporting ........................................................ 63 
8.4.1. 
Time period and frequency for collecting AE, SAE and 
other safety information ............................................................... 63 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 66 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 66 
8.4.4. 
AESI ............................................................................................ 66 
8.4.4.1. 
pIMDs ......................................................................... 66 
8.4.4.2. 
Other AESIs ............................................................... 71 
8.4.4.2.1. 
Myocarditis and pericarditis: 
definitions and assessment ..................... 71 
8.4.4.2.2. 
SARS-CoV-2 infection and 
COVID-19 definitions and 
assessment ............................................ 73 
8.4.5. 
Regulatory reporting requirements for SAEs/AESIs ..................... 75 
8.4.6. 
Pregnancy ................................................................................... 75 
8.4.7. 
Contact information for reporting SAEs, AESIs, 
pregnancies and study holding rules ............................................ 76 
8.4.8. 
Participant card ............................................................................ 77 


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8.5. 
Pharmacokinetics ....................................................................................... 77 
8.6. 
Genetics ..................................................................................................... 77 
8.7. 
Biomarkers ................................................................................................. 77 
8.8. 
Immunogenicity assessments ..................................................................... 77 
8.9. 
Health outcomes ......................................................................................... 77 
8.10. 
Study procedures during special circumstances ......................................... 77 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 78 
9.1. 
Statistical hypotheses ................................................................................. 78 
9.2. 
Sample size determination .......................................................................... 78 
9.3. 
Analysis sets ............................................................................................... 79 
9.3.1. 
Criteria for elimination from analysis ............................................ 79 
9.4. 
Statistical analyses ..................................................................................... 79 
9.4.1. 
Primary endpoint .......................................................................... 80 
9.4.2. 
Secondary endpoints/estimands analyses ................................... 81 
9.4.2.1. 
Safety endpoints ......................................................... 81 
9.4.2.2. 
Immunogenicity endpoints .......................................... 81 
9.4.3. 
Analyses of exploratory immunogenicity endpoints ...................... 82 
9.5. 
Interim analyses .......................................................................................... 82 
9.5.1. 
Sequence of analyses.................................................................. 82 
9.5.2. 
Statistical consideration for Interim analyses ............................... 83 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 83 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 83 
10.1.1. 
Regulatory and ethical considerations ......................................... 83 
10.1.2. 
Financial disclosure ..................................................................... 84 
10.1.3. 
Informed consent process ............................................................ 84 
10.1.4. 
Data protection ............................................................................ 85 
10.1.5. 
Committees structure ................................................................... 85 
10.1.6. 
Dissemination of clinical study data ............................................. 86 
10.1.7. 
Data quality assurance ................................................................ 86 
10.1.8. 
Source documents ....................................................................... 88 
10.1.9. 
Study and site start and closure ................................................... 88 
10.1.10. Publication policy ......................................................................... 89 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 89 
10.2.1. 
Protocol required safety laboratory assessments ......................... 89 
10.2.2. 
Toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials................. 90 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 92 
10.3.1. 
Definition of AE ............................................................................ 92 
10.3.2. 
Definition of SAE .......................................................................... 93 
10.3.3. 
Solicited events............................................................................ 94 
10.3.4. 
Unsolicited AE ............................................................................. 95 
10.3.5. 
Recording, assessment and follow-up of AE, SAE, AESIs 
and pregnancies .......................................................................... 95 
10.3.5.1. AE, SAE and AESI recording ...................................... 95 
10.3.5.2. Assessment of intensity .............................................. 96 
10.3.5.3. Assessment of causality ............................................. 98 
10.3.5.4. Assessment of outcomes............................................ 98 


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10.3.5.5. Follow-up of AEs, SAEs, AESIs, pregnancies 
or any other events of interest .................................... 99 
10.3.5.6. Updating of SAE, AESI and pregnancy 
information after removal of write access to the 
participant’s eCRF .................................................... 100 
10.3.5.7. Reporting of SAEs, AESIs and pregnancies ............. 100 
10.4. 
Appendix 4: Contraceptive guidance and collection of pregnancy 
information ................................................................................................ 101 
10.4.1. 
Definitions .................................................................................. 101 
10.4.1.1. WOCBP .................................................................... 101 
10.4.1.1.1. Women not considered as 
WOCBP (WONCBPs) ........................... 101 
10.4.2. 
Contraception guidance ............................................................. 101 
10.5. 
Appendix 5: Protocol amendment history .................................................. 103 
11. REFERENCES ..................................................................................................... 106 
 
 


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LIST OF TABLES 
PAGE 
Table 1 
SoA ........................................................................................................ 28 
Table 2 
Intervals between study visits ................................................................. 31 
Table 3 
Study objectives, endpoints and estimands ............................................ 34 
Table 4 
Part A study groups, interventions, and blinding ..................................... 37 
Table 5 
Part B study groups, interventions, and blinding ..................................... 37 
Table 6 
Part A study interventions administered ................................................. 43 
Table 7 
Part B study interventions administered ................................................. 44 
Table 8 
Contact information for emergency unblinding ....................................... 46 
Table 9 
Biological samples ................................................................................. 52 
Table 10 
Laboratory assays .................................................................................. 53 
Table 11 
Immunological read-outs ........................................................................ 54 
Table 12 
Study holding rules ................................................................................. 59 
Table 13 
Timeframes for collecting and reporting of safety information ................. 64 
Table 14 
List of pIMDs .......................................................................................... 67 
Table 15 
Timeframes for submitting SAE, AESI, pregnancy and other 
events reports to CRO............................................................................ 75 
Table 16 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules ................................................................................. 76 
Table 17 
Analysis sets .......................................................................................... 79 
Table 18 
Protocol required safety laboratory assessments ................................... 89 
Table 19 
Toxicity grading scales for biochemistry parameters evaluated in 
the current study* ................................................................................... 90 
Table 20 
Toxicity grading scales for hematology parameters evaluated in 
the current study* ................................................................................... 91 
Table 21 
Solicited administration site events......................................................... 94 
Table 22 
Solicited systemic events ....................................................................... 94 
Table 23 
Intensity scales for solicited events ........................................................ 97 


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Table 24 
Highly effective contraceptive methods ................................................ 102 
 


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219112 (MRNA CLINRES-001) 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 26 
Figure 2 
Probability of not meeting holding rules 1 and 2 for 8 participants 
per study group ...................................................................................... 61 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ab 
Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLS 
Clinical laboratory sciences 
CoP 
Correlate of protection 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CRO 
Contract research organization 
CSL 
Clinical science lead 
CSR 
Clinical study report 
ECL 
Electro-chemiluminescence assay 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
electronic Case report form 
EKG 
Electrocardiogram 
EMA 
European Medicines Agency 
EoS 
End-of-study 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 


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FSFV 
First subject first visit 
FSH 
Follicle stimulating hormone 
FTIH 
First time in human 
GCP 
Good clinical practice 
GMC  
Geometric mean concentration 
GMR 
Geometric mean ratio 
GMT 
Geometric mean titer 
GSB 
Global safety board 
GSK 
GlaxoSmithKline Biologicals SA 
hCG 
human Chorionic gonadotropin 
HIPAA 
Health insurance portability and accountability act 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
ICS 
Intracellular cytokine staining 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
iSRC 
Internal safety review committee 


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IUD 
Intrauterine device  
IUS 
Intrauterine hormone-releasing system  
LNP 
Lipid nano particles 
LSLV 
Last subject last visit 
MAAE 
Medically attended adverse event 
MedDRA 
Medical dictionary for regulatory activities 
mRNA-CR vaccine 
SARS-CoV-2 Omicron variant S glycoprotein vaccine 
N 
Nucleocapsid 
NCT 
National Clinical Trial 
PaO2 
Partial pressure of oxygen 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PI 
Personal information 
pIMD 
Potential immune-mediated disease 
PM 
Pharmacy manual 
PP 
Per Protocol 
PPD 
Pharmaceutical Product Development 
PPS 
Per Protocol Set 
PRAC 
Pharmacovigilance Risk Assessment Committee 
PT 
Preferred term 
QTL 
Quality tolerance limit 
RNASeq 
RNA sequencing 
RT-PCR 
Real-time polymerase chain reaction 
S 
Spike 
SAE 
Serious adverse event 


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SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of activities 
SOC 
System organ class 
SpO2 
Pulse oximetry 
SRT 
Safety review team 
TC 
Telephone call 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of non-child-bearing potential  
WT 
SARS-CoV2 Wuhan ancestral strain or Wild type strain 


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Adverse Drug Reaction:  
An adverse event where a causal relationship between a 
medicinal product and the adverse event is at least a 
reasonable possibility, i.e., the relationship cannot be 
ruled out.  
a. 
In the context of a clinical trial, an ADR can be 
serious or non-serious. Serious ADRs may be 
subject to expedited reporting if they are considered 
unexpected (see SUSAR definition).  
b. For marketed products, ADRs are subject to 
expedited reporting within the country where they 
are authorized 
Adverse Event (AE): 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the 
use of a medicinal product, whether or not considered 
related to the medicinal product. 
An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For 
marketed medicinal products, this also includes failure 
to produce expected benefits (i.e., lack of efficacy), 
abuse or misuse. 
Auxiliary Medicinal 
Product (AxMP): 
Medicinal products used in the context of a clinical trial 
but not as investigational medicinal products, such as 
medicinal products used for background treatment, 
challenge agents, rescue medication, or used to assess 
end-points in a clinical trial. Auxiliary medicinal 
products should not include concomitant medications, 
that is medications unrelated to the clinical trial and not 
relevant for the design of the clinical trial. 
a. Authorized AxMP: 
Medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State 
concerned in accordance with Directive 2001/83/EC, 
irrespective of changes to the labelling of the medicinal 
product.  
Safety reporting with regard to auxiliary medicinal 
products shall be made in accordance with Chapter 3 of 
Title IX of Directive 2001/83/EC. 


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b. Unauthorized AxMP: 
Medicinal product not authorized in accordance with 
Regulation (EC) No 726/2004.  
Safety reporting for unauthorized auxiliary medicinal 
products will follow the same processes and procedures 
as SUSAR safety reporting 
Background treatment: 
Type of medicinal product administered to each of the 
clinical trial participant, regardless of randomization 
group, to treat the indication that is the object of the 
study. Background treatment is generally considered to 
be the current standard care for the particular indication. 
In these trials, the IMP is given in addition to the 
background treatment and safety efficacy are assessed. 
The protocol may require that the IMP plus the 
background treatment is compared with an active 
comparator or with placebo plus background treatment. 
Blinding: 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a serious Aes 
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.  
Challenge agents:  
A product given to trial participants to produce a 
physiological response that is necessary before the 
pharmacological action of the IMP can be assessed. 
Co-administered 
(concomitant) products: 
A product given to clinical trial participants as required 
in the protocol as part of their standard care for a 
condition which is not the indication for which the IMP 
is being tested and is therefore not part of the objective 
of the study. 
Comparator: 
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an 
investigational product being tested in a clinical trial. 
This is any product that is being used to assess the 
safety, efficacy, or other measurable value against the 
test product (IMP). 


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eDiary: 
Electronically registered patient data and automated data 
entries on, for example, a handheld mobile device, tablet 
or computer. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrollment: 
The process of registering a participant into a clinical 
study by assigning participant identification number 
after signing the ICF. 
Essential documents: 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced. 
eTrack: 
GSK’s tracking tool for clinical studies. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per protocol analysis. 
Immunological CoP: 
A correlate of risk that has been validated to predict a 
certain level of protection from the targeted endpoint. 
Intervention: 
Term used throughout the clinical study to denote a set 
of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a participant. 
Intervention number: 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational Product: 
A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical trial, 
including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, 
or when used for an unauthorized indication, or when 
used to gain further information about the authorized 
form. 
Investigational vaccine: 
A pharmaceutical form of an active ingredient being 
tested in a clinical study, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an 
unapproved indication, or when used to gain further 
information about an approved use. 
Synonym: IMP 


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Investigator: 
A person responsible for the conduct of the clinical 
study at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator. 
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 
individual or party to perform those study-related duties 
and functions. 
Medicinal products used 
to assess end-points: 
A product given to the participant in a Clinical Trial as a 
tool to assess a relevant clinical trial endpoint; it is not 
being tested or used as a reference in the clinical trial. 
Participant: 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject 
Participant number: 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Placebo: 
An inactive substance or treatment that looks the same 
as, and is given in the same way as, an active drug or 
intervention/treatment being studied. 
Randomization: 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Rescue medication: 
Medicines identified in the protocol as those that may be 
administered to the participants when the efficacy of the 
IMP is not satisfactory, or the effect of the IMP is too 
great and is likely to cause a hazard to the patient, or to 
manage an emergency situation. 
Solicited event: 
Events to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the participant or an observer 
during a specified follow-up period following study 
intervention administration. 
Source data: 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 


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Source documents: 
Original legible documents, data, and records (e.g. 
hospital records, clinical and office charts, laboratory 
notes, memoranda, participants’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, participant files, and records 
kept at the pharmacy, laboratories and at medico-
technical departments involved in the clinical study). 
Standard of Care: 
Medicine(s) for a specific indication, or a component of 
the standard care for a particular medical indication, 
based on national and/or international consensus; there 
is no regulatory significance to this term.  
Products/regimens considered standard of care may 
differ country to country, depending on consensus in 
individual countries 
Study intervention: 
Any investigational or marketed product(s) or placebo 
intended to be administered to a participant during the 
study. 
Study monitor: 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
SUSAR: 
Suspected Unexpected Serious Adverse Reaction; in a 
clinical trial, a serious adverse reaction that is 
considered unexpected, i.e., the nature or severity of 
which is not consistent with the reference safety 
information (e.g., Investigator’s Brochure for an 
unapproved investigational medicinal product). All 
adverse drug reactions (ADRs) that are both serious and 
unexpected are subject to expedited reporting. 
Telemedicine: 
The use of electronic information and 
telecommunications technologies (both video-based and 
audio-only) to facilitate remote health care delivery, 
patient and professional health-related education, public 
health and health administration. 
Unsolicited AE: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited AE. 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Rationale: GSK is developing a novel mRNA vaccine platform where the SARS-CoV-2 
Omicron variant S glycoprotein will be used as an antigen model (hereafter referred to as 
mRNA-CR vaccines). This mRNA vaccine platform development includes several 
mRNA constructs (mRNA-CR-XX) currently under development that will be progressing 
into clinical research in humans. 
Objectives, endpoints and estimands: This exploratory, FTIH study is to evaluate the 
safety, reactogenicity and immune responses of the mRNA-CR-04 vaccine construct 
when administered in healthy adults previously vaccinated with SARS-CoV-2 mRNA 
vaccines. For details on objectives, endpoints and estimands, refer to Section 3. 
Overall design: This will be a Phase 1, observer-blind, randomized, placebo-controlled, 
multicenter, dose-escalation study evaluating in Part A of the study, 3 doses (10 µg, 30 
µg, and 100 µg) of the mRNA-CR-04 (Omicron BA.5 strain) vaccine. Approximately 72 
participants will be enrolled with 24 participants per group (Group 1, Group 2 and Group 
3). Within each group, participants will be randomly assigned in a 3:1 ratio to receive: 
• 
investigational mRNA-CR-04 vaccine (SPK001-AC01 mRNA-LNP) or 
• 
saline placebo. 
For each group, 8 sentinel participants will first be enrolled and vaccinated. Enrollment 
of participants in Group 1 and Group 2 will be done in parallel with the first participant to 
be enrolled in Group 1. Only if no safety signal is observed, vaccination of the 
non-sentinel participants in that group will continue. If no safety signals observed in 
sentinel participant in Group 1 and Group 2, enrollment, and vaccination of the sentinel 
participants in Group 3 will be initiated. Refer to Section 4.1 and Figure 1 for more 
details on the study design. 
Part B of the study will commence only after all Part A participants have completed their 
Day 15 study visits and the Day 15 interim analysis is completed. In Part B, 2 doses (3 µg 
and 10 µg) of the mRNA-CR-04 (Omicron BA.5 strain) vaccine will be evaluated. 
Approximately 42 participants will be enrolled in parallel in Part B and there will be no 
sentinel participants. Part B participants will be randomly assigned in a 3:3:1 ratio to 
receive: 
• 
3 µg investigational mRNA-CR-04 vaccine (SPK001-AC01 mRNA-LNP) or 
• 
10 µg investigational mRNA-CR-04 vaccine (SPK001-AC01 mRNA-LNP) or 
• 
saline placebo. 
Data Monitoring/Other committees: Safety monitoring and safety data review will be 
performed by a GSK SRT (blinded data review until Part A Day 15 interim analysis, 
unblinded data review subsequently) and a GSK iSRC (unblinded data review). Safety 
holding rules and safety monitoring are presented in Section 8.3.7. 


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1.2. 
Schema 
This is an exploratory, FTIH, observer-blind, randomized, multicenter, controlled study. 
In Part A of the study, three doses (10 µg, 30 µg, and 100 µg) of the mRNA-CR-04 
vaccine will be evaluated. Approximately 72 eligible healthy adults, 18 to 49 years, 
inclusive, will be enrolled with 24 participants per group (Group 1, Group 2 and Group 
3). Within each group, participants will be randomly assigned in a 3:1 ratio: 
• 
18 participants will receive the investigational mRNA-CR-04 vaccine and 
• 
6 participants will receive a saline placebo (sodium chloride [NaCl] isotonic solution 
[0.9%]). 
In Part B of the study, two doses (3 µg and 10 µg) of the mRNA-CR-04 vaccine will be 
evaluated. Approximately 42 eligible healthy adults, 18 to 49 years, inclusive, will be 
enrolled in Part B and will be randomly assigned in a 3:3:1 ratio: 
• 
18 participants will receive 3 µg of the investigational mRNA-CR-04 vaccine and 
• 
18 participants will receive 10 µg of the investigational mRNA-CR-04 vaccine and 
• 
6 participants will receive a saline placebo (sodium chloride [NaCl] isotonic solution 
[0.9%]). 
Study duration for all the participants will be approximately 6 months, and they will be 
evaluated for safety, reactogenicity and immunogenicity. Safety monitoring and safety 
data review will be performed by a GSK SRT (blinded data review until Part A Day 15 
interim analysis, unblinded data review subsequently) and a GSK iSRC (unblinded data 
review). 
Overview of study design is presented in Section 4.1. Safety holding rules and safety 
monitoring are presented in Section 8.3.7. 


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Figure 1 
Study design overview 
 


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CMI: Cell-mediated immunity; D: Day; M: Month; mRNA: mRNA-CR-04 vaccine; n: Number of participants; SE: 
Solicited events; TC: Telephone call; V: Visit. 
* TC1 D2 only for sentinel participants in each group. ** The first participant is to be enrolled in Group 1. In addition to 
the defined intervals between doses within each group, an interval of at least 60 minutes will be maintained between 
the vaccination of sentinel participants across Group 1 and Group 2. *** TC1 review will be performed by the SRT on 
blinded data. 


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1.3. 
Schedule of Activities (SoA) 
Table 1 
SoA 
Type of contact 
Screening 
period 
Visit 1 
TC1* 
Visit 2 Visit 3 Visit 4 
TC2 
Visit 5 
Early 
termination 
Unscheduled 
COVID-19+ 
Unscheduled 
cardiac 
evaluation 
Notes 
Time points 
D1  
D2 
D8  
D15  
D31  
M3 
M6  
Window (D) 
D–14 to –1 
0 
0 
+2 
±2 
±3 
±5 
±7 
Assessment and sampling time 
points 
Pre-Vacc  
Pre-
Vacc  
Post-
Vacc  
Post-
Vacc 
Post-
Vacc 
Post-
Vacc 
Post-
Vacc 
Post-
Vacc 
Screening 
 
Informed consent  
● 
 
 
 
 
 
 
 
 
 
 
Section 10.1.3 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
 
 
 
 
Section 5.1 and 
Section 5.2 
Demography 
● 
 
 
 
 
 
 
 
 
 
 
Section 8.1.1 
Medical history  
● 
 
 
 
 
 
 
 
 
● 
 
Section 8.1.2 
Vaccination history 
● 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2 
Physical examination 
● 
●*** 
 
 
 
 
 
 
 
● 
 
Section 8.3.1 
Vital signs measurement 
● 
●*** 
 
 
 
 
 
 
 
● 
 
Section 8.3.1 
Body temperature 
● 
●*** 
 
 
 
 
 
 
 
● 
 
Section 8.3.2 
The preferred 
location for 
measuring 
temperature will be: 
oral. 
Fever is defined as 
body temperature 
≥38ºC/100.4ºF. 
Pregnancy test ** 
● 
● 
 
 
 
 
 
 
 
 
 
Section 8.3.3 
Study intervention 
 
Participant randomization 
 
● 
 
 
 
 
 
 
 
 
 
Section 6.3 
Vaccine administration 
 
● 
 
 
 
 
 
 
 
 
 
Section 6.1 
Initiation of eDiary 
 
● 
 
 
 
 
 
 
 
 
 
Section 8.1.3 


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Type of contact 
Screening 
period 
Visit 1 
TC1* 
Visit 2 Visit 3 Visit 4 
TC2 
Visit 5 
Early 
termination 
Unscheduled 
COVID-19+ 
Unscheduled 
cardiac 
evaluation 
Notes 
Time points 
D1  
D2 
D8  
D15  
D31  
M3 
M6  
Window (D) 
D–14 to –1 
0 
0 
+2 
±2 
±3 
±5 
±7 
Assessment and sampling time 
points 
Pre-Vacc  
Pre-
Vacc  
Post-
Vacc  
Post-
Vacc 
Post-
Vacc 
Post-
Vacc 
Post-
Vacc 
Post-
Vacc 
Laboratory assessment  
 
SARS-CoV-2 N protein serology 
 
● 
 
 
● 
● 
 
● 
● 
 
 
Section 8.2.1 
SARS-CoV-2 RT-PCR 
(nasopharyngeal swab) 
● 
● 
 
● 
● 
 
 
 
 
● 
 
Section 8.2.1 
Blood sample for binding IgG 
 
● 
 
 
● 
● 
 
● 
● 
 
 
Section 8.2.1 
Blood sample for neutralization 
 
● 
 
 
● 
● 
 
● 
● 
 
 
Section 8.2.1 
Blood sample for PBMC ICS assay 
preparation 
 
● 
 
 
● 
● 
 
● 
● 
 
 
Section 8.2.1 
Safety assessments 
 
Hematology and serum chemistry 
● 
● 
 
● 
● 
 
 
 
 
 
● 
Section 8.3.6 
Cardiac troponin I  
● 
 
 
● 
 
 
 
 
 
 
● 
Section 8.2.1 
Record any concomitant 
medication/vaccination 
● 
● 
 
● 
● 
● 
● 
● 
● 
● 
 
Section 6.8 
Record solicited AEs in eDiary (up 
to 7 days after vaccination) 
 
○ 
 
○ 
 
 
 
 
 
 
 
Section 8.4 
Record unsolicited AEs (up to 30 
days after vaccination) 
 
● 
● 
● 
● 
● 
 
 
 
 
 
Section 8.4 
Reporting of SAEs, MAAEs, AESI 
(including COVID-19), and 
pregnancies 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Section 8.4 
Recording of SAEs related to 
study participation, or to a 
concurrent GSK 
medication/vaccine  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Section 8.4 
EKG  
● 
 
 
● 
 
 
 
 
 
 
● 
Section 8.3.4 
Study Conclusion  
 
 
 
 
 
 
 
● 
● 
 
 
 
AE: Adverse event; AESI: Adverse events of special interest; D: Day; eCRF: electronic Case report form; eDiary: electronic Diary card; EKG: Electrocardiogram; GSK: GlaxoSmithKline 
Biologicals SA; ICS: Intracellular cytokine staining; IgG: Immunoglobulin G; M: Month; MAAE: Medically attended adverse event; N: Nucleocapsid; PBMC: Peripheral blood 
mononuclear cell; pIMD: potential Immune-mediated disease; RT-PCR: Real-time polymerase chain reaction; SAE: Serious adverse event; TC: Telephone call; Vacc: Vaccination. 


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Diagnosis of COVID-19 should be made in accordance with the World Health Organization [WHO, 2023] case definitions. Cases should be reported as AESIs or SAEs, and routine 
procedures for recording, evaluation, follow-up, and reporting of AESIs, and SAEs should be followed in accordance with the protocol-defined time periods. 
* TC1 is only for sentinel participants in each group in Part A. 
** Female participants of childbearing potential must perform a urine pregnancy test before the administration of the study intervention. For screening, if time allows, a serum pregnancy 
test can be done, in place of the urine pregnancy test, as per local requirements. 
*** Physical examination, vital signs, and body temperature measurement at D1 will occur before vaccination. 
+ Procedures apply to both suspected and convalescent visits for COVID-19. 
Note: The double-line border following D15 indicates the analyses which will be performed on all data (i.e., data that are as clean as possible) obtained up to D15. 
● Is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ Is used to indicate a study procedure that requires documentation in the eDiary. 
 


