A Phase 1, Open-label, Safety, Reactogenicity, and Immunogenicity Trial of the CV2CoV mRNA Vaccine Against SARS CoV 2 in Seropositive Adult Participants
Phase: PHASE1
Conditions: COVID-19, SARS-CoV-2
Sponsor: GlaxoSmithKline

Protocol Amendment 2
Study ID:  217741
Official Title of Study: A Phase 1, Open-label, Safety, Reactogenicity, and 
Immunogenicity Trial of the CV2CoV mRNA Vaccine Against SARS-CoV-2 in 
Seropositive Adult Participants
NCT number: NCT05260437
Date of Document: 14-Jun-2022

CLINICAL STUDY PROTOCOL 
 
A Phase 1, Open-label, Safety, Reactogenicity, and Immunogenicity Trial of 
the CV2CoV mRNA Vaccine Against SARS-CoV-2 in Seropositive Adult 
Participants 
 
PROTOCOL 217741 (CV2 SARS-COV2-002 BST) 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
Sponsor Contact: 
, MD, MPH 
Clinical Epidemiology Project Lead 
GSK Rockville Center for Vaccines Research 
14200 Shady Grove Road 
Rockville, MD 20850 
Telephone: 
 
 
 
PPD Safety Hotline: 
+1-800-201-8725 
 
 
Protocol Number: 
217741 
Abbreviated Title: 
CV2 SARS-COV2-002 BST 
Amendment Number:  
Amendment 2 
Date of Amendment 2 
13 Jun 2022 
Date of Amendment 1:  
20 Apr 2022 
Date of Original Protocol:  
11 Feb 2022 
Compound Name: 
CV2CoV mRNA vaccine 
Study Phase: 
1 
IND Number: 
27859 
EudraCT Number 
2021-003093-31 
 
 
PPD
PPD

CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by GSK Biologicals 
SA. The concepts and information contained in this document or generated during the 
study are considered proprietary and may not be disclosed in whole or in part without the 
express written consent of GSK Biologicals SA. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R2): Good Clinical Practice.  
 

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential 
Protocol Approval – Sponsor Signatory 
Study Title: 
A Phase 1, Open-label, Safety, Reactogenicity, and Immunogenicity 
Trial of the CV2CoV mRNA Vaccine Against SARS-CoV-2 in 
Seropositive Adult Participants 
Protocol Number: 
217741 
Abbreviated Title: CV2 SARS-COV2-002 BST 
Protocol Date and 
Version: 
13 Jun 2022; Amendment 2 
IND Number: 
27859 
EudraCT Number 2021-003093-31 
Protocol accepted and approved by: 
Clinical Epidemiology Project Lead 
Roshan Ramanathan, MD, MPH 
GSK Rockville Center for Vaccines Research 
14200 Shady Grove Road 
Rockville, MD 20850, United States 
Date 
14 Jun 2022
Page 3
PPD

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Declaration of Investigator 
I have read and understood all sections of the protocol titled “A Phase 1, Open-label, Safety, 
Reactogenicity, and Immunogenicity Trial of the CV2CoV mRNA Vaccine Against 
SARS-CoV-2 in Seropositive Adult Participants” and the accompanying IB. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Protocol Amendment 2 dated 13 Jun 2022, the International Council for 
Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with GSK Biologicals SA or PPD or implement protocol changes without independent ethics 
committee approval except to eliminate an immediate risk to participants. I agree to 
administer study vaccine only to participants under my personal supervision or the 
supervision of a subinvestigator. 
I will not supply the study vaccine to any person not authorized to receive it. Confidentiality 
will be protected. Participant identity will not be disclosed to third parties or appear in any 
study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from GSK Biologicals SA. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
Page 4

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Table of Contents 
CLINICAL STUDY PROTOCOL ..................................................................................... 1 
Table of Contents ............................................................................................................... 5 
List of Tables ...................................................................................................................... 9 
List of Figures .................................................................................................................... 9 
List of Abbreviations........................................................................................................ 10 
Protocol Amendment Summary of Changes .................................................................... 12 
Protocol Synopsis............................................................................................................. 15 
1 
Introduction .............................................................................................................. 20 
1.1 
Background Information ................................................................................. 20 
1.2 
Risk/Benefit Considerations ........................................................................... 21 
2 
Study Objectives and Endpoints............................................................................... 24 
3 
Investigational Plan .................................................................................................. 26 
3.1 
Study Design ................................................................................................... 26 
3.2 
Rationale for Study Design ............................................................................. 29 
4 
Participant Selection and Withdrawal Criteria ......................................................... 32 
4.1 
Selection of Study Participants ....................................................................... 32 
4.1.1 
Inclusion Criteria ............................................................................. 32 
4.1.2 
Exclusion Criteria ............................................................................ 33 
4.1.3 
Screen Failures ................................................................................. 36 
4.2 
Discontinuation From Study Vaccine and/or Withdrawal From the Study ..... 37 
4.2.1 
Discontinuation From Study Vaccine .............................................. 38 
4.2.2 
Withdrawal From the Study ............................................................. 38 
4.2.3 
Lost to Follow-Up ............................................................................ 38 
4.2.4 
Replacements ................................................................................... 38 
5 
Study Vaccines ......................................................................................................... 40 
5.1 
Method of Assigning Participants to Study Vaccine Groups .......................... 40 
5.2 
Study Vaccines Administered ......................................................................... 40 
5.3 
Identity of Investigational Product.................................................................. 40 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
5.4 
Management of Clinical Supplies ................................................................... 42 
5.4.1 
Investigational Product Packaging and Storage............................... 42 
5.4.2 
Investigational Product Accountability ............................................ 42 
5.4.3 
Other Supplies ................................................................................. 42 
5.5 
Overdose Management ................................................................................... 43 
5.6 
Blinding .......................................................................................................... 43 
5.7 
Compliance With Study Vaccine .................................................................... 43 
5.8 
Prior, Concomitant, and Rescue Medications, Vaccines, and Therapies ........ 44 
5.8.1 
Prior and Concomitant Medications ................................................ 44 
5.8.2 
Allowed Concomitant Therapy ........................................................ 44 
5.8.3 
Rescue Medicine .............................................................................. 45 
5.9 
Study Holding Rules ....................................................................................... 45 
6 
Study Assessments and Procedures .......................................................................... 48 
6.1 
Safety and Reactogenicity Assessments ......................................................... 48 
6.1.1 
Adverse Events ................................................................................ 49 
6.1.1.1 
Definitions ....................................................................................... 49 
6.1.1.1.1 
Adverse Events .................................................................... 49 
6.1.1.1.2 
Serious Adverse Events ........................................................ 50 
6.1.1.1.3 
Suspected Unexpected Serious Adverse Reactions ............. 50 
6.1.1.1.4 
Adverse Events of Special Interest ...................................... 50 
6.1.1.2 
Eliciting and Documenting Adverse Events .................................... 51 
6.1.1.2.1 
Assessment of Severity ........................................................ 52 
6.1.1.2.2 
Assessment of Causality ...................................................... 54 
6.1.1.3 
Reporting Adverse Events ............................................................... 55 
6.1.1.3.1 
Reporting Serious Adverse Events and Adverse Events of 
Special Interest ..................................................................... 55 
6.1.1.3.2 
Reporting Suspected Unexpected Serious Adverse Reactions
 56 
6.1.1.4 
Follow-Up of Participants Reporting Adverse Events ..................... 56 
6.1.1.5 
eDiary .............................................................................................. 56 
6.1.2 
Clinical Safety Laboratory Assessments.......................................... 57 
6.1.3 
Physical Examinations ..................................................................... 58 
6.1.4 
Vital Signs ........................................................................................ 58 
6.1.5 
Sentinel Participant Safety Follow-up Call ..................................... 59 
6.2 
Pregnancy Reporting ....................................................................................... 59 
Page 6

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
6.3 
Pharmacokinetics ............................................................................................ 59 
6.4 
Pharmacodynamics and Biomarkers ............................................................... 60 
6.5 
Immunogenicity Assessments ......................................................................... 60 
6.6 
SARS-CoV-2 and COVID-19 Disease Assessment and Definitions .............. 60 
6.7 
Genetics .......................................................................................................... 62 
7 
Statistical Considerations ......................................................................................... 63 
7.1 
Statistical Hypothesis ...................................................................................... 63 
7.2 
Sample Size Determination............................................................................. 63 
7.3 
Analysis Sets ................................................................................................... 63 
7.4 
Description of Subgroups to Be Analyzed ...................................................... 64 
7.5 
Statistical Analysis Methodology ................................................................... 64 
7.5.1 
General Considerations .................................................................... 64 
7.5.2 
Analysis of the Primary Safety Endpoints ....................................... 64 
7.5.3 
Analysis of Secondary Immunogenicity Endpoints ........................ 64 
7.5.4 
Analyses of Exploratory Immunogenicity Endpoints ...................... 65 
7.5.5 
Safety Analyses ................................................................................ 65 
7.5.6 
Other Analyses ................................................................................. 65 
7.6 
Handling of Missing Data ............................................................................... 65 
7.7 
Interim Analyses ............................................................................................. 65 
7.8 
Safety Review Team ....................................................................................... 66 
8 
Data Quality Assurance ............................................................................................ 67 
8.1 
Data Management ........................................................................................... 67 
9 
Ethics ........................................................................................................................ 68 
9.1 
Independent Ethics Committee or Institutional Review Board ...................... 68 
9.2 
Ethical Conduct of the Study .......................................................................... 68 
9.3 
Participant Information and eConsent ............................................................ 69 
10 Investigator’s Obligations ........................................................................................ 70 
10.1 Confidentiality ................................................................................................ 70 
10.2 Data Protection ............................................................................................... 70 
10.3 Financial Disclosure and Obligations ............................................................. 70 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
10.4 Investigator Documentation ............................................................................ 71 
10.5 Study Conduct ................................................................................................. 71 
10.6 Adverse Events and Study Report Requirements ........................................... 71 
10.7 Investigator’s Final Report ............................................................................. 71 
10.8 Records Retention ........................................................................................... 72 
10.9 Publications and Results Disclosures ............................................................. 72 
11 Study Management ................................................................................................... 73 
11.1 Monitoring ...................................................................................................... 73 
11.1.1 
Monitoring of the Study ................................................................... 73 
11.1.2 
Inspection of Records ...................................................................... 73 
11.2 Management of Protocol Amendments and Deviations.................................. 74 
11.2.1 
Modification of the Protocol ............................................................ 74 
11.2.2 
Protocol Deviations ......................................................................... 74 
11.3 Study Termination ........................................................................................... 75 
11.4 Final Report .................................................................................................... 75 
12 References ................................................................................................................ 76 
13 Appendices ............................................................................................................... 77 
13.1 Appendix 1: Schedule of Events ..................................................................... 77 
13.2 Appendix 2: Contraceptive Guidance and Pregnancy Information ................ 80 
13.3 Appendix 3: Bayesian Logistic Regression Model ......................................... 83 
13.4 Appendix 4: Potential Immune-mediated Diseases ........................................ 85 
13.5 Appendix 5: Tables for Laboratory Abnormalities ......................................... 93 
13.6 Appendix 6: Protocol Amendment History..................................................... 95 
 
Page 8

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
List of Tables 
Table 2-1 
Study Objectives and Endpoints ..................................................................... 24 
Table 3-1 
CV2CoV Study Cohorts, Dose Groups, and Dose Levels .............................. 26 
Table 5-1 
Investigational Product Information ............................................................... 41 
Table 5-2 
Study Holding Rules ....................................................................................... 46 
Table 6-1 
Intensity Scales for Solicited Symptoms ........................................................ 53 
Table 13-1 
Schedule of Events .......................................................................................... 78 
Table 13-2 
Hypothetical Data Scenarios Illustrating Posterior Probabilities .................... 84 
Table 13-3 
List of Potential Immune-Mediated Diseases ................................................. 85 
Table 13-4 
Toxicity Grading for Serum Laboratory Abnormalities .................................. 94 
 
List of Figures 
Figure 3-1 
Study Design Figure ....................................................................................... 28 
Page 9

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
List of Abbreviations 
Abbreviation 
Definition 
Ab 
antibody  
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COVID-19 
coronavirus disease caused by SARS-CoV-2 
CV2CoV 
SARS-CoV-2 second-generation vaccine (monovalent; targets 
wild type Wuhan strain [D614]) 
CVnCoV 
SARS-CoV-2 first-generation vaccine (monovalent; targets 
wild type Wuhan strain [D614]) 
D 
day 
EDC 
electronic data capture 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EOS 
end of study 
ET 
early termination 
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GMI 
geometric mean increase 
GMT 
geometric mean titer 
GSK 
GlaxoSmithKline Biologicals SA 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICS 
intracellular cytokine staining assay 
Page 10