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Table 2 
Intervals between study visits 
Interval 
Planned visit interval  
Allowed interval range 
Screening → Visit 1 (D1) 
1-14 days* 
1-14 days 
Visit 1 (D1) → TC1 (D2) 
1 day 
1 day 
Visit 1 (D1) → Visit 2 (D8) 
7 days 
7-9 days 
Visit 1 (D1) → Visit 3 (D15) 
14 days 
12-16 days 
Visit 1 (D1) → Visit 4 (D31) 
30 days 
27-33 days 
Visit 1 (D1) → TC2 (M3) 
90 days 
85-95 days 
Visit 1 (D1) → Visit 5 (M6) 
180 days 
173-187 days 
D: Day; M: Month; PCR: Polymerase chain reaction; TC: Telephone call. 
* Visit 1 should take place no longer than 14 days after the Screening visit. All screening procedures, except the 
SARS-CoV-2 PCR test, need to be performed within 14 days of Visit 1 (see Section 8.1 and Section 8.3). A SARS-
CoV-2 PCR test needs to be performed within 7 days of Visit 1. When applicable, a sample may be collected for repeat 
testing at any time (but only once to assess eligibility) before Visit 1. Only laboratory results from the repeat test, if it 
occurs, will be taken into consideration. The participant can only be assigned to a study intervention group once the 
investigator receives the results and confirms eligibility. 
2. 
INTRODUCTION 
2.1. 
Study rationale 
As part of developing a novel mRNA vaccine platform, GSK selected the SARS-CoV-2 
S glycoprotein as a model antigen (mRNA-CR vaccine). This is an exploratory, FTIH, 
observer-blind, randomized, controlled study, evaluating various doses of mRNA-CR-04 
in individuals who have previously received: 
• 
2-dose primary series and booster dose(s) of an authorized or licensed mRNA 
COVID-19 vaccine (only Moderna or Pfizer vaccines) with the last booster dose 
administered at least 6 months or more prior to screening. 
The safety, reactogenicity and immunogenicity of the mRNA-CR-04 vaccine 
administered in healthy adults previously vaccinated with a SARS-CoV-2 mRNA vaccine 
will be evaluated. The decision to move this mRNA construct and dose forward for the 
development of vaccines for a specific disease will be based on safety, reactogenicity, 
and immunogenicity profiles of the construct compared to the current standard of care. 
2.2. 
Background 
Due to the ongoing impact of COVID-19, there is a need for vaccines to provide 
protection against COVID-19 caused by SARS-CoV-2 variants of concern. As of 03 
March 2023, more than 675 million cases have been reported worldwide, leading to more 
than 6.8 million deaths [Mathieu, 2023]. To date, there are multiple licensed or 
conditionally approved vaccines available that rely on a variety of vaccine technologies. 
With the surge in Omicron predominance worldwide, its greater transmissibility, and a 
higher risk of SARS-CoV-2 reinfection with Omicron [Garcia-Beltran, 2021; Zhou, 
2021], it is reasonable to anticipate an urgent need for booster vaccines to expand 
immunity against Omicron and additional future variants of concern. Bivalent boosters 
encoding Omicron BA.4/5 and the ancestral S protein sequences, followed by 
monovalent boosters encoding XBB.1.5 since 11 September 2023, have been authorized 


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for all doses administered to individuals 6 months of age and older [FDA, 2023a; FDA, 
2023b]. 
Please refer to the current IB for information regarding preclinical studies of mRNA-CR-
04 vaccine. 
2.3. 
Benefit/risk assessment 
Detailed information about the known and expected benefits and risks and expected AEs 
of mRNA-CR-04 vaccine can be found in the IB. 
With 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 be resolved within a few days of 
onset. 
Syncope can occur following an injectable vaccine or even before any vaccination as a 
vasovagal response to the needle injection. Similarly, hypersensitivity reactions may also 
occur. 
Currently, there are no identified preclinical risks for the investigational mRNA-CR-04 
vaccine. However, the following important potential risks and mitigation strategies have 
been defined for this vaccine: 
Risk Assessment 
Important/potential/risk of 
clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
All study vaccines 
Hypersensitivity reactions 
including allergic reactions 
such as anaphylaxis 
Acute allergic reactions such as a 
rare case of anaphylactic event may 
occur with any vaccine -
administration. These are serious, 
but rare occurrences estimated in 
the range of 1 to 10 cases per 
million of vaccinations, depending 
on the vaccine studied [Rüggeberg, 
2007]. 
A history of hypersensitivity or severe 
allergic reaction (including anaphylaxis) is 
an exclusion criterion for study participation 
and a contraindication to vaccination. 
The onset of vaccine-related allergic 
symptoms is typically quite prompt. To treat 
participants with a serious allergic 
vaccination reaction, all participants will 
need to remain under observation (i.e., 
visibly followed; no specific procedure) at 
the study site for at least 60 minutes after 
vaccination. 
Participants will be instructed to contact the 
study site immediately for occurrence of 
any possible hypersensitivity reaction within 
1 day following study intervention 
administration. 
Bleeding following 
intramuscular injection 
As with other intramuscular 
injections, study intervention should 
be given with caution in individuals 
with bleeding disorders, such as 
hemophilia or on anticoagulant 
To minimize the risk of bleeding, study 
intervention should be given with caution in 
individuals with thrombocytopenia or any 
coagulation disorder. 


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Important/potential/risk of 
clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
therapy, to avoid the risk of 
hematoma following the injection. 
Participants with any medical condition that 
in judgment of the investigator would make 
intramuscular injection unsafe will be 
excluded from study enrollment. 
mRNA-CR-04 vaccine 
Myocarditis/pericarditis 
Myocarditis/pericarditis are 
considered as an important 
identified risk for marketed mRNA 
COVID-19 vaccines [EMA, 2021a; 
EMA, 2021b; FDA, 2021a; 
FDA, 2021b] 
 
The estimated reporting rates of 
myocarditis in younger adults [25- to 
29-year old] following the first and 
the second doses of BNT162b2 
vaccine were 0.7 and 5.7 per 100 
000, respectively and following the 
first and the second doses of 
mRNA-1273 vaccine were 1.8 and 
11.2 per 100 000, respectively 
[CDC, 2021]. The same reporting 
trend was observed following 
booster mRNA vaccination, except 
for age, with most cases reported in 
older adults [ACIP, 2021]. 
Participants at increased risk of 
myocarditis/pericarditis or with medical 
history of myocarditis/pericarditis are 
excluded from study enrollment. 
Participants will also be instructed (via 
informed consent form) to be alert for 
symptoms of myocarditis/pericarditis and 
immediately contact the site if any of these 
symptoms occur. 
Participants will be tested for cardiac 
troponin I and undergo EKG at the 
screening and on D8 after study 
intervention administration. 
Participants will receive close medical 
supervision and medical assessments (e.g., 
laboratory testing) during the study. 
Moreover, myocarditis/pericarditis will be 
collected as an AESI and adjudicated (refer 
to Section 8.3.8,Section 8.4.4 and Section 
10.3.5) 
Vaccine-associated disease 
enhancement 
Enhanced disease following 
vaccination has been observed in 
pre-clinical or clinical studies with 
various vaccines (e.g., RSV, 
Dengue, SARS) and the mechanism 
is poorly understood [Peeples, 
2020]. While there are literature 
reports of enhanced disease in 
animals vaccinated with previous 
SARS vaccines, some other reports 
fail to see this effect. 
During informed consent process, 
participants will be informed of this 
theoretical risk and asked to report any 
symptoms consistent with COVID-19 and/or 
for which they received medical attention at 
any point during the study. 
Any suspected, probable, or confirmed 
case of COVID-19 (regardless of severity) 
is an AESI; and will be captured and 
described (refer to Section 8.4.4 and 
Section 10.3.5) 
AESI: Adverse event of special interest; EKG: Electrocardiogram; D: Day; RSV: Respiratory syncytial virus; SARS: 
Severe acute respiratory syndrome. 
Benefit assessment 
Participants may gain information about their general health status through medical 
evaluations/assessments associated with this study (i.e., physical examinations and blood 
testing [hematology and biochemistry data]). 
Overall Benefit: Risk conclusion 
The investigational mRNA-CR-04 vaccine is currently in an early stage of clinical 
development and vaccine efficacy, immunogenicity, and safety have not yet been 
demonstrated in humans. 


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Based on the available data for currently authorized/licensed mRNA COVID-19 
vaccines, some potential risks have been defined. Appropriate safety monitoring and 
evaluation methodologies are in place to quickly identify any such events, should they 
occur. 
Thus, while the benefit of this vaccine has not yet been proven, the anticipated potential 
risks for the mRNA-CR-04 vaccine are justified by the anticipated potential benefits. 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 3 
Study objectives, endpoints and estimands 
Objective(s) 
Endpoints/Estimands 
Primary 
• 
To evaluate the safety and reactogenicity of 
investigational mRNA-CR-04 vaccine up to D31  
• 
Solicited administration site events and systemic 
events during the 7-day follow-up period after 
study vaccine administration (day of study 
vaccine administration and 6 subsequent days); 
• 
Unsolicited AEs during the 30-day follow-up 
period after study vaccine administration (day of 
study vaccine administration and 29 subsequent 
days); 
• 
Any hematological and biochemical laboratory 
abnormality during the 15-day follow-up period 
after study vaccine administration (day of study 
vaccine administration and 14 subsequent days); 
• 
MAAEs; SAEs; AESIs* up to D31. 
Secondary Safety 
• 
To assess safety of investigational mRNA-CR-04 
vaccine from study vaccine administration up to 
study conclusion. 
• 
MAAEs; SAEs; AESIs* up to study conclusion 
(M6). 
Secondary Immunogenicity 
• 
To evaluate the Ab functionality (neutralizing 
capacity induced by the mRNA-CR-04 vaccine 
against vaccine encoded SARS-CoV-2 and WT 
strains) up to study conclusion. 
• 
Neutralizing titer GMTs against pseudovirus 
bearing S protein from vaccine encoded 
SARS-CoV-2 and WT strains at each collection 
timepoint (D1, D15, D31, M6). 
• 
GMR from baseline (D1) of neutralizing titer 
against pseudovirus bearing S protein from 
vaccine encoded SARS-CoV-2 and WT strains at 
each collection timepoint. 
• 
Vaccine response rate based on neutralizing titers 
against vaccine encoded SARS-CoV-2 and WT 
strains at each collection timepoint. 
Tertiary 
• 
To describe serum-binding antibody (IgG) 
responses induced by the mRNA-CR-04 vaccine 
specific for vaccine encoded SARS-CoV-2 and WT 
strains S protein up to study conclusion. 
• 
GMCs of binding IgG Ab specific for S protein 
encoded by the vaccine SARS-CoV-2 and WT 
strains at each timepoint (D1, D15, D31, M6). 
• 
GMR from baseline of binding IgG Ab specific for 
S protein encoded by the vaccine SARS-CoV-2 
and WT strains S proteins at each timepoint. 
• 
Seroresponse rates based on binding IgG 
concentrations specific for S protein encoded by 
the vaccine SARS-CoV-2 and WT strains S 
protein at each timepoint. 


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Objective(s) 
Endpoints/Estimands 
• 
To describe cell-mediated immune responses 
induced by the mRNA-CR-04 vaccine up to study 
conclusion. 
• 
Frequency of CD4+/CD8+ T-cells specific for S 
protein encoded by the vaccine SARS-CoV-2 
and WT strains measured by intracellular 
cytokine staining assay at each time point (D1, 
D15, D31, M6). 
• 
Cellular immune responses including, but not 
limited to Th1 and Th2 profiles as determined by 
flow cytometry using ICS at each time point (D1, 
D15, D31, M6). 
• 
To describe the incidence of confirmed 
symptomatic and asymptomatic SARS-CoV-2 
infection. 
• 
Percentage of laboratory-confirmed (N protein 
seroconversion) asymptomatic SARS-CoV-2 
infection at each time point (D1, D15, D31, M6). 
• 
Percentage of laboratory-confirmed (RT-PCR) 
symptomatic SARS-CoV-2 infection at screening, 
D1, D8, D15, as well as at unscheduled visits.  
• 
To evaluate the genetic sequence of SARS-CoV-2 
variant S protein in confirmed (RT-PCR) SARS-
CoV-2 positive participants. 
• 
Comparison of SARS-CoV-2 S protein genetic 
sequence of viral isolates (when available) to the 
vaccine mRNA sequence 
• 
Identification of SARS-CoV-2 variants. 
• 
To further characterize the humoral response 
(including, but not limited to functionality of 
antibodies) and cellular response, specific for the 
vaccine encoded SARS-CoV-2, WT and other 
relevant strains. 
• 
S-specific responses at D1, D15, D31, M6 
• 
Other read-outs may be performed if deemed 
necessary. 
Ab: Antibody; AE: Adverse event; AESI: Adverse events of special interest; D: Day; GMR: Geometric mean ratio; GMT: 
Geometric mean titer; ICS: intracellular cytokine staining; IgG: Immunoglobulin G; M: Month; MAAE: Medically 
attended adverse events; N: Nucleocapsid; pIMD: potential Immune-mediated disease; RT-PCR: Real-time 
polymerase chain reaction; S: Spike; SAE: Serious adverse event; VAED: Vaccine associated enhanced disease; WT: 
Wild type. 
*AESI include pIMDs, myocarditis/pericarditis, virologically confirmed COVID-19 cases and anaphylaxis or severe 
hypersensitivity within 24 hours after study vaccination (Section 8.4.4). 
Details related to attributes of estimands covering intercurrent events and strategies, 
population, treatment condition, and population level summary will be provided in SAP. 
4. 
STUDY DESIGN 
4.1. 
Overall design 
Experimental Design: Phase 1, observer-blind, randomized, placebo-controlled, 
multicenter, dose-escalation study to evaluate in Part A of the study, 3 doses (10 µg, 30 
µg, and 100 µg) of the mRNA-CR-04 (Omicron BA.5 strain) vaccine (Figure 1) in 3 
groups (Group 1, Group 2 and Group 3) (Table 4). Part B of the study will commence 
only after all Part A participants have completed their Day 15 study visits and the Day 15 
interim analysis is completed. In Part B (Table 5), 2 doses (3 µg and 10 µg) of the 
mRNA-CR-04 (Omicron BA.5 strain) vaccine will be evaluated (Figure 1). The study 
will be conducted in the United States (US). 
Duration of the study: Approximately 6 months after dosing. 
Sentinel dosing: In Part A of the study, each group will have 8 sentinel participants (6 
receiving the mRNA-CR-04 vaccine and 2 receiving a placebo) who will be enrolled and 


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vaccinated in each group. The first and second sentinel participant in each group will be 
vaccinated and followed-up for 24 hours before the next sentinel participant can be 
vaccinated. Vaccination of the remaining sentinel participants in the same group will then 
continue with an interval of at least 60 minutes between participants. Additionally, an 
interval of at least 60 minutes will be maintained between the vaccination of sentinel 
participants across groups. 
Dose-escalation: In Part A of the study, enrollment of participants in Group 1 and Group 
2 will be done in parallel with the first participant to be enrolled in Group 1. All safety 
data up to Day 8 post-vaccination from sentinel participants in both groups will be 
reviewed by the iSRC (unblinded review). The iSRC members will determine whether 
any of the pre-defined holding rules are met or if there is any other safety signal. If no 
safety signal is observed, vaccination of the non-sentinel participants in that group will 
continue. If no safety signal observed from sentinel participants in Group 1 and Group 2, 
enrollment and vaccination of the sentinel participants in Group 3 will be initiated. In 
Part B, irrespective of dose, all participants in the three study groups will be enrolled in 
parallel. 
Safety Data: Safety data will be collected for 6 months post-vaccination. Solicited AEs 
will be collected for 7 days (day of vaccination and 6 subsequent days) and unsolicited 
AEs will be collected up to Day 31. MAAEs, SAEs, pIMDs, and AESIs will be collected 
for the duration of the study. In addition to the review of unblinded data by iSRC, blinded 
data until Part A Day 15 interim analysis, and unblinded data subsequently, will be 
regularly reviewed by the SRT. For more detailed information, refer to Section 8.3 and 
Section 8.4. 
For the vendors that will perform key study-related duties or activities, please refer to the 
separate list of vendors. 


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Table 4 and Table 5 describe the Part A and Part B study groups, interventions, and 
blinding, respectively. 
Table 4 
Part A study groups, interventions, and blinding 
Study 
groups 
Number of 
participants 
Age (Min-
Max years of 
age) 
Study intervention(s)/vaccine(s) mode of 
administration 
Blinding 
Screening→Visit 5 
Group 1 
18 
18 – 49 
mRNA-CR-04 vaccine 
10 µg 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the non-
dominant arm. 
Observer-blind 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
Group 2 
18 
18 – 49 
mRNA-CR-04 vaccine 
30 µg 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the non-
dominant arm. 
Observer-blind 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
Group 3 
18 
18 – 49 
mRNA-CR-04 vaccine 
100 µg 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the non-
dominant arm. 
Observer-blind 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
NaCl: Sodium chloride. 
 
Table 5 
Part B study groups, interventions, and blinding 
Study 
groups 
Number of 
participants 
Age (Min-
Max years 
of age) 
Study intervention(s)/vaccine(s) mode of 
administration 
Blinding 
Part B 
3 µg 
18 
18 – 49 
mRNA-CR-04 
vaccine 3 µg 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the 
non-dominant arm. 
Observer-blind (except 
sponsor) 
Part B 
10 µg 
18 
18 – 49 
mRNA-CR-04 
vaccine 10 µg 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the 
non-dominant arm. 
Observer-blind (except 
sponsor) 
Part B 
Placebo 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the 
non-dominant arm. 
Observer-blind (except 
sponsor) 
NaCl: Sodium chloride. 
 
4.2. 
Scientific rationale for study design 
To ensure maximum safety of the participants, as this will be the first time that the 
mRNA-CR-04 vaccine will be administered in humans, the study will follow an 
observer-blind design with staggered enrollment and dosing for Part A of the study, with 
study holding rules and close safety monitoring throughout the study as specified in 
Section 4.1 and Section 8.3.7. Part B of the study adds an even lower dose (3 µg) of 


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mRNA-CR-04 vaccine group to allow exploration of a wider range of vaccine doses, as 
well as a repeat of the Part A low dose (10 µg) of mRNA-CR-04 vaccine group, which 
may assist in standardizing the new 3 µg dose group in Part B to the earlier Part A study 
groups. 
4.3. 
Justification for dose 
The proposed doses will be 3 µg, 10 µg, 30 µg, and 100 µg. The monovalent SARS-
CoV-2 mRNA vaccines (Pfizer-BioNTech Comirnaty mRNA vaccine [FDA, 2023a] and 
Spikevax Moderna COVID-19 Vaccine [FDA, 2023b]) have been licensed in the US as a 
2 or 3-dose primary series. Bivalent formulations of the Moderna and Pfizer-BioNTech 
COVID-19 vaccines encoding S protein sequences from Omicron BA.4/5 and the 
ancestral strain followed by monovalent boosters encoding XBB.1.5 since 11 September 
2023, have been authorized for primary and booster vaccinations [FDA, 2023a; FDA, 
2023b]. 
The maximum planned dose is 100 µg. The rationale for evaluating doses from 3 µg to 
100 µg is based on the following considerations: 
• 
The optimal dose required to confer cross-protective immunity against non-Omicron 
variants, including new/emerging variants needs to be determined. 
• 
Moderna has evaluated doses up to 250 µg (2-dose regimen) in their Phase 1 studies 
[Jackson, 2020]. 
• 
The doses of the authorized bivalent booster vaccines from Pfizer-BioNTech and 
Moderna are 30 µg and 50 µg, respectively. The initial starting dose of 10 µg of the 
mRNA-CR-04 vaccine in Part A of the study is well below these doses. 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if he/she returns for the last visit 
as described in the protocol. 
EoS: LSLV (Visit 5, Month 6) or date of the last testing released of the human biological 
samples, related to primary and secondary endpoints, whichever occurs later. EoS must 
be achieved no later than 8 months after LSLV. EoS cannot be before LSLV. 
5. 
STUDY POPULATION 
Adherence to the inclusion and exclusion criteria specified in the protocol is essential. 
Deviations from these criteria are not allowed because they can jeopardize the scientific 
integrity, regulatory acceptability of the study or safety of the participant. 


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5.1. 
Inclusion criteria 
All participants must satisfy ALL the following criteria prior to dose administration: 
1. Written or witnessed informed consent obtained from the participant prior to 
performance of any study-specific procedure. 
2. Participants, who in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g., completion of the eDiary and study procedures). 
3. Has received 2 doses of primary series and booster dose(s) of an authorized or 
licensed mRNA COVID-19 vaccine (only Moderna or Pfizer vaccines) with the last 
booster dose administered at least 6 months or more prior to screening and has 
provided documentation of receiving the vaccination series (e.g., vaccination card). 
4. Negative for SARS-CoV-2 infection by RT-PCR test at screening within 7 days prior 
to study vaccination. 
5. Is a male or nonpregnant female of 18 to 49 years, inclusive, at screening. 
6. If the participant is a WOCBP, the participant agrees to practice true abstinence or 
use at least 1 highly effective form of contraception for at least 30 days prior to study 
vaccination up to 1 month after study vaccination. 
7. Agrees to refrain from blood or plasma donation from screening and up to 6 months 
after vaccination. 
8. Is healthy or medically stable as determined by investigator judgment based on 
medical history, clinical laboratory tests, vital sign measurements, and physical 
examination findings. 
5.2. 
Exclusion criteria 
The following criteria should be checked at the time of screening and on D1 prior to dose 
administration. The potential participant MUST NOT be included in the study if ANY 
exclusion criterion applies: 
5.2.1. 
Medical conditions 
1. Has a new onset, clinically significant, abnormal biochemistry or hematology finding 
(defined as ≥Grade 1) at screening (participants with Grade 1 laboratory 
abnormalities that have been stable for at least 6 months before enrollment may be 
included in the study). 
2. Has any medical disease or condition that, in the opinion of the investigator, 
precludes study participation. This includes any acute, subacute, intermittent, or 
chronic medical disease or condition that would place the participant at an 
unacceptable risk of injury, render the participant unable to meet the requirements of 
the protocol, or may interfere with the evaluation of responses or the participant’s 
successful completion of the trial. 
3. Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 


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4. History of myocarditis, pericarditis, second and third degree heart block or idiopathic 
cardiomyopathy, or presence of any medical condition that increases risk of 
myocarditis or pericarditis, including cocaine abuse, cardiomyopathy, 
endomyocardial fibrosis, hypereosinophilic syndrome, hypersensitivity myocarditis 
eosinophilic granulomatosis with polyangiitis, persistent myocardial viral infection 
(e.g., due to enterovirus or adenovirus). 
5. Has an acute febrile illness with a temperature ≥38.0°C or ≥100.4°F observed by the 
participant or at the study site within 72 hours prior to study vaccination. Participants 
with suspected COVID-19 symptoms (Section 8.4.4.2.2) should be excluded and 
referred for medical care. 
6. Has a history of hypersensitivity or severe allergic reaction, including anaphylaxis, 
generalized urticaria, angioedema, and other significant reactions to any previous 
vaccine, or any component of the study vaccine. 
7. Has a body mass index >40 kg/m². 
8. Has had known close contact with anyone who had a confirmed SARS-CoV-2 
infection within 14 days before study vaccination. 
9. Has a history of documented SARS-CoV-2 infection or COVID-19 within 6 months 
before the date of screening visit. 
10. Has any self-reported or medically documented clinically significant medical or 
psychiatric condition. Significant medical conditions include, but are not limited to, 
the following: 
a. 
Moderate or severe respiratory disease (e.g., chronic obstructive pulmonary 
disease, asthma). 
b. Uncontrolled hypertension, defined as an average systolic blood pressure ≥140 
mmHg or an average diastolic blood pressure ≥90 mmHg, based on an average 
of up to 3 blood pressure measurements. 
c. 
Clinically significant cardiovascular disease (e.g., congestive heart failure, 
cardiomyopathy, ischemic heart disease). 
d. Neurological or neurodevelopmental conditions (e.g., Down syndrome, 
dementia, chronic migraine not controlled by medication, epilepsy, stroke or 
seizures in the last 3 years, encephalopathy, focal neurologic deficits, Guillain-
Barré syndrome, encephalomyelitis, or transverse myelitis). 
e. 
Ongoing malignancy or recent diagnosis of malignancy in the last 5 years 
(excluding basal cell and squamous cell carcinoma of the skin). 
f. 
Tuberculosis or non-tuberculosis mycobacterial infection. 
g. Autoimmune disease, including hypothyroidism without a defined 
nonautoimmune cause. 
h. Immunodeficiency of any cause, including from solid organ transplant, blood, or 
bone marrow transplant, or use of other immune-weakening medicine. 
i. 
Type 1 or 2 diabetes mellitus regardless of disease control. 
11. Has any of the following self-reported or medically documented risk factors for 
severe COVID-19: 


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a. 
Chronic kidney disease 
b. Cerebrovascular disease 
c. 
Cystic fibrosis 
d. Chronic liver disease 
e. 
Pulmonary fibrosis 
5.2.2. 
Prior/concomitant therapy 
12. Has participated or plans to participate in another investigational study involving any 
investigational drug or device within 60 days or 5 half-lives, whichever is longer, 
before study vaccination and throughout the study. 
13. Has received a licensed or authorized non-mRNA COVID-19 vaccine (primary 
series or booster dose). 
14. Has received or plans to receive any licensed vaccine within 4 weeks before or after 
study vaccination. Inactivated vaccines for influenza are permitted during the study 
if they are administered at least 14 days before or after study vaccination. 
15. Is planning to receive an authorized or licensed COVID-19 booster vaccination for 
the duration of the study (for participants who are not covered by local 
recommendations to receive booster per current standard of care) OR is planning to 
receive an authorized or licensed COVID-19 booster vaccination on or before Day 
31 of the study (for participants covered by local recommendations to receive 
booster). 
16. Has received or plans to receive immunoglobulins or any blood or blood products 
within 90 days before study vaccination and throughout the study. 
17. Reports chronic use (more than 14 continuous days) of any medication that may be 
associated with changes in immune function including, but not limited to, systemic 
corticosteroids exceeding 20 mg/day of prednisone equivalent, allergy injections, 
immunoglobulins, interferons, immunomodulators, cytotoxic drugs, or other similar 
or toxic drugs within 6 months of study vaccination. Note: The use of low-dose 
topical, ophthalmic, inhaled, intra-articular and intranasal steroid preparations is 
permitted. 
5.2.3. 
Other exclusions 
18. Pregnant or lactating female. 
19. Female participant planning to become pregnant or planning to discontinue 
contraceptive precautions within 1 month following study vaccination. 
20. Participant is an employee or family member of the investigator or study site 
personnel. 
5.3. 
Screen failures 
A screen failure is an individual who consents to participate in this study but is not 
entered in the study/assigned to a study intervention. 


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Limited data for screening failures (including informed consent, inclusion/exclusion 
criteria, demographic data, pregnancy reason for screening failure and any SAEs that 
occurred at the visit) will be collected and reported in the eCRF. 
If the investigator believes there is a reasonable justification to do so, all screening 
procedures may be repeated (maximum 1 re-screening per participant is allowed) under a 
new participant number. The participant can only be randomized into the study once the 
investigator receives the results and confirms the eligibility criteria. 
Participants with hematological/biochemical values out of normal range which are 
expected to be temporary may be re-screened at a later date, as per the above conditions. 
5.4. 
Criteria for temporarily delaying enrollment, randomization 
and study intervention administration 
Enrollment, randomization and study intervention administration may be postponed 
within the 14-day screening interval until transient conditions cited below are resolved: 
• 
Acute disease and/or fever at the time of enrollment and/or study intervention 
administration. Refer to the Section 1.3 for definition of fever and oral temperature 
in this study. 
• 
Participants with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be enrolled and/or dosed at the discretion of the 
investigator. 
• 
If antipyretics and/or analgesics and/or antibiotics have been used within 3 days prior 
to study intervention administration. 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Refer to the Definition of terms for the definition of study intervention. 
6.1. 
Study interventions administered 
Refer to Section 1.2 for the study intervention administration schedule. Table 6 and Table 
7 describe study interventions to be administered for Part A and Part B, respectively. 


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Table 6 
Part A study interventions administered 
 
mRNA-CR-04 
Placebo  
Study intervention#: 
Group 1 
COV08A/DL001Z 
PL001Z 
Group 2 
COV08B/DL001Z 
PL001Z 
Group 3 
COV08C  
PL001Z 
Study intervention formulation#: 
Group 1 
GSKVx000000037755 (Dose Aa GSKVx000000037754); 
Excipients; Water for injections 
Excipients; Water for 
injections 
Excipients; Water for injections  
Group 2 
GSKVx000000037755 (Dose Ab GSKVx000000037754); 
Excipients; Water for injections 
Excipients; Water for 
injections 
Excipients; Water for injections  
Group 3 
GSKVx000000037755 (Dose Ac GSKVx000000037754); Excipients; Water for 
injections  
Excipients; Water for injections  
Presentation: 
Group 1 
Concentrate for dispersion for injection (vial) 
Solution for dispersion 
for injection (vial) 
Solution for injection (vial) 
Group 2 
Concentrate for dispersion for injection (vial) 
Solution for dispersion 
for injection (vial) 
Solution for injection (vial) 
Group 3 
Dispersion for injection (vial) 
Solution for injection (vial) 
Type: 
Investigational 
Placebo 
Product category: 
Biologic 
Drug 
Route of administration: 
IM 
IM 
Location 
Deltoid 
Deltoid 
Directionality 
NA 
NA 
Laterality* 
Non-Dominant 
Non-Dominant 
Number of doses to be administered 
1 
1 
Volume to be administered by dose ** 
0.3 mL 
0.3 mL 
Packaging and labeling: 
Refer to the PM for more details 
Refer to the PM for more details 
Manufacturer: 
GSK  
Hospira 
Ab: Antibody; IM: Intramuscular; GSK: GlaxoSmithKline Biologicals SA; NA: Not applicable; PM: Pharmacy manual. 
*The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the study intervention in the non-dominant arm, an injection in the dominant arm may be 
performed. 
**Refer to the PM for the volume after reconstitution. 
#Coding serves for internal sponsor anonymization 


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Table 7 
Part B study interventions administered 
 
mRNA-CR-04 
Placebo  
Study Groups 
Part B 3 µg 
Part B 10 µg 
Part B Placebo 
Study intervention# 
COV08D/DL001Z 
COV08A/DL001Z 
PL001Z 
Study intervention 
formulation#: 
GSKVx000000037755 (Dose Ad 
GSKVx000000037754); Excipients; 
Water for injections 
Excipients; 
Water for 
injections 
GSKVx000000037755 (Dose Aa 
GSKVx000000037754); Excipients; 
Water for injections 
Excipients; 
Water for 
injections 
Excipients; Water for injections  
Presentation: 
Concentrate for dispersion for 
injection (vial) 
Solution for 
dispersion for 
injection (vial) 
Concentrate for dispersion for 
injection (vial) 
Solution for 
dispersion for 
injection (vial) 
Solution for injection (vial) 
Type: 
Investigational 
Investigational 
Placebo 
Product category: 
Biologic 
Drug 
Route of administration: 
IM 
IM 
Location 
Deltoid 
Deltoid 
Directionality 
NA 
NA 
Laterality* 
Non-Dominant 
Non-Dominant 
Number of doses to be 
administered 
1 
1 
Volume to be administered 
by dose ** 
0.3 mL 
0.3 mL 
Packaging and labeling: 
Refer to the PM for more details 
Refer to the PM for more details 
Manufacturer: 
GSK  
Hospira 
Ab: Antibody; IM: Intramuscular; GSK: GlaxoSmithKline Biologicals SA; NA: Not applicable; PM: Pharmacy manual. 
*The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the study intervention in the non-dominant arm, an injection in the dominant arm may be 
performed. 
**Refer to the PM for the volume after reconstitution. 
#Coding serves for internal sponsor anonymization 
 


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6.2. 
Preparation, handling, storage, and accountability 
The study interventions must be stored in a secured place within the temperature range 
specified on the study intervention’s label. The storage temperature should be 
continuously monitored and recorded with a calibrated (if not validated) temperature 
monitoring device. 
Only unblinded staff should be allowed access to the study interventions. Storage 
conditions will be assessed by a sponsor study contact during pre-study activities. Refer 
to the PM for more details on storage and handling of the study interventions. 
6.3. 
Measures to minimize bias: randomization and blinding 
This is a dose-escalation, observer-blind, randomized study. 
6.3.1. 
Participant identification 
Participant identification numbers will be assigned sequentially to the individuals who 
have consented to participate in the study by using an automated internet-based system 
(e.g., IRT). 
6.3.2. 
Randomization to study intervention 
The randomization of study interventions will be performed using the IRT system. 
6.3.3. 
Intervention allocation to the participant 
In Part A of the study, approximately 72 participants will be enrolled with 24 participants 
per group. These 24 eligible participants will be randomly assigned to investigational 
mRNA-CR-04 vaccine or saline placebo in a (3:1) ratio. In Part B of the study, 
approximately 42 participants will be enrolled and randomly assigned to 3 µg 
investigational mRNA-CR-04 vaccine, 10 µg investigational mRNA-CR-04 vaccine, or 
saline placebo in a (3:3:1) ratio. 
6.3.4. 
Blinding and unblinding 
In Part A of the study, data will be collected in an observer-blind manner. The 
participant, the site and sponsor personnel involved in the clinical evaluation of the 
participants are blinded while other study personnel may be aware of the treatment 
assignment. To do so, study interventions will be prepared and administered by qualified 
study personnel who will not participate in data collection, evaluation, review, or the 
entry of any study endpoint data (i.e., reactogenicity, safety, immunogenicity). In Part B 
of the study (i.e., following the Part A Day 15 interim analysis), continuation of the 
observer-blind design will be restricted to study participants and site personnel involved 
in the clinical evaluation of the participants, while sponsor personnel will no longer 
remain blinded to treatment assignment. 


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Unblinding a participant’s individual study randomization number should occur ONLY in 
case of a medical emergency when this information is essential for the clinical 
management or welfare of the participant. 
In case of emergency, the investigator can have unrestricted, immediate and direct access 
to the participant’s study intervention information via the IRT. The investigator may 
contact Signant Health support (refer to Table 8) if help is needed to access participant’s 
study intervention information (i.e., if the investigator is unable to access IRT). 
A physician other than the investigator (e.g., an emergency room physician) or 
participant may also request emergency access to the participant’s study intervention 
information via the investigator. 
Table 8 
Contact information for emergency unblinding 
Signant Health support 
Available 24/24 hours and 7/7 days 
The Signant Health support is available by phone and email 
US: 1-888-794-0122 
IRTHelpdesk@SignantHealth.com 
A participant may continue in the study if that participant’s treatment 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 
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. 
Study intervention compliance 
When the study intervention is administered at the site, participants will receive the dose 
of study vaccine directly from the investigator or designee, under medical supervision. 
The date and time of administration of each study intervention dose in the clinic will be 
recorded in the source documents. 
6.5. 
Dose modification 
Not applicable. 
6.6. 
Continued access to study intervention after the end of the 
study 
Not applicable. 


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6.7. 
Treatment of overdose 
An overdose is any dose of study vaccine given to a participant that exceeds the planned 
dose for an individual participant within a given group. 
There is no specific treatment recommended for an overdose. 
Any overdose must be promptly reported to the CRO team within 24 hours. Overdose 
itself is not to be reported as an AE. However, any AEs associated with the overdose are 
to be reported in the relevant AE/SAE sections of the eCRF. 
In the event of an overdose, the investigator should: 
1. Contact the CRO medical monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities for at 
least 3 days. Refer the participant to a higher level of care as clinically indicated. 
3. Document the quantity of the excess dose in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant. 
6.8. 
Concomitant therapy 
At each study visit/contact, the investigator(s) or their delegate(s) should question the 
participant about all medications/products taken, and vaccinations received by the 
participant. 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF: 
• 
All concomitant medications, except vitamins and dietary supplements, administered 
during the entire study. 
• 
Any concomitant use of antipyretic/analgesic medication from Day 1 to Day 7 after 
vaccination. 
• 
Any concomitant vaccination administered in the period starting 30 days before 
study intervention administration and ending 30 days after vaccination. 
• 
Any booster COVID-19 vaccines received during the study will be recorded. 
• 
All concomitant medication associated with an AE, including vaccines/products, 
administered after study intervention vaccination (Day 1 to Day 31). 
• 
All concomitant medication leading to discontinuation of the study intervention or 
elimination from the analysis, including products/vaccines. Please refer to Section 
5.2.2 and Section 9.3.1 for further details. 


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• 
All concomitant medication which may explain/cause/be used to treat an SAE/AESI 
including vaccines/products, as defined in Section 8.4.1. These must also be recorded 
in the electronic AE report. 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
Not applicable. 
7.1.1. 
Contraindications to subsequent study interventions 
administration 
Not applicable. 
7.2. 
Participant discontinuation/withdrawal from the study 
Individual participants may withdraw from the study at any time at their own request for 
any reason without prejudice to their future medical care by the investigator or at the 
study site.  
A participant is considered to have withdrawn from the study if no new study procedure 
has been performed or no new information has been collected for them since the date of 
withdrawal/last contact. 
From an analysis perspective, a study ‘withdrawal’ refers to any participant who did not 
return for the concluding visit planned in the protocol. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
At the time of discontinuing from the study, if possible, an early termination visit should 
be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to 
be completed. 
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. 


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The primary reason for study withdrawal will be documented in the eCRF based on the 
list below: 
Reasons 
Additional items/Sub-reasons 
AE 
Unsolicited AE 
Solicited AE 
Lost to follow-up 
Participant Relocated 
Other, specify 
Unknown 
Study Terminated by Sponsor 
 
Withdrawal by Participant (not due to an 
AE) 
Participant Relocated 
Other, specify 
Other 
Specify 
AE: Adverse event 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.5.5). 
7.3. 
Lost to follow-up 
Participants will be considered ‘lost to follow-up’ if they fail to return for scheduled visits 
and cannot be contacted by the study site. 
Please refer to the PM for a description of actions to be taken before considering the 
participant lost to follow-up. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are only permitted when necessary for the management 
of immediate safety concerns for the participant. 
Immediate safety concerns should be discussed with the CRO team as soon as they occur 
or when the study team becomes aware of them. The purpose of this communication is to 
determine if the participant(s) should discontinue the study intervention. 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
All screening evaluations must be completed, and the results reviewed before confirming 
that potential participants meet all eligibility criteria. 
The investigator will maintain a log of all participants screened. All relevant information, 
such as confirmation of eligibility and reasons for screening failure will be mentioned in 
this screening log. 
Procedures conducted as part of routine clinical management (e.g., hematologic profiles), 
and obtained before the participant signed the ICF, may be used for screening and/or for 


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establishing a clinical baseline (provided the procedure met protocol specified criteria 
and was performed within the time frame defined in the SoA in Section 1.3). 
The PM provides the investigator and site personnel with detailed administrative and 
technical information that does not impact participant safety. 
During special circumstances (e.g., COVID-19 pandemic), certain study procedures may 
be adapted to protect the participant’s welfare, and as far as possible to ensure the 
potential benefit to the participant and promote data integrity. See Section 8.10. 
8.1. 
Administrative procedures 
All screening procedures, except the SARS-CoV-2 PCR test, need to be performed within 
14 days of Visit 1 (see Section 5.1). A SARS-CoV-2 PCR test needs to be performed 
within 7 days of Visit 1. A sample may be collected for repeat testing at any time (but 
only once to assess eligibility) before Visit 1. 
8.1.1. 
Collection of demographic data 
At screening, 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 
At screening, 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, vaccination history, signs and/or symptoms present prior to study intervention 
in the eCRF. 
8.1.3. 
Distribution of eDiary or installing the application for devices 
Participants will be encouraged to bring their own devices at screening visit, or if not 
feasible, at Visit 1 (Day 1). The study staff will check the compatibility of participant’s 
device (e.g., smart phone or tablet) with respect to eDiary application. 
At Visit 1 (Day 1), participant will download the eDiary application on his/her own 
electronic device or will receive an electronic device to record information related to 
his/her health and participation in the study. The participant will also be trained on the 
use of eDiary. 


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Refer to Section 8.4.1 for details of collection of safety information and Section 10.3.5 
for guidelines. 
For the vendors that will perform eDiary-related activities, please refer to the separate list 
of vendors. 
8.2. 
Immunogenicity assessments 
Blood samples will be taken to assess both the humoral and cellular immune responses 
induced by the vaccine candidate on Day 1, Day 15, Day 31, and Month 6. 
In addition, 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. 


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8.2.1. 
Biological samples 
Table 9 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Subset name 
Nasopharyngeal swab for 
SARS-CoV-2 test 
NA 
NA 
Screening (D-7 to D-1) 
All screened participants 
Visit 1 (D1) 
All enrolled participants 
Visit 2 (D8) 
Visit 3 (D15) 
Blood for FSH  
~2.5 
mL 
Screening (D-14 to D-1) 
Female participants to confirm 
non-childbearing potential 
Blood for Troponin I  
~2.5 
mL 
Screening (D-14 to D-1) 
All screened participants 
Visit 2 (D8) 
All enrolled participants 
Blood for hematology/ 
biochemistry 
~6 
mL 
Screening (D-14 to D-1) 
All screened participants 
Visit 1 (D1) 
All enrolled participants 
Visit 2 (D8) 
Visit 3 (D15) 
Blood (serum) for vaccine-
induced humoral immune 
response and to assess SARS-
CoV2 N protein serology  
~15 
mL 
Visit 1 (D1) 
All enrolled participants 
Visit 3 (D15) 
Visit 4 (D31) 
Visit 5 (M6) 
Blood (PBMCs) for cellular 
immune response 
~50 
mL 
Visit 1 (D1) 
All enrolled participants 
Visit 3 (D15) 
Visit 4 (D31) 
Visit 5 (M6) 
D: Day; FSH: Follicle stimulating hormone; M: Month; N: Nucleocapsid; NA: Not applicable; PBMC: Peripheral blood 
mononuclear cell. 
8.2.2. 
Laboratory assays 
Following laboratory assays will be performed (Table 10). 
• 
PCR assay will be used to detect SARS-CoV-2 infection. If the sample is positive 
and sufficient material is available, sequencing of the SARS-CoV-2 isolate will be 
performed by genomic RNASeq. 
• 
Serological assay to monitor the asymptomatic infection will be performed using an 
ECL to measure serum-binding Abs IgG levels specific for N protein of SARS-CoV-
2. 
• 
The vaccine-induced humoral immunity will be evaluated using serological assays 
determining the capacity of the serum of SARS-CoV-2 vaccinated participants to 
neutralize pseudoviruses bearing S protein from vaccine encoded SARS-COV-2 and 
from the WT (D614G). 
• 
Further characterization of the humoral immune response will be performed using 
ECL for measurement of IgG antibodies binding to the SARS-CoV-2 S protein (at 
least vaccine encoded SARS-CoV-2 variant and WT). 
• 
The cell-mediated immunity will be evaluated by assessing the frequency of SARS-
CoV-2 S-specific CD4+ and CD8+ T-cells expressing specific activation or immune 
markers using ICS per million of total CD4+ or CD8+ T-cells respectively. 


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Table 10 
Laboratory assays 
Assay Type 
System 
Component 
Challenge 
Method 
Laboratory** 
Humoral immunity 
(antibody 
determination)* 
Serum 
Anti-S binding IgG 
Ab 
NA 
ECL 
PPD 
Serum 
Anti-SARS-CoV-2 
neutralizing titer  
Pseudo 
Neutralization 
assay 
Nexelis 
Cell-mediated 
immunity 
PBMCs 
CD4+/CD8+ T-cells 
expressing IL-
2/IFNγ/TNFα/IL-
13/IL-17/4-
1BB/CD40L 
Peptide pools 
covering the 
SARS-CoV-2 
S protein  
ICS 
GSK 
Detection of SARS-
CoV-2 Infection 
Serum 
Anti-N IgG Ab 
NA  
ECL 
PPD 
Detection of SARS-
CoV-2 Infection 
Nasopharyngeal 
Swab 
SARS-CoV-2 RNA 
NA 
RT-PCR 
PPD 
Sequencing of 
SARS-CoV-2 
Isolates 
Nasopharyngeal 
Swab 
SARS-CoV-2 RNA 
NA 
RNASeq 
PPD 
Ab: Antibody; CD40L: Cluster of differentiation 40 ligand; 4-1BB: CD137 (tumor necrosis factor receptor superfamily 9); 
CRO: Contract research organization; ECL: Electro-chemiluminescence assay; GSK: GlaxoSmithKline Biologicals SA; 
ICS: Intracellular cytokine staining; IgG: Immunoglobulin G; IFNγ: Interferon gamma; IL-2: Interleukin-2; IL-13: 
Interleukin-13; IL-17: Interleukin-17; NA: Not applicable; N: Nucleocapsid; PPD: Pharmaceutical Product Development; 
RNASeq: RNA Sequencing; RT-PCR: Real-time polymerase chain reaction; S: Spike; TNFα: Tumor necrosis factor 
alpha; WT: Wild type. 
* Measurement of humoral immunity against vaccine encoded SARS-CoV-2 and WT strains. 
** Refer to the list of clinical laboratories for details. 
Please refer to Section 10.2 for further details. 
The addresses of clinical laboratories used for sample analysis are provided in a separate 
document accompanying this study protocol. 
GSK clinical laboratories have established a quality system supported by procedures. The 
activities of GSK clinical laboratories are audited regularly for quality assessment by an 
internal (sponsor-dependent) but laboratory-independent quality department. 


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8.2.3. 
Immunological read-outs 
Table 11 
Immunological read-outs 
Blood sampling timepoint 
Subset 
name 
No. participants 
Component 
Type of contact 
and timepoint 
Sampling timepoint 
 
 
 
Visit 1 (D1) 
Pre-Dose 1 
All enrolled 
participants 
72 (Part A) + 
42 (Part B) 
SARS-CoV-2 neutralizing titer 
Anti-S binding IgG Ab 
Anti-N IgG Ab 
S-specific CD4+/CD8+ T-cells 
Visit 3 (D15) 
14 days Post-Dose 1 
All enrolled 
participants 
72 (Part A) + 
42 (Part B) 
SARS-CoV-2 neutralizing titer 
Anti-S binding IgG Ab 
Anti-N IgG Ab 
S-specific CD4+/CD8+ T-cells 
Visit 4 (D31) 
30 days Post-Dose 1 
All enrolled 
participants 
72 (Part A) + 
42 (Part B) 
SARS-CoV-2 neutralizing titer 
Anti-S binding IgG Ab 
Anti-N IgG Ab 
S-specific CD4+/CD8+ T-cells 
Visit 5 (M6) 
6 months Post-Dose 1 
All enrolled 
participants 
72 (Part A) + 
42 (Part B) 
Anti-SARS-CoV-2 neutralizing titer 
Anti-S IgG Ab 
Anti-N IgG Ab 
S-specific CD4+/CD8+ T-cells 
Ab: Antibody; D: Day; IgG: Immunoglobulin G; M: Month; N: Nucleocapsid; S: Spike. 
8.2.4. 
Cytology 
Not applicable. 
8.2.5. 
Immunological correlates of protection 
No validated mechanistic immunological correlate of protection has been demonstrated 
so far for the antigens used in the study intervention. 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical examination 
• 
At screening and prior to dosing at Visit 1 (Day 1), the investigator will perform a 
physical examination of the participant. The following information needs to be 
recorded in the eCRF: weight, oral temperature, resting vital signs (before blood 
collection for laboratory test); systolic/diastolic blood pressure and heart rate after at 
least 10 minutes of rest. 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 eligibility 
criteria. Height and BMI will only be recorded at screening. 


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• 
A targeted physical examination at each study visit after the Screening 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. 
• 
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 5.4 for the list of criteria for temporary delay of 
study intervention administration. 
• 
Treatment of any abnormality observed during post-vaccination visits must be 
performed according to local medical practice outside this study or by referral to an 
appropriate health care provider and recorded as AE. 
8.3.2. 
Pre-dosing body temperature 
The body temperature of each participant needs to be measured orally 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. 
Pregnancy test 
Female participants of childbearing potential must perform a urine pregnancy test before 
the administration of the study intervention. At screening, if time allows, a serum 
pregnancy test can be done, in place of the urine pregnancy test, 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. 
For WONCBP, document the specific reason for not performing a pregnancy test in the 
eCRF. 
8.3.4. 
EKGs 
• 
12-lead EKGs will be obtained as outlined in the SoA (see Section 1.3) using an 
EKG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals. 


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8.3.5. 
Warnings and precautions to administration of study intervention 
Vital signs, including oral temperature, systolic/diastolic blood pressure and heart rate 
after at least 10 minutes of rest for each participant needs to be measured prior to 
administration of study intervention, i.e., at Visit 1. Collected information will be 
recorded in the eCRF. 
8.3.6. 
Clinical safety laboratory tests 
• 
See Section 10.2.1 for the list of clinical laboratory tests to be performed in 
accordance with lab manual 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. 
• 
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 or within 31 days after the last dose of study intervention 
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 Section 
10.3.1 and Section 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. 
• 
Analyses of safety laboratory samples collected at Day 1 through the EoS will be 
performed at the central laboratory using the same grading standards. 
• 
Laboratory data will be graded according to the FDA guidance for industry “Toxicity 
grading scale for healthy adults and adolescent volunteers enrolled in preventive 
vaccine clinical trials” dated September 2007 [FDA, 2007]. These laboratory values 
serve as guidelines and are dependent upon laboratory normal parameters. Normal 
reference ranges should be provided to demonstrate that they are appropriate. Any 
laboratory parameters not listed in Table 19 and Table 20 (Section 10.2.2) will not be 
graded and will be assessed on case-by-case basis. 


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8.3.7. 
Study holding rules and safety monitoring 
Safety monitoring is specified in the SoA (Section 1.3), Section 8.3.7.1 and Table 12. 
For the vendors that will perform safety monitoring activities, please refer to the separate 
list of vendors. 
8.3.7.1. 
Staggered administration of study intervention 
Part A of the study will be conducted in a staggered manner to ensure maximum safety of 
the participating participants. 
• 
Within each group, 8 sentinel participants (6 receiving the mRNA-CR-04 vaccine 
and 2 receiving the placebo) will first be enrolled and vaccinated. 
• 
Enrollment of participants in Group 1 and Group 2 will be done in parallel with the 
first participant to be enrolled in Group 1. The first and second sentinel participant in 
each group will be vaccinated and followed-up for 24 hours before the next sentinel 
participant can be vaccinated. If no safety concerns are identified (as confirmed 
through individual phone call – TC1, see Table 1), vaccination of the remaining 
sentinel participants in the same group will then continue with an interval of at least 
60 minutes between participants. Additionally, an interval of at least 60 minutes will 
be maintained between the vaccination of sentinel participants across groups. 
• 
If no safety concerns are identified by the iSRC during the review of unblinded 
Day 8 safety data of sentinel participants from Group 1 and Group 2, the remaining 
participants in these groups may receive the study intervention without limitation of 
the number of participants per day or the time between consecutive participants. 
Additionally, vaccination of sentinel participants in Group 3 may be initiated. 
• 
If no safety concerns are identified by the iSRC review of unblinded Day 8 safety 
data of sentinel participants from Group 3, the remaining participants in Group 3 
may receive the study intervention without limitation of the number of participants 
per day or the time between consecutive participants. 
All participants will be closely observed (visibly followed, no specific procedure) during 
the 60 minutes after dose administration. 
In addition to iSRC, blinded data will be reviewed by the SRT. The SRT and iSRC will 
meet regularly to review safety data throughout the study and may request escalation to 
the GSB to address any potential safety concerns or study holds at any point during the 
study. See Section 8.3.7.3. 
In Part B of the study, irrespective of dose, all participants will be enrolled in parallel, 
and the SRT will also be able to review unblinded data. 
 


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8.3.7.2. 
Outcome of safety evaluation 
Outcome of safety evaluations will be documented and provided in a written way to the 
investigator. Refer to iSRC charter for more details. 
• 
If no safety signal is observed, the favorable outcome of the safety evaluations by 
the iSRC will be documented and provided, authorizing the investigator to start the 
enrollment and study intervention administration to the remaining participants in the 
group and the sentinel participants in the next group. 
• 
If a safety signal is observed during the safety evaluations or if any of the holding 
rules is met, the iSRC Chair is responsible for the urgent communication and 
escalation of the concern to the GSB. The GSB will decide and communicate 
whether to suspend, modify or continue the conduct of the study on all groups or on 
selected groups, including the rationale for the decision to put the study intervention 
administration on hold or not. 
• 
The study sponsor will be accountable for notifying the decision whether to suspend, 
modify or continue the conduct of the study on all groups or on selected groups to 
the CRO. The CRO will be responsible to inform all investigators of this decision. 
8.3.7.3. 
Study holding rules 
The safety holding rules are defined in the Table 12. Holding rules 1a-d will be assessed 
by the investigator on a continuous basis. Meeting any of these holding rules will trigger 
a hold of study intervention administration irrespective of number of participants enrolled 
and/or timing of the event. Holding rules 2a-c will be assessed by the iSRC during the 
safety evaluations on unblinded data. 
These holding rules have been written under the assumption that the safety data from all 
participants will be available. If the data from all participants are not available (i.e., in 
case a participant is lost to follow-up), then the holding rules will be assessed on a pro-
rata basis (expressed as percentage of participants to be evaluated) i.e., 3 out of 6 sentinel 
participants or 30% of all participants, whichever is met earlier. 
Of note, no formal holding rules will be applied for other safety data such as non-life-
threatening SAEs, missed visits due to study intervention related AEs, Grade 1 and 
Grade 2 solicited and unsolicited AEs in the 7-day follow-up period (Day 1 to Day 7) and 
unsolicited AEs collected from Day 8 to Day 31 after study intervention administration. 
However, if available, these data will also be reviewed by the iSRC to allow an overall 
assessment of the benefit/risk ratio of study intervention administration. 


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Table 12 
Study holding rules 
Holding rule 
Event (per dose and per individual study group) 
Number of participants 
to pause vaccination in 
all groups, pending 
further evaluation by 
iSRC 
1a 
Death or any life-threatening SAE regardless of causality 
≥1 
1b 
Any non-life-threatening SAE that cannot be reasonably attributed 
to a cause other than vaccination as per investigator or sponsor 
assessment 
≥1 
1c 
Any withdrawal from the study (by investigator or participant 
request) following a Grade 3 AE 
≥1 
1d 
Any administration site or systemic solicited AE leading to 
hospitalization, 
OR 
Necrosis at the injection site, 
Each with an event onset within the 7-day (Day 1-7) post-
vaccination period 
≥1 
2a* 
Any Grade 3 solicited administration site events, with an event 
onset within the 7-day (Day 1-7) post-vaccination period 
≥3/6 or 30%** 
2b* 
Any Grade 3 solicited systemic events, with an event onset within 
the 7-day (Day 1-7) post-vaccination period 
≥3/6 or 30%** 
2c* 
Any Grade 3 unsolicited AE, that can be reasonably attributed to 
the vaccination as per investigator or sponsor assessment, with an 
event onset within the 7-day (Day 1-7) post-vaccination period 
OR 
Any Grade 3 or above abnormality in pre-specified hematological or 
biochemical laboratory parameters with an event onset within the 8-
day (Day 1-8) post-vaccination period except for non-clinically 
significant leukopenia  
≥2/6 or 10%*** 
AE: Adverse event; iSRC: Internal safety review committee; SAE: Serious adverse event. 
*Refer to the FDA guidance for industry “Toxicity grading scale for healthy adults and adolescent volunteers enrolled in 
preventive vaccine clinical trials” [FDA, 2007]. Any laboratory parameters not listed in Section 10.2.2 will not be graded 
and will be assessed on case-by-case basis. 
**3/6 sentinel participants or 30% of all participants, whichever is met earlier. 
***2/6 sentinel participants or 10% of all participants, whichever is met earlier. 
Rule 2a-2c will be analyzed and reviewed during the scheduled iSRC meetings. During 
these scheduled iSRC meetings, iSRC will decide to: 
• 
allow for dosing of the remaining non-sentinel participants (12 receiving mRNA-
CR-04 and 4 receiving placebo) within the same group 
• 
allow for randomization of the sentinel participants in the next group. 
More details on the composition, objectives, and responsibilities of the iSRC, and the 
schedule and conduct of the iSRC meetings will be described in the iSRC charter. 