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Abbreviation 
Definition 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IND 
investigational new drug 
IM 
intramuscular(ly) 
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
LNP 
lipid nanoparticle 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
NA 
not applicable 
NIH 
National Institutes of Health 
N protein 
nucleocapsid protein 
PBMC 
peripheral blood mononuclear cell 
pIMD 
potential immune-mediated diseases 
PP 
per protocol 
SAP 
statistical analysis plan 
RBD 
receptor-binding domain 
RT-PCR 
reverse transcription polymerase chain reaction 
S protein 
spike protein 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOE 
schedule of events 
SRT 
Safety Review Team 
SUSAR 
suspected unexpected serious adverse reaction 
Th 
T helper 
WHO 
World Health Organization 
WHODRUG 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 
WT 
wild type 
Page 11

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Protocol Amendment Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 
13 Jun 2022 
Amendment 1 
20 Apr 2022 
Original Protocol 
11 Feb 2022 
 
Amendment 2, 13 Jun 2022: Current Amendment 
Rationale for Amendment 2: 
The main purposes of Amendment 2 are to make use of early trial experiences to further 
enhance study management at study sites, the scientific integrity of results, and further align 
the trial parameters with best medical practices and previous practices in similar trials.  
The summary of changes table provided here describes the important changes made in 
Amendment 2 relative to Amendment 1, including the sections modified and the 
corresponding rationales. The synopsis of Amendment 2 has been modified, as needed, to 
correspond to changes in the body of the protocol. Minor editorial, grammatical, and 
formatting corrections are not included in this summary table. 
Throughout the document, the protocol date and version were updated to reflect 
Amendment 2 and the title page was updated to reflect the protocol history.  
Summary of Important Changes from Amendment 1 to Amendment 2: 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 3.1 (Study Design) 
Reduced the target number for total 
enrollment, from 210 to 180 
participants, with a total of 30 
participants in each dose group and 
a minimum of 10 and maximum of 
20 participants in each age group 
within a dose group 
To specify minimum target 
requirements for enrollment of 
older adults enrolled in the 
ongoing study 
Section 3.1 (Study Design) 
Section 6.6 (SARS--CoV-2 and 
COVID-19 Disease Assessment 
and Definitions) 
Section 13.1 (Appendix 1: 
Schedule of Events) 
Increased the length of the 
screening period from 7 to 14 days; 
SARS-CoV-2 RT-PCR sampling 
and testing will still occur within 7 
days before Day 1 
To allow investigators more time 
to assess eligibility of 
participants in the ongoing study  
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Section Number and Name 
Description of Change 
Brief Rationale 
Section 3.2 (Rationale for Study 
Design) 
Section 6 (Study Assessments and 
Procedures) 
Section 13.1 (Appendix 1: 
Schedule of Events) 
Clarified the use of televisits during 
the study 
To enhance study management 
at study sites 
Section 4.1.1 (Inclusion Criteria) 
Changed inclusion criterion 3 to 
narrow enrollment to participants 
who received only Comirnaty® or 
Spkevax® vaccines, while opening 
enrollment to participants who had 
received booster vaccination at least 
6 months prior to Screening 
To permit enrollment of 
participants who have received 
booster vaccines per current 
standard of care 
Section 4.1.1 (Inclusion Criteria) 
Changed inclusion criterion 6 to 
permit inclusion of participants with 
BMI up to 34.9 kg/m2 
To clarify the eligibility criterion 
for persons in this BMI range 
who are not expected to be at 
increased risk due to study 
participation 
Section 4.1.2 (Exclusion Criteria) 
Deleted exclusion criterion 7 and 
moved it to exclusion criterion 24, 
removing distant smoking history 
from the exclusion criterion 
To clarify the eligibility criterion 
for distant smokers who are not 
expected to be at increased risk 
due to study participation 
Section 4.1.2 (Exclusion Criteria) 
Edited exclusion criterion 24b to 
reflect a higher systolic blood 
pressure threshold for uncontrolled 
hypertension (150 mmHg) for 
participants > 60 years old 
Clarification provided, since 
individuals with well controlled 
essential hypertension may be 
eligible for enrollment 
Section 4.1.2 (Exclusion Criteria) 
Added a new exclusion criterion 25, 
to exclude participants with a 
history of documented 
SARS-CoV-2 infection or COVID-
19 within 6 months before 
Screening 
To minimize the risk that a 
SARS-CoV-2 infection within 
the 6 months before Screening 
will confound the 
immunogenicity evaluation of 
study vaccine and to enhance the 
scientific integrity of results 
Section 4.1.3 (Screen Failures) 
Added a definition of screen 
failures and procedures both for 
documenting screen failures and for 
rescreening 
To clarify that rescreening is 
permitted and what 
documentation and procedures 
are required 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Section Number and Name 
Description of Change 
Brief Rationale 
Section 5.9 (Study Holding Rules) 
Clarified the application of the 
Bayesian logistic regression model  
To clarify how the Bayesian 
logistic regression model is 
intended to be used  
Section 6.1.2 (Clinical Safety 
Laboratory Assessments) 
Added that SARS-CoV-2 RT-PCR 
testing may be repeated once for 
enrollment requirements 
To enhance study management 
at study sites 
Section 6.1.4 (Vital Signs) 
Clarified that blood pressure 
measured at Screening for 
eligibility may be based on an 
average of up to 3 blood pressure 
measurements 
Individual blood pressure 
measurements may be 
insufficient to provide a 
comprehensive hypertension 
assessment based on the 
dynamic nature of blood 
pressure fluctuation. 
Section 13.2 (Appendix 2: 
Contraceptive Guidance and 
Pregnancy Information) 
Added tubal ligation to the list of 
acceptable forms of primary 
contraception 
To provide clarity to 
Investigators on acceptable 
forms of primary contraception 
and to enhance study 
management at study sites 
Section 13.3 (Appendix 3: 
Bayesian Logistic Regression 
Model) 
Clarified the use and interpretation 
of the Bayesian logistic regression 
model by the SRT  
To clarify that the Bayesian 
logistic regression model is used 
by the SRT to evaluate Grade 3 
solicited events and help make 
recommendations on dose 
expansion and escalation. The 
model is not used to determine 
when study hold rule 2a is 
triggered.  
Section 13.5 (Appendix 5: Tables 
for Laboratory Abnormalities) 
Added an instruction to 
investigators to provide institutional 
normal reference ranges for local 
laboratories 
To enhance study management 
at study sites and enhance the 
scientific integrity of results 
 
 
 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Protocol Synopsis 
Protocol Number: 217741 (CV2 SARS-COV2-002 BST)  
Title: A Phase 1, Open-label, Safety, Reactogenicity, and Immunogenicity Trial of the 
CV2CoV mRNA Vaccine Against SARS-CoV-2 in Seropositive Adult Participants 
Short Title: Phase 1 Safety, Reactogenicity, and Immunogenicity Trial of CV2CoV mRNA 
Vaccine Against SARS-CoV-2 in Seropositive Adult Participants 
Sponsor: GlaxoSmithKline Biologicals SA, Rue de l’Institut 89, 1330 Rixensart, Belgium 
Study Phase: 1 
Indication: Prevention of COVID-19 disease caused by SARS-CoV-2 
Rationale: Due to the ongoing COVID-19 pandemic and the need for vaccines to provide 
protection against SARS-CoV-2 and variants of concern, GSK and CureVac are collaborating 
to develop the CV2CoV mRNA second-generation vaccine based on CureVac’s mRNA 
vaccine platform. The second-generation vaccine is based on a modified mRNA construct 
from the first-generation CVnCoV vaccine. This is a Phase 1 first-time-in-human study 
designed to evaluate the safety, reactogenicity, and immunogenicity of the GSK-CureVac 
second-generation CV2CoV mRNA vaccine in a booster vaccination setting. The proposed 
study will support development of the platform, guide dose selection and support decisions as 
to whether the candidate vaccine should be further evaluated in advanced phase clinical 
trials. 
 
 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary – Safety  
To evaluate the safety and reactogenicity of 
CV2CoV at each dose level in SARS-CoV-2 
seropositive healthy adult participants after 
booster vaccination 
• 
Percentage of participants with MAAEs, SAEs, and 
AESIs from study vaccination through the end of the 
study (approximately 180 days after the study 
vaccine administration), each summarized separately 
• 
Percentage of participants with each solicited local 
and systemic AE within the 7-day postvaccination 
period (Days 1 to 7) 
• 
Percentage of participants with unsolicited AEs up to 
28 days after study vaccination, including clinically 
relevant abnormal laboratory findings 
Secondary – Immunogenicity  
To explore the dose response and effect of 
CV2CoV at each dose level on neutralizing Ab 
titers against pseudovirus bearing spike protein 
from SARS-CoV-2 WT in SARS-CoV-2 
seropositive healthy adult participants after 
booster vaccination 
• 
GMTs of neutralizing Ab titers against pseudovirus 
bearing spike protein from SARS-CoV-2 WT at each 
collection time point (Days 1, 8, 15, 29, 85, and 180)  
• 
Percentage of participants with seroresponse (≥4-fold 
rise from baseline) at Day 29 after the booster dose 
• 
GMI from baseline of neutralizing Ab titers against 
pseudovirus bearing spike protein from 
SARS-CoV-2 WT at each collection time point 
(Days 8, 15, 29, 85, and 180)  
To describe serum-binding Ab (IgG) levels 
specific for vaccine antigens in SARS-CoV-2 
seropositive healthy adult participants after 
booster vaccination 
• 
GMTs of binding IgG against SARS-CoV-2 
S protein and RBD at each collection time point 
(Days 8, 15, 29, 85, and 180) 
• 
GMI from baseline of binding IgG against 
SARS-CoV-2 S protein and RBD at each collection 
time point (Days 8, 15, 29, 85, and 180) 
Note: Tertiary objectives and endpoints are included in the main protocol. 
 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Diagnosis and Main Criteria for Inclusion and Exclusion: The study will enroll healthy 
adults (≥18 to <65 years of age for the younger adult group and ≥65 years of age for the older 
adult group) who have received at least 2 doses of Pfizer-BioNTech (Comirnaty®) or 
Moderna (Spikevax®) mRNA COVID-19 vaccine (with the last dose of vaccine received at 
least 6 months prior to Screening and has provided documentation of receiving the 
vaccination series) and is negative for SARS-CoV-2 infection (by RT-PCR test) at Screening. 
History of documented SARS-CoV-2 infection or COVID-19 within 6 months before 
Screening, previous participation in an investigational vaccine study with investigational 
vaccine administered within 6 months of study vaccination or close contact with anyone who 
had a confirmed SARS-CoV-2 infection within 14 days before study vaccination will exclude 
individuals from study participation. 
Study Design: This Phase 1 study will evaluate the safety, reactogenicity, and 
immunogenicity of the CV2CoV vaccine in SARS-CoV-2 seropositive healthy adult 
participants. The study will be conducted in 5 sequential cohorts with dose escalation from 2 
µg to 20 µg. A total of up to approximately 180 healthy adult participants will be enrolled, 30 
per dose group. The 30 participants will be distributed between the younger (≥18 to <65 
years old) and older (≥65 years old) age groups, with a minimum of 10 and a maximum of 20 
participants in each age group. There will be 3 sentinel participants in each age group within 
each dose group. 
The study will be open-label. Participants in all cohorts will be screened for eligibility up to 
14 days before enrollment. On Day 1, participants will receive study vaccine according to 
their cohort (dose group) and age group, and study visits will proceed according to the SOE. 
Participants will be sequentially enrolled to the dose level assigned to their cohort. 
Three sentinel participants in the younger age group (Cohort 1) will be enrolled before 
opening enrollment in the older age group (Cohort 1). Study vaccine administration must be 
separated by at least 20 hours between sentinel participants in all cohorts and all dose groups. 
Sentinel participants will remain on site for approximately 4 hours after study vaccination 
and the remainder of participants in each group will remain on site for approximately 60 
minutes after study vaccination for safety monitoring. A safety follow-up telephone call to 
each sentinel participant in each dose group will be performed on Day 2 (at least 20 hours 
postvaccination). Vaccination of the next sentinel participant will proceed, provided the 
safety was acceptable for the prior sentinel(s) per investigator’s assessment. 
Page 17