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If a holding rule is met, the investigator must suspend enrollment and administration of 
the study intervention and inform the CRO team immediately (holding rules 1a-d). Refer 
to Table 16 for contact information. 
The CRO team will inform the investigator if holding rules 2a-c are met. Investigators 
will be responsible to inform the IRB/IEC if a holding rule has been met. 
The following communication sequence must be followed when a holding rule 1a-1d is 
met: 
• 
The concerned site staff must put study intervention randomization and 
administration on hold. 
• 
The concerned site staff must immediately inform the CRO team contact defined in 
the Section 8.4.6. 
• 
Enrollment and intervention allocation through IRT will be stopped on a study level. 
• 
The CRO team will inform all investigators about the stopping of enrollment and 
intervention. 
• 
All informed site staff will confirm to the CRO team that action has been taken 
providing appropriate documentation to the CRO team. 
• 
The CRO team will inform GSK and provide the blinded data to GSK’s CSL for 
further SRT and GSK GSB review. 
• 
The CRO team will forward the relevant unblinded safety information to iSRC for 
evaluation. 
• 
Based on the recommendation from iSRC, GSK’s GSB will make the decision 
whether the study can resume, be modified, or stopped. GSK will notify the CRO 
team on this decision. The CRO team will notify all investigators on this decision. 
• 
Depending on the outcome of the safety evaluation, the study will be re-started, 
terminated, or resumed under a protocol amendment. 
The following communication sequence must be followed when a holding rule 2a-2c is 
being met: 
• 
The study CSL will ensure that the CRO team is notified upon meeting holding rules 
2a-2c. 
• 
The CRO team will inform all the sites 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 the CRO team that action has been taken 
providing appropriate documentation to the CRO team. 
• 
GSK will further evaluate the case with the iSRC and GSK GSB and will take the 
decision to stop or to restart the study intervention administration or to amend the 
protocol. GSK will notify the CRO team on this decision and the CRO team will 
inform all site staff. 


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Risk assessment: 
• 
Figure 2 illustrates that with 6 participants receiving the mRNA-CR-04 vaccine per 
group: 
• 
Rule 1: when at least 1 SAE is observed within 6 participants receiving the 
mRNA-CR-04 vaccine, there is 90% probability of not holding for a 1.7% SAE 
true incidence and 80% (=1-20%) probability of holding it for an SAE true 
incidence >23%. 
• 
Rule 2a-2b: when at least 3 participants with an AE are observed within 6 
participants receiving the mRNA-CR-04 vaccine, there is 90% probability of not 
holding for a 20% AE true incidence and 80% (=1-20%) probability of holding 
it with a true AE incidence >58%. 
• 
Rule 2c: when at least 2 participants with an AE are observed within 6 
participants receiving the mRNA-CR-04 vaccine, there is 90% probability of not 
holding for a 9% AE true incidence and 80% (=1-20%) probability of holding it 
with a true AE incidence >42%. 
• 
With 18 participants receiving the mRNA-CR-04 vaccine, and rule 1 (1/18), 
there is 90% probability of not holding for a 0.59% AE true incidence and 80% 
(=1-20%) probability of holding it with a true incidence >8.5%. 
Figure 2 
Probability of not meeting holding rules 1 and 2 for 8 participants 
per study group 
 


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8.3.7.4. 
SRT and iSRC evaluation 
The study will be overseen by an iSRC operating under a charter. Core members of the 
iSRC will include a GSK safety physician, a CSL and a biostatistician who are not 
otherwise involved in the conduct of the project. The iSRC safety reviews will be 
conducted using unblinded data. The iSRC will have access to the participant 
randomization and will review unblinded data. 
In addition to the iSRC, the project SRT will review blinded data until the Part A Day 15 
interim analysis, and unblinded data subsequently, on a regular basis throughout the 
study. 
The iSRC will review accumulated unblinded safety data of the sentinel participants of 
each group up to 7 days post-vaccination. The iSRC will include all safety data sources in 
their Day 8 safety review (i.e., solicited safety data, unsolicited safety data, SAEs and 
AESIs, as well as laboratory safety data). If no pre-defined holding rule is met (refer to 
Section 8.3.7.3) or if no safety signal is observed the remaining participants in the group 
can be vaccinated and vaccination in the next group can be initiated. 
In case the iSRC, through the in-stream data monitoring of all the accumulated safety 
data available detects that a holding rule is met, the study vaccination will be temporarily 
paused in all study groups and sites pending review of safety data by the iSRC. The iSRC 
will make relevant recommendations to the GSB chair(s), who will make the final 
decision whether vaccination can be safely resumed or not. 
In addition, at any time during the study, if one of the holding rules 1a through 1d (refer 
to Table 12 for details) is met, the investigator will immediately inform the CRO team. 
Vaccination will be paused and an urgent ad-hoc meeting of the iSRC will be called to 
thoroughly review the event(s) and recommend to the GSB whether vaccination can be 
safely resumed or not. The GSB chair(s) will make the final decision whether vaccination 
can be safely resumed or not. 
In Part B of the study, the iSRC will only be requested to review unblinded data if a study 
holding rule is met or if the SRT identifies a safety concern through in-stream data 
monitoring of unblinded data. 
8.3.8. 
Cardiac adjudication 
Myocarditis and pericarditis are considered as important potential risk and are collected 
as AESI. All surveillance EKGs occurring at Screening, Day 8, and unscheduled visits, 
will be reviewed by an independent external cardiologist in a blinded fashion to identify 
potential myocarditis or pericarditis cases. All EKGs identified with changes suggestive 
of potential myocarditis and pericarditis and related available medical records requested 
from treating cardiologists evaluating potential cases of myocarditis and pericarditis, will 
then be provided to an independent external adjudication committee for case adjudication 
according to the case definition from the Brighton Collaboration [Sexson, 2022]. The 
committee members will remain blinded to study intervention assignment. 


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For details on who will perform the reading and adjudication activities, please refer to the 
separate list of vendors. 
8.4. 
AEs, 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 study intervention or study procedures, AESIs for this study and AEs leading to 
discontinuation (see Section 7). This includes events reported by the participant (or, when 
appropriate, by a caregiver or surrogate). 
The method of recording, evaluating, and assessing causality of AEs/SAEs/AESIs and 
the procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time period and frequency for collecting AE, SAE and other 
safety information 
All SAEs will be collected from the start of study intervention until Visit 5 at the time 
points specified in the SoA (Section 1.3). 
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. 
All AEs will be collected from the start of study intervention until Visit 4 at the 
timepoints specified in the SoA (Section 1.3). 


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Table 13 
Timeframes for collecting and reporting of safety information 
 
Screening 
Dose 1 
 
 
 
 
Study Conclusion 
Event 
D1 
D8 
D15 
D31 
M3 
M6 
Administration site and systemic solicited 
events* 
 
 
 
 
 
 
 
 
D 1-7 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
D1-31 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to withdrawal from the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to the study intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study participation** or 
concurrent GSK medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening 
Dose 1 
 
 
 
 
Study Conclusion 
Event 
D1 
D8 
D15 
D31 
M3 
M6 
Pregnancy outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: Adverse events; AESI: Adverse event of special interest; D: Day, GSK: GlaxoSmithKline Biologicals SA; MAAEs: Medically attended adverse event; M: Month; pIMDs: potential 
Immune-mediated diseases; SAEs: Serious adverse events. 
* Administration site and systemic solicited events will be collected through eDiaries. 
** Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a participant consents to participate in the study. 
The shaded region in the table indicates time period of data collection. 


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All SAEs will be recorded and reported to the sponsor immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3.The investigator 
will submit any updated SAE data to the sponsor within 24 hours of it being available. 
A poststudy AE/SAE is defined as any event that occurs outside of the AE/SAE reporting 
period defined in Table 13. 
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. 
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/eDiaries 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 AESI (as defined in Section 8.4.4) 
will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Section 10.3.5.5. 
8.4.4. 
AESI 
8.4.4.1. 
pIMDs 
pIMDs are a subset of AESIs that include autoimmune diseases and other inflammatory 
and/or neurologic disorders of interest which may or may not have an autoimmune 
etiology. AEs that need to be recorded and reported as pIMDs include those listed in the 
Table 14. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of PTs and PT codes corresponding to the above diagnoses will 
be available to investigators at study start. 
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. 


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Table 14 
List of pIMDs 
Medical Concept 
Additional Notes 
Blood disorders and coagulopathies 
Antiphospholipid syndrome 
 
Autoimmune aplastic anemia 
 
Autoimmune hemolytic anemia 
• 
Includes warm antibody hemolytic anemia and cold antibody hemolytic 
anemia 
Autoimmune lymphoproliferative 
syndrome (ALPS) 
 
Autoimmune neutropenia  
 
Autoimmune pancytopenia 
 
Autoimmune thrombocytopenia 
• 
Frequently used related terms include: “autoimmune thrombocytopenic 
purpura”, “idiopathic thrombocytopenic purpura (ITP)”, “idiopathic 
immune thrombocytopenia”, “primary immune thrombocytopenia”. 
Evans syndrome 
 
Pernicious anemia 
 
Thrombosis with 
thrombocytopenia syndrome 
(TTS) 
 
Thrombotic thrombocytopenic 
purpura 
• 
Also known as “Moschcowitz-syndrome” or “microangiopathic hemolytic 
anemia” 
Cardio-pulmonary inflammatory disorders 
Idiopathic 
Myocarditis/pericarditis 
Including but not limited to: 
• 
Autoimmune / Immune-mediated myocarditis 
• 
Autoimmune / Immune-mediated pericarditis 
• 
Giant cell myocarditis 
Idiopathic pulmonary fibrosis 
Including but not limited to: 
• 
Idiopathic interstitial pneumonia (frequently used related terms include 
“Interstitial lung disease”, “Pulmonary fibrosis”, “Immune-mediated 
pneumonitis”) 
• 
Pleuroparenchymal fibroelastosis (PPFE) 
Pulmonary alveolar proteinosis 
(PAP) 
• 
Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-mediated 
thyroiditis  
Including but not limited to: 
• 
Hashimoto thyroiditis (autoimmune hypothyroidism, lymphocytic 
thyroiditis) 
• 
Atrophic thyroiditis 
• 
Silent thyroiditis 
• 
Thyrotoxicosis 
Autoimmune diseases of the 
testis and ovary 
• 
Includes autoimmune oophoritis, autoimmune ovarian failure and 
autoimmune orchitis 
Autoimmune hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s disease 
• 
Includes Marine Lenhart syndrome and Graves’ ophthalmopathy, also 
known as thyroid eye disease (TED) or endocrine ophthalmopathy 
Insulin autoimmune syndrome 
 
Polyglandular autoimmune 
syndrome 
• 
Includes Polyglandular autoimmune syndrome type I, II and III 


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Medical Concept 
Additional Notes 
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 
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) 


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Medical Concept 
Additional Notes 
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 
Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies 
Including but not limited to: 
• 
Acute Brachial Radiculitis (also known as Parsonage-Turner Syndrome 
or neuralgic amyotrophy) 
• 
Antibody-mediated demyelinating neuropathy 
• 
Chronic idiopathic axonal polyneuropathy (CIAP) 
• 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), 
including atypical CIDP variants (e.g., multifocal acquired demyelinating 
sensory and motor neuropathy also known as Lewis-Sumner 
syndrome) 
• 
Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
• 
Includes acute partial transverse myelitis (APTM) and acute complete 
transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / immune-mediated 
glomerulonephritis  
Including but not limited to: 
• 
IgA nephropathy 
• 
IgM nephropathy 
• 
C1q nephropathy 
• 
Fibrillary glomerulonephritis 
• 
Glomerulonephritis rapidly progressive 
• 
Membranoproliferative glomerulonephritis 
• 
Membranous glomerulonephritis 
• 
Mesangioproliferative glomerulonephritis 
• 
Tubulointerstitial nephritis and uveitis syndrome 


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


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Medical Concept 
Additional Notes 
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 
 
IgA: Immunoglobulin A; IgM: Immunoglobulin M. 
8.4.4.2. 
Other AESIs 
• 
Myocarditis and pericarditis 
• 
Virologically confirmed COVID-19 cases 
• 
Anaphylaxis or severe hypersensitivity within 24 hours after study vaccination 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as AESI. Symptoms, signs or conditions which might (or might not) lead to one 
of the above diagnoses, should be recorded and reported as AEs but not as AESI until the 
final or definitive diagnosis has been made, and alternative diagnoses eliminated or 
shown to be less likely. 
8.4.4.2.1. Myocarditis and pericarditis: definitions and assessment 
All potential cases of myocarditis and pericarditis will be provided to the independent 
external adjudication committee for case adjudication according to the case definition 
from the Brighton Collaboration [Sexson, 2022]. 
Source documentation of suspected cases of myocarditis and pericarditis to be provided 
for adjudication as it becomes available may include (but are not limited to) the 
following:  
• 
Clinical notes (including history, physical examination, EKG findings) 
• 
Emergency department notes (including history, physical examination, EKG 
findings) 
• 
Hospital discharge summary 
• 
Clinical laboratory values 
• 
Concomitant medications 


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• 
Chest X-ray reports 
• 
Cardiac imaging 
Following adjudication, all probable and definitive cases of myocarditis and pericarditis 
will be reviewed by SRT (blinded data review until Part A Day 15 interim analysis, 
unblinded data review subsequently) and iSRC (unblinded data review). An ad-hoc iSRC 
will be conducted on receiving any probable or definitive cases of myocarditis and 
pericarditis. An independent external cardiologist may be part of iSRC to provide input 
on the potential myocarditis and pericarditis cases. 
Clinical myocarditis/pericarditis: 
The participants reporting acute chest pain, shortness of breath or other signs/symptoms 
of myocarditis/pericarditis within 6 weeks after vaccination must be evaluated by a 
cardiologist with evaluation and management following current practice guidelines 
(e.g., American heart association or local standard of care). 
The changes suggestive of myocarditis and pericarditis (but not limited to) are listed 
below: 
• 
EKG changes: 
• 
ST segment or T wave abnormalities (elevation or inversion) 
• 
Paroxysmal or sustained atrial or ventricular arrhythmias 
• 
AV nodal conduction delays or intraventricular conduction defects. 
• 
An abnormal troponin I value (> 2 ULN of baseline value) that is confirmed 
abnormal on repeat testing. 
• 
Cardiac imaging: 
• 
Echocardiogram: New left or right ventricular function abnormalities including: 
segmental wall motion abnormalities; decreased ejection fraction (EF <55% for 
≤54 yrs; or <50% for >55 yrs); global systolic or diastolic function 
depression/abnormality; ventricular dilation or wall thickness change; 
pericardial effusion or intracavitary thrombi 
• 
Cardiac MRI: Patchy edema on T2 weighted images or late gadolinium 
enhancement on T1 weighted images with increased enhancement ratio between 
myocardial skeletal muscle involving ≥1 non-ischemic regional distribution with 
recovery 
The participants will be followed-up until the resolution of symptoms and/or cardiac 
troponin levels return back to normal. 
Asymptomatic myocarditis/pericarditis: 
At the Day 8 (Visit 2), all participants will be assessed by 12-lead EKG for evidence of 
asymptomatic myocarditis or pericarditis, based on evidence that rare cases of 
myocarditis or pericarditis have occurred most frequently within 7 days of vaccination 


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[CDC, 2023]. All participants will also have a 12-lead EKG examination at screening, to 
provide a baseline for comparison. 
Asymptomatic acute myocarditis/pericarditis is defined as electrocardiographic changes 
suggestive of acute myocardial injury occurring in an asymptomatic participant within 6 
weeks after administration of a COVID-19 mRNA vaccine, if other causes of acute 
cardiac disease are excluded. If any of the EKG changes suggestive of myocarditis and 
pericarditis listed above are detected at the surveillance EKG occurring at the Day 8 visit, 
the findings will be reviewed by the investigator. 
If deemed appropriate the participant will be referred to a local cardiologist. If a 
diagnosis of myocarditis or pericarditis is confirmed, then the participant will be further 
evaluated and receive cardiology consultation, including cardiac enzyme assessment, 
echocardiography, or other assessments deemed clinically warranted by the treating 
clinician. 
8.4.4.2.2. SARS-CoV-2 infection and COVID-19 definitions and assessment 
Vaccine efficacy will not be evaluated in this study, but all laboratory-confirmed 
asymptomatic SARS-CoV-2 infections should be reported by the participant and 
documented as AEs, while virologically confirmed cases of COVID-19 are reported as 
AESIs. Any available isolate genotyping results will also be requested. Participants will 
be instructed to inform the investigator in the event of a positive SARS-CoV-2 diagnostic 
test. Serology testing for SARS-CoV-2 N protein will be performed pre-vaccination and 
post-vaccination to monitor for undetected SARS-CoV-2 infections at the time points 
specified in the SoA (Section 1.3). 
All participants with suspected COVID-19 are required to have an unscheduled visit for 
suspected COVID-19, as detailed in the SoA (Section 1.3). At this visit, participants will 
undergo the following assessments: 
• 
Medical history 
• 
SARS-CoV-2 RT-PCR (nasopharyngeal or mid-turbinate swab) 
• 
Physical examination 
• 
Vital sign measurements 
• 
Body temperature 
• 
Review of AEs 
• 
Concomitant medication/vaccination 
All participants with confirmed COVID-19 are required to have an unscheduled COVID-
19 convalescent visit as detailed in the SoA (Section 1.3). At this visit, participants will 
undergo the following assessments: 
• 
Medical history 
• 
SARS-CoV-2 RT-PCR (nasopharyngeal or mid-turbinate swab) 


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• 
Physical examination 
• 
Vital sign measurements 
• 
Body temperature 
• 
COVID-19 evaluation 
• 
Review of AEs 
• 
Concomitant medication/vaccination 
To complete the COVID-19 evaluation, the investigator will review the history of the 
participants, including medical records to define the severity of COVID-19. 
Any confirmed cases of SARS-CoV-2 infection or COVID-19 during the study will be 
assigned one of the following definitions and recorded in the eCRF: 
Asymptomatic 
SARS-CoV-2 
infection: 
Laboratory-confirmed SARS-CoV-2 by RT-PCR or SARS-CoV-
2 N protein seroconversion without any of the following 
symptoms: fever or chills, cough, shortness of breath or 
difficulty breathing, fatigue, muscle or body aches, headache, 
new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea 
COVID-19: 
Virologically confirmed SARS-CoV-2 by RT-PCR with 1 or 
more of the following symptoms: fever or chills, cough, 
shortness of breath or difficulty breathing, fatigue, muscle or 
body aches, headache, new loss of taste or smell, sore throat, 
congestion or runny nose, nausea or vomiting, diarrhea 
Severe COVID-19: 
Virologically confirmed SARS-CoV-2 infection with any 1 of 
the following: 
• 
Clinical signs at rest indicative of severe systemic illness 
(respiratory rate ≥ 30 per minute, heart rate ≥ 125 per 
minute, SpO2 ≤ 93% on room air at sea level or PaO2/ FiO2 
< 300 mm Hg) 
• 
Respiratory failure (defined as needing high-flow oxygen, 
non-invasive ventilation, mechanical ventilation, or ECMO) 
• 
Evidence of shock (systolic blood pressure <90 mmHg, 
diastolic blood pressure <60 mmHg, or requiring 
vasopressors) 
• 
Significant acute renal, hepatic, or neurologic dysfunction 
• 
Admission to a hospital or an intensive care unit 
• 
Death 


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8.4.5. 
Regulatory reporting requirements for SAEs/AESIs 
• 
Prompt notification by the investigator to the sponsor of an SAE/AESI is essential so 
that legal obligations and ethical responsibilities toward the safety of participants and 
the safety of a study intervention under clinical investigation are met. See 
Section 8.4.1 for reporting timeframes. 
• 
For SAEs/AESIs, the investigator must always provide an assessment of causality at 
the time of the initial report, as defined in the Section 10.3.5.3. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• 
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/AESI/pregnancy, it must be reported to the CRO medical 
monitor using the required documentation and within the timeframes mentioned in 
Table 15. This is essential for GSK to meet legal obligations and ethical 
responsibilities for participant safety and the safety of a study intervention under 
clinical investigation. 
• 
The sponsor has the legal responsibility to notify local authorities/regulatory 
agencies about the safety of an investigational study intervention. The sponsor will 
comply with country-specific regulatory requirements related to safety reporting to 
the regulatory authority, IRB/IEC and investigators. 
• 
Please refer to Section 10.3.5.7 for further details regarding the reporting of 
SAEs/AESIs/pregnancies. 
Table 15 
Timeframes for submitting SAE, AESI, pregnancy and other events 
reports to CRO 
Type of event 
Initial reports 
Follow-up of relevant information on a 
previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡‡ 
electronic AE report 
24 hours* 
electronic AE report 
Pregnancies  24 hours* 
electronic pregnancy report 
24 hours * 
electronic pregnancy report 
AESIs  
24 hours** ‡‡  
electronic AE report 
24 hours* 
electronic AE report 
AE: Adverse event; Adverse event of special interest; SAE: Serious adverse event. 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of an AESI. 
‡‡ 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. 
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 Day 31. 


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• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant pregnancy. 
• 
Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant/pregnant female 
partner and the neonate and the information will be forwarded to the sponsor. See 
Table 15 for reporting timeframes. 
• 
Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 10.3.5.7. 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. 
8.4.7. 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules 
Table 16 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules 
Study contact for questions regarding SAEs, AESIs, 
pregnancies  
Study contact for reporting of study holding rules  
If a SAEs, AESIs, pregnancies are reported, the 
investigator must inform the CRO medical monitor 
If a holding rule is met, the investigator must 
immediately inform the CRO medical monitor. 
Back up study contact for reporting SAEs, AESIs, 
pregnancies 
Available 24/24 hours and 7/7 days: 
Back up study contact for escalation of holding 
rules  
Available 24/24 hours and 7/7 days: 
CRO hotline 
North America: 
+1 800 201 8725 (phone) 
+1 888 488 9697 (fax) 


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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 that the 
participant is in a clinical study and that relevant information may be obtained by 
contacting the investigator(s). 
8.5. 
Pharmacokinetics 
Not applicable. 
8.6. 
Genetics 
Not applicable. 
8.7. 
Biomarkers 
Not applicable. 
8.8. 
Immunogenicity assessments 
Immunogenicity is described in Section 8.2. 
8.9. 
Health outcomes 
Not applicable. 
8.10. 
Study procedures during special circumstances 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, the 
following measures may be implemented for enrolled participants: 
• 
Further in-person clinic visits may be suspended. 
• 
Safety follow-up may be made by a telephone call, other means of virtual contact or 
home visit, if appropriate. 
• 
If the eDiary device was provided to the participant, it may be returned to the site by 
conventional mail after the end of the safety period for collection of solicited events 
following Visit 2 (Day 8), inclusive of the allowable window period). 


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• 
Visits for suspected COVID-19 may take place in a different location* other than the 
study site or at participant’s home. If this is not feasible, then the medical evaluation 
of COVID-19 may take place virtually with documentation of event by 
telephone/telemedicine. 
• 
Biological samples may be collected at a different location* other than the study site 
or at participant’s home. Biological samples should not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use. 
*It is the investigator’s responsibility to identify an alternate location. The 
investigator should ensure that this alternate location meets ICH GCP requirements, 
such as adequate facilities to perform study procedures, appropriate training of the 
staff and documented delegation of responsibilities in this location. This alternate 
location should be covered by proper insurance for the conduct of study on 
participants by investigator and staff at a site other than the designated study site. 
Refer to the EMA guidance on the management of clinical trials during the COVID-
19 (Coronavirus) pandemic (version 2, 27 March, 2020) for more details. 
Impact on the PPS for immunogenicity will be determined on a case-by-case basis. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical hypotheses 
There is no hypothesis testing in this study; all analysis will be performed in a descriptive 
manner. Means and proportions for different objectives will be computed with their 95% 
CIs. 
9.2. 
Sample size determination 
The sample size is based on clinical considerations to inform dose regimen decisions for 
continued clinical development. 
With 18 participants receiving mRNA-CR-04 vaccine in each group, there is a 60.3% 
probability to observe at least 1 AE if the incidence rate is 5% and 85% probability to 
observe at least 1 AE if the incidence rate is 10%. 
With 16 participants receiving mRNA-CR-04 vaccine in each group (PPS for 
immunogenicity, 10% unevaluable), and a standard deviation of 0.45 for log10 
transformed increase from Day 1, the ratio of the upper limit of a 2-sided 95% CI and the 
point estimate of GMR is 1.74. 


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9.3. 
Analysis sets 
Table 17 
Analysis sets 
Analysis set 
Description 
Screened 
All participants who were screened for eligibility. 
Enrolled  
Participants who completed the informed consent process, meet 
screening/eligibility criteria and undergone an invasive procedure. 
Note: screening failures (who never passed screening even if re-screened) 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  
All participants who received the dose of the study intervention. Analysis per group 
using the enrolled set based on the administered intervention. 
Per Protocol  
All eligible participants who received dose of study intervention as per protocol, 
without intercurrent conditions that may interfere with immunogenicity and without 
prohibited concomitant medication/vaccination, and who have values for pre-dose 
and post-dose neutralizing antibody titer against pseudovirus bearing S protein 
data for the relevant timepoint, and without major protocol deviations. 
The PPS for immunogenicity will be defined by time point. 
Solicited Safety  
All participants who received the dose of the study intervention (Exposed Set) who 
have reported the presence or absence of any solicited AE at least once.  
AE: Adverse event; D: Day; S: Spike; PPS: Per Protocol Set 
9.3.1. 
Criteria for elimination from analysis 
If a participant meets one of the criteria mentioned below, they may be eliminated from 
per protocol analysis. 
• 
Receive any of the medications/products/vaccines listed in Section 5.2.2. 
• 
Incur an intercurrent medical condition that could alter their immune response 
(i.e., varicella, HIV, lymphoma) or are confirmed to have an alteration of their initial 
immune status. 
• 
Major protocol deviation(s) linked to the eligibility criteria (Section 5.1 and Section 
5.2). 
• 
Study intervention not administered as specified by the protocol. 
• 
Failure to comply with the post-dose immunogenicity blood sampling schedule at a 
given timepoint (Section 1.3). 
• 
Other major protocol deviation during vaccination phase that led to exclusion. 
The SAP will provide a complete list of criteria for elimination from PP analyses. 
9.4. 
Statistical analyses 
The SAP will be finalized prior to FSFV and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and 
secondary endpoints. 