Gla x o S mit h Kli ne Bi ol o gicals S A  
C V 2 C o V Vacci ne  
Pr ot oc ol 2 1 7 7 4 1 ( C V 2 S A R S -C O V 2 -0 0 2 B S T ) A me n d me nt 2 
1 3 J u n  2 0 2 2  
C o nfi de ntial   
Escalati o n t o t he ne xt hi g her d ose c o h orts will be base d o n t he S R T re vie w of safet y data 
fr o m t he sa me a ge gr o u p. E nr oll me nt i nt o C o h orts 2 a n d 3 ( 8 a n d 1 2 µ g, res pecti vel y) will 
be gi n after t he S R T has re vie we d Da ys 1 t o 8 safet y data (i ncl u di n g Da y 8 lab orat or y data)  
fr o m 3 se nti nel partici pa nts fr o m t he pre vi o us d ose c o h ort. E nr oll me nt i nt o C o h orts 4, a n d 5 
( 1 6 µ g, a n d 2 0 µ g, res pecti vel y), will be gi n after t he S R T has re vie we d Da ys 1 t o 8 safet y 
data fr o m all partici pa nts i n t he pre vi o us d ose c o h orts. 
St u d y D ur ati o n: T he scree ni n g peri o d will be u p t o 1 4 da ys, st u d y vacci ne a d mi nistrati o n 
will occ ur o n Da y 1, a n d partici pa nts will ha ve u p t o a p pr o xi matel y 1 8 0 da ys ( 6 m o nt hs) of 
f oll o w-u p after st u d y vacci ne a d mi nistrati o n. St u d y assess me nts will be perf or me d i n a n 
o ut patie nt setti n g at q ualifie d st u d y sites. 
S afet y Assess me nts: Safet y will be assesse d t hr o u g h t he c ollecti o n a n d e val uati o n of 
s olicite d a n d u ns olicite d A Es, M A A Es, S A Es, a n d A E SIs. Safet y will als o be assesse d base d 
o n p h ysical e xa mi nati o ns , vital si g n meas ure me nts, a n d cli nical la b orat or y assess me nts. 
I m m u n o ge nicit y Assess me nts: Bl o o d sa m ples will be c ollecte d t o e val uate vacci ne -i n d uce d 
ne utralizi n g a n d bi n di n g I g G A b  le vels a n d cell-me diate d i m m u nit y. Ne utralizi n g A b le vels 
a gai nst pse u d o vir us beari n g s pi ke pr otei n fr o m S A R S- C o V - 2 W T a n d p ote ntiall y 
pse u d o vir us beari n g s pi ke pr otei n fr o m ot her varia nts will be meas ure d. Bi n di n g A b I g G 
le vels a gai nst S A R S-C o V - 2 S pr otei n, R B D, N pr otei n (fr o m W T) , a n d S A R S -C o V -2 s pi ke 
(fr o m ot her varia nts) will be meas ure d. A ntis pi ke (fr o m W T a n d p ote ntiall y ot her varia nts) 
T- cell res p o nses will be e x pl ore d.  
I n vesti g ati o n al Pr o d uct, D os a ge, a n d R o ute of A d mi nistr ati o n: St u d y vacci ne will be 
a d mi nistere d o n Da y 1 as a si n gle I M i njecti o n of 0. 3 m L i n t he delt oi d area, prefera bl y i n t he 
n o n d o mi na nt ar m. 
T he f oll o wi n g I P will be use d i n t he st u d y: 
Descri pti o n  
I n vesti g ati o n al Pr o d uct 
C V 2 C o V a 
 
 
 
W T  
 
 
a. 
Pr o d uct refere nce: C V 0 7 0 5 0 2 0 1.  
Pa ge 1 8
C CI
C CI
C CI
C CI
C CI
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b. 
 
 
Sample Size: Approximately 180 participants will be enrolled in the study, apportioned 
among cohorts, dose groups, and age groups according to the table below.  
Cohort 
Dose 
Group 
Dose 
Level 
Younger Adults 
≥18 to <65 Years of Age 
Older Adults 
≥65 Years of Age 
Total Dose Group 
Sample Size 
1 
1a 
2 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
1b 
4 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
2 
2 
8 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
3 
3 
12 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
4 
4 
16 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
5 
5 
20 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
 
Statistical Methods: No formal significance testing will be performed. Analysis details, 
including any subgroup analysis, will be provided in the SAP. 
For all safety endpoints, descriptive summary statistics will be provided for the Safety Set. 
Safety data listings will be provided, and graphical presentations will be considered as 
needed. In addition to the planned summary of SAEs throughout the study, any SAEs that are 
reported within 28 days of study vaccine administration will also be summarized. 
For the immunogenicity endpoints, the GMTs of specific Ab with corresponding 95% CIs) at 
each time point and percentage of participants with seroresponse (≥4-fold rise from baseline) 
at Day 29 after the booster dose, and GMI from baseline of specific Ab with corresponding 
95% CIs at each postbaseline time point over prevaccination baseline will be provided by 
dose group. The GMT, the GMI, and their 95% CI in all cohorts will be analyzed using an 
ANCOVA with treatment and age group as fixed factors and prevaccination baseline value as 
a covariable. 
Version and Date of Protocol: Amendment 2; 13 Jun 2022 
Page 19
CCI

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
1 Introduction 
1.1 Background Information 
The COVID-19 pandemic caused by SARS-CoV-2 virus was declared by the WHO on 
11 March 2020 (WHO 2020). As of 11 November 2021, more than 250 million cases have 
been reported worldwide, leading to more than 5.0 million deaths (WHO 2021). To date, 
there are several vaccines available, licensed, under emergency use authorizations or 
conditional approvals using different technologies. All available vaccines utilize antigens 
from the ancestral Wuhan strain (D614; wild type, hereafter referred to as “WT”). 
Recent scientific data highlight the potential for SARS-CoV-2 variants to escape from 
neutralizing humoral immunity and emphasize the need to develop broadly protective 
interventions, such as reformulation of existing SARS-CoV-2 vaccines to include diverse 
spike sequences. The development of new vaccines capable of eliciting broad neutralizing Ab 
responses is necessary. 
CureVac developed a first-generation mRNA vaccine (CVnCoV) using WT, for which 
vaccine safety and efficacy are being evaluated (NCT04652102). Results from the Phase 2b/3 
trial of CVnCoV showed a vaccine efficacy of 48% against COVID-19 of any severity across 
all age groups and 15 different virus strains; the vaccine safety profile was acceptable. In 
participants 18 to 60 years of age, significant vaccine efficacy was demonstrated, which 
included 53% efficacy against disease of any severity, and 77% efficacy against moderate 
and severe disease. The virus was sequenced in 204 cases to identify the variant causing the 
infection. Approximately 86% of these cases were caused by variants of concern (~51%) and 
variants of interest (~35%). Approximately 3% of cases were attributable to the ancestral 
SARS-CoV-2 virus while the remaining 11% were caused by less-explored strains; thus, 
further demonstrating the need for protection against emerging SARS-CoV-2 variants 
(Kremsner 2021). 
To continue addressing an unmet public health need for products that provide protection 
against COVID-19 disease, GSK and CureVac are collaborating to develop CV2CoV mRNA 
second-generation vaccine based on CureVac’s mRNA vaccine platform. The CV2CoV 
vaccine is based on a new mRNA backbone that features targeted optimizations designed to 
improve intracellular mRNA stability and translation for increased and extended protein 
expression. These optimizations potentially allow for strong immune responses at low doses, 
Page 20

Gla x o S mit h Kli ne Bi ol o gicals S A  
C V 2 C o V Vacci ne  
Pr ot oc ol 2 1 7 7 4 1 ( C V 2 S A R S -C O V 2 -0 0 2 B S T ) A me n d me nt 2 
1 3 J u n  2 0 2 2  
C o nfi de ntial   
w hic h are i nte n de d t o  s u p p ort t he de vel o p me nt of m ulti vale nt vacci nes t o tar get ra pi dl y 
s prea di n g C O VI D- 1 9 varia nts (C ure Vac 2 0 2 1 ). 
N o ncli nical data ha ve s h o w n pr o misi n g res ults t hat i n dicate t he sec o n d - ge nerati o n m R N A 
vacci nes ha ve e n ha nce d i m m u n o ge nicit y c o m pare d wit h t he S A R S- C o V - 2 first- ge nerati o n 
C V n C o V m R N A vacci ne. Precli nical data i n rats i m m u nize d wit h C V 2 C o V i n t he d ose ra n ge 
of 
 de m o nstrate d fast o nset of str o n g i m m u ne res p o nses after t he first d ose. I n 
a d diti o n, t he ser u m of vacci nate d a ni mals s h o we d si g nific a nt cr oss -ne utralizati o n a gai nst 
varia nts first disc o vere d i n De n mar k ( B. 1. 1. 2 9 8), t he U nite d Ki n g d o m ( B. 1. 1. 7), a n d 
S o ut h Africa ( B. 1. 3 5 1) ( C ure Vac 2 0 2 1 ; R ot h et al 2 0 2 1 ). Refer t o t he I B f or a d diti o nal 
n o ncli nical i nf or mati o n.  
T he C V 2 C o V vacci ne will tar get S A R S -C o V -2 W T. T his sec o n d - ge nerati o n vacci ne will be 
i nte n de d f or use as a b o oster d ose i n i n di vi d uals w h o are S A R S-C o V - 2 ser o p ositi ve d ue t o 
pri or C O VI D - 1 9 vacci nati o n.  
G S K, i n c olla b orati o n wit h C ure Vac, are c o n d ucti n g t his P hase 1 cli nical st u d y wit h t he ai m 
of e val uati n g t he sec o n d -ge nerati o n S A R S -C o V -2 i m pr o ve d vacci ne i n a b o oster vacci nati o n 
setti n g. T his st u d y will e val uate t he C V 2 C o V m R N A vacci ne o ver a ra n ge of d ose le vels a n d 
a d ult a ge gr o u ps. 
1. 2  Ris k /Be nefit C o nsi der ati o ns  
Detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d ris ks a n d be nefits a n d reas o na bl y 
e x pecte d A Es of t he C V 2 C o V vacci ne is pr o vi de d i n t he I B. A hi g h-le vel s u m mar y is 
pr o vi de d here. 
Partici pa nts are n ot e x pecte d t o directl y be nefit fr o m st u d y partici pati o n.  H o we ver, t heir 
partici pati o n i n t his st u d y will c o ntri b ute t o ge nerati n g i nf or mati o n re gar di n g t he vacci ne 
platf or m bei n g e val uate d a n d t he p ote ntial f or t his c o nstr uct t o be f urt her e val uate d i n 
P hase  2 a n d 3 cli nical trials.  
D ue t o t he lac k of e x perie nce i n h u ma n partici pa nts, t here is c urre ntl y n ot e n o u g h 
i nf or mati o n a vaila ble a b o ut t he relati o ns hi p of A Es a n d t he a d mi nistrati o n of t he C V 2 C o V 
m R N A i n vesti gati o nal vacci ne. 
Pa ge 2 1
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As for any vaccine, local (eg, pain, swelling, erythema at the injection site) and systemic (eg, 
fatigue, headache, myalgia) postvaccination symptoms may occur within the first 3 days of 
vaccination, and are anticipated to resolve within a few days of onset. 
Important potential risks for the CV2CoV mRNA investigational vaccine are the following: 
• Hypersensitivity reactions, including anaphylaxis. 
• Myocarditis.  
• Pericarditis. 
• Syncope and vasovagal reactions to injection. 
• Vaccine-associated disease enhancement is an important risk for all SARS-CoV-2 
vaccines. 
To mitigate these important potential risks, the following risk strategies have been 
implemented in the study: 
• All participants will remain under observation at the vaccination center for at least 
60 minutes after vaccination. 
• Participants with history of hypersensitivity or severe allergic reaction to any 
previous vaccine or any component of the IP are excluded from the study enrollment 
and participants will be instructed to contact the study site immediately for 
occurrence of any possible hypersensitivity reaction within 1 day of vaccination. 
• Participants at increased risk of myocarditis or pericarditis and participants with 
history of myocarditis or pericarditis are excluded from the study enrolment.  
• Participants will be instructed (via the informed consent form) to be alert to 
symptoms of myocarditis or pericarditis and to contact the study site immediately if 
occurrence of any of these symptoms. 
• As syncope and other anxiety-related reactions may occur before vaccination, the 
decision to vaccinate the participant will be depending on the clinical judgment of the 
investigator. 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
• Participants with medically documented risk factors for severe COVID-19 disease 
will be excluded from the study and the occurrence of 2 cases of severe COVID-19 
disease will trigger the hold of the whole Phase 1 study. 
Participants will receive close medical supervision and medical assessments (eg, laboratory 
testing) during the study. 
The investigational CV2CoV vaccine is currently in an early stage of clinical development 
and vaccine efficacy, immunogenicity, and safety have not yet been demonstrated in humans. 
Considering the risk mitigation strategies, measures taken, and planned to be taken to 
minimize risk to participants in this Phase 1 clinical trial, the potential risks associated with 
the investigational vaccines are considered acceptable. 
 