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For the vendors that will perform statistical activities, please refer to the separate list of 
vendors for details. 
9.4.1. 
Primary endpoint 
Analysis of primary safety endpoints will be performed on the Exposed Set, except for 
solicited AEs, which will be performed on the Solicited Safety Set. The analysis will be 
performed separately for study Part A and Part B participants. In addition, pooled 
analyses where groups common in Part A and Part B are combined as one group 
respectively will be performed. 
Statistical analysis methods 
The number and percentage of participants reporting AEs up to 30 days after the dose 
(Day 31): 
• 
At least one administration site event (solicited and unsolicited), with at least one 
systemic event (solicited and unsolicited) and with any AE (solicited and unsolicited) 
during the 7-day and 30-day follow-up period will be tabulated by treatment. Same 
tabulations will be performed for Grade 3 AEs (all and causally related) and for any 
causally related AEs. 
• 
Each individual solicited administration site event (any grade and Grade 3) and 
solicited systemic event (any grade and Grade 3) during the 7-day follow-up period 
will be tabulated by maximum intensity per participant for each treatment group. 
• 
Fever will be reported as number and percentage of participants reporting 
temperature per 0.5°C cumulative increments as from ≥38°C or 100.4°F during the 
7-day follow-up period (i.e., on the day of study intervention administration and 6 
subsequent days) and will be tabulated for each treatment group. 
• 
At least one unsolicited AE during the 30-day follow-up period after the dose, as 
classified by the MedDRA SOC and PT will be tabulated by treatment group. The 
same tabulation will be performed for Grade 3, any causally related, Grade 3 
causally related unsolicited AEs and unsolicited AEs with medically attended visits. 
• 
For each treatment group and for each hematology and biochemistry parameter: 
• 
The number and percentage of participants having hematology and biochemistry 
results below or above the laboratory normal ranges will be tabulated by time 
point. 
• 
The maximum grading post-dose up to Day 15 will be tabulated versus baseline 
(Day 1, or if not available, closest visit available to D1 before IMP 
administration). Grades will be based on the FDA guidance for industry 
“Toxicity grading scale for healthy adults and adolescent volunteers enrolled in 
preventive vaccine clinical trials” (Section 10.2.2). 
• 
At least one MAAE, SAE and AESIs after the dose, as classified by the MedDRA 
SOC and PT, will be tabulated by treatment group. The same tabulation will be 
performed for causally related MAAEs, SAEs and AESIs during this period. The 
detailed listings of SAEs, AESIs and COVID-19 cases will also be produced. 


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• 
At least one concomitant medication (any medication or any antipyretic) during the 
7-day follow-up period and during the 30-day follow-up will be summarized by 
treatment group. 
9.4.2. 
Secondary endpoints/estimands analyses 
9.4.2.1. 
Safety endpoints 
Analysis of secondary safety endpoints will be performed on the Exposed Set. The 
analysis will be performed separately for study Part A and Part B participants. In 
addition, pooled analyses where groups common in Part A and Part B are combined as 
one group respectively will be performed. 
Statistical analysis methods 
The number and percentage of participants with AEs up to study conclusion (Month 6): 
• 
At least one MAAE, SAE and AESIs after the dose, as classified by the MedDRA 
SOC and PT, will be tabulated by treatment group. The same tabulation will be 
performed for causally related MAAEs, SAEs and AESIs during this period. The 
detailed listings of SAEs, AESIs and COVID-19 cases will also be produced. 
• 
A listing of AEs/SAEs leading to withdrawal from the study will be provided. 
9.4.2.2. 
Immunogenicity endpoints 
The analysis of the secondary immunogenicity endpoints will be performed on the PPS 
separately for study Part A and Part B participants. In addition, pooled analyses where 
groups common in Part A and Part B are combined as one group respectively will be 
performed. If more than 10% of participants are eliminated from any of the PPS in any 
treatment group, a sensitivity analysis will be carried out using the Exposed Set. 
Statistical analysis methods 
Following humoral immune responses (neutralizing titer) will be summarized by 
treatment group using descriptive statistics, using corresponding blood sample collected 
for assessment of humoral immune responses: 
• 
Neutralizing titer (GMT) against pseudovirus bearing S protein from vaccine 
encoded SARS-CoV-2 and WT strains will be tabulated with 95% CI and 
represented graphically. 
• 
GMR from baseline of neutralizing titer against pseudovirus bearing S protein from 
vaccine encoded SARS-CoV-2 and WT strains at each collection time point after 
administration of study intervention over time point before administration of study 
intervention will be tabulated with 95% CI. 
• 
GMTs and GMRs from baseline of neutralizing titer, with their 95% CI, using an 
ANCOVA on log-transformed titer with treatment group as a fixed factor, and Day 1 


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baseline value as a covariable. GMTs and GMRs will also be represented 
graphically. Once Part B data are available, Part A and Part B data will be pooled 
together for model based analyses. When pooled, the study part will be added as a 
fixed factor and adjusted GMT/GMR will be estimated under Part A condition. 
Groups common in Part A and Part B will be combined as one group respectively for 
the pooled analysis. 
• 
Percentage of participants with vaccine responses of a 4-fold increase from Day 1, 
with their exact 95% CI will be tabulated. 
9.4.3. 
Analyses of exploratory immunogenicity endpoints 
Additional exploratory immunological assays evaluating S-specific or disease-related 
antigen specific humoral or cellular immune responses, including but not limited to 
antibody functionality (Fcγ R binding capacity, IgG affinity), isotype titer and isotype 
avidity, deep immunophenotyping of cellular responses might also be performed. The 
analyses will be performed separately for study Part A and Part B participants. In 
addition, pooled analyses where groups common in Part A and Part B are combined as 
one group respectively will be performed. Appropriate pooled analyses, such as the 
ANCOVA planned on neutralizing antibody titers will also be performed on the IgG 
antibody responses. 
Analysis of tertiary endpoints detailed in Section 3 will be described in the SAP. 
9.5. 
Interim analyses 
No interim analysis requiring statistical adjustment will be performed. However, analyses 
to evaluate objectives and endpoints will be performed in steps. The sequence of analyses 
is described below. 
9.5.1. 
Sequence of analyses 
• 
In preparation of the safety review during the dose-escalation safety lead-in, analyses 
of available safety data will be performed 
• 
Day 15 interim analysis for each group in Part A of the study will include all the 
data (Day 1 and Day 15) pertaining to primary and secondary safety; humoral 
immunogenicity (including at least neutralizing titer against pseudovirus bearing S 
protein from vaccine encoded SARS-COV-2 endpoints). This analysis will be 
performed when all data of each study group up to Day 15 (i.e., data that are as clean 
as possible) are available. 
• 
Results of this analysis will be presented in a Day 15 statistical analysis report. 
• 
This analysis will be performed by independent unblinded statistician who will 
be unblinded for this analysis, who will generate a statistical report by treatment 
group but no individual listings. 
• The investigators and study participants will stay blinded (i.e., will not have 
access to the individual participant treatment assignment) until EoS. 


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• 
A similar to Part A Day 15 interim analysis for participants in Part B of the study 
may be conducted separately or incorporated into a Day 31 interim analysis. 
• 
Day 31 interim analysis for each group in Part A of the study will include all the 
data (Day 1, Day 15, and Day 31) pertaining to primary and secondary safety; 
humoral immunogenicity (including at least neutralizing titer against pseudovirus 
bearing S protein from vaccine encoded SARS-COV-2 endpoints). This analysis will 
be performed when all data of each study group up to Day 31 (i.e., data that are as 
clean as possible) are available. 
• 
Results of this analysis will be presented in a Day 31 statistical analysis report. 
• 
The investigators and study participants will stay blinded (i.e., will not have 
access to the individual participant treatment assignment) until EoS. 
• 
A similar to Part A Day 31 interim analysis for participants in Part B of the study 
may be conducted separately or incorporated into the final analysis. 
• 
The final analysis will include all the data pertaining to primary and secondary 
safety and immunogenicity endpoints, and any available tertiary endpoint(s). This 
analysis will be performed at the EoS when all data up to study conclusion (Month 6) 
are available. This includes Day 1, Day 15, Day 31, and Month 6, as all the data 
analyzed in the Day 15 and Day 31 analyses will be included in the final analysis as 
well. 
The final study report will contain at least the final analyses of all primary and secondary 
endpoints, including individual listings. 
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/ analyses will be performed. These analyses will be documented in annex(es) to 
the study report. 
9.5.2. 
Statistical consideration for Interim analyses 
Not applicable. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
• 
Applicable ICH GCP Guidelines 


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• 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, and other relevant documents 
(e.g., eDiary) must be submitted to an IRB/IEC by the investigator for review and 
approval. These documents will be signed and dated by the investigator before the 
study is initiated. 
• 
Any protocol amendments will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
• 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 
10.1.3. 
Informed consent process 
The investigator(s) or their representative(s) must fully explain the nature of the study to 
the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. 
Freely given and written informed consent must be obtained from each participant, as 
appropriate, prior to participation in the study. 
The content of the ICF must meet the requirements of 21 CFR 50, local regulations, ICH 
guidelines, HIPAA requirements, privacy and data protection requirements, where 
applicable, and the IRB/IEC or study center. 


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The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) or an ICF 
addendum during their participation in the study. 
In case of unexpected pregnancy, participant must be informed that PI such as the date of 
birth and 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. 
A physical or digital copy of the ICF must be provided to the participants. 
Participants who are re-screened are required to sign a new ICF. 
10.1.4. 
Data protection 
Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets transferred to the sponsor will contain only the identifier. Name and 
any other information which would identify the participant will not be transferred. 
GSK will ensure protection of the personal data of the investigator and site staff which is 
collected within the framework of and for the purpose of the study. 
The participants must be informed that: 
• 
Their personal study-related data will be used by the sponsor in accordance with 
local data protection law. 
• 
Their medical records may be examined by clinical quality assurance auditors or 
other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
The participants must be notified about their rights regarding the use of their personal 
data in accordance with the data privacy section of the ICF. 
10.1.5. 
Committees structure 
The study will be overseen by an SRT, and iSRC operating under a charter. 
The SRT is an internal team, with representatives of different functions (including safety 
physician, a CSL and a biostatistician) involved in the conduct of the study/project. 
A SRT is in place for each GSK product. It comprises of a global cross-functional team 
responsible for the ongoing assessment of benefit-risk for a product. The SRT contribute 
to the continual assessment of incoming new efficacy and safety information. 
The iSRC is an internal committee including a GSK safety physician, a CSL and a 
biostatistician who are not otherwise involved in the conduct of the project. 


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More details on the composition, objectives, and responsibilities of the iSRC will be 
described in the charter. 
Furthermore, to enhance independent, systematic, and standardized identification, 
processing and review of probable or confirmed cases of myocarditis or pericarditis; an 
independent external cardiologist will review and assess all performed EKGs (Screening, 
Day 8, unscheduled visits) and an independent adjudication committee will perform case 
adjudication according to the case definition from the Brighton Collaboration 
[Sexson, 2022]. Details of data collection and frequency of data review are provided in 
Section 8.4.4.2.1. 
10.1.6. 
Dissemination of clinical study data 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK clinical study register in compliance with applicable 
regulations/GSK policy. GSK will aim to register protocols summaries prior to study start 
and target results summaries submission within 12 months of primary/study completion 
date. Where external regulations require earlier disclosure, GSK will follow those 
timelines. 
Where required by regulation, summaries will also be posted on applicable national or 
regional clinical study registers. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results. The investigator is encouraged to share the 
summary results with the study participants, as appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
GSK intends to make anonymized patient-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by study 
participants are used to maximum effect in the creation of knowledge and understanding. 
10.1.7. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents, including source documents (see Definition of terms for the exact definition 
of essential and source documents). The document storage system used during the study 
and for archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval. 
Essential study documents may be added or removed where justified (in advance of study 
initiation) based on their importance and relevance to the study. When a copy is used to 
replace an original document (e.g., source documents, CRF), the copy should fulfill the 


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requirements for certified copies (see Definition of terms for the exact definition of 
certified copies). 
All participant data related to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
The investigator must maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the site’s study participants (see 
Definition of terms for the exact definition of source documents) that supports 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies for such review and inspection. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data (see Definition of terms for the exact definition of 
source data). 
Study monitors will perform ongoing source data verification to confirm that data entered 
in the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data must be traceable, not obscure 
the original entry, and be fully explained if necessary (e.g., via an audit trail). The safety 
and rights of participants must be protected, and the study conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
QTLs will be pre-defined in the centralized monitoring plan to identify systematic issues 
that can impact participant safety and/or the reliability of study results. These pre-defined 
parameters will be monitored during the study. Important deviations from the QTLs and 
remedial actions taken will be summarized in the CSR. 
Study records and source documents pertaining to the conduct of this study, including 
signed ICFs, must be retained by the investigator for 25 years from issuance of the final 
CSR/equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
When copies of source documents are shared externally for review by a central reader 
mechanism (e.g., independent external cardiologist, adjudication committee), documents 
are stored by the external body for approximately 3 years. 


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10.1.8. 
Source documents 
Source documents provide evidence to establish the existence of the participant and 
substantiate the integrity of collected data. The investigator should maintain a record of 
the location(s) of their source documents. 
Data transcribed into the eCRF from source documents must be consistent with those 
source documents; any discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
Definitions of what constitutes source data and documents can be found in the Definition 
of terms. 
Copies of documents are shared with external third parties contracted by GSK for review 
by a central reader mechanism (e.g., independent external cardiologist, adjudication 
committee). The non-exhaustive list of documents shared to inform the central reader 
may include EKG reports, lab data, medical records etc. Participant names or any 
information which would make the participant identifiable or is not essential for the 
central reader mechanism will be redacted prior to transfer. Details of the list of 
documents and the redaction procedure are provided in the site manual or equivalent. 
These documents will be used by the third party solely for the purpose indicated within 
this protocol. 
10.1.9. 
Study and site start and closure 
First act of recruitment 
The start of study is defined as FSFV at a country-level. 
Study/Site termination 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion, provided there is sufficient notice given to 
account for all participants safe exit from study. 
Regular closure of study sites will occur upon study completion. A study site is 
considered closed when all required data/documents and study supplies have been 
collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and enough notice in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 


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• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the 
study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication policy 
GSK aims to submit the results of the study for publication in searchable, peer reviewed 
scientific literature within 18 months from the LSLV for interventional studies and 
follows the guidance from the ICMJE. 
10.2. 
Appendix 2: Clinical laboratory tests 
10.2.1. 
Protocol required safety laboratory assessments 
The tests detailed in Table 18 will be performed by the CRO PPD. 
Table 18 
Protocol required safety laboratory assessments 
Laboratory 
assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Prothrombin Time / 
INR 
Clinical chemistry 
BUN 
 
AST 
Total and direct bilirubin 
 
Creatinine 
 
ALT 
 
 
 
 
ALP 
 
Other tests 
• 
Follicle stimulating hormone (as needed in WONCBP only) 
• 
Cardiac troponin (troponin I) 
• 
[Serum or urine hCG pregnancy test (as needed for WOCBP)] 
The results of each test carried out locally must be entered in the eCRF. 
NOTES: 
All events of ALT ≥ 3x ULN AND total bilirubin ≥ 2x ULN (>35% direct bilirubin) or INR >1.5, which may indicate 
severe liver injury (possible Hy’s Law), must be reported as an SAE. 
All events of Troponin I ≥ 2 x baseline value, may require clinical review. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea 
nitrogen; eCRF: electronic Case report form; hCG: human Chorionic gonadotropin; INR: International normalized 
ratio; IEC: Independent ethics committee; IRB: Institutional review board; MCH: Mean corpuscular hemoglobin; MCV: 
Mean corpuscular volume; RBC: Red blood cell; SAE: Serious adverse event; ULN: upper limit of normal; WBC: 
White blood cell; WONCBP: Woman of non-child-bearing potential; WOCBP: Woman of childbearing potential. 


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10.2.2. 
Toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials  
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 19 
Toxicity grading scales for biochemistry parameters evaluated in the 
current study* 
Serum ** 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially life 
threatening 
(Grade 4)*** 
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  
ALP – increase by 
factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
> 10 x ULN 
Bilirubin – when liver 
function test is normal; 
increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
Bilirubin – when 
accompanied 
by any increase in liver 
function test 
increase by factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
> 1.75 x ULN 
ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea 
nitrogen; ULN: upper limit of normal. 
* Toxicity grading taken from FDA guidance for industry: Toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials [FDA, 2007]. 
** 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. 


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Table 20 
Toxicity grading scales for hematology parameters evaluated in the 
current study* 
Hematology** 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially life-
threatening 
(Grade 4) 
Hemoglobin (Female) - 
gm/dL  
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL  12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm
3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
> 25,000 
WBC Decrease - cell/mm
3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes decrease - 
cell/mm
3 
750 – 1 000 
500 – 749 
250 – 499 
< 250 
Neutrophils decrease - 
cell/mm
3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm
3 
650 – 1 500 
1,501 – 5,000 
> 5,000 
Hypereosinophilic 
Platelets decreased - 
cell/mm
3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
< 25,000 
Prothrombin Time – 
increase by factor 
1.03 – 1.10 x ULN  
1.11 – 1.20 x ULN  
1.21 – 1.25 x ULN 
>1.25 x ULN  
ULN: Upper limit of the normal range; WBC: White blood cell. 
* Toxicity grading taken from FDA guidance for industry: toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials [FDA, 2007]. 
** 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. 
In order to determine the grading, the following rules will be used: 
1. In case a conversion is needed, the original results will be used for the conversion 
without a previous rounding. 
2. In case an approximation is needed to determine the grading, the result (or the result 
divided by the ULN range, depending on the test) expressed in the expected unit will 
be rounded to the number of decimals used for the grading. 


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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., EKG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
Events that occur as a result of protocol-mandated procedures (i.e. invasive 
procedures, modification of participant’s previous therapeutic regimen). 
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.). 


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• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. Pre-existing 
diseases will be recorded in the medical history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death 
b. Is life threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
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. Other situations: 
• 
Possible Hy’s Law case: ALT ≥ 3x ULN AND total bilirubin ≥ 2x ULN (>35% 
direct bilirubin) or INR >1.5 must be reported as SAE 


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• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.3.3. 
Solicited events 
• 
Definition of solicited event 
• 
Solicited events are predefined 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 21 
Solicited administration site events 
Pain at administration site 
Redness at administration site 
Swelling at administration site  
Lymphadenopathy 
(Axillary swelling/ tenderness ipsilateral to the site of injection) 
b. Solicited systemic events 
The following systemic events will be solicited: 
Table 22 
Solicited systemic events 
Fever 
Headache 
Myalgia (muscle pain) 
Arthralgia (joint pain) 
Fatigue (tiredness) 
Chills 
Abdominal pain 
Vomiting 
Diarrhea 
Note: Participants will be instructed to measure and record the oral 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. 


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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 signed the informed consent. Unsolicited 
AEs include both serious and nonserious AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The participants will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant concern. Detailed information about reported 
unsolicited AEs will be collected by qualified site personnel and documented in 
the participant’s records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participants and by 
review of available medical records at the next visit. 
10.3.5. 
Recording, assessment and follow-up of AE, SAE, AESIs and 
pregnancies 
10.3.5.1. 
AE, SAE and AESI recording 
• 
When an AE/SAE/AESI 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/AESI information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to CRO in lieu of completion of the eCRF/required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by CRO. 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 CRO. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
• 
An eDiary will be used in this study to capture solicited administration site or 
systemic events. The participant should be trained on how and when to complete the 
eDiary. 
• 
Anyone who measures administration site or systemic events and who will record the 
event in the eDiary should be trained on using the eDiary. This training must be 
documented in the participant’s source record. 


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• 
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 (for solicited AEs) 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, 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. 
• 
Any unreturned eDiary will be sought from the participant through telephone call(s) 
or any other convenient procedure. 
10.3.5.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE, AESI and SAE 
reported during the study and assign it to one of the following categories: 
• 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• 
Severe:  
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
The intensity of the following solicited AEs will be assessed as described: 


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Table 23 
Intensity scales for solicited events 
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 
Greatest surface diameter < 25 mm 
 
1 
Greatest surface diameter 25 - 50 mm 
 
2 
Greatest surface diameter 51 - 100 mm 
 
3 
Greatest surface diameter > 100 mm 
Swelling at administration site 
0 
Greatest surface diameter < 25 mm 
 
1 
Greatest surface diameter 25 - 50 mm 
 
2 
Greatest surface diameter 51 - 100 mm 
 
3 
Greatest surface diameter > 100 mm 
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 
>38.9°C (102.0°F) 
Arthralgia (joint pain) 
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 
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 (tiredness) 
0 
None 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Lymphadenopathy 
0 
None 
 
1 
Mild: No interference with activity 
 
2 
Moderate: Some interference with daily activity or requires 
repeated use of non-narcotic pain reliever 
 
3 
Severe: Prevents daily activity or requires use of narcotic pain 
reliever 
Chills 
0 
None 
 
1 
Mild sensation of cold; shivering; chattering of teeth 
 
2 
Moderate tremor of the entire body; narcotics indicated 
 
3 
Severe or prolonged, not responsive to narcotics 
Myalgia (muscle pain) 
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 
Abdominal pain 
0 
Normal 
 
1 
Mild: No interference with daily activity 
 
2 
Moderate: Interferes with daily activity 
 
3 
Severe: Prevents daily activity 


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Event 
Intensity grade 
Parameter 
Vomiting 
0 
None 
 
1 
Mild: No interference with activity or 1-2 episodes/24 hours 
 
2 
Moderate: Some interference with activity or >2 episodes in 24 
hours 
 
3 
Severe: Prevents daily activity, requires outpatient intravenous 
hydration 
Diarrhea 
0 
None 
 
1 
Mild: 2-3 loose stools or <400g in 24 hours  
 
2 
Moderate: 4-5 stools or 400-800 g in 24 hours  
 
3 
Severe: 6 or more water stools or >800g in 24 hours 
or requires outpatient intravenous hydration 
* Refer to the SoA (Section 1.3) for the definition of fever and the preferred location for temperature measurement. 
10.3.5.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/AESI. 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/AESI and document this in the medical notes There may be situations in 
which an SAE has occurred and the investigator has minimal information to include 
in the initial report to GSK. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial 
transmission of the SAE data to GSK. 
• 
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.5.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and nonserious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 


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• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.3.5.5. 
Follow-up of AEs, SAEs, AESIs, pregnancies or any other events of 
interest 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
After the initial AE/SAE/AESI/pregnancy or any other event of interest, the investigator 
is required to proactively follow each participant at subsequent visits/contacts. will be 
followed until the event is resolved, stabilized, otherwise explained, or the participant is 
lost to follow-up. 
Other nonserious AEs be followed 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 or the participant is lost to follow-up. 
If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available postmortem findings, including 
histopathology. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the electronic pregnancy report and the 
AE Report if applicable. Generally, the follow-up period does not need to be longer than 
6 to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 


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Furthermore, the investigator must report any SAE occurring as a result of a poststudy 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in the Section 10.3.5.7. 
10.3.5.6. 
Updating of SAE, AESI and pregnancy information after removal of 
write access to the participant’s eCRF 
When additional SAE, AESI or pregnancy information is received after write access to 
the participant’s eCRF is removed, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be sent to the Study contact for reporting SAEs (refer to Section 
8.4.3). 
10.3.5.7. 
Reporting of SAEs, AESIs and pregnancies  
SAE Reporting to CRO via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to CRO 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 CRO by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK 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 CRO via Paper Data Collection Tool 
• 
Facsimile transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the CRO medical monitor. 
• 
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. 


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10.4. 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information 
10.4.1. 
Definitions 
10.4.1.1. 
WOCBP 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
10.4.1.1.1. Women not considered as WOCBP (WONCBPs) 
• 
Premenarchal 
Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development 
and pubic hair growth. 
Additional evaluation should be considered if a participant’s fertility status is unclear 
(e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention. 
• 
Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview. 
• 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more than 1 
FSH measurement >40 IU/L (or mIU/mL) is required. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use a 
non-hormonal, highly effective contraception method if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
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 
24). 


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Table 24 
Highly effective contraceptive methods 
Highly effective contraceptive methods that are user dependenta 
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 
• 
IUD 
• 
IUS 
• 
Bilateral tubal occlusion 
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.)  
Male partner sterilization prior to the female participant’s entry into the study, and this male is the sole partner for that 
participant, 
(The information on the male sterility can come from the site personnel’s review of the participant’s medical records; 
medical examination and/or semen analysis, or medical history interview provided by her or her partner). 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.) 


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10.5. 
Appendix 5: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment 
is located directly before the TOC. 
Amendment 2 
Overall Rationale for the Amendment: 
The Protocol Amendment 2 has been amended to align with the updated guidance 
released by the FDA on “Development and Licensure of Vaccines to Prevent COVID-
19”. In this guidance, the FDA indicated that safety monitoring longer than 6 months will 
only be “warranted for certain vaccine platforms (e.g., those that include novel 
adjuvants)”. Hence, the follow-up of participants has been reduced from 12 months to 6 
months. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 (Schema), Table 1 (SoA), 
Table 3 (Study objectives, endpoints 
and estimands), Section 4.1 (Overall 
design), Section 4.4 (End-of-study 
definition), Section 8.2 
(Immunogenicity assessments), 
Table 7 (Biological samples), Table 9 
(Immunological read-outs), Section 
8.4.1 (Time period and frequency for 
collecting AE, SAE and other safety 
information), Table 11 (Timeframes 
for collecting and reporting of safety 
information), Section 9.4.2.1 (Safety 
endpoints), Section 9.5.1 (Sequence 
of analyses)  
Participant follow-up was reduced 
from 12 months to 6 months (i.e., 
study concludes at Visit 5 in Month 
6 instead of Visit 6 in Month 12). 
To align with updated FDA 
guidance and facilitate 
assessments and visits for study 
participants 
LIST OF ABBREVIATIONS AND 
DEFINITION OF TERMS 
Section 10.1.3 (Informed consent 
process) 
Deleted “Legally authorized 
representative” and “LAR”. 
“Legally authorized representative” 
is not applicable for this study 
since all participants are adults. 
Table 1 (SoA) 
Under “Unscheduled COVID-19” 
column, Medical History, Physical 
examination, Vital signs 
measurement, and Body 
temperature were added as study 
procedures requiring documentation 
in the individual eCRF. 
To align with protocol text in 
Section 8.4.4.2.2. 
Section 9.4.1 
Deleted “and any antipyretic taken 
prophylactically” 
This is analysed descriptively from 
the Concomitant Medication eCRF. 
Section 11 (References) 
Included the reference to the 
guidance released by the FDA on 
“Development and Licensure of 
Vaccines to Prevent COVID-19”. 
This guidance serves as the basis 
for the amendment described 
above; hence, it has been included 
as a reference. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore not summarized. 