Page 23

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
2 Study Objectives and Endpoints 
The study objectives and endpoints are described in Table 2-1. 
Table 2-1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary – Safety  
To evaluate the safety and reactogenicity of 
CV2CoV at each dose level in SARS-CoV-2 
seropositive healthy adult participants after 
booster vaccination 
• 
Percentage of participants with MAAEs, SAEs, and 
AESIs from study vaccination through the end of the 
study (approximately 180 days after the study 
vaccine administration), each summarized separately 
• 
Percentage of participants with each solicited local 
and systemic AE within the 7-day postvaccination 
period (Days 1 to 7) 
• 
Percentage of participants with unsolicited AEs up to 
28 days after study vaccination, including clinically 
relevant abnormal laboratory findings 
Secondary – Immunogenicity  
To explore the dose response and effect of 
CV2CoV at each dose level on neutralizing Ab 
titers against pseudovirus bearing spike protein 
from SARS-CoV-2 WT in SARS-CoV-2 
seropositive healthy adult participants after 
booster vaccination 
• 
GMTs of neutralizing Ab titers against pseudovirus 
bearing spike protein from either SARS-CoV-2 WT 
at each collection time point (Days 1, 8, 15, 29, 85, 
and 180) 
• 
Percentage of participants with seroresponse (≥4-fold 
rise from baseline) at Day 29 after the booster dose 
• 
GMI from baseline of neutralizing Ab titers against 
pseudovirus bearing spike protein from 
SARS-CoV-2 WT at each collection time point 
(Days 8, 15, 29, 85, and 180) 
To describe serum-binding Ab (IgG) levels 
specific for vaccine antigens in SARS-CoV-2 
seropositive healthy adult participants after 
booster vaccination 
• 
GMTs of binding IgG against SARS-CoV-2 
S protein and RBD at each collection time point 
(Days 8, 15, 29, 85, and 180) 
• 
GMI from baseline of binding IgG against 
SARS-CoV-2 S protein and RBD at each collection 
time point (Days 8, 15, 29, 85, and 180) 
Page 24

Gla x o S mit h Kli ne Bi ol o gicals S A  
C V 2 C o V Vacci ne  
Pr ot oc ol 2 1 7 7 4 1 ( C V 2 S A R S -C O V 2 -0 0 2 B S T ) A me n d me nt 2 
1 3 J u n  2 0 2 2  
C o nfi de ntial   
O bjecti ves  
E n d p oi nts  
Terti ar y O bjecti ves  
Pa ge 2 5
C CI

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
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3 Investigational Plan 
3.1 Study Design 
This Phase 1 study will evaluate the safety, reactogenicity, and immunogenicity of the 
CV2CoV vaccine in SARS-CoV-2 seropositive healthy adult participants. The study will be 
conducted in 5 sequential cohorts with dose escalation from 2 µg to 20 µg. A total of up to 
approximately 180 healthy adult participants will be enrolled, 30 per dose group as indicated 
in Table 3-1. The 30 participants will be distributed between the younger (≥18 to <65 years 
old) and older (≥65 years old) age groups, with a minimum of 10 and a maximum of 20 
participants in each age group. There will be 3 sentinel participants in each age group within 
each dose group. A study design schematic is provided in Figure 3-1. 
Table 3-1 
CV2CoV Study Cohorts, Dose Groups, and Dose Levels 
Cohort 
Dose 
Group 
Dose 
Level 
Younger Adults 
≥18 to <65 Years of 
Age 
Older Adults 
≥65 Years of Age 
Total Dose Group 
Sample Size 
1 
1a 
2 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
1b 
4 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
2 
2 
8 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
3 
3 
12 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
4 
4 
16 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
5 
5 
20 µg 
10 ≤ n ≤ 20 
10 ≤ n ≤ 20 
30 
Note: The first 3 participants enrolled in each age group within each dose group will be sentinel participants.  
The screening period will be up to 14 days, study vaccine administration will occur on Day 1, 
and participants will have approximately 180 days (6 months) of follow-up after study 
vaccine administration. Study assessments will be performed in an outpatient setting at 
qualified study sites. 
The study will be open-label. Participants in all cohorts will be screened for eligibility up to 
14 days before enrollment. Participants will receive study vaccine according to their cohort 
(Table 3-1), dose group, and age group; and study visits will proceed according to the SOE 
(Table 13-1). Participants will be sequentially enrolled to the dose level assigned to their 
cohort. 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Enrollment in each dose cohorts and the progression from vaccination in younger to older 
adult participants will be staggered based on SRT data review will progress as described in 
Section 7.8. Holding rules for dosing are described in Section 5.9. 
Three sentinel participants in the younger age group (Cohort 1) will be enrolled before 
opening enrollment to the older age group (Cohort 1). Study vaccine administration must be 
separated by at least 20 hours between sentinel participants in all cohorts and all dose groups. 
Sentinel participants will remain on site for approximately 4 hours after study vaccination 
and the remainder of participants in each group will remain on site for approximately 60 
minutes after study vaccination for safety monitoring. A safety follow-up telephone call to 
each sentinel participant in each dose group will be performed on Day 2 (at least 20 hours 
postvaccination). Vaccination of the next sentinel participant will proceed, provided the 
safety was acceptable for the prior sentinel(s) per investigator’s assessment. 
Escalation to the next higher dose cohorts will be based on the SRT review of safety data 
from the same age group. Enrollment into Cohorts 2 and 3 (8 and 12 µg, respectively) will 
begin after the SRT has reviewed Days 1 to 8 safety data (including Day 8 laboratory data) 
from 3 sentinel participants from the previous dose cohort. Enrollment into Cohorts 4 and 5 
(16 µg and 20 µg, respectively), will begin after the SRT has reviewed Days 1 to 8 safety 
data from all participants in the previous dose cohorts. 
A first interim analysis of safety and immunogenicity data up to 14 days after study vaccine 
administration in participants enrolled in Cohorts 1, 2, and 3 will be performed. A second 
interim analysis of safety and immunogenicity data will be performed 14 days after 
participants in Cohorts 4 and 5 have received study vaccine. 
 
Page 27

GlaxoSmithKline Biologicals SA 
 
CV2CoV mRNA Vaccine 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
 
13 Jun 2022 
Confidential  
Figure 3-1 
Study Design Figure 
 
 
CV2CoV 8 µg (10 ≤ n ≤ 20) [Group 2]
≥18 - <65 years
CV2CoV 4 µg 10 ≤ n ≤ 20) [Group 1b]
≥18 - <65 years
CV2CoV 2 µg (10 ≤ n ≤ 20) [Group 1a]
≥18 - <65 years
D180 EOS
D1 Vac
Cohort 1
Cohort 2
CV2CoV 2 µg (10 ≤ n ≤ 20) [Group 1a]
≥65 years
D15
D29
D85
D180 EOS
D1 Vac
D15
D8 SRT
D29
D85
CV2CoV 4 µg (10 ≤ n ≤ 20) [Group 1b]
≥65 years
CV2CoV 8 µg (10 ≤ n ≤ 20) [Group 2]
≥65 years
D180 EOS
D1 Vac
D15
D8 SRT
D29
D85
D180 EOS
D1 Vac
D15
D8 SRT
D29
D85
CV2CoV 12 µg (10 ≤ n ≤ 20) [Group 3]
≥18 - <65 years
Cohort 3
CV2CoV 12 µg (10 ≤ n ≤ 20) [Group 3]
≥65 years
D1 Vac
D15
D8 SRT
D29
D85
D180 EOS
D1 Vac
D15
D8 SRT
D29
D85
D180 EOS
CV2CoV 16 µg (10 ≤ n ≤ 20) [Group 4]
≥18 - <65 years
Cohort 4
CV2CoV 16 µg (10 ≤ n ≤ 20) [Group 4]
≥65 years
D1 Vac
D15
D8 SRT
D29
D85
D180 EOS
D1 Vac
D15
D8 SRT
CV2CoV 20 µg (10 ≤ n ≤ 20) [Group 5]
≥18 - <65 years
Cohort 5
CV2CoV 20 µg (10 ≤ n ≤ 20) [Group 5]
≥65 years
D1 Vac
D15
D8 SRT
D29
D85
D180 EOS
D1 Vac
D15
D8 SRT
D180 EOS
D180 EOS
D29
D85
D29
D85
D8 SRT
Page 28

Gla x o S mit h Kli ne Bi ol o gicals S A  
C V 2 C o V m R N A Vacci ne  
Pr ot oc ol 2 1 7 7 4 1 ( C V 2 S A R S -C O V 2 -0 0 2 B S T ) A me n d me nt 2 
1 3 J u n  2 0 2 2  
C o nfi de ntial   
3. 2  R ati o n ale f or St u d y Desi g n  
T his is a P hase 1 first -ti me-i n- h u ma n st u d y desi g ne d t o e val uate t he safet y, react o ge nicit y, 
a n d i m m u n o ge nicit y of t he G S K- C ure Vac sec o n d -ge nerati o n C V 2 C o V vacci ne t o pre ve nt 
C O VI D - 1 9 disease ca use d b y e xisti n g a n d ne w e mer gi n g strai ns of t he S A R S -C o V - 2 vir us. 
T his st u d y will e val uate t he C V 2 C o V vacci ne i n a b o oster vacci nati o n setti n g. T he st u d y 
c o m prises  a n a d ult p o p ulati o n of partici pa nts w h o ha ve recei ve d a d oc u me nte d f ull pri mar y 
vacci nati o n series  ( 2 d oses o nl y) wit h a lice nse d or a ut h orize d m R N A C O VI D - 1 9 vacci ne 
( o nl y M o der na or Pfizer vacci nes ). T he sec o n d -ge nerati o n vacci nes are  base d o n t he first-
ge nerati o n C V n C o V vacci ne, f or w hic h efficac y a n d safet y data ha ve bee n c ollecte d i n t he 
o n g oi n g P hase 2 b/ 3 st u d y ( N C T 0 4 6 5 2 1 0 2). T he rati o nale f or e val uati o n of d oses fr o m 2 t o 
2 0 µ g is base d o n t he f oll o wi n g: 1) T he data fr o m t his st u d y will s u p p ort decisi o ns as t o 
w het her t he ca n di date vacci ne s h o ul d be f urt her e val uate d i n a d va nce d p hase cli nical trials. 
2) T he data fr o m t his st u d y will g ui d e d ose selecti o n. 3) T he pr o p ose d st u d y will s u p p ort 
de vel o p me nt of t he platf or m. S pecificall y, if t he C V 2 C o V m o n o vale nt ca n di date i n d uces 
r o b ust i m m u ne res p o nses wit h a n acce pta ble safet y pr ofile, t here ma y be p ote ntial t o de vel o p 
f ut ure m ulti vale nt vacci nes t o pre ve nt C O VI D- 1 9 disease base d o n t his platf or m. T he 
rati o nale f or i ncl u di n g ol der a d ults i n t his st u d y is beca use t his a ge gr o u p is at i ncrease d ris k 
f or se vere C O VI D- 1 9. I n a d diti o n, t he efficac y of t he C V n C oV vacci ne was l o wer i n ol der 
a d ults t ha n i n y o u n ger a d ults < 6 5 years of a ge. T h us, safet y a n d i m m u n o ge nicit y data o n 
C V 2 C o V i n t his a ge gr o u p will be critical t o g ui di n g decisi o ns o n w het her t he C V 2 C o V  
vacci ne ca n di date s h o ul d be a d va nce d f urt her i n de vel o p me nt. 
T he starti n g d oses of t he C V 2 C o V vacci ne are 2 µ g a n d 4 µ g i n C o h ort 1. T hese starti n g 
d oses are base d o n pre vi o usl y teste d d oses f or t he first- ge nerati o n C V n C o V vacci ne. 
T he ma xi m u m pla n ne d d ose of t he C V 2 C o V vacci ne is 2 0 µ g i n t he prese nt st u d y. I n t he 
P hase 1 st u d y, t he react o ge nici t y pr ofile of t he first- ge nerati o n C V n C o V vacci ne was d ose-
de pe n de nt fr o m 2 µ g t o 2 0 µ g. S olicite d reacti o ns were m ore c o m m o n l y s yste mic wit h a 
fre q ue nc y of re p orts ge nerall y si milar after t he a d mi nistrati o n of t he first a n d t he sec o n d d ose 
(e xce pt f or 8 µ g a n d 1 6 µ g). T he se verit y of s yste mic s olicite d e ve nts i ncrease d wit h d osa ges 
wit h a n o verall rate of  
 of partici pa nts re p orti n g a Gra de 3 e ve nt. H o we ver, Gra de 3 
s olicite d e ve nts were m ostl y s h ort-li ve d a n d self-li miti n g, e g, Gra de 3 A Es 
 