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Amendment 1 
Overall Rationale for the Amendment 
The Protocol Amendment 1 has been amended to comply with CBER requests, to provide 
clarification, to remove unnecessary restrictions, and to correct errors in the original 
protocol. 
Summary of changes table of previous amendments: 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document 
formatting revisions 
Minor; therefore, not summarized 
Title Page 
Change in Sponsor Signatory; 
IND number was added 
GSK Signatory has been changed to 
reflect the current Sponsor Signatory; 
IND number was added once 
available. 
List of Abbreviations 
FAS (Full Analysis Set) was 
removed 
FAS is no longer in the protocol 
Definition of Terms 
The terms Adverse Event, Adverse 
Drug Reaction, Auxiliary Medicinal 
Product (AxMP), Background 
treatment, Challenge agents, Co-
administered (concomitant) 
products, Comparator, 
Investigational Product, Medicinal 
products used to assess end-
points, Placebo, Rescue 
medications, Standard of Care, 
and SUSAR were added  
These terms were added for 
compliance reasons 
Section 1.1 (Synopsis), Section 1.2 
(Schema); Section 4.1 (Overall 
design) 
“multicenter” was added 
To comply with a CBER request 
Section 2.1 (Study rationale), 
Section 5.1 (Inclusion criteria) 
“the booster administered between 
6 and 18 months prior to 
screening” was changed to “the 
last booster dose administered at 
least 6 months or more prior to 
screening” 
To remove this unnecessary restriction 
in the original protocol  
Section 2.2 (Background) 
“ongoing COVID-19 pandemic” 
was replaced with “ongoing impact 
of COVID-19” 
Since the pandemic is officially over 
Table 3 (Study objectives, 
endpoints, and estimands) 
“30” was changed to “29”;  
“GMTs” was changed to “GMCs”;  
“M6” was changed to “study 
conclusion”;  
“titers” was changed to 
“concentrations”;  
“M12” was added to the third 
tertiary endpoint; 
To correct errors 
Section 4.1 (Overall design) 
“The study will be conducted in the 
United States (US)” was added  
To comply with a CBER request 
Table 4 (Study groups, 
intervention, and blinding) 
“TC: Telephone call” was deleted 
from the table caption 
“TC” was not present in the table 
Section 6.3.4 (Blinding and 
unblinding) 
“efficacy” was replaced with 
“immunogenicity” 
To correct an error 


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Section # and Name 
Description of Change 
Brief Rationale 
Table 15 (Analysis sets) 
“Full analysis” and “Unsolicited 
safety” were deleted 
These are not applicable to planned 
analyses for this study (refer to Section 
9.4 for details) 
Table 15 (Analysis sets) 
“D15 neutralizing titers against 
pseudovirus bearing S protein from 
the Omicron variant of SARS-CoV-
2” was replaced with “post-dose 
specified immunogenicity data for 
the relevant timepoint”;  
In the Solicited Safety section, 
“reported the presence or absence 
of any” was added, and “safety 
data” was replaced with “AE at 
least once” 
To provide clarification 
Table 15 (Analysis sets) 
In the Overall Safety section, 
“Unsolicited” was replaced with 
“Exposed” 
To be consistent with planned 
analyses 
Section 9.4.1 (Primary endpoint) 
“Exposed Set, except for solicited 
AEs, which will be performed on 
the” was added;  
“and the Unsolicited Safety Set” 
was deleted;  
To be consistent with planned 
analyses 
Section 9.4.1 (Primary endpoint) 
“screening” was replaced with “Day 
1, or if not available, closest visit 
available to D1 before IMP 
administration 
To correct an error 
Section 9.4.2.2 (Immunogenicity 
endpoints) 
“FAS” was replaced with “Exposed 
Set”;  
“and binding IgG Ab” was 
removed;  
“GMCs/” was removed;  
“number of doses received pre-Day 
1 and time from last dose” was 
replaced with “treatment group”  
To be consistent with planned 
analyses 
Table 16 (Protocol required safety 
laboratory assessments) 
“Prothrombin Time / INR” was 
added 
This safety lab was inadvertently 
missed in this Table in the original 
protocol, even though INR had been 
noted in the footnote 
Table 18 (Toxicity grading scales 
for hematology parameters 
evaluated in the current study) 
“Prothrombin Time – increase by 
factor,” “1.03 – 1.10 x ULN,” “1.11 
– 1.20 x ULN,” “1.21 – 1.25 x 
ULN,” and “>1.25 x ULN” were 
added  
This safety lab (i.e., Prothrombin Time) 
was inadvertently missed in this Table 
in the original protocol 


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106 
11. 
REFERENCES 
Advisory Committee on Immunization Practices (ACIP). COVID-19 Vaccine Booster 
Dose Safety. November 19, 2021. Accessed 07 April 2023. 
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-19/04-COVID-
Shimabukuro-508.pdf 
Centers for Disease Control (CDC). CDC COVID-19 Vaccine Task Force. 
Myopericarditis following COVID-19 vaccination: updates from the Vaccine Adverse 
Event Reporting System (VAERS). October 21, 2021. Accessed on 07 April 2023. 
https://stacks.cdc.gov/view/cdc/110920 
Centers for Disease Control (CDC). Clinical considerations: myocarditis and pericarditis 
after receipt of mRNA COVID-19 vaccines among adolescents and young adults. March 
23, 2023. Accessed 31 March 2023. https://www.cdc.gov/vaccines/covid-19/clinical-
considerations/myocarditis.html. 
European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee 
(PRAC). Signal assessment report on Myocarditis, pericarditis with Tozinameran 
(COVID-19 mRNA vaccine (nucleoside-modified) – COMIRNATY). December 2, 
2021a. Accessed 30 March 2023. https://www.ema.europa.eu/en/documents/prac-
recommendation/signal-assessment-report-myocarditis-pericarditis-tozinameran-covid-
19-mrna-vaccine_en.pdf 
European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee 
(PRAC). Signal assessment report on myocarditis and pericarditis with Spikevax 
(previously COVID-19 Vaccine Moderna). December 2, 2021b. Accessed 30 March 
2023. https://www.ema.europa.eu/en/documents/prac-recommendation/signal-
assessment-report-myocarditis-pericarditis-spikevax-previously-covid-19-vaccine-
moderna-covid_en.pdf 
Food and Drug Administration (FDA). Guidance for Industry. Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
September, 2007. Accessed 07 April 2023. https://www.fda.gov/media/73679/download 
Food and Drug Administration (FDA). Vaccines and Related Biological Products 
Advisory Committee Meeting, October 14-15, 2021. EUA amendment request for a 
booster dose of the Moderna COVID-19 Vaccine. October 14, 2021a. Accessed 07 April 
2023. https://www.fda.gov/media/152991/download 
Food and Drug Administration (FDA). Comirnaty Summary Basis for Regulatory Action 
(2021b). November 8, 2021b. Accessed 07 April 2023. 
https://www.fda.gov/media/151733/download 
Food and Drug Administration (FDA). Pfizer-BioNTech COVID-19 Vaccine, Bivalent 
Now Authorized For All Doses. April 18, 2023a. Accessed 19 April 2023. 
https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-
covid-19/pfizer-biontech-covid-19-vaccines 


CONFIDENTIAL 
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107 
Food and Drug Administration (FDA). Moderna COVID-19 Vaccine, Bivalent Now 
Authorized For All Doses. April 18, 2023b. Accessed on 19 April 2023. 
https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-
covid-19/moderna-covid-19-vaccines 
Garcia-Beltran WF, Lam EC, St Denis K, et al. Multiple SARS-CoV-2 variants escape 
neutralization by vaccine-induced humoral immunity. Cell. 2021;184(9):2372-83. 
Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 
- Preliminary Report. N Engl J Med. 2020;383(20):1920-1931. 
Mathieu E, Ritchie H, Rodés-Guirao L, et al. Coronavirus Pandemic (COVID-19). March 
03, 2023. Accessed on 23 March 2023. https://ourworldindata.org/coronavirus 
Peeples, L. News Feature: Avoiding pitfalls in the pursuit of a COVID-19 vaccine. Proc 
Natl Acad Sci USA. 2020;117(15): 8218-21. 
Rüggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines 
for data collection, analysis, and presentation of immunization safety data. Vaccine. 
2007;25(31):5675-84. 
Sexson Tejtel SK, Munoz FM, Al-Ammouri I, et al. Myocarditis and pericarditis: Case 
definition and guidelines for data collection, analysis, and presentation of immunization 
safety data. Vaccine. 2022;40(10):1499-511. 
World Health Organization [WHO]. Advice for the public: Coronavirus disease (COVID-
19). March 18, 2023. Accessed 31 March 2023. 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public 
Zhou B, Thao TTN, Hoffmann D, et al. SARS-CoV-2 spike D614G change enhances 
replication and transmission. Nature. 2021;592(7852):122-7. 


Signature Page for  219112 TMF-18266190 v1.0
Signature Page for TMF-18266190 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 07-Feb-2024 13:11:36 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan Amendment 2
Study ID:  219112
Official Title of Study: Exploratory, FTIH, observer-blind, randomized, 
controlled study to evaluate safety, reactogenicity and immunogenicity of 
various doses of GSK’s investigational mRNA-CR-04 vaccine when 
administered intramuscularly in healthy adults 18 to 49 years of age 
NCT number: NCT05972993
Date of Document: 15 Feb 2024


CONFIDENTIAL 
219112 
Page 1 of 48 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
Exploratory, FTIH, observer-blind, randomized, controlled 
study to evaluate safety, reactogenicity and immunogenicity of 
various doses of GSK’s investigational mRNA-CR-04 vaccine 
when administered intramuscularly in healthy adults 18 to 49 
years of age 
Study Number: 
219112 
Compound Number: GSK4768069A 
Abbreviated Title: 
MRNA CLINRES-001 
Sponsor Name: GlaxoSmithKline Biologicals SA (GSK) 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
Clintrials.gov 
IND 29606 
Statistical Analysis Plan (SAP) Template v3.0   14 September 2022 
©2024 GSK group of companies or its licensor. 


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Page 2 of 48 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
LIST OF ABBREVIATIONS ............................................................................................. 7 
VERSION HISTORY ....................................................................................................... 9 
1. 
INTRODUCTION .................................................................................................... 13 
1.1. 
Objectives, Endpoints, and Estimands ........................................................ 14 
1.2. 
Study Design .............................................................................................. 21 
2. 
STATISTICAL HYPOTHESES ............................................................................... 24 
2.1. 
Multiplicity Adjustment ................................................................................ 24 
3. 
ANALYSIS SETS ................................................................................................... 24 
3.1. 
Definition..................................................................................................... 24 
4. 
STATISTICAL ANALYSES ..................................................................................... 24 
4.1. 
General Considerations .............................................................................. 24 
4.1.1. 
General Methodology .................................................................. 25 
4.1.2. 
Baseline Definition ....................................................................... 25 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 25 
4.2.1. 
Safety and Reactogenicity ........................................................... 25 
4.2.1.1. 
Analysis of safety and reactogenicity planned 
in the protocol ............................................................. 25 
4.2.1.2. 
Additional considerations ............................................ 27 
4.2.1.2.1. 
Analysis of solicited events ..................... 27 
4.2.1.2.2. 
Analysis of unsolicited events ................. 28 
4.2.1.2.3. 
Combined solicited events and 
unsolicited events excluding 
serious AEs ............................................ 28 
4.2.1.3. 
Adverse Events of Special Interest ............................. 28 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 29 
4.3.1. 
Safety .......................................................................................... 29 
4.3.1.1. 
Analysis of safety and reactogenicity planned 
in the protocol ............................................................. 29 
4.3.2. 
Immunogenicity............................................................................ 29 
4.3.2.1. 
Analysis of immunogenicity planned in the 
protocol ...................................................................... 29 
4.3.2.2. 
Additional considerations ............................................ 32 
4.4. 
Tertiary Endpoint(s) Analyses ..................................................................... 32 
4.4.1. 
Analysis of Serum-Binding Antibody (IgG) ................................... 32 
4.4.1.1. 
GMCs and GMR from baseline of binding IgG 
Ab against SARS-CoV-2 Spike WT (D614), 
SARS-CoV-2 Spike BA.5, SARS-CoV-2 Spike 
D614G, SARS-CoV-2 Spike (B.1.617.2, AY.4),  


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SARS-CoV-2 Spike (B.1.1.529, BA.1, 
BA.1.15), SARS-CoV-2 Spike BQ.1, SARS-
CoV-2 Spike XBB.1, SARS-CoV-2 Spike 
BA.2.275, SARS-CoV-2 Spike XBB.1.5, SARS-
CoV-2 Spike XBB.1.16 variants at each 
collection timepoint ..................................................... 32 
4.4.1.2. 
Seroresponse rates, based on binding IgG Ab 
concentrations against SARS-CoV-2 Spike WT 
(D614), SARS-CoV-2 Spike BA.5, SARS-CoV-
2 Spike D614G, SARS-CoV-2 Spike 
(B.1.617.2, AY.4),  SARS-CoV-2 Spike 
(B.1.1.529, BA.1, BA.1.15), SARS-CoV-2 
Spike BQ.1, SARS-CoV-2 Spike XBB.1, SARS-
CoV-2 Spike BA.2.275, SARS-CoV-2 Spike 
XBB.1.5, SARS-CoV-2 Spike XBB.1.16 
variants. ...................................................................... 33 
4.4.2. 
Analysis of Cell-Mediated Immune Response .............................. 33 
4.4.3. 
Incidence of confirmed symptomatic and asymptomatic 
SARS-CoV-2 infection ................................................................. 35 
4.4.4. 
Other Tertiary Endpoints .............................................................. 35 
4.5. 
Analysis Interpretation ................................................................................ 35 
4.6. 
Other Safety Analysis ................................................................................. 35 
4.6.1. 
COVID-19 Assessment and COVID-19 AEs ................................ 35 
4.7. 
Other Analysis ............................................................................................ 36 
4.7.1. 
Subgroup analyses ...................................................................... 36 
4.8. 
Interim Analyses ......................................................................................... 36 
4.8.1. 
Sequence of analyses.................................................................. 36 
4.9. 
Changes to Protocol Defined Analyses ....................................................... 37 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 37 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 38 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 38 
6.1.1. 
Participant Disposition ................................................................. 38 
6.1.2. 
Demographic and Baseline Characteristics .................................. 38 
6.1.2.1. 
Analysis of demographics/baseline 
characteristics ............................................................ 38 
6.1.2.2. 
Additional considerations ............................................ 38 
6.1.3. 
Protocol Deviations ...................................................................... 39 
6.1.4. 
Concomitant Medications ............................................................. 39 
6.1.5. 
Additional Analyses Due to the COVID-19 Pandemic .................. 40 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 40 
6.2.1. 
Study Day and Reference Dates .................................................. 40 
6.2.2. 
Handling of missing data .............................................................. 40 
6.2.2.1. 
Dates .......................................................................... 40 
6.2.2.2. 
Laboratory data .......................................................... 41 
6.2.2.3. 
Daily recording of solicited events .............................. 43 
6.2.2.3.1. 
Studies with electronic diaries ................. 43 
6.2.2.4. 
Unsolicited adverse events ......................................... 43 


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6.2.3. 
Data derivation ............................................................................ 44 
6.2.3.1. 
Weight ........................................................................ 44 
6.2.3.2. 
Height ......................................................................... 44 
6.2.3.3. 
Body mass index (BMI) .............................................. 44 
6.2.3.4. 
Temperature ............................................................... 44 
6.2.3.5. 
Numerical serology results ......................................... 44 
6.2.3.6. 
Geometric mean titres (GMTs) and GMCs ................. 45 
6.2.3.7. 
Onset day ................................................................... 45 
6.2.3.8. 
Duration of events ...................................................... 45 
6.2.3.9. 
Counting rules for combining solicited and 
unsolicited adverse events ......................................... 46 
6.2.3.10. Counting rules for occurrences of solicited 
events......................................................................... 46 
6.2.3.11. AESIs ......................................................................... 46 
6.2.4. 
Display of decimals ...................................................................... 46 
6.2.4.1. 
Percentages ............................................................... 46 
6.2.4.2. 
Differences in percentages ......................................... 47 
6.2.4.3. 
Demographic/baseline characteristics statistics .......... 47 
6.2.4.4. 
Serological summary statistics ................................... 47 
6.2.5. 
Statistical methodology ................................................................ 47 
6.2.5.1. 
Exact confidence intervals around proportions ........... 47 
7. 
REFERENCES ....................................................................................................... 48 
 


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LIST OF TABLES 
PAGE 
Table 1 
Study objectives, and endpoints ............................................................. 14 
Table 2 
Estimands .............................................................................................. 16 
Table 3 
Part A study groups, intervention and blinding ....................................... 23 
Table 4 
Part B study groups, interventions, and blinding ..................................... 23 
Table 5 
Analysis sets .......................................................................................... 24 
Table 6 
Toxicity grading scales for biochemistry parameters evaluated in 
the current study* ................................................................................... 42 
Table 7 
Toxicity grading scales for hematology parameters evaluated in 
the current study* ................................................................................... 43 
 


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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 22 
 


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LIST OF ABBREVIATIONS  
Ab 
Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CSR 
Clinical study report 
eCRF 
electronic Case report form 
EKG 
Electrocardiogram 
EoS 
End-of-study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FTIH 
First time in human 
GMC  
Geometric mean concentration 
GMR 
Geometric mean ratio 
GMT 
Geometric mean titer 
GSK 
GlaxoSmithKline Biologicals SA 
ICE 
Intercurrent events  
IgG 
Immunoglobulin G 
iSRC 
Internal safety review committee 
LLOQ 
Lower limit of quantitation 
MAAE 
Medically attended adverse event 
MedDRA 
Medical dictionary for regulatory activities 
mRNA-CR vaccine 
SARS-CoV-2 Omicron variant S glycoprotein vaccine 


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N 
Nucleocapsid 
PCR 
Polymerase chain reaction 
pIMD 
Potential immune-mediated disease 
PP 
Per Protocol 
PPS 
Per Protocol Set 
PT 
Preferred term 
RT-PCR 
Real-time polymerase chain reaction 
S 
Spike 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SOC 
System organ class 
SpO2 
Pulse oximetry 
SRT 
Safety review team 
TC 
Telephone call 
ULN 
Upper limit of normal 
WT 
SARS-CoV2 Wuhan ancestral strain or Wild type strain 


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VERSION HISTORY 
 SAP Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rational
e 
SAP 
31 July 2023 
Final: (11 May 
2023) 
Not Applicable 
Original 
version 
SAP 
Amendment 1 
20 November 
2023 
Protocol 
amendment 2 (15 
November 2023) 
Updated the SAP 
to follow the 
changes in 
protocol 
amendment.  
Changed the 
intercurrent event 
strategy from 
Principal Stratum 
Strategy to 
Hypothetical 
strategy for the 
immunogenicity 
endpoints 
(Section 1.1). 
Removed the 
temperature by 
0.5°C summary 
table. Only 
grading summary 
will be kept 
(Section 4.2.1.1).  
Updated the shift 
of hematological 
and biochemical 
laboratory 
abnormality table 
(Section 4.2.1.1).  
Added the 
management of 
solicited 
symptoms when 
Version 
2.0 


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 SAP Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rational
e 
the investigators 
provide input 
(Section 
4.2.1.2.1).   
Added the 
analyses of 
tertiary endpoints 
(Section 4.4). 
Clarified that RT-
PCR at screening 
and Day 1 do not 
contribute to 
SARS-CoV-2 
infection (Section 
4.9). 
Updated the 
partial data 
handling rules 
(Section 6.2.2). 
SAP 
Amendment 2 
15 Feb 2024 
Protocol 
amendment 3 (07 
February 2024) 
Updated the SAP 
to align with the 
changes in 
protocol 
amendment 3.  
This study is 
divided into two 
parts (Parts A and 
B). Part B will 
commence only 
after all Part A 
participants have 
completed their 
Day 15 study 
visits and the Day 
15 interim 
analysis is 
 


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 SAP Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rational
e 
completed. In 
Part B, 42 more 
participants will 
be enrolled in 
parallel and 
randomly 
assigned in a 
3:3:1 ratio to 
receive: 
(a) 3 µg mRNA-
CR-04 vaccine, 
or (b) 10 µg 
mRNA-CR-04 
vaccine, or (c) 
saline placebo. 
(Section 1.2). 
Clarified that the 
descriptive 
statistical 
analyses will be 
performed 
separately for 
study Part A and 
Part B , and for 
combined part A 
& B with 
aggregated 
common groups 
(Section 4.1.1, 
Section 6.1.2.2, 
Section 6.1.3, and 
Section 6.1.4). 


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Updated the 
management of 
solicited 
symptoms when 
the investigators 
provide input, 
i.e., the update of 
solicited 
symptoms was 
not allowed if 
solicited 
symptoms is 
missing (Section 
4.2.1.2.1).  
Updated AE of 
SARS-CoV-2 
infection 
categories to be 
consistent with 
protocol (Section 
4.6.1). 
Added text to 
perform a Day 31 
interim analysis 
on Part A 
participants and 
to allow for 
potential Day 15 
and Day 31 
interim analyses 
for Part B 
participants 
(Section 4.8.1). 
The GSK 
statistical team 
will be unblinded 
after Part A Day 
15 interim 
analyses (Section 
4.8.1).  


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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the CSR for 
219112 (MRNA CLINRES-001). 


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1.1. 
Objectives, Endpoints, and Estimands 
Table 1 
Study objectives, and endpoints 
Objective(s) 
Endpoints 
Primary 
• 
To evaluate the safety and reactogenicity of investigational mRNA-CR-04 vaccine 
up to D31  
• 
Solicited administration site events and systemic events during the 7-day follow-up 
period after study vaccine administration (day of study vaccine administration and 
6 subsequent days); 
• 
Unsolicited AEs during the 30-day follow-up period after study vaccine 
administration (day of study vaccine administration and 29 subsequent days); 
• 
Any hematological and biochemical laboratory abnormality during the 15-day 
follow-up period after study vaccine administration (day of study vaccine 
administration and 14 subsequent days); 
• 
MAAEs; SAEs; AESIs* up to D31. 
Secondary Safety 
• 
To assess safety of investigational mRNA-CR-04 vaccine from study vaccine 
administration up to study conclusion. 
• 
MAAEs; SAEs; AESIs* up to study conclusion (M6). 
Secondary Immunogenicity 
• 
To evaluate the Ab functionality (neutralizing capacity induced by the mRNA-CR-
04 vaccine against vaccine encoded SARS-CoV-2 and WT strains) up to study 
conclusion. 
• 
Neutralizing titer against pseudovirus bearing S protein from vaccine encoded 
SARS-CoV-2 and WT strains at each collection timepoint (D1, D15, D31, M6). 
• 
GMR from baseline (D1) of neutralizing titer against pseudovirus bearing S protein 
from vaccine encoded SARS-CoV-2 and WT strains at each collection timepoint. 
• 
Vaccine response rate based on neutralizing titers against vaccine encoded SARS-
CoV-2 and WT strains at each collection timepoint. 
Tertiary 
• 
To describe serum-binding antibody (IgG) responses induced by the mRNA-CR-04 
vaccine specific for vaccine encoded SARS-CoV-2 and WT strains S protein up to 
study conclusion. 
• 
GMCs of binding IgG Ab specific for S protein encoded by the vaccine SARS-CoV-
2 and WT strains at each timepoint (D1, D15, D31, M6). 


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Objective(s) 
Endpoints 
• 
GMR from baseline of binding IgG Ab specific for S protein encoded by the vaccine 
SARS-CoV-2 and WT strains S proteins at each timepoint. 
• 
Seroresponse rates based on binding IgG concentrations specific for S protein 
encoded by the vaccine SARS-CoV-2 and WT strains S protein at each timepoint. 
• 
To describe cell-mediated immune responses induced by the mRNA-CR-04 
vaccine up to study conclusion. 
• 
Frequency of CD4+/CD8+ T-cells specific for S protein encoded by the vaccine 
SARS-CoV-2 and WT strains measured by intracellular cytokine staining assay at 
each time point (D1, D15, D31, M6). 
• 
Cellular immune responses including, but not limited to Th1 and Th2 profiles as 
determined by flow cytometry using ICS at each time point (D1, D15, D31, M6). 
• 
To describe the incidence of confirmed symptomatic and asymptomatic SARS-
CoV-2 infection. 
• 
Percentage of laboratory-confirmed (N protein seroconversion) asymptomatic 
SARS-CoV-2 infection at each time point (D1, D15, D31, M6). 
• 
Percentage of laboratory-confirmed (RT-PCR) symptomatic SARS-CoV-2 infection 
at D8, D15, as well as at unscheduled visits.  
• 
To evaluate the genetic sequence of SARS-CoV-2 variant S protein in confirmed 
(RT-PCR) SARS-CoV-2 positive participants. 
• 
Comparison of SARS-CoV-2 S protein genetic sequence of viral isolates (when 
available) to the vaccine mRNA sequence 
• 
Identification of SARS-CoV-2 variants. 
• 
To further characterize the humoral response (including, but not limited to 
functionality of antibodies) and cellular response, specific for the vaccine encoded 
SARS-CoV-2, WT and other relevant strains. 
• 
S-specific responses at D1, D15, D31, M6 
• 
Other read-outs may be performed if deemed necessary. 
Ab: Antibody; AE: Adverse event; AESI: Adverse events of special interest; D: Day; GMR: Geometric mean ratio; GMT: Geometric mean titer; ICS: intracellular cytokine staining; IgG: 
Immunoglobulin G; M: Month; MAAE: Medically attended adverse events; N: Nucleocapsid; pIMD: potential Immune-mediated disease; RT-PCR: Real-time polymerase chain 
reaction; S: Spike; SAE: Serious adverse event; VAED: Vaccine associated enhanced disease; WT: Wild type. 
*AESI include pIMDs, myocarditis/pericarditis, virologically confirmed COVID-19 cases and anaphylaxis or severe hypersensitivity within 24 hours after study vaccination (Protocol 
Section 8.4.4). 


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Table 2 
Estimands  
Estimand 
Attributes 
Summary 
measure 
Treatment 
Population 
Endpoint (Variable) 
Intercurrent events (ICEs) 
Description 
Handling strategy 
Primary   
One dose of 
the 
investigational 
mRNA-CR 
vaccine. 
Healthy adults, 18 
to 49 years of 
age, who were 
primed and 
received booster 
dose(s) of an 
authorized or 
licensed mRNA 
COVID -19 
vaccine with the 
last booster dose 
administered at 
least 6 months or 
more prior to 
screening, 
inclusive at the 
time of the 
vaccination. 
• 
Solicited 
administration site 
events and systemic 
events with onset 
during the 7-day 
follow-up period after 
study vaccine 
administration (day of 
study vaccine 
administration and 6 
subsequent days); 
• 
Unsolicited AEs with 
onset during the 30-
day follow-up period 
after study vaccine 
administration (day of 
study vaccine 
administration and 29 
subsequent days); 
• 
Any hematological 
and biochemical 
laboratory 
abnormality during 
• 
Study vaccination not 
administered as per protocol 
• 
Any intercurrent conditions or 
any concomitant 
medication/vaccination that 
may confound the safety 
investigational product 
causality assessment prior to 
D31 
The data collected from all 
participants receiving one 
dose of investigational vaccine 
will be used regardless of 
whether the intercurrent event 
occurs (Treatment policy) 
Rationale: treatment policy 
strategy is used as all data will 
contribute to evaluate the 
safety parameters. 
 
Proportion of 
participants in 
each treatment 
group for each 
endpoint 
 


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Estimand 
Attributes 
Summary 
measure 
Treatment 
Population 
Endpoint (Variable) 
Intercurrent events (ICEs) 
Description 
Handling strategy 
the 15-day follow-up 
period after study 
vaccine 
administration (day of 
study vaccine 
administration and 14 
subsequent days); 
• 
MAAEs; SAEs; 
AESIs up to D31. 
Secondary  
One dose of 
the 
investigational 
mRNA-CR 
vaccine. 
Healthy adults, 18 
to 49 years of 
age, who were 
primed and 
received booster 
dose(s) of an 
authorized or 
licensed mRNA 
COVID -19 
vaccine with the 
last booster dose 
administered at 
least 6 months or 
more prior to 
screening, 
MAAEs; SAEs; AESIs from 
Day 1 up to study 
conclusion (M6). 
 