 o nl y laste d f or 1 da y a n d, 1 partici pa nt  
 re p orte d a Gra de 3 m yal gia after t he 
sec o n d d ose f or 3 c o nsec uti ve da ys a n d res ol ve d o n t he f o urt h da y. A d here nce of partici pa nts 
Pa ge 2 9
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to administration of the second dose remained very high, even for the higher doses. Until 
24 October 2021, no vaccine-related SAEs, AESIs, or fatalities were reported for any dose in 
the Phase 1 study. Increases in frequency or severity were not observed for Grade 3 solicited 
AEs in the later clinical phases with larger sample sizes.  
Risk to study participants will be mitigated in several ways:  
1) A stagger will occur between the younger and older adults based on SRT review of 
Days 1 to 8 safety data (including Day 8 laboratory data) from 3 sentinels (Cohort 1). 
2) Each sentinel will be called at Day 2 (at least 20 hours postvaccination) to monitor 
their safety postvaccination prior to vaccination of the next sentinel.  
3) The SRT will review Days 1 to 8 safety data (including Day 8 laboratory data) from 3 
sentinels in each dose cohort (Cohorts 1-5) prior to expansion in the same dose 
cohort. 
4) The SRT will review Days 1 to 8 safety data (including Day 8 laboratory data) from 3 
sentinels prior to escalation to the next higher dose cohort (Cohorts 1-3). 
5) The SRT will review data from the entire dose cohort prior to escalation to the next 
higher dose cohort (Cohorts 4-5). 
6) The SRT will continue to review all available safety data to determine study 
progression. 
7) Study holding rules have been specifically predefined so that the study will be 
fittingly put on hold pending the review of all accumulated safety data by the SRT 
and to decide whether expansion of vaccination and escalation through the higher 
dosages may continue. 
Participants will be monitored for 6 months after receiving study vaccine on Day 1. Safety 
monitoring, including physical examinations, clinical laboratory assessments, vital sign 
measurements, and AEs (solicited and unsolicited AEs, SAEs, MAAEs, and AESIs), will be 
performed throughout the study via outpatient site visits and participant eDiary completion. 
Due to the ongoing pandemic, safety follow-up visits may be completed via televisits, as 
permitted by country regulations. In-person visits should be maintained in the study unless 
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there is a public health emergency limiting access to study sites. During such an emergency 
or extenuating circumstance, televisits can be employed to keep personal access to subjects 
and ascertain their safety at a high level. 
Refer to the IB for nonclinical data for the CV2CoV vaccine. Refer to Section 1.2 for 
risk-benefit considerations. 
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4 Participant Selection and Withdrawal Criteria 
4.1 Selection of Study Participants 
A total of up to approximately 210 healthy adult participants (approximately 90 younger 
adults [≥18 to <65 years of age] and approximately 120 older adults [≥65 years of age]) will 
be enrolled in the study. Participants will be assigned to study vaccine only if they meet all of 
the inclusion criteria and none of the exclusion criteria. 
4.1.1 Inclusion Criteria 
Each participant must meet all the following criteria to be enrolled in this study: 
1. Must provide documented informed consent prior to any study procedures being 
performed. 
2. Is capable of understanding and agrees to comply with planned study procedures and 
to be available for all study visits, including being willing and able to use electronic 
devices during the study. 
3. Has received at least 2 doses of Pfizer-BioNTech (Comirnaty®) or Moderna 
(Spikevax®) mRNA COVID-19 vaccine, with the last dose of vaccine received at 
least 6 months prior to Screening and has provided documentation of receiving the 
vaccination series (eg, vaccination card). 
4. Negative for SARS-CoV-2 infection by RT-PCR test at Screening. 
5. Is a male or nonpregnant female 18 to <65 years of age (younger adult group) or 
≥65 years of age (older adult group) at Screening. 
6. Has a body mass index of 18 to 34.9 kg/m2, inclusive, at Screening. 
7. If the participant is a WOCBP, as described in Section 13.2, 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 3 months after study vaccination. 
8. Agrees to refrain from blood or plasma donation from Screening and throughout the 
end of the study. 
9. Is healthy or medically stable as determined by medical history, clinical laboratory 
tests, vital sign measurements, and physical examination findings, as determined by 
investigator judgment. 
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4.1.2 Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from the study: 
1. 
Participant is female and has a positive serum pregnancy test result at Screening or 
plans to become pregnant during the study. 
2. 
Participant is female and is breastfeeding or plans to breastfeed from study 
vaccination to 3 months after study vaccination. 
3. 
Has any clinically significant abnormal biochemistry or hematology finding (defined 
as ≥Grade 1; Section 6.1.2) at Screening. Note: Older adults (aged ≥65 years) with 
Grade 1 laboratory abnormalities which have been stable for at least 6 months prior 
to enrollment may be included in the study.  
4. 
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. 
5. 
Any confirmed or suspected immunosuppressive or immunodeficient condition 
resulting from disease (eg, malignancy) or immunosuppressive/cytotoxic therapy 
(eg, medications used during cancer chemotherapy, organ transplantation, or to treat 
autoimmune disorders). 
6. 
History of myocarditis, pericarditis, 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 (eg, due to enterovirus or 
adenovirus), and celiac disease.  
7. 
[Edited and moved to exclusion criterion 24i] 
8. 
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 6.6) should be excluded and referred 
for medical care. 
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9. 
Has a prior confirmed diagnosis of chronic hepatitis B, hepatitis C, or HIV 1/2 
infection or evidence of active infection at Screening. 
10. 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 end of the study. 
11. Has previously participated in another investigational vaccine study with 
investigational vaccine administered within 6 months of study vaccination.  
12. 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. 
13. Is planning to receive an authorized or licensed COVID-19 booster vaccination for 
the duration of the study (for adults 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 29 of the study (for adults covered by local recommendations to receive 
booster). 
14. Has received or plans to receive immunoglobulins or any blood or blood products 
within 90 days before study vaccination and throughout the study. 
15. 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 IP. 
16. Has a history of hypersensitivity or severe allergic reaction (including anaphylaxis, 
generalized urticaria, angioedema, and other significant reactions) to beta lactam 
antibiotics. 
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 10 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, and intranasal steroid preparations is permitted. 
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18. Has a bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder), or 
prior history of significant bleeding or bruising after IM injections or venipuncture. 
19. Has a history of alcohol abuse or other recreational drug use (excluding cannabis) 
within 6 months before study vaccination. 
20. Has any abnormal skin condition or permanent body art (eg, tattoo) that would 
interfere with the ability to observe local reactions at the study vaccination injection 
site. 
21. Has had known close contact with anyone who had a confirmed SARS-CoV-2 
infection within 14 days before study vaccination. 
22. Participant is an employee or family member of the investigator or study site 
personnel. 
23. Has any self-reported or medically documented significant medical or psychiatric 
condition. Significant medical conditions include, but are not limited to, the 
following:  
a. Moderate or severe respiratory disease (eg, chronic obstructive pulmonary 
disease, asthma) 
b. Uncontrolled hypertension, defined as an average systolic blood pressure 
≥140 mmHg for participants ≤60 years old, and ≥150 mmHg for participants >60 
years old, or a diastolic blood pressure ≥90 mmHg for any age  
c. Significant cardiovascular disease (eg, congestive heart failure, cardiomyopathy, 
ischemic heart disease) or history of myocarditis or pericarditis  
d. Neurological or neurodevelopmental conditions (eg, Down’s syndrome, dementia, 
chronic migraine not controlled by medication, epilepsy, stroke, or seizure 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 nontuberculosis mycobacterial infection 
g. Autoimmune disease, including hypothyroidism without a defined 
nonautoimmune cause 
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h. Immunodeficiency of any cause, including from solid organ transplant, blood or 
bone marrow transplant, use of corticosteroids, or use of other 
immune-weakening medicines 
i. Type 1 or 2 diabetes mellitus regardless of disease control 
24. Has any of the following self-reported or medically documented risk factors for 
severe COVID-19: 
a. Cancer 
b. Chronic kidney disease 
c. Sickle cell disease 
d. Cerebrovascular disease 
e. Cystic fibrosis 
f. Chronic liver disease 
g. Pulmonary fibrosis 
h. Thalassemia 
i. Smoking or other inhaled substance use, including tobacco, cannabis, or nicotine 
vapors, with an average of ≥5 cigarettes a day or equivalent (currently or within 1 
year of Screening). 
25. Has a history of documented SARS-CoV-2 infection or COVID-19 within 6 months 
before Screening. 
4.1.3 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened under a different participant number. A maximum of one rescreen is allowed.  
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Participants who are rescreened are required to sign a new ICF prior to undergoing 
rescreening assessments. 
4.2 
Discontinuation From Study Vaccine and/or Withdrawal From the 
Study 
As this is a single dose booster vaccination study, discontinuation from IP does not apply; 
however, participants may withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the investigator or at the study site. Every effort 
should be made to keep participants in the study for follow-up evaluations. The reasons for 
participants withdrawing from the study will be recorded. 
Participants will be informed of any authorized or licensed booster vaccines available for 
COVID-19 during the study to support an informed choice for whether to continue or 
discontinue participation in the study. 
A participant may withdraw or be withdrawn from the study for any of the following reasons: 
1. The participant does not meet the protocol inclusion or exclusion criteria. 
2. The participant is noncompliant with the protocol. 
3. The participant has a serious or intolerable AE(s) that, in the investigator’s opinion, 
requires withdrawal from the study. 
4. The participant has safety laboratory results that reveal clinically significant 
hematological or biochemical changes from the baseline values, per investigator 
judgment. 
5. The participant has symptoms or an intercurrent illness not consistent with the 
protocol requirements or that justify withdrawal. Note: Such events should also be 
reported as AEs. 
6. The participant is lost to follow-up. 
7. Other reasons (eg, pregnancy, development of contraindications of use of the IP). 
8. The participant withdraws consent, or the investigator or sponsor decides to 
discontinue their participation in the study. 
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4.2.1 Discontinuation From Study Vaccine 
Only a single dose booster vaccination will be administered to each participant; thus, 
discontinuation from study vaccine is not applicable. 
4.2.2 Withdrawal From the Study 
If a participant withdraws or is withdrawn from the study, the ET procedures as indicated in 
the SOE (Table 13-1) should be completed. 
The investigator will also withdraw a participant if the sponsor terminates the study. 
4.2.3 Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 2 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
If the participant continues to be unreachable, he/she will be considered to have withdrawn 
from the study. 
4.2.4 
Replacements 
Participants who withdraw may be replaced at the discretion of the sponsor after consultation 
with the SRT. In particular, any participants who are assigned to a group in error and not 
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vaccinated may be replaced. In general, participants who withdraw for reasons connected to 
the study vaccine (eg, safety concerns after study vaccination) should not be replaced. 
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5 Study Vaccines 
5.1 Method of Assigning Participants to Study Vaccine Groups 
Participants will receive study vaccine on Day 1 according to a specific cohort, dose group, 
and age group. Interactive response technology will be used to track enrollment. Biostatistics 
will generate the treatment schedule using SAS software Version 9.4 or later (SAS Institute 
Inc, Cary, North Carolina) for IRT, which will link sequential participant numbers to 
treatment codes. Note: If a participant is consented electronically, a participant number may 
be generated; however, that number will be updated to align with the IRT number after 
enrollment is complete for consistency in each participant’s study records. 
5.2 Study Vaccines Administered 
Study vaccine will be administered on Day 1. Study vaccine will be administered as a single 
IM injection of 0.3 mL in the deltoid area, preferably in the nondominant arm. 
Refer to the IB and Pharmacy Manual for further details regarding the study vaccine 
preparation and administration. 
5.3 Identity of Investigational Product 
Investigational product refers to the CV2CoV vaccine that will be administered during the 
study. 
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Gla x o S mit h Kli ne Bi ol o gicals S A  
C V 2 C o V m R N A Vacci ne  
Pr ot oc ol 2 1 7 7 4 1 ( C V 2 S A R S -C O V 2 -0 0 2 B S T ) A me n d me nt 2 
1 3 J u n  2 0 2 2  
C o nfi de ntial   
 
 
 
 
 T he dil ue nt c o m p ositi o n f or C V 2 C o V is 0. 9 % s o di u m 
c hl ori de. 
G S K Bi ol o gicals S A a n d/ or C ure Vac will pr o vi de a de q uate s u p plies of I P t o P P D f or 
distri b uti o n t o t he st u d y sites. T he f oll o wi n g I P will be use d i n t he st u d y: 
Ta ble  5- 1 
I n vesti g ati o n al Pr o d uct I nf or m ati o n 
Descri pti o n  
I n vesti g ati o n al Pr o d uct 
C V 2 C o V a 
 
 
 
W T  
 
 
a. 
Pr o d uct refere nce: C V 0 7 0 5 0 2 0 1.  
b.  
 
T he L N P e nca ps ulate d m R N A pr o d uct, C V 2 C o V, is s u p plie d i n glass vials as a sterile 
c oll oi dal dis persi o n i n a fr oze n li q ui d f or m ulati o n. A dil ue nt will be use d t o dil ute t he 
pr o d ucts t o t he a p pr o priate d ose le vels. 
Refer t o t he P har mac y Ma n ual f or a n y details re gar di n g bli n di n g re q uire me nts, st ora ge, a n d 
pre parati o n f or t he I P.  
Pa ge 4 1
C CI
C CI
C CI
C CI
C CI
C CI
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5.4 Management of Clinical Supplies 
5.4.1 Investigational Product Packaging and Storage 
Investigational product will be supplied in vials that will require further dilution and 
preparation procedures; please refer to the Pharmacy Manual for additional packaging and 
preparation details. The IP must be stored in a secure, restricted freezer and kept at the 
temperature noted in the Pharmacy Manual at each stage of preparation for IM 
administration. 
Once prepared and diluted for IM administration, refer to the Pharmacy Manual for storage 
conditions. The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all IP received and any discrepancies are reported 
and resolved before use of the IP.  
Refer to the Pharmacy Manual for further details regarding storage and preparation 
requirements. 
5.4.2 Investigational Product Accountability 
The investigator will maintain accurate records of receipt of all IP, including dates of receipt. 
In addition, accurate records will be kept regarding when and how much IP is administered to 
each participant in the study. Only participants enrolled in the study may receive the IP and 
only authorized site personnel may supply or administer the IP. Reasons for departure from 
the expected dispensing regimen must also be recorded. At the completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all IP will be reconciled and 
retained or destroyed according to applicable regulations. Further guidance and information 
for the final disposition of unused IP are provided in the Pharmacy Manual. 
5.4.3 Other Supplies 
Refer to the Pharmacy Manual for ancillary formulation preparation or injection materials 
that will be distributed by PPD to the study sites or that the study sites will need to procure.  
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5.5 Overdose Management 
An overdose is any dose of study vaccine given to a participant that exceeds the planned dose 
for an individual within a given dose group.  
There is no specific treatment recommended for an overdose. 
Any overdose must be promptly reported to PPD 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 medical monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities for at 
least 3 days. 
3. Document the quantity of the excess dose in the eCRF. 
Decisions regarding any overdoses will be made by the investigator in consultation with the 
medical monitor based on the clinical evaluation of the participant. 
5.6 Blinding 
Participants will receive study vaccine as described in Section 5.1. The study will be 
open-label. The laboratories responsible for immunogenicity analyses will be blinded. 
In the event of a quality assurance audit, auditors will be allowed access to study vaccine 
records at the study sites to verify that dispensing was performed accurately. 
A statistical and programming team may perform interim analyses during the study. 
Unblinded safety and immunogenicity summaries, if applicable, will be provided to the SRT 
to inform study decision for progressing enrollment (Section 7.8). 
5.7 Compliance With Study Vaccine 
All participants will be vaccinated at the study site by the investigator or designee, under 
medical supervision. The date and time of study vaccine administration will be recorded in 
the source documents and in the eCRF. The dose of study vaccination and participant 
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identification will be confirmed at the time of dosing by a member of the study site personnel 
other than the person administering the study vaccination.  
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site personnel.  
5.8 Prior, Concomitant, and Rescue Medications, Vaccines, and Therapies 
5.8.1 Prior and Concomitant Medications 
Use of all prior and concomitant medications (within 6 months of Screening) and 
vaccinations (within 18 months of Screening) will be recorded in the participant’s eCRF. The 
minimum requirement is that drug name and the dates of administration are to be recorded. 
This will include all prescription drugs and vaccinations. In addition, any herbal products, 
vitamins, minerals, and over-the-counter medications taken within 2 weeks of study 
vaccination should also be recorded in the participant's eCRF. Any changes in concomitant 
medications also will be recorded in the participant’s eCRF throughout the study. 
5.8.2 Allowed Concomitant Therapy 
Any concomitant medication deemed necessary for the welfare of the participant during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 
The following concomitant therapies are allowed during the study: 
• Acetaminophen/paracetamol  
• Contraception, as described in Appendix 13.2 
• Low-dose topical, ophthalmic, inhaled, and intranasal steroid preparations 
• Local intra-articular steroids that are expected to remain localized in the joint space in 
which they are administered 
• Inactivated influenza vaccines are allowed if received at least 14 days before or after 
study vaccination. Note: If other nonstudy vaccines are received during the study, 
participants may continue to complete the remaining study assessments. Any impact 
on the immunogenicity data will be addressed in the data analysis. 
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• Participants may take concomitant medications for management of medically stable 
chronic conditions as long as the medication and medical conditions are not 
exclusionary (Section 4.1.2) 
Participants will be allowed to receive a booster dose of a licensed or authorized (conditional 
regulatory approvals, including emergency use authorizations are acceptable) COVID-19 
vaccine, per national recommendations, if received after the Day 29 visit. 
No concomitant medications will be provided by the sponsor or PPD. 
5.8.3 Rescue Medicine 
There are no known rescue medications for the IP; supportive care should be provided to 
participants. 
5.9 Study Holding Rules 
The study holding rules in Table 5-2 will be applied independently to each dose group. 
 
 
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Table 5-2 
Study Holding Rules 
Study 
Holding Rule 
Study Holding Rule Description 
Number of 
Participants Needed to 
Trigger a Study Hold 
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 local or general solicited AE leading to hospitalization OR necrosis at 
the injection site; each with an event onset within the 7-day postvaccination 
period (Days 1 to 7) 
≥1 
1e 
Severe cases of SARS-CoV-2 infection 
≥2 
1f 
Any same or similar Grade 3 related unsolicited events, including but not 
limited to the identical MedDRA high-level term 
≥2 
1g 
Same Grade 3 solicited local or systemic AE in an investigational group 
>3 
1h 
Same Grade 3 or above abnormality in prespecified hematological or 
biochemical laboratory parameters with an event onset by Day 8 (± 1 day) 
postvaccination, except nonclinically significant lymphopenia 
≥3 
2a 
Any Grade 3 solicited events in an investigational group, with an event onset 
within the 7-day postvaccination period (Days 1 to 7) 
2 out of 3 first exposed 
participants 
3 out of 5 first exposed 
participants 
7 out of 16 first exposed 
participants 
9 out of 22 first exposed 
participants 
11 out of 28 first 
exposed participants 
12 out of 30 first 
exposed participants 
(combined younger and 
older adult age groups) 
2b 
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 (Days 1 to 7) postvaccination period  
 
2 out of 15 first exposed 
participants 
3 out of 30 first exposed 
participants 
(combined younger and 
older adult age groups) 
Study holding rules 1a through 1d will be assessed by the investigators on a continuous basis. 
Study holding rules will lead to a halting of the entire study, with the exception of study 
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holding rule 1c, which will lead to halting of the concerned cohort and the next cohorts with 
higher doses. 
Study holding rules 1e, 1f, 1g, 1h, 2a and 2b will be assessed by the SRT on an ongoing 
basis. An adaptive Bayesian logistic regression model will be used during SRT meetings 
(scheduled or ad-hoc according to Table 5-2) to evaluate the posterior probability for the 
percentage of severe solicited AEs at the current and the next dose (Appendix 13.3). A lower 
than 50% posterior probability, that the percentage is above the maximal tolerable dose, will 
be favorable to progress at the next dose. Each study holding rule will be applied per cohort 
and age group. Based on the historical Phase 1 data from CVnCoV, Moderna and Pfizer 
mRNA COVID vaccines, the maximum tolerable rate has been set up to 30%. 
The SRT will review all available safety data at scheduled time points and at the time when 
any of the study holding rules are met. A recommendation will be made to the sponsor on 
whether a cohort or group should be permanently stopped, modified, or continued 
unchanged. If a study holding rule is met, it will be escalated according to process to the SRT 
who will decide whether other participants can be enrolled/vaccinated. Medical judgment, 
taking into account all available safety data at the time of review, should be the basis for 
decision to continue the study or not.  
In the event of a halting of the study, ethical and regulatory authorities will be notified per 
local requirements. 
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6 Study Assessments and Procedures 
Before any study procedures are performed, all potential participants will be consented using 
an IRB/IEC-approved ICF. Additional procedural details related to the ICF are provided in 
Section 9.3. Study assessments will be performed in an outpatient setting at qualified study 
sites. Due to the ongoing pandemic, safety follow-up visits may be completed via televisits, 
as permitted by country regulations. In-person visits should be maintained in the study unless 
there is a public health emergency limiting access to study sites. During such an emergency 
or extenuating circumstance, televisits can be employed to keep personal access to subjects 
and ascertain their safety at a high level. 
Refer to the SOE table in Appendix 13.1 for a full list of visits and assessments (Table 13-1). 
A maximum of 150 mL of blood will be collected per participant per visit. This may include 
50 mL of blood collected at 2 visits for participants enrolled at sites where PBMCs are 
collected (ie, cell-mediated immunity subset). The maximum amount of blood collected over 
the 6-month duration of the study is approximately 800 mL. Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples. 
6.1 Safety and Reactogenicity Assessments 
Safety will be assessed through the collection and evaluation of solicited and unsolicited 
AEs, MAAEs, SAEs, and AESIs. Safety will also be assessed based on physical 
examinations, vital sign measurements, and clinical laboratory assessments. Refer to the SOE 
table in Appendix 13.1 for assessment time points and a full list of visit and assessments 
(Table 13-1). 
All suspected cases of COVID-19 in study participants will be diagnosed and clinically 
evaluated, which require unscheduled study site visits and additional SARS-CoV-2 
laboratory testing. 
Any abnormal laboratory test results or other safety assessments (eg, physical examinations, 
vital sign measurements), including those that worsen from baseline or are clinically 
significant in the medical and scientific judgment of the investigator, are to be recorded as 
AEs or SAEs as applicable. 
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6.1.1 Adverse Events 
6.1.1.1 Definitions 
6.1.1.1.1 
Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to the IP or their clinical significance. 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to the IP. Participants will be instructed to contact the 
investigator at any time after enrollment if any symptoms develop. 
A solicited AE is defined as an AE that is reported with onset within 7 days of study 
vaccination (Days 1 to 7), as recorded by participants in an eDiary (Section 6.1.1.5). After 
study vaccination all participants will be instructed to record selected local and systemic 
postvaccination reactions (solicited AEs) in an eDiary. Local solicited AEs will include 
injection site pain, redness, swelling, and lymphadenopathy. Systemic solicited events will 
include fever, headache, fatigue, myalgia, arthralgia, and chills. Solicited local and systemic 
AEs will be used to assess reactogenicity and will be assigned a grade as described in 
Section 6.1.1.2.1. Any such AEs reported after the 7-day window will be reported as 
unsolicited AEs. 
An unsolicited AE is defined as any AE that is volunteered from the participant and occurs 
within 28 days after vaccination. 
An MAAE is defined as an AE that results in a visit to a medical professional. Medically 
attended visits are defined as a telemedicine visit, physician’s office visit, urgent care visit, 
emergency room visit, hospitalization, or death. 
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6.1.1.1.2 
Serious Adverse Events 
An SAE is defined as any event that: 
• Results in death 
• Is immediately life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is a spontaneous miscarriage (see also Section 6.2) 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the participant or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.1.1.1.3 
Suspected Unexpected Serious Adverse Reactions 
A SUSAR is defined as an adverse reaction, the nature or severity of which is not consistent 
with the applicable product information (eg, IB for an unapproved IP). 
6.1.1.1.4 
Adverse Events of Special Interest 
An AESI (serious or nonserious) is defined as an AE or SAE of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor could be appropriate (ICH E2F; 
CIOMS VI). 
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For this study, AESIs will include the following events: 
• Virologically confirmed SARS-CoV-2 infections (see Section 6.6 for disease 
definitions) 
• Potential immune-mediated disorders (Appendix 13.4) 
• Anaphylaxis or severe hypersensitivity within 24 hours after study vaccine 
administration 
• Pericarditis or myocarditis 
Refer to Section 6.1.1.3.1 for reporting AESIs. 
6.1.1.2 Eliciting and Documenting Adverse Events 
Adverse events will be reported throughout the study. Nonserious AEs will be reported from 
the time of the administration of IP until 28 days after the administration of IP; SAEs will be 
reported from the time the participant signs the ICF until exit from the study. 
If the investigator learns of any SAE, including a death, at any time after a participant has 
been discharged from the study, and he/she considers the event to be reasonably related to the 
IP, the investigator must notify PPD Pharmacovigilance within 24 hours of learning of the 
event (Section 6.1.1.3.1). 
At every study visit, participants will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. 
In addition to participant observations, AEs identified from any study data (eg, laboratory 
values, physical examination findings) or identified from review of other documents (eg, 
participant eDiaries) that are relevant to participant safety will be documented on the AE 
page in the eCRF. 
As described in Section 6.1.1.1.1, participant eDiaries will be used to collect solicited AEs. 
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6.1.1.2.1 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the 
participant’s daily activities.  
Solicited AEs will be graded in intensity by the participant. The investigator will assess the 
maximum intensity that occurred over the duration of the event for all unsolicited AEs, 
including SAEs, recorded during the study. The assessment will be based on the 
investigator’s clinical judgment. 
The intensity of the following solicited events will be assessed as described in Table 6-1. 
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Table 6-1 
Intensity Scales for Solicited Symptoms 
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 
<2.5 cm 
1 
2.5 – 5 cm 
2 
5.1 – 10 cm 
3 
>10 cm 
Swelling at administration site 
0 
<2.5 cm 
1 
2.5 – 5 cm and does not interfere with activity 
2 
5.1 – 10 cm or interferes with activity 
3 
>10 cm or prevents daily activity 
Lymphadenopathya 
0 
None 
1 
Mild: No interference with activity 
2 
Moderate: Some interference with daily activity 
3 
Severe: Prevents daily activity 
Temperatureb 
0 
<38.0°C or <100.4°F 
1 
38.0 – 38.4°C or 100.4 – 101.1°F 
2 
38.5 – 38.9°C or 101.2 – 102.0°F 
3 
>38.9°C or >102.0°F 
Headache 
0 
Normal 
1 
Mild: Headache that is easily tolerated 
2 
Moderate: Headache that interferes with normal activity 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
1 
Mild: Fatigue that is easily tolerated 
2 
Moderate: Fatigue that interferes with normal activity 
3 
Severe: Fatigue that prevents normal activity 
Myalgia 
0 
Normal 
1 
Mild: No interference with daily activity 
2 
Moderate: Interferes with daily activity 
3 
Severe: Prevents daily activity 
Arthralgia 
0 
Normal 
1 
Mild: No interference with daily activity 
2 
Moderate: Interferes with daily activity 
3 
Severe: Prevents daily activity 
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 
a. 
Defined as localized axillary, cervical or supraclavicular swelling or tenderness ipsilateral to the vaccination arm. 
b. 
Refer to Section 6.1.4 for the definition of fever.  
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The intensity of AEs will be assigned to one of the following categories: 
• Grade 1 (Mild): An AE that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities. 
• Grade 2 (Moderate): An AE that is sufficiently discomforting to interfere with normal 
everyday activities. 
• Grade 3 (Severe): An AE that prevents normal, everyday activities. In adults, such an 
AE would, for example, prevent attendance at work and would necessitate the 
administration of corrective therapy. 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 3 is a 
category used for rating the intensity of an event; and both AEs and SAEs can be assessed as 
Grade 3. An event is defined as “serious” when it meets one of the predefined outcomes 
(Section 6.1.1.1.2). 
Refer to Section 13.5 (Appendix 5) for grading of laboratory-associated AEs. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity. Adverse events characterized as intermittent 
do not require documentation of onset and duration of each episode. 
6.1.1.2.2 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to the IP is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is 
any doubt as to whether a clinical observation is an AE, the event should be reported. 
The relationship or association of the IP in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
YES: 
There is a reasonable possibility that the IP contributed to the AE. 
NO: 
There is no reasonable possibility that the AE is causally related to the 
administration of IP. There are other, more likely causes and administration of 
IP is not suspected to have contributed to the AE. 
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6.1.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes, but is not limited to, the following: 
• Event term 
• Investigator-specified assessment of severity and causality to IP 
• Seriousness/grade 
• Time of onset of the event 
• Time of resolution of the event 
• Any required treatment or evaluations 
• Outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. MedDRA will be used to code all AEs. 
Any medical condition that is present at the time that the participant is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE.  
6.1.1.3.1 
Reporting Serious Adverse Events and Adverse Events of 
Special Interest 
Any AE that meets SAE criteria (Section 6.1.1.1.2) must be reported to PPD 
Pharmacovigilance within 24 hours after site personnel first learn of the event. Events should 
be captured electronically in the EDC system; however, if the EDC is unavailable, a backup 
paper option is available and this form can be faxed to the fax number listed below. 
 