• 
Study vaccination not 
administered as per protocol 
• 
Any intercurrent conditions or 
any concomitant 
medication/vaccination that 
may confound the safety 
investigational product 
causality assessment prior to 
M6 
The data collected from all 
participants receiving one 
dose of investigational vaccine 
will be used regardless of 
whether the intercurrent event 
occurs (Treatment policy) 
Rationale: treatment policy 
strategy is used as all data will 
contribute to evaluate the 
safety parameters 
Proportion of 
participants in 
each treatment 
group for each 
endpoint 
 


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Estimand 
Attributes 
Summary 
measure 
Treatment 
Population 
Endpoint (Variable) 
Intercurrent events (ICEs) 
Description 
Handling strategy 
inclusive at the 
time of the 
vaccination. 
Secondary 
One dose of 
the 
investigational 
mRNA-CR 
vaccine. 
Healthy adults, 18 
to 49 years of 
age, who were 
primed and 
received booster 
dose(s) of an 
authorized or 
licensed mRNA 
COVID -19 
vaccine with the 
last booster dose 
administered at 
least 6 months or 
more prior to 
screening, 
inclusive at the 
time of the 
vaccination. 
Neutralizing titer against 
pseudovirus bearing S 
protein from vaccine 
encoded SARS-CoV-2 and 
WT strains at each 
collection timepoint (D1, 
D15, D31, M6). 
 
• 
Study vaccination not 
administered as per protocol 
• 
A condition that has the 
capability of altering the 
immune 
response (e.g., HIV, 
lymphoma, COVID) to the 
study intervention or is 
confirmed to have an 
alteration of the participant’s 
initial immune status 
• 
Major protocol deviations 
including out of visit window 
blood samples.    
The Hypothetical strategy will 
be used. The data after the 
ICEs will be ignored.  
Rationale: To estimate the 
treatment effect on participants 
who are dosed and have no 
major protocol deviations. 
Geometric Mean 
Titer for each 
treatment group 


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Estimand 
Attributes 
Summary 
measure 
Treatment 
Population 
Endpoint (Variable) 
Intercurrent events (ICEs) 
Description 
Handling strategy 
Secondary 
One dose of 
the 
investigational 
mRNA-CR 
vaccine. 
Healthy adults, 18 
to 49 years of 
age, who were 
primed and 
received booster 
dose(s) of an 
authorized or 
licensed mRNA 
COVID -19 
vaccine with the 
last booster dose 
administered at 
least 6 months or 
more prior to 
screening, 
inclusive at the 
time of the 
vaccination. 
GMR from baseline (D1) of 
neutralizing titer against 
pseudovirus bearing S 
protein from vaccine 
encoded SARS-CoV-2 and 
WT strains at each 
collection timepoint. 
 
• 
Study vaccination not 
administered as per protocol 
• 
A condition that has the 
capability of altering the 
immune 
response (e.g. HIV, 
lymphoma, COVID) to the 
study intervention or is 
confirmed to have an 
alteration of the participant’s 
initial immune status 
• 
Major protocol deviations 
including out of visit window 
blood samples.    
 
The Hypothetical  strategy will 
be used. The data after the 
ICEs will be ignored.   
Rationale: To estimate the 
treatment effect on participants 
who are dosed and have no 
major protocol deviations. 
Geometric Mean 
Ratio for each 
treatment group 
Secondary 
One dose of 
the 
investigational 
mRNA-CR 
vaccine. 
Healthy adults, 18 
to 49 years of 
age, who were 
primed and 
received booster 
Vaccine response rate 
based on neutralizing titers 
against vaccine encoded 
SARS-CoV-2 and WT 
• 
Study vaccination not 
administered as per protocol 
• 
A condition that has the 
capability of altering the 
immune 
The Hypothetical strategy will 
be used. The data after the 
ICEs will be ignored.   
Rationale: To estimate the 
treatment effect on participants 
Vaccine response 
rate in each 
treatment group 
for each endpoint 
 


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Estimand 
Attributes 
Summary 
measure 
Treatment 
Population 
Endpoint (Variable) 
Intercurrent events (ICEs) 
Description 
Handling strategy 
dose(s) of an 
authorized or 
licensed mRNA 
COVID -19 
vaccine with the 
last booster dose 
administer at least 
6 months or more 
prior to screening, 
inclusive at the 
time of the 
vaccination. 
strains at each collection 
timepoint. 
response (e.g. HIV, 
lymphoma, COVID) to the 
study intervention or is 
confirmed to have an 
alteration of the participant’s 
initial immune status 
• 
Major protocol deviations 
including out of visit window 
blood samples.    
 
who are dosed and have no 
major protocol deviations. 
 


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1.2. 
Study Design 
This is an exploratory, FTIH, observer-blind, randomized, controlled study. 
In part A of this study, three doses (10 µg, 30 µg, and 100 µg) of the mRNA-CR-04 
vaccine will be evaluated. Approximately 72 eligible healthy adults, 18 to 49 years, 
inclusive, will be enrolled with 24 participants per group (Group 1, Group 2 and Group 
3). Within each group, participants will be randomly assigned in a 3:1 ratio: 
• 
18 participants will receive the investigational mRNA-CR-04 vaccine and 
• 
6 participants will receive a saline placebo (sodium chloride [NaCl] isotonic solution 
[0.9%]). 
In Part B of the study, 2 doses (3 µg and 10 µg) of the mRNA-CR-04 vaccine will be 
evaluated. Approximately 42 eligible healthy adults, 18 to 49 years, inclusive, will be 
enrolled in Part B and will be randomly assigned in a 3:3:1 ratio: 
• 
18 participants will receive 3 µg of the investigational mRNA-CR-04 vaccine and 
• 
18 participants will receive 10 µg of the investigational mRNA-CR-04 vaccine and 
• 
6 participants will receive a saline placebo (sodium chloride [NaCl] isotonic solution 
[0.9%]). 
Study duration for all the participants will be approximately 6 months, and they will be 
evaluated for safety, reactogenicity and immunogenicity. Safety monitoring and safety 
data review will be performed by a GSK SRT (blinded data review until Part A Day 15 
interim analysis, unblinded review subsequently) and a GSK iSRC (unblinded data 
review). 
Overview of the study design is presented in Figure 1. 


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Figure 1 
Study design overview 
 
CMI: Cell-mediated immunity; D: Day; M: Month; mRNA: mRNA-CR-04 vaccine; n: Number of participants; SE: 
Solicited events; TC: Telephone call; V: Visit. 
* TC1 D2 only for sentinel participants in each group. ** The first participant is to be enrolled in Group 1. In addition to 
the defined intervals between doses within each group, an interval of at least 60 minutes will be maintained 
between the vaccination of sentinel participants across Group 1 and Group 2. *** TC1 review will be performed by 
the SRT on blinded data. 


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Table 3 and Table 4 describe the Part A and Part B study groups, interventions, and 
blinding, respectively. 
Table 3 
Part A study groups, intervention and blinding 
Study 
groups 
Number of 
participants 
Age (Min-
Max years of 
age) 
Study intervention(s)/vaccine(s) mode of 
administration 
Blinding 
Screening→Visit5 
Group 1 
18 
18 – 49 
mRNA-CR-04 vaccine 
10 µg 
Intramuscular injection 
into the deltoid muscle, 
preferably of the non-
dominant arm. 
Observer-blind 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
Group 2 
18 
18 – 49 
mRNA-CR-04 vaccine 
30 µg 
Intramuscular injection 
into the deltoid muscle, 
preferably of the non-
dominant arm. 
Observer-blind 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
Group 3 
18 
18 – 49 
mRNA-CR-04 vaccine 
100 µg 
Intramuscular injection 
into the deltoid muscle, 
preferably of the non-
dominant arm. 
Observer-blind 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
NaCl: Sodium chloride. 
Table 4 
Part B study groups, interventions, and blinding 
Study 
groups 
Number of 
participants 
Age (Min-
Max years 
of age) 
Study intervention(s)/vaccine(s) mode of 
administration 
Blinding 
Part B 
3 µg 
18 
18 – 49 
mRNA-CR-04 
vaccine 3 µg 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the 
non-dominant arm. 
Observer-blind 
(except sponsor) 
Part B 
10 µg 
18 
18 – 49 
mRNA-CR-04 
vaccine 10 µg 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the 
non-dominant arm. 
Observer-blind 
(except sponsor) 
Part B 
Placebo 
6 
18 – 49 
Saline placebo 
(NaCl [0.9%]) 
Intramuscular 
injection into the 
deltoid muscle, 
preferably of the 
non-dominant arm. 
Observer-blind 
(except sponsor) 
NaCl: Sodium chloride. 


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2. 
STATISTICAL HYPOTHESES  
There is no hypothesis testing in this study; all analysis will be performed in a descriptive 
manner. Means and proportions for different objectives will be computed with their 95% 
confidence intervals (CIs). 
2.1. 
Multiplicity Adjustment 
N/A 
3. 
ANALYSIS SETS 
3.1. 
Definition 
Table 5 
Analysis sets 
Analysis set 
Description 
Analyses Evaluated 
Screened 
All participants who were screened for eligibility. 
Study Population 
Enrolled  
Participants who completed the informed consent process, 
meet screening/eligibility criteria and undergone an invasive 
procedure. 
Note: screening failures (who never passed screening even if 
re-screened) and participants screened but never enrolled 
into the study (Met eligibility but not needed) are excluded 
from the Enrolled analysis set as they did not enter the study. 
Study Population 
Exposed  
All participants who received the dose of the study 
intervention. Analysis per group using the enrolled set based 
on the administered intervention. 
Safety excluding solicited AE 
Per Protocol  
All eligible participants who received dose of study 
intervention as per protocol, without intercurrent conditions 
that may interfere with immunogenicity and without prohibited 
concomitant medication/vaccination, and who have values for 
pre-dose and post-dose neutralizing titer against pseudovirus 
bearing BA. 5 S protein data for the relevant timepoint, and 
without major protocol deviations. 
The PPS for immunogenicity will be defined by time point. 
Immunogenicity 
Solicited 
Safety  
All participants who received the dose of the study 
intervention (Exposed Set) who have reported the presence 
or absence of any solicited AE at least once.  
Safety 
AE: Adverse event; D: Day; S: Spike; PPS: Per Protocol Set 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
Standard data derivation rules and statistical methods are described in section 6.2. 
Unless otherwise specified, analysis of safety endpoints will be performed on the 
Exposed Set. The primary analysis of the immunogenicity endpoints will be performed 
on the Per Protocol Set (PPS). 


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4.1.1. 
General Methodology 
Participants who prematurely withdrew from study will not be replaced.  
For a given participant and given immunogenicity measurement, missing or non-
evaluable measurements will neither be imputed nor be replaced, and therefore will not 
be included in immunogenicity analysis. 
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. Unless otherwise specified, summary table will be presented by treatment 
group for Part A and Part B separately (i.e. 10 µg, 10 µg placebo, 30 µg, 30 µg placebo, 
100 µg, 100 µg placebo, and pooled placebo for Part A safety analyses,  and 10 µg, 30 
µg, 100 µg, and pooled placebo for Part A immunogenicity analyses, and 3 µg, 10 µg, 
and placebo for Part B), and for combined part A & B with aggregated common groups 
(i.e. 3 µg, 10 µg, 30 µg, 100 µg, placebo). 
The exact confidence intervals around within-group proportions are derived using the 
method of Clopper and Pearson [Clopper, 1934]. 
4.1.2. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Safety and Reactogenicity 
4.2.1.1. 
Analysis of safety and reactogenicity planned in the protocol 
Solicited safety endpoints will be performed on the Solicited Safety Set. Unsolicited 
safety endpoints will be performed on the Exposed Set. Other adverse events/medically 
attended events, and safety lab data will be performed on the Exposed Set.   


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Primary Safety Endpoints 
Statistical Analysis Methods 
Solicited administration site events and systemic events 
during the 7-day follow-up period after study vaccine 
administration (day of study vaccine administration and 
6 subsequent days); 
Solicited AEs are prespecified as administration site and 
systemic. Solicited AEs are AEs with onset from Day 1 – 
Day 7 after the dosing and captured in eDiary.  
The number and percentage with exact 95% CI of 
participants reporting at least one solicited 
administration site event, with at least one solicited 
systemic event, and with any solicited AE during the 7-
day period (i.e. with onset from Day 1- Day 7 post 
vaccination) will be tabulated by treatment group. The 
same tabulations will be performed for Grade 3 AEs.  
The number and percentage with exact 95% CI of 
participants reporting each individual solicited 
administration site event (any grade, Grade 1, Grade 2, 
Grade 3, medically attended events) and solicited 
systemic event (any grade, Grade 1, Grade 2, Grade 3, 
medically attended events) during the 7-day follow-up 
period (i.e. with onset from Day 1- Day 7 post 
vaccination) will be tabulated by maximum intensity per 
participant for each treatment group. 
Unsolicited AEs during the 30-day follow-up period after 
study vaccine administration (day of study vaccine 
administration and 29 subsequent days); 
 
The number and percentage with exact 95% CI of 
participants reporting at least one unsolicited AE during 
the 30-day follow-up period (i.e. with onset from Day 1 
to Day 30 post vaccination), as classified by the Medical 
Dictionary for Regulatory Activities (MedDRA) System 
Organ Class (SOC) and Preferred Term (PT) will be 
tabulated by treatment group.  
The same tabulations will be performed for Grade 3, any 
causally related, Grade 3 causally related unsolicited 
AEs and unsolicited AEs with medically attended visits.  
In the AE summaries, a participant with 2 or more AEs 
within the same SOC or PT level but different 
relationship will be counted only once in the level using 
the related incident. 
Any hematological and biochemical laboratory 
abnormality during the 15-day follow-up period after 
study vaccine administration (day of study vaccine 
administration and 14 subsequent days); 
For each treatment group and for each Hematology and 
biochemistry parameter: 
• 
The number and percentage with exact 95% CI of 
participants having hematology and biochemistry 
results below, within, or above the laboratory 
normal ranges will be tabulated by time point. 
• 
The number and percentage of subjects reporting 
a grading increase from baseline at Day 8 and 


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Primary Safety Endpoints 
Statistical Analysis Methods 
Day 15 separately. The maximum grading post 
vaccination up to Day 15 (i.e. Day 1 – Day 15) will 
be tabulated versus baseline. Grades will be 
based on the FDA guidance for industry “Toxicity 
grading scale for healthy adults and adolescent 
volunteers enrolled in preventive vaccine clinical 
trials” (Protocol Section 10.2.2). 
• 
The listing of safety laboratory results will be 
provided 
MAAEs; SAEs; AESIs up to D31. 
The number and percentage with exact 95% CI of 
participants reporting MAAEs, SAEs, and AESIs after 
the dose up to Day 31 (i.e. with onset from Day 1 to Day 
30 post vaccination), as classified by the MedDRA SOC 
and PT, will be tabulated by treatment group. The same 
tabulation will be performed for causally related MAAEs, 
SAEs and AESIs during this period (i.e. with onset from 
Day 1 to Day 30 post vaccination).   
The detailed listings of SAEs, AESIs and COVID-19 
cases will also be produced. 
4.2.1.2. 
Additional considerations 
4.2.1.2.1. Analysis of solicited events 
The analysis of solicited events will be performed on Solicited Safety Set.  
Grading or actual temperature/redness and swelling will be captured in the eDiary as per 
a modified grading of symptoms based on the FDA toxicity grading guidance for industry 
[Food and Drug Administration , 2007] with Grades 3 and 4 combined and swelling 
evaluated using the actual measurement only.  Analysis by grade will use the maximum 
grade from Day 1 to Day 7 post vaccination. 
When solicited AE data entered by the participant are incorrect, data collected by study 
investigator/staff on eDiary Follow-up Assessment form in Subject Case Report Forms 
will be used in the summaries if available. 
The duration of solicited AEs of any grade will be summarized by treatment. The start 
date is the first day during the 7-day solicitation period with the symptom at grade > 0 
while the stop date is the last day with the symptom at grade > 0 in or beyond the 
solicited period. In addition, the duration for specific grade(s) for each symptom defined 
as the number of days in the report period (i.e. from Day 1 to Day 7) with grade above or 
equal to specific grade will be summarized by treatment. 
Duration in days of solicited administration site and systemic events will be listed. 
Prolonged solicited AEs that continue beyond Day 7 will be identified using a flag in 
listing of AEs. 


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The derivation rule of duration in days for solicited events is detailed in section 6.2.3.8. 
4.2.1.2.2. Analysis of unsolicited events 
The analysis of unsolicited events will be performed on Exposed Set. 
4.2.1.2.3. Combined solicited events and unsolicited events excluding serious 
AEs 
The combined analysis of solicited and unsolicited events will be performed on the 
Exposed Set. A listing of participants with all combined solicited and unsolicited adverse 
events will be provided.  
Solicited adverse events will be coded by MedDRA.  
For clintrial.gov posting purposes, a summary of combined solicited and unsolicited 
adverse events excluding serious AEs will be produced by System Organ Class and 
preferred terms and according to occurrence of each event. 
4.2.1.3. 
Adverse Events of Special Interest 
The analysis of adverse events of special interest will be performed on Exposed Set. 
For adverse events of special interest (AESI) collected up to study conclusion (M6), the 
following will be considered for the purpose of analyses:  
• pIMDs 
• Anaphylaxis or severe hypersensitivity reactions within 24 hours after study 
intervention administration 
• Pericarditis and myocarditis. 
• Virologically confirmed COVID-19 cases (Protocol Section 8.4.4.2.2) 
The summary of event characteristics will be provided for each AESI as well as any 
potential immune-mediated diseases (pIMDs), including number and percentage of 
participants with any event. In addition, summary will be provided by relationship to 
study intervention, maximum grade/severity, outcome, and the action taken. The worst-
case approach will be applied at participant level for the maximum grade/severity, i.e., a 
participant will only be counted once as the worst case from all the events experienced by 
the participant.  
The percentage of participants with at least 1 report of SAE (any, related, fatal and fatal 
related), and with at least 1 report of AESI respectively, classified by the MedDRA PT 
and SOC and reported from dosing up to study end and from D1 to D30 post-dose will be 
tabulated with exact 95% CI. 
In the AESI/SAE summaries, a participant with 2 or more AEs within the same SOC or 
PT level but different relationship will be counted only once in the level using the related 
incident.  


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4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Safety 
4.3.1.1. 
Analysis of safety and reactogenicity planned in the protocol 
The analysis of secondary safety endpoints will be performed on the Exposed Set. 
4.3.2. 
Immunogenicity 
4.3.2.1. 
Analysis of immunogenicity planned in the protocol 
The analysis of the secondary immunogenicity endpoints will be performed on the PPS. 
The descriptive summary will consist in the number of results available (N), standard 
deviation, median, interquartile, minimum, and maximum, GMT or GMR, and associated 
95% CIs. For the analysis of immunogenicity, missing or non-evaluable measurements 
will not be replaced. Therefore, a participant will be excluded from an analysis if all 
measurements are missing or non-evaluable. 
If more than 10% of participants with BA.5 immunogenicity data at Day 15 are 
eliminated from any of the PPS in any treatment group, a sensitivity analysis will be 
carried out using the Exposed Set. 
Secondary Safety Endpoints 
Statistical Analysis Methods 
MAAEs; SAEs; AESIs up to study conclusion (M6). 
The number and percentage with exact 95% CI of 
participants reporting MAAEs, SAEs, and AESIs after 
the dose up to study conclusion (Month 6), as 
classified by the MedDRA SOC and PT, will be 
tabulated by treatment group. The same tabulation will 
be performed for causally related MAAEs, SAEs and 
AESIs during this period.  The detailed listings of 
SAEs, AESIs and COVID-19 cases will also be 
produced. The number and percentage with exact 95% 
CI of participants reporting AEs/SAEs leading to 
withdrawal from the study will be tabulated. 


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Secondary Immunogenicity Endpoints 
Statistical Analysis Methods 
Neutralizing titer against pseudovirus bearing S protein 
from vaccine encoded SARS-CoV-2 and WT strains at 
each collection timepoint (D1, D15, D31, M6). 
Neutralizing titer (GMT) against pseudovirus bearing S 
protein from vaccine encoded SARS-CoV-2 and WT 
strains will be tabulated with 95% CI at baseline and 
each post vaccination visit by treatment. The 95% CI will 
be calculated based on the t-distribution of the log-
transformed value of GMT, then back-transformed to the 
original scale for presentation with the assumption that 
log-transformed concentration is normally distributed 
with variance specific to each treatment group.  
Bar charts (including 95% CIs) of GMT in log10 scale at 
each visit by treatment will be provided. 
At each post vaccination timepoint, the adjusted GMTs 
of neutralizing titer, with their 95% CI, will be obtained 
using an ANCOVA model on log10 transformed titers 
with treatment group as a fixed factor, and log10 
transformed Day 1 baseline value as a covariable.  
Once Part B data are available, Part A and Part B data 
will be pooled together for model based analyses. When 
pooled, the study part will be added as a fixed factor 
and adjusted GMT will be estimated under Part A 
condition. Groups common in Part A and Part B will be 
combined as one group respectively for the pooled 
analysis. Outputs will be displayed by 3 µg, 10 µg, 30 
µg, 100 µg, and pooled placebo.   
Listing of neutralizing titers sorted by treatment and 
participant number will be provided. 
GMR from baseline (D1) of neutralizing titer against 
pseudovirus bearing S protein from vaccine encoded 
SARS-CoV-2 and WT strains at each collection 
timepoint. 
GMR from baseline of neutralizing titer against 
pseudovirus bearing S protein from vaccine encoded 
SARS-CoV-2 and WT strains will be tabulated with 95% 
CI at each post vaccination visit by treatment. The 95% 
CI will be calculated based on the t-distribution of the 
log-transformed fold rise value for GMR, then back-
transformed to the original scale for presentation. 
Bar charts (including 95% CIs) of GMR in log2 scale at 
each post vaccination visit by treatment will be provided.  
At each post vaccination timepoint, the adjusted GMRs 
from baseline of neutralizing titer, with their 95% CI, will 
be obtained using an ANCOVA on log10 transformed 


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Secondary Immunogenicity Endpoints 
Statistical Analysis Methods 
titers with treatment group as a fixed factor, and log10 
transformed Day 1 baseline value as a covariable.  
Once Part B data are available, Part A and Part B data 
will be pooled together for model based analyses. When 
pooled, the study part will be added as a fixed factor 
and adjusted GMR will be estimated under Part A 
condition. Groups common in Part A and Part B will be 
combined as one group respectively for the pooled 
analysis. Outputs will be displayed by 3 µg, 10 µg, 30 
µg, 100 µg, and pooled placebo. 
In addition, the similar ANCOVA model for GMR from 
baseline will be performed to further evaluate the linear 
dose effect, using dose level as a continuous variable. 
Vaccine response rate based on neutralizing titers 
against vaccine encoded SARS-CoV-2 and WT strains 
at each collection timepoint. 
The number and percentage with exact 95% CI of 
participants with vaccine responses of at least a 2, 4, 
and 8 fold increases from Day 1 baseline, with their 
exact 95% CI will be tabulated by treatment and visit. 
 
The following SAS code will be used to calculate GMT/GMR from baseline, where 
LOGVAL is the log10 transformed GMT/GMR values at each post vaccination point, 
and Base is log10 transformed pre-dose GMT value. The analyses will be performed on 
PPS only.  
Proc sort data = study; by group step; run; /** group will be sorted with order of Placebo, 3, 10 , 30, 
100***/; 
proc MIXED data=study; 
class group (ref=‘Placebo’)  step (ref=‘1’); /**step=‘1’ indicates Part B,  base=log pre-vaccination titer**/; 
      model LOGVAL = BASE group step/ solution noint;  
      estimate  ‘Placebo’    base X    group 0 0 0 0 1 step 1 0/ cl; 
      estimate  '3’               base X    group 1 0 0 0 0 step 1 0/ cl; 
      estimate '10’              base X    group 0 1 0 0 0 step 1 0/ cl; 
      estimate '30’              base X    group 0 0 1 0 0 step 1 0/ cl; 
      estimate '100’            base X    group 0 0 0 1 0 step 1 0/ cl; 
  ods output estimates=estmrnalin;  
quit; 
where X is GMT at pre-dose across groups for Part A.  


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The following SAS code will be used to further evaluate the linear dose effect on GMR 
from baseline of neutralizing titer against pseudovirus bearing S protein from vaccine 
encoded SARS-CoV-2 and WT strains, where LOGVAL is the log10 transformed GMR 
values at each post vaccination point, and Base is log10 transformed pre-dose titer value. 
The analyses will be performed on PPS only.  
proc MIXED data=study;  
      class step (ref=‘1’); /**step=‘1’ indicates Part B, base=log pre-vaccination titer**/; 
      model LOGVAL = BASE dose step/ solution;  
      estimate    ‘Placebo’     intercept 1 base X  dose 0     step 1 0/ cl;  
      estimate    '3’                intercept 1 base X  dose 3     step 1 0/ cl;; 
      estimate   '10’               intercept 1 base X dose 10    step 1 0/ CL; 
      estimate   '30’               intercept 1 base X dose 30    step 1 0/ CL; 
      estimate  '100’              intercept 1 base X dose 100  step 1 0/ CL; 
      ods output estimates=estmrnalin;  
    quit; 
where X is GMT at pre-dose across groups for Part A.  
Geometric mean ratios (GMRs) will be computed at each sampling timepoint after dosing 
versus baseline (D1). The GMRs and 95% Cis will be constructed by exponentiating 
(base 10) the means of within-participant differences between log-transformed titers after 
each sampling timepoint and log-transformed titers at baseline. GMR will be calculated 
only for participants with valid baseline immunogenicity results. 
4.3.2.2. 
Additional considerations  
NA. 
4.4. 
Tertiary Endpoint(s) Analyses 
The analysis will be based on the PPS. 
4.4.1. 
Analysis of Serum-Binding Antibody (IgG) 
If more than 10% of participants are eliminated from any of the PPS in any treatment 
group, a sensitivity analysis will be carried out using the Exposed Set. 
4.4.1.1. 
GMCs and GMR from baseline of binding IgG Ab against SARS-CoV-2 
Spike WT (D614), SARS-CoV-2 Spike BA.5, SARS-CoV-2 Spike D614G, 
SARS-CoV-2 Spike (B.1.617.2, AY.4),  SARS-CoV-2 Spike (B.1.1.529, 
BA.1, BA.1.15), SARS-CoV-2 Spike BQ.1, SARS-CoV-2 Spike XBB.1, 
SARS-CoV-2 Spike BA.2.275, SARS-CoV-2 Spike XBB.1.5, SARS-CoV-2 
Spike XBB.1.16 variants at each collection timepoint 
The descriptive summary will consist in the number of results available (N), standard 
deviation, median, interquartile, minimum, and maximum, GMC/GMR, and associated 
95% CIs.  