SAE Hotline:  
+1-800-201-8725 
 
Fax: 
 
 
+1-888-488-9697 
Any AE that meets AESI criteria (Section 6.1.1.1.4) must be reported to PPD 
Pharmacovigilance within 24 hours after site personnel first learn of the event. 
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If the EDC is unavailable and a faxed form is used to report an SAE or AESI, the site should 
update the EDC with exactly the same information reported on paper (by fax) as soon as 
possible after the EDC becomes available again.  
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IP under clinical investigation. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information from the sponsor will review and then file it as appropriate and 
will notify the IRB/IEC according to local requirements. 
6.1.1.3.2 
Reporting Suspected Unexpected Serious Adverse Reactions 
The sponsor will promptly evaluate all SUSARs against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to investigators, 
IRB/IECs, and applicable health authorities based on applicable legislation. 
Reporting requirements will also be based on the investigator’s assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
6.1.1.4 Follow-Up of Participants Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, the event is considered to be stable, or the participant is lost to follow-up. 
6.1.1.5 eDiary 
An eDiary will be used after study vaccination to record solicited local injection site and 
systemic AEs, body temperature, and any concomitant medications during 7 days after study 
vaccination (Days 1 to 7) for reactogenicity assessment. Study site personnel will instruct the 
participants on use of the eDiary. The site staff will review the eDiary data at Day 8. 
Participants will be instructed to contact the study site as needed at any time point during the 
study with safety concerns. Any AE that meets SAE criteria (Section 6.1.1.1.2) must be 
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reported to PPD Pharmacovigilance immediately (ie, within 24 hours) after site personnel 
first learn of the event (Section 6.1.1.3.1). 
6.1.2 Clinical Safety Laboratory Assessments 
The following laboratory assessments will be performed at the time points specified in the 
SOE (Table 13-1): 
Hematology: 
Basophils, eosinophils, erythrocytes (red blood cells), hemoglobin, 
leukocytes (white blood cells), lymphocytes, monocytes, 
neutrophils, and platelets 
Chemistry: 
Bilirubin (total and direct), alkaline phosphatase, alanine 
aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, and uric acid 
SARS-CoV-2: 
• SARS-CoV-2 serology (Ab), which will include S and N protein 
for prevaccination timepoints and N protein for postvaccination 
timepoints to monitor for undetected SARS-CoV-2 infections 
• SARS-CoV-2 RT-PCR (nasal swab) 
HIV/HBV/HCV 
• Hepatitis B surface antigen test 
• HIV 4th generation antigen/Ab test 
• Anti-HCV test 
Other analyses: 
Female participants of childbearing potential:  
β-human chorionic gonadotropin (serum test at Screening; urine 
test at additional time points)  
Serum FSH, to confirm postmenopausal status (Section 13.2) 
The clinical safety laboratory assessments will be performed by a local or central laboratory 
as detailed in the Laboratory Manual. Screening laboratory tests and SARS-CoV-2 RT-PCR 
may be repeated once for enrollment requirements.  
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The investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study. If the laboratory reports are not 
transferred electronically, the values must be filed with the source information (including 
reference ranges). Any clinically relevant laboratory results should be reported as an AE or 
SAE, as appropriate, using the AE intensity grading (Section 6.1.1.2.1). 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or medical monitor. If such 
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. 
All protocol-required laboratory assessments must be conducted in accordance with the 
Laboratory Manual. If laboratory values from nonprotocol-specified laboratory assessments 
performed at the local study site laboratory require a change in participant management or 
are considered clinically significant by the investigator, then the results must be recorded in 
the eCRF. 
6.1.3 Physical Examinations 
A complete physical examination including height and weight will be performed at Screening 
as indicated in the SOE (Table 13-1). Symptom-directed physical examinations will be 
performed as clinically indicated at subsequent visits. 
6.1.4 Vital Signs 
Vital sign measurements will be performed at the time points indicated in the SOE 
(Table 13-1). Vital signs will be measured in a sitting position after at least 5 minutes of rest 
and will include temperature, pulse, respiration rate, oxygen saturation by pulse oximetry, 
and systolic and diastolic blood pressure. For participants who have an abnormal blood 
pressure reading at Screening, blood pressure measurement may be repeated and the blood 
pressure measurement for eligibility may be based on an average of up to 3 blood pressure 
measurements, to better assess whether known hypertension is well controlled or to evaluate 
for undiagnosed hypertension. These assessments can be made on separate visits during the 
screening period to provide more comprehensive sampling. Self-reported baseline 
measurements documented in a personal log or from medical records taken on consecutive 
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days in the week before the screening visit can also be accepted, subject to the investigator´s 
discretion. Vital sign measurements should be collected before and after study vaccination on 
Day 1. Vital sign measurements should also be performed before any scheduled blood 
collection. Per standard clinical practice, vital sign measurements may be repeated per 
investigator discretion. 
Body temperature will be measured throughout the study. Participants who are febrile 
(temperature ≥38.0°C or ≥100.4°F) before study vaccination should be rescheduled for study 
vaccination within the relevant window period of Screening. 
6.1.5 Sentinel Participant Safety Follow-up Call 
A safety follow-up telephone call to each sentinel participant in each dose group will be 
performed on Day 2 (at least 20 hours postvaccination). Vaccination of the next sentinel 
participant will proceed, provided the safety was acceptable for the prior sentinel(s) per 
investigator’s assessment. 
6.2 Pregnancy Reporting 
Any pregnancy that occurs during study participation must be reported using the PPD paper 
pregnancy report form (Section 13.2) faxed to the same fax number as may be used for 
backup SAE reports (Section 6.1.1.3.1). To ensure participant safety, site personnel must 
report each pregnancy to PPD within 24 hours of learning of its occurrence. The pregnancy 
must be followed to determine outcome (including spontaneous miscarriage, elective 
termination, normal birth, or congenital abnormality) and status of mother and child, even if 
the participant was discontinued from the study. Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Spontaneous 
miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the participant has completed the study, and considered by the investigator as possibly 
related to the study vaccine, must be promptly reported to PPD as described in 
Section 6.1.1.3.1. 
6.3 Pharmacokinetics 
Pharmacokinetics will not be assessed in this study. 
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6.4 Pharmacodynamics and Biomarkers 
Pharmacodynamics and biomarkers will not be assessed in this study. 
6.5 Immunogenicity Assessments 
Immunogenicity evaluations will be performed at sponsor designated laboratories as detailed 
in the Laboratory Manual. 
Blood samples will be collected to evaluate vaccine-induced neutralizing and binding (IgG) 
Ab levels and cell-mediated immunity as indicated in the SOE (Table 13-1). On Day 1, the 
immunogenicity sample should be collected before study vaccine administration. 
Neutralizing Ab levels against pseudovirus bearing spike from SARS-CoV-2 WT, and 
potentially pseudovirus bearing spike protein from other variants will be measured. Binding 
Ab IgG levels against SARS-CoV-2 S protein, RBD, N protein (from WT), and SARS-CoV-2 
spike antigens (from other variants) will be measured. Antispike (from WT and potentially 
other variants) T-cell responses will be explored. 
At a subset of study sites, PBMC samples will be collected and assessed by ICS assay 
(Table 13-1) to evaluate, but not limited to, antispike specific T-cell profiles. Additional 
T-cell parameters may be evaluated. 
6.6 SARS-CoV-2 and COVID-19 Disease Assessment and Definitions 
Vaccine efficacy will not be evaluated in this study, but all virologically confirmed 
SARS-CoV-2 infections should be reported by the participant and documented as clinical 
events as well as AESIs (Section 6.1.1.1.4). 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. Clinical serology testing, including N protein, will be 
performed at Screening, Day 1, Day 85, and Day 180 to monitor for undetected SARS-CoV-2 
infections. A nasal (nasopharyngeal or mid-turbinate) swab sample is scheduled for 
SARS-CoV-2 RT-PCR testing at Screening and Day 1. The screening sampling and 
SARS-CoV-2 RT-PCR testing must be performed within the 7 days before Day 1.  
All participants with suspected COVID-19 are required to have an unscheduled visit for 
suspected COVID-19. At this visit, participants will undergo the following assessments:  
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• Medical history  
• SARS-CoV-2 RT-PCR (nasal swab [nasopharyngeal or mid-turbinate])  
• Physical examination  
• Vital sign measurements 
• Review of adverse events  
• Concomitant medication/vaccination 
All participants with confirmed COVID-19 are required to have an unscheduled COVID-19 
convalescent visit. At this visit, participants will undergo the following assessments:  
• Medical history 
• Physical examination  
• Vital sign measurements  
• COVID-19 evaluation  
• Review of adverse events 
• 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 
virologically confirmed cases of SARS-CoV-2 infection or COVID-19 during the study will 
be assigned one of the following definitions: 
Asymptomatic 
SARS-CoV-2 
infection: 
Virologically confirmed SARS-CoV-2 by RT-PCR or 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 
Symptomatic 
COVID-19: 
Virologically confirmed by RT-PCR and include one or more of the 
following: 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 
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Severe COVID-19: 
Laboratory-confirmed SARS-CoV-2 infection with any of the 
following: 
• Clinical signs at rest indicative of severe systemic illness 
(respiratory rate ≥30 per minute, heart rate ≥125 per minute, 
blood oxygen saturation ≤93% on room air at sea level or 
partial pressure of oxygen/fraction of inspired oxygen 
<300 mmHg) 
• Respiratory failure (defined as needing high-flow oxygen, 
noninvasive ventilation, mechanical ventilation, or 
extracorporeal membrane oxygenation) 
• 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 an intensive care unit 
• Death 
The genetic sequence of the spike-encoding gene or the genome of SARS-CoV-2 strains will 
also be evaluated in relation to the vaccine sequence, when available. 
6.7 Genetics 
Human genetics will not be assessed in this study. 
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Gla x o S mit h Kli ne Bi ol o gicals S A  
C V 2 C o V m R N A Vacci ne  
Pr ot oc ol 2 1 7 7 4 1 ( C V 2 S A R S -C O V 2 -0 0 2 B S T ) A me n d me nt 2 
1 3 J u n  2 0 2 2  
C o nfi de ntial   
7  St atistic al C o nsi der ati o ns  
A nal yses will be perf or me d b y treat me nt gr o u p c o m bi ni n g t he y o u n ger a n d ol der a d ult 
partici pa nts t o get her, u nless s pecifie d ot her wise. S u ba nal yses ma y be perf or me d wit hi n eac h 
a ge gr o u p. F or cate g orical varia bles, fre q ue ncies, a n d perce nta ges will be prese nte d. 
C o n ti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics ( n u m ber of partici pa nts, 
mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m). 
7. 1  
St atistic al H y p ot hesis  
T here is n o h y p ot hesis testi n g i n t his st u d y; w here statistical met h o ds are a p plie d, t he 
e m p hasis will be o n esti mati o n wit h 9 5 % CIs.  
7. 2  S a m ple Size Deter mi n ati o n  
T he sa m ple size is base d o n cli nical c o nsi derati o ns t o i nf or m d ose re gi me n decisi o ns f or 
c o nti n ue d cli nical de vel o p me nt.  
A p pr o xi matel y 1 8 0 partici pa nts will be e nr olle d i n t his P hase 1 st u d y, wit h 6 d ose- le vel 
c o h orts eac h c o m prisi n g 2 a ge gr o u ps. Wit h 3 0 partici pa nts i n eac h c o h ort, t here is a 7 8. 5 % 
pr o ba bilit y t o o bser ve at least 1 A E if t he i nci de nce rate is 5 % a n d a 9 5. 8 % pr o ba bilit y t o 
o bser ve at least 1 A E if t he i nci de nce rate  is 1 0 %. Wit h 3 0 partici pa nts i n eac h c o h ort, a 1 0 % 
u ne val ua ble rate f or i m m u n o ge nicit y res ults, a n d a sta n dar d de viati o n of 0. 4 5 f or l o g 1 0-
tra nsf or me d i ncrease fr o m Da y 1, t he rati o of t he u p per li mit of a 2-si de d 9 5 % CI a n d t he 
p oi nt esti mate of G MI is 1 . 5. 
7. 3  A n al ysis Sets  
T he f oll o wi n g a nal ysis sets will be use d i n t he statistical a nal yses.  
•  E nr olle d Set: All partici pa nts w h o ha ve a si g ne d I C F a n d were assi g ne d t o a gr o u p, 
vacci nate d, or ha d a n i m m u n o ge nicit y bl o o d dra w. 
•  P er Pr ot oc ol Set : T he P P set i ncl u d es all eli gi ble partici pa nts w h o recei ve d a d ose of 
st u d y i nter ve nti o n I P per pr ot oc ol a n d w h o ha ve val ues f or pre d ose a n d Da y 2 9 
ne utralizi n g A b titers a gai nst pse u d o vir us beari n g S pr otei n fr o m  
 