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Immunogenicity of the study vaccine will be assessed through GMCs with associated CI 
at each collection time point before the vaccination (Day 1) and after the vaccination 
(Day 15, Day 31, M6). Likewise GMRs from baseline, percentage above Lower Limit of 
Quantitation (LLOQ), and corresponding 95% CI will be reported.  The corresponding 
bar charts for GMC and GMR will be provided in log scale (log10 will be used for GMC 
while log2 will be used for GMR).  For these analyses, CI for GMC and GMR will be 
derived from a student distribution assuming that log-transformed concentration is 
normally distributed with variance specific to each treatment group.  
Distribution of geometric mean concentration fold changes from baseline for at least 2, 4, 
and 8 folds, with their exact 95% CI will be tabulated, by study group and visit.  
The GMC at each post dose time point, the GMR from baseline, and the 95% CIs in all 
treatment groups will also be analysed using an ANCOVA model on log10 transformed 
concentrations with treatment group as fixed in the model, and log10 transformed Day 1 
baseline value as covariable.  
Once Part B data are available, Part A and Part B data will be pooled together for model 
based analyses. When pooled, the study part will be added as a fixed factor and adjusted 
GMC or GMR from baseline will be estimated under Part A condition. Groups common 
in Part A and Part B will be combined as one group respectively for the pooled analysis. 
Output will be displayed by 3 µg, 10 µg, 30 µg, 100 µg, and pooled placebo.   
4.4.1.2. 
Seroresponse rates, based on binding IgG Ab concentrations against 
SARS-CoV-2 Spike WT (D614), SARS-CoV-2 Spike BA.5, SARS-CoV-2 
Spike D614G, SARS-CoV-2 Spike (B.1.617.2, AY.4),  SARS-CoV-2 Spike 
(B.1.1.529, BA.1, BA.1.15), SARS-CoV-2 Spike BQ.1, SARS-CoV-2 Spike 
XBB.1, SARS-CoV-2 Spike BA.2.275, SARS-CoV-2 Spike XBB.1.5, 
SARS-CoV-2 Spike XBB.1.16 variants.  
IgG seroresponse rate is defined as the percentage of participants who have either a 
baseline concentration < LLOQ and a post-dose concentration ≥4*LLOQ or a baseline 
concentration ≥LLOQ and at least a 4-fold increase from baseline to post-dose 
concentration. 
The percentage of participants with IgG seroresponse of serum SARS-CoV-2 Spike WT, 
SARS-CoV-2 Spike BA.5, SARS-CoV-2 Spike D614G, SARS-CoV-2 Spike (B.1.617.2, 
AY.4),  SARS-CoV-2 Spike (B.1.1.529, BA.1, BA.1.15), SARS-CoV-2 Spike BQ.1, 
SARS-CoV-2 Spike XBB.1, SARS-CoV-2 Spike BA.2.275, SARS-CoV-2 Spike 
XBB.1.5, SARS-CoV-2 Spike XBB.1.16 variants specific binding IgG from baseline at 
day 15, Day 31, M6 will be tabulated by study group with 2-sided 95% exact CIs. 
4.4.2. 
Analysis of Cell-Mediated Immune Response   
CMI Analysis will be performed using the Intracellular Cytokine Staining assay for 
WT(D614) and BA5 variants. 


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Descriptive statistics at each timepoint (Day 1, Day 15, Day 31, and M6) and change 
from baseline will be provided by treatment group for: 
1. SARS-COV-2 spike-specific polypositive CD4+ T cell responses (frequency per 
million CD4) expressing at least 2 different markers with at least one cytokine, 
among CD40 Ligand (CD40L), 41-BB, IL-2, TNF- α, IFN- γ, IL-13 and IL-17 upon 
in vitro stimulation 
2. SARS-COV-2 spike-specific polypositive CD8+ T cell responses (frequency per 
million CD8) expressing at least 2 different markers with at least one cytokine, 
among CD40 Ligand (CD40L), 41-BB, IL-2, TNF- α, IFN- γ, IL-13 and IL-17 upon 
in vitro stimulation. 
Descriptive statistics of  
1. CD4 T helper profile expressing at least IFN- γ (Th1);  
2. CD4 T helper profile expressing at least IL-13 (Th2);  
3. CD4 T helper profile expressing at least IL-17 (Th17)  
at each timepoint (Day 1, Day 15, Day 31, and M6) will be provided by treatment group.  
The descriptive summary will consist in the number of results available (N), standard 
deviation, median, interquartile, minimum, and maximum, GMF and associated 95% CIs.  
The 95% CI will be calculated based on the t-distribution of the log-transformed values, 
then back-transformed to the original scale for presentation.  
For polypositive CD4+ T cell and CD8+ T cell frequencies, geometric mean of frequency 
fold rise from baseline (GMFR) with 95% CI as well as the frequency of cells above 
LLOQ will also be provided. For the GMF and GMFR computation, titer below the 
LLOQ will be assigned the LLOQ value.  
Bar Charts of each cell-mediated response for cytokines by treatment group and 
timepoint will also be produced on log10 transformed scale for GMF and log2 
transformed scale for GMFR, including fold rise from baseline for polypositive CD4+ T 
cell and CD8+ T cell frequencies. 
Supporting listing of CMI parameters will be sorted by treatment group and participant 
number. 
As the frequency of CD4 (or CD8) by in vitro stimulation is separated for different 
antigen peptides or spikes, the frequency of antigen specific CD4 (or CD8) T cells for 
each individual participant will be calculated as follows: 
1. For each antigen peptides or spikes, the difference between the frequency of CD4 (or 
CD8), upon in vitro stimulation with the antigen peptides or spikes (induction 
condition), and the frequency of CD4 (or CD8), upon in vitro stimulation in medium 
only (background condition) will be computed. Differences less or equal to one (1) 


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per 106 CD4 (or CD8) T cells will be imputed to 1 antigen specific CD4 (or CD8) T 
cell per 106 CD4 (or CD8) T cells. 
2. The frequency associated to an antigen will then be obtained by summing the 
frequency of associated peptides or spikes as applicable: 
− for Wuhan antigen, S1 WU and S2 WU-SA frequencies will be added. 
− for Omicron, P1 Omicron and P2 Omicron frequencies will be added. 
The imputation to LLOQ will be done on the frequency sum. 
4.4.3. 
Incidence of confirmed symptomatic and asymptomatic SARS-
CoV-2 infection 
The percentage of participants of laboratory-confirmed SARS-CoV-2 by N protein 
seroconversion at either (D15, D31, and M6) or RT-PCR at either (D8, D15) will be 
summarized by treatment. 
Percentage of laboratory-confirmed (RT-PCR) SARS-CoV-2 infection reported as AESI 
post-vaccination will be summarized by treatment. 
Percentage of laboratory-confirmed (RT-PCR) SARS-CoV-2 infection reported as AESI 
or SARS-CoV-2 detected by N-protein and R-PCR post-vaccination will be summarized 
by treatment. 
4.4.4. 
Other Tertiary Endpoints 
Genetic sequence of SARS-CoV-2 variant S protein in confirmed (RT-PCR) SARS-CoV-
2 positive participants will not be reported. 
4.5. 
Analysis Interpretation 
All analyses are descriptive.  
4.6. 
Other Safety Analysis 
4.6.1. 
COVID-19 Assessment and COVID-19 AEs 
A participant with an AE of SARS-CoV-2 infection can be categorized as 
“Asymptomatic SARS-CoV-2 infection”, “COVID-19” or “Severe COVID-19” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment electronic 
Case Report Form (eCRF).  
Any case of “COVID-19” or “Severe COVID-19”  is an AESI; and will be captured and 
described.  
The listing of participants with any category of  SARS-CoV-2 infection will be provided 
based on the Exposed Set. 
The listing of participants who had a COVID-19 test performed with their results will be 
provided on the Exposed Set. 


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4.7. 
Other Analysis 
4.7.1. 
Subgroup analyses 
N/A. 
4.8. 
Interim Analyses 
No interim analysis requiring statistical adjustment will be performed. Immunogenicity 
analysis will be performed on PPS, while safety analyses will be performed on Solicited 
Set for solicited AEs, Exposed Set for lab and unsolicited AEs. However, analyses to 
evaluate objectives and endpoints will be performed in steps. The sequence of analyses is 
described below. 
4.8.1. 
Sequence of analyses 
• 
In preparation of the safety review during the dose-escalation safety lead-in, analyses 
of available safety data will be performed. 
• 
Day 15 interim analysis for each group in Part A of the study will include all the 
data (Day 1 and Day 15) pertaining to primary and secondary safety endpoints; 
humoral immunogenicity endpoints (including at least neutralizing titer against 
pseudovirus bearing S protein from vaccine encoded SARS-COV-2 endpoints). This 
analysis will be performed when all data of each study group up to Day 15 (i.e., data 
that are as clean as possible) are available. 
− Results of this analysis will be presented in a Day 15 statistical analysis report. 
− This analysis will be performed by independent unblinded statistician who will 
be unblinded for this analysis, who will generate a statistical report by treatment 
group but no individual listings. 
− GSK restricted unblinded team will have access to the unblinded individual data.   
−  The investigators and study participants will stay blinded (i.e., will not have 
access to the individual participant treatment assignment) until EoS. 
− For subsequent analyses the GSK statistical team will be unblinded to individual 
participants. 
− A similar to Part A Day 15 interim analysis for each group in Part B of the study 
may be conducted separately or incorporated into a Day 31 interim analysis. 
• 
Day 31 interim analysis for each group in Part A of the study will include all the 
data (Day 1, Day 15, and Day 31) pertaining to primary and secondary safety 
endpoints; humoral immunogenicity endpoints (including at least neutralizing titer 
against pseudovirus bearing S protein from vaccine encoded SARS-COV-2 
endpoints). This analysis will be performed when all data of each study group up to 
Day 31 (i.e., data that are as clean as possible) are available. 
− 
Results of this analysis will be presented in a Day 31 statistical analysis report. 


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− 
The investigators and study participants will stay blinded (i.e., will not have 
access to the individual participant treatment assignment) until EoS. 
• 
A similar to Part A Day 31 interim analysis for each group in Part B of the study 
may be conducted separately or incorporated into the final analysis.  
• 
The final analysis will include all data from Part A and B pertaining to primary and 
secondary safety and immunogenicity endpoints, and any available tertiary 
endpoint(s). This analysis will be performed at the EoS when all data up to study 
conclusion (Month 6) are available, this includes Day 1, Day 15, Day 31, and Month 
6, as all the data analyzed in the Day 15 and Day 31 analyses will be included in the 
final analysis as well. 
The final study report will contain at least the final analyses of all primary and secondary 
endpoints, including individual listings. 
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/ analyses will be performed. These analyses will be documented in annex(es) to 
the study report. 
4.9. 
Changes to Protocol Defined Analyses 
Because RT-PCR at screening and Day 1 do not contribute to the incidence of SARS-
CoV-2 infection they have been removed from the SARS-CoV-2 infection endpoint and 
summary. 
5. 
SAMPLE SIZE DETERMINATION 
The sample size is based on clinical considerations to inform dose regimen decisions for 
continued clinical development. 
With 18 participants receiving mRNA-CR-04 vaccine in each group, there is a 60.3% 
probability to observe at least one participant with an AE if the incidence rate is 5% and 
85% probability to observe at least one participant with an AE if the incidence rate is 
10%. 
With 16 participants receiving mRNA-CR-04 vaccine in each group (PPS for 
immunogenicity, 10% unevaluable), and a standard deviation of 0.45 for log10 
transformed increase from Day 1, the ratio of the upper limit of a 2-sided 95% CI and the 
point estimate of GMR is 1.74. 


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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
6.1.1. 
Participant Disposition 
Participant disposition will be summarized by treatment and overall using descriptive 
statistics: 
• 
Number of participants screened, randomised, vaccinated including withdrawal 
reasons will be tabulated. 
Withdrawal status will be summarized using descriptive statistics: 
• 
The number of participants exposed as well as the number of participants excluded 
from PPS analyses will be tabulated at D15, D31, and M6.  
• 
The numbers of withdrawn participants will be tabulated according to the reason for 
withdrawal. 
6.1.2. 
Demographic and Baseline Characteristics 
6.1.2.1. 
Analysis of demographics/baseline characteristics  
These analyses will be performed on the Exposed set and PP set at Day 15, Day 31. 
The demographic characteristics including height, weight, body mass index (BMI), age at 
screening in years, sex, race, ethnicity, and N protein) will be summarized by treatment 
using descriptive statistics.  
• 
Frequency tables will be generated for categorical variable such as sex, race and 
ethnicity. 
• 
Mean, median, standard error and range will be provided for continuous data such as 
age, height, weight and BMI. 
The distribution of participants will be tabulated as a whole and per treatment group. 
6.1.2.2. 
Additional considerations 
• 
Demographic characteristics will also be summarized on Enrolled Set for web public 
disclosure for Part A and Part B separately. 
• 
The listing of past medical history and current medical conditions will be provided 
on the Exposed Set by Medical Dictionary for Regulatory Activities (MedDRA) term 
for Part A and Part B separately. Un-coded medical conditions or medical history 
will be listed under ‘Other’ category. 
• 
Vaccination history will be coded using WHODRUG dictionary. The listing of 
vaccination history will be provided on the Exposed Set for Part A and Part B 
separately. 


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6.1.3. 
Protocol Deviations 
Important protocol deviations will be listed based on the Exposed Set for Part A and Part 
B separately.  
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to freezing the database to ensure all important 
deviations captured and categorised in the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 
• 
A listing of protocol deviations will be provided. 
Protocol deviations which result in exclusion from the analysis set will also be listed.  
• 
Data will be reviewed prior to freezing the database to ensure all deviations leading 
to analysis population exclusions are captured and categorised in the protocol 
deviations ADaM dataset (note these exclusions are not captured in the SDTM 
dataset). 
In addition to the overall listing of important protocol deviations, separate listings will be 
produced for important protocol deviations related to COVID-19, and important protocol 
deviations not related to COVID-19 respectively if deemed necessary. 
An individual listing of important protocol deviations leading to elimination will be 
provided. 
6.1.4. 
Concomitant Medications 
Concomitant medications and vaccinations will be coded using the WHODRUG 
dictionary.  
The listing of participants taking concomitant medications /vaccinations within 7 days 
following study intervention administration, and 30 days following study intervention 
administration will be provided for Part A and Part B separately. 
The antipyretic classification is derived from the following ATC code: 
ATC Code 
A03D, A03DA, A03DB, A03DC, A03EA  
M01, M01A, M01AA, M01AC, M01AE, M01AG, M01AB, M01AH, M01AX, M03B, M03BA, M03BB, M03BC, M03BX  
N02BG, N02AC, N02AG, N02AX, N02B, N02BA, N02BB, N02BE, N02AA 
R05, R05D, R05X 
The number and percentage with exact 95% CI of participants reporting concomitant 
medication coded using the WHODRUG dictionary (any medication or any antipyretic) 
during the 7-day follow-up period (i.e. from Day 1 – Day 7) and during the 30-day 


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follow-up (i.e. from Day 1- Day 30) will be summarized by treatment group for Part A 
and Part B separately.  
The analysis will be performed on the Exposed Set. 
6.1.5. 
Additional Analyses Due to the COVID-19 Pandemic 
Depending on how the Covid-19 situation evolves, the SAP might be amended to reflect 
the analysis corresponding to Covid-19. 
6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1 
6.2.2. 
Handling of missing data 
6.2.2.1. 
Dates 
Partial dates will be displayed as captured in participant listing displays.  
When partially completed dates (i.e. with missing day or month) are used in calculations, 
the following standard rules will be applied: 
• 
A missing day will be replaced by 15; 
• 
A missing day and month will be replaced by June 30th; 
• 
For stop date, the maximum between the start and imputed stop date by above rule 
will be used instead. 
The following exceptions apply: 
• 
Adverse events start dates on the same day as the vaccination but with missing time: 
− Onset day will be day 1.   
• 
Adverse event start dates with missing day: 
− If the event starts in the same month as the study intervention administration, 
then the imputed start date will match the study dose given during that month.  
• 
Adverse event start dates with missing day and month: 
− If the event starts in the same year as the study intervention administration, the 
imputed start date will match the study dose given during that year.  


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• 
Adverse event end dates with missing day: 
− If the event ends in the same month and year as the end of study date (if it exists) 
then the imputed end date will match the end of study date; 
− Otherwise, day will be imputed to the last day of the month. 
• 
Adverse event end dates with missing day and missing month: 
− If the event ends in the same year as the end of study date (if it exists) then the 
imputed end date will match the end of study date 
− Otherwise, day and month will be imputed to the last day and month of the year 
i.e. 31st DEC 
All other cases of incomplete AE or concomitant medication/vaccination start date will 
follow the standard rules above. 
6.2.2.2. 
Laboratory data 
Missing laboratory results (including immunological data) will not be replaced. 
Missing laboratory results (including immunological data) will not be replaced.  
Haematology/chemistry laboratory data requiring grading as per the protocol toxicity 
grading scale, which is based upon the FDA Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, may have 
more decimals than expected or may require conversion to the unit associated to the 
grade, leading to more decimals than expected. 
In order to determine the grading the following rule will be used: 
1. In case a conversion is needed, the original results will be used for the conversion 
without a previous rounding. 
2. In case an approximation is needed to determine the grading, the result (or the result 
divided by the upper limit of the normal range (ULN), depending on the test) 
expressed in the expected unit will be rounded to the number of decimals used for 
the grading. 


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Table 6 
Toxicity grading scales for biochemistry parameters evaluated in the 
current study* 
Serum ** 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially life 
threatening 
(Grade 4)*** 
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  
ALP – increase by 
factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
> 10 x ULN 
Bilirubin – when liver 
function test is normal; 
increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
Bilirubin – when 
accompanied 
by any increase in liver 
function test 
increase by factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
> 1.75 x ULN 
ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea 
nitrogen; ULN: upper limit of normal. 
* Toxicity grading taken from FDA guidance for industry: Toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials [Food and Drug Administration , 2007]. 
** 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. 


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Table 7 
Toxicity grading scales for hematology parameters evaluated in the 
current study* 
Hematology** 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially life-
threatening 
(Grade 4) 
Hemoglobin (Female) - 
gm/dL  
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from baseline value 
- gm/dL  
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL  
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) 
change from baseline value 
– gm/dL  
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm
3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
> 25,000 
WBC Decrease - cell/mm
3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes decrease - 
cell/mm
3 
750 – 1 000 
500 – 749 
250 – 499 
< 250 
Neutrophils decrease - 
cell/mm
3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm
3 
650 – 1 500 
1,501 – 5,000 
> 5,000 
Hypereosinophilic 
Platelets decreased - 
cell/mm
3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
< 25,000 
Prothrombin Time – 
increase by factor 
1.03 – 1.10 x ULN  
1.11 – 1.20 x ULN  
1.21 – 1.25 x 
ULN 
>1.25 x ULN  
ULN: Upper limit of the normal range; WBC: White blood cell. 
* Toxicity grading taken from FDA guidance for industry: toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials [Food and Drug Administration , 2007]. 
** 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. 
6.2.2.3. 
Daily recording of solicited events 
6.2.2.3.1. Studies with electronic diaries 
For studies using electronic diaries for the collection of solicited events, a solicited event 
will be considered present only when a daily recording of grade 1 or more is present. 
6.2.2.4. 
Unsolicited adverse events 
Unsolicited AE summaries are including SAEs unless specified otherwise.  
Missing severity, relationship with study intervention, and outcome of unsolicited AEs 
will not be replaced and will appear as ‘UNKNOWN’ when displayed in a statistical 
output. 


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6.2.3. 
Data derivation 
6.2.3.1. 
Weight 
Weight will be presented in kilograms. Weights reported in pounds will be converted as 
follows: 
Weight in kilograms = Weight in pounds / 2.2 
6.2.3.2. 
Height 
Height will be presented in centimeters. Heights reported in feet and inches will be 
converted as follows: 
Height in centimeters = Height in inches x 2.54 
6.2.3.3. 
Body mass index (BMI) 
BMI will be calculated as follows: 
BMI = (Weight in kilograms) / (Height in meters)2 
6.2.3.4. 
Temperature 
Temperatures will be presented in degrees Celsius (°C). Temperatures reported in degrees 
Fahrenheit (°F) will be converted as follows: 
Temperature (Celsius) = ((Temperature (Fahrenheit) - 32) x 5)/9 
6.2.3.5. 
Numerical serology results 
Numerical serology results will be derived from the content of IS.ISORRES in the SDTM 
dataset. For assays with a specific cut-off, the following derivation rules apply: 
IS.ISORRES 
Derived value 
“NEG”, “-“, or “(-)” 
cut-off/2 
“POS”, “+”, or “(+)” 
cut-off 
“< value” and value is <= assay cut-off* 
cut-off/2 
“< value” and value is > assay cut-off 
value 
“> value” and value is < assay cut-off 
cut-off/2 
“> value” and value is >= assay cut-off 
value 
“value” and value is < cut-off 
cut-off/2 
“value” and value is >= cut-off 
value 
All other cases 
missing 
* Lower limit of quantitation (LLOQ) 


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LLOQs for different assays 
Antigen 
Assay and assay unit 
LLOQ 
SARS-CoV-2 Spike BA.5 
PNA (NT50) 
10 
SARS-CoV-2 Spike D614G 
PNA (NT50) 
10 
SARS-CoV-2 Spike Wuhan (D614) 
IgG (AU/mL) 
360 
SARS-CoV-2 Spike D614G 
IgG (AU/mL) 
410 
SARS-CoV-2 Spike XBB.1 
IgG (AU/mL) 
120 
SARS-CoV-2 Spike B.1.617.2 (Delta) 
IgG (AU/mL) 
790 
SARS-CoV-2 Spike XBB.1.5 
IgG (AU/mL) 
230 
SARS-CoV-2 Spike BA.2.75 
IgG (AU/mL) 
200 
SARS-CoV-2 Spike XBB.1.16 
IgG (AU/mL) 
170 
SARS-CoV-2 Spike B.1.1.529 (BA.1) 
IgG (AU/mL) 
150 
SARS-CoV-2 Spike BQ.1 
IgG (AU/mL) 
170 
SARS-CoV-2 Spike BA.5 
IgG (AU/mL) 
220 
SARS-CoV-2 Spike Wuhan (D614) 
Polypositive CD4+ T (10E6 cells) 
590 
SARS-CoV-2 Spike Wuhan (D614) 
Polypositive CD8+ T (10E6 cells) 
590 
SARS-CoV-2 Spike Wuhan (D614) 
CD4+ expressing at least IFN- γ (10E6 cells) 
N/A 
SARS-CoV-2 Spike Wuhan (D614) 
CD4+ expressing at least IL-13 (10E6 cells) 
N/A 
SARS-CoV-2 Spike Wuhan (D614) 
CD4+ expressing at least IL-17 (10E6 cells) 
N/A 
SARS-CoV-2 Spike BA.5 
Polypositive CD4+ T (10E6 cells) 
590 
SARS-CoV-2 Spike BA.5 
Polypositive CD8+ T (10E6 cells) 
590 
SARS-CoV-2 Spike BA.5 
CD4+ expressing at least IFN- γ (10E6 cells) 
N/A 
SARS-CoV-2 Spike BA.5 
CD4+ expressing at least IL-13 (10E6 cells) 
N/A 
SARS-CoV-2 Spike BA.5 
CD4+ expressing at least IL-17 (10E6 cells) 
N/A 
6.2.3.6. 
Geometric mean titres (GMTs) and GMCs 
Geometric Mean Titre (GMT) or GMC calculations are performed by taking the inverse 
logarithm of the mean of the log titre or concentration transformations. Non quantifiable 
antibody titres or concentrations will be converted as described in Section 6.2.3.5 for the 
purpose of GMT/GMC calculation. The cut-off value is defined by the laboratory before 
the analysis. If not otherwise specified, the cut-off refers to the LLOQ. 
6.2.3.7. 
Onset day 
The definition of onset day for an event (e.g. AE, concomitant medication/vaccination) is 
the number of days between the last study dose and the start date of the event. This is 1 
for an event occurring on the same day as a study dose (and reported as starting after 
study dose). 
6.2.3.8. 
Duration of events 
The duration of an event with a start and end date will be the difference between the start 
and end date plus one day, i.e. an event that starts on 03MAR2018 and ends on 
12MAR2018 has a duration of 10 days. 


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6.2.3.9. 
Counting rules for combining solicited and unsolicited adverse events 
For output combining solicited and unsolicited AEs, all SAEs might have to be 
considered general events since the administration site flag is not included in the 
expedited adverse event CRF pages. 
Multiple events with the same preferred term which start on the same day are counted as 
only one occurrence. 
6.2.3.10. 
Counting rules for occurrences of solicited events 
When the occurrences of solicited events are summarized, each event recorded as having 
occurred during a specific period will be counted as only one occurrence regardless of the 
number of days on which it occurs.  
6.2.3.11. 
AESIs 
GSK MedDRA queries will be used to identify AESI: 
• 
PIMD: refer to Table 12 from the protocol  
• 
Severe hypersensitivity (including anaphylaxis): Grade 3 unsolicited AEs under 
MedDRA SMQ hypersensitivity, narrow search (includes anaphylaxis), with an 
onset within 24 hours after dosing  
• 
Myocarditis/Pericarditis. In addition to identification based on the medical and 
scientific judgement of the investigator, the following list of MedDRA SMQs will be 
used: Cardiac arrhythmia, Cardiac failure, Cardiomyopathy, Ischaemic heart disease, 
Non-infectious myocarditis/ pericarditis, narrow search.  
• 
Virologically confirmed COVID-19 cases: In addition to identification based on the 
medical and scientific judgement of the investigator, AEs under MedDRA SMQ 
COVID-19, narrow search will be used 
This PIMD, Virologically confirmed COVID- 19 cases, Myocarditis and Pericarditis 
queries may be revised based on MedDRA dictionary. 
AESI summaries will include AE identified by either the investigator or the MedDRA 
queries. 
6.2.4. 
Display of decimals 
6.2.4.1. 
Percentages 
Percentages will be displayed with one decimal except for 100% in which case no 
decimal will be displayed.  


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6.2.4.2. 
Differences in percentages 
Differences in percentages and their corresponding confidence limits will be displayed 
with one more decimal than the maximum number used to display the individual 
percentages, for example the difference between two percentages displayed with one 
decimal will be displayed with two decimals. 
6.2.4.3. 
Demographic/baseline characteristics statistics 
The mean, median, and SD for continuous baseline characteristics (height, weight, BMI, 
pre-dose body temperature) will be presented with one decimal. 
The minimum and maximum values and quartile values (if required) will be presented 
with the same number of decimals as the observed values.  
The minimum and maximum of transformed height variables will be displayed with no 
decimals. 
The minimum and maximum of transformed weight variables will be displayed with no 
decimals with the exception of values are below 10kg where one decimal will be 
displayed. 
The maximum and minima of transformed body temperatures will be displayed with one 
decimal. 
6.2.4.4. 
Serological summary statistics 
The number of decimals used when displaying GMTs or GMCs and their confidence 
limits is shown in the following table: 
GMT or GMC value 
Number of decimals to display 
<0.1 
3 
>=0.1 and <10 
2 
>=10 and <1000 
1 
>=1000 
0 
When multiple categories of GMT or GMC values are present in the same table, the 
number of decimals displayed should match that of the smallest category (i.e. the one 
with the higher number of decimals). For example, if GMT or GMC values of <0.1 
appear in the same table as values of >=0.1 and <10, 3 decimals should be displayed for 
both. 
GMT or GMC ratios and their confidence limits will be displayed with 2 decimals 
regardless of the actual values. 
6.2.5. 
Statistical methodology 
6.2.5.1. 
Exact confidence intervals around proportions 
The exact CIs around within-group proportions are derived using the method of Clopper 
and Pearson [Clopper, 1934]. 


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7. 
REFERENCES 
Clopper CJ, Pearson E. The Use of Confidence or Fiducial Limits Illustrated in the case 
of the Binomial. Biometrika. 1934;26:404-13. 
Food and Drug Administration (FDA). Guidance for Industry. Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
September, 2007. Accessed 07 April 2023. https://www.fda.gov/media/73679/download