Res ults fr o m a bl o o d sa m ple de viati n g fr o m t he d osi n g or bl o o d sa m pli n g sc he d ule 
(Ta ble  1 3- 1) a n d res ults fr o m a bl o o d sa m ple after i nterc urre nt c o n diti o ns t hat ma y 
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interfere with immunogenicity (eg, virologically confirmed SARS-CoV-2 infections 
or immunosuppressive or immunodeficient conditions) or from participants who 
received COVID-19 vaccination within 29 days postvaccination will be excluded 
from the PP set. The analysis will be done according to the dose that participants 
received at Day 1. The PP set will be used for the immunogenicity analyses.  
• Safety Set: All participants who received any IP. All analyses using the Safety Set will 
group participants according to the study vaccine actually received. The Safety Set 
will be used for safety analyses. 
7.4 Description of Subgroups to Be Analyzed 
Subgroup analysis for safety and immunogenicity endpoints may be performed in selected 
groups and will be described in the SAP. 
7.5 Statistical Analysis Methodology 
7.5.1 General Considerations 
Statistical analysis will be performed using SAS software Version 9.4 or later. Details of the 
statistical analyses, methods, and data conventions are described in the SAP. No formal 
significance testing will be performed. 
7.5.2 Analysis of the Primary Safety Endpoints 
The primary safety endpoints as detailed in Section 2 will be analyzed as described in the 
SAP. For all safety endpoints, descriptive summary statistics will be provided for the Safety 
Set. Safety data listings will also be provided and graphical presentations will be considered 
as needed. 
In addition to the planned summary of SAEs throughout the study, any SAEs that are 
reported will also be summarized within 28 days of study vaccine administration. 
7.5.3 Analysis of Secondary Immunogenicity Endpoints 
The secondary endpoints detailed in Section 2 will be analyzed as described in the SAP. 
Listings will be provided and graphical presentations will be considered as needed. 
For the immunogenicity endpoints, the GMTs of specific Ab with corresponding 95% CIs at 
each time point and percentage of participants with seroresponse (≥4-fold rise from baseline) 
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Gla x o S mit h Kli ne Bi ol o gicals S A  
C V 2 C o V m R N A Vacci ne  
Pr ot oc ol 2 1 7 7 4 1 ( C V 2 S A R S -C O V 2 -0 0 2 B S T ) A me n d me nt 2 
1 3 J u n  2 0 2 2  
C o nfi de ntial   
at Da y 2 9 after t he b o oster d ose, a n d G MI fr o m baseli ne of s pecific A b wit h c orres p o n di n g 
9 5 % CIs at eac h p ost vacci nati o n ti me p oi nt o ver pre vacci nati o n baseli ne will b e pr o vi de d b y 
d ose gr o u p. T he G M T, t he G MI, a n d t heir 9 5 % CI i n all c o h orts will be a nal yze d usi n g a n 
A N C O V A wit h treat me nt a n d a ge gr o u p as fi xe d fact ors a n d pre vacci nati o n baseli ne val ue as 
a c o varia ble. 
7. 5. 4  A n al yses of E x pl or at or y I m m u n o ge nicit y E n d p oi nts  
T he e x pl orat or y e n d p oi nts detaile d i n Secti o n 2  will be a nal yze d as descri be d i n t he S A P. F or 
c o nti n u o us i m m u n o ge nicit y vari a bles, s u m mar y statistics, CIs, a n d i nter q uartile ra n ges will 
be pr o vi de d. I m m u n o ge nicit y data listi n gs will als o be pr o vi de d a n d gra p hical prese ntati o ns 
will be c o nsi dere d as nee de d.  
7. 5. 5  S afet y A n al yses  
Safet y a n d react o ge nicit y are t he pri mar y st u d y o bjecti ves; t h us, refer t o Secti o n 7. 5. 2  f or t he 
a nal ysis descri pti o n.  
7. 5. 6  Ot her A n al yses  
S u m mar y statistical a nal yses will be pr o vi de d f or de m o gra p hics a n d vita l si g ns at baseli ne. 
S u b gr o u p a nal ysis f or safet y a n d i m m u n o ge nicit y e n d p oi nts ma y be perf or me d i n selecte d 
gr o u ps a n d will be descri be d i n t he S A P. 
7. 6  H a n dli n g of Missi n g D at a  
Details re gar di n g ha n dli n g of missi n g safet y, react o ge nicit y, a n d i m m u n o ge nicit y d ata will be 
descri be d i n t he S A P.  
7. 7  I nteri m A n al yses 
A first i nteri m a nal ysis of safet y a n d i m m u n o ge nicit y data c o veri n g at least ne utralizi n g A b 
titers a gai nst pse u d o vir us beari n g S pr otei n fr o m 
 u p t o 1 4 da ys after st u d y 
vacci ne a d mi nistrati o n  i n all partici pa nts e nr olle d i n C o h orts 1, 2, a n d 3 will be perf or me d. A 
sec o n d i nteri m a nal ysis of safet y a n d i m m u n o ge nicit y data will be perf or me d 1 4 da ys after 
partici pa nts i n C o h orts 4 a n d 5 ha ve recei ve d st u d y vacci ne. Details of t hese i nteri m a nal yses 
will be descri be d i n t he S A P. 
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7.8 Safety Review Team 
The SRT activities and committee formation will be described in a separate SRT charter. 
Cohorts 1 and 2 
In the Cohort 1, the SRT will review sentinel Days 1 to 8 safety data (including Day 8 
laboratory data) for the 2 µg and 4 µg dose in the younger age groups and make 
recommendations to open the enrollment in the older age group. The SRT will also review 
sentinel Day 8 safety data for the 2 µg, 4 µg, and 8 µg dose groups and make 
recommendations to progress to expanded enrollment in the same dose cohort and to begin 
enrollment in the next higher cohort. 
Cohorts 3, 4, 5 
The SRT will review sentinel Days 1 to 8 safety data (including Day 8 laboratory data) for 
the 12 µg, 16 µg, and 20 µg dose groups and make recommendations to progress to expanded 
enrollment in the same dose cohort. The SRT will review Day 8 safety data for the entire 
dose group (eg, 12 µg) and make recommendations to begin enrollment in the next higher 
dose cohort (eg, 16 µg). 
The SRT will take into consideration the study holding rules in Section 5.9. 
The SRT review based on interim analysis data will be performed as described in the SRT 
charter. 
Based on SRT review and recommendations, dose groups may be dropped at any time during 
the study if an unfavorable safety profile is observed in that group or based on safety or 
immunogenicity data from other groups. 
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8 Data Quality Assurance 
This study will be conducted according to the ICH E6(R2) risk and quality processes 
described in the applicable procedural documents. The quality management approach to be 
implemented in this study will be documented and will comply with the current ICH 
guidance on quality and risk management. The sponsor assumes accountability for actions 
delegated to other individuals (eg, contract research organizations). 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the participants treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include eDiary information, 
laboratory reports, etc. 
Investigative site personnel will enter participant data into an EDC system. The analysis data 
sets will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable PPD standards 
and data cleaning procedures to ensure the integrity of the data (eg, removing errors and 
inconsistencies in the data). Adverse event terms will be coded using MedDRA, an internal 
validated medical dictionary, and concomitant medications will be coded using WHODRUG. 
After database lock, each study site will receive electronic files of study media (eCRF data) 
from PPD, including full discrepancy and audit history. Additionally, electronic files of all of 
the study site’s data from the study will be created and sent to GSK Biologicals SA for 
storage. PPD will maintain a duplicate copy in their electronic records. In all cases, 
participant initials will not be collected or transmitted to the sponsor.  
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9 Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an 
IRB/IEC before human participation in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study participants, and 
any other written information regarding this study to be provided to the participant must be 
approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC 
compliance with ICH harmonised tripartite guideline E6(R2): GCP will be maintained by the 
site and will be available for review by the sponsor or its designee. 
The IRB/IEC approval should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to participants. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
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9.3 Participant Information and eConsent 
Documented informed consent, in compliance with regulatory authority regulations and US 
Title 21 CFR Part 50, shall be obtained from each participant before entering the study or 
performing any unusual or nonroutine procedure that involves risk to the participant. Consent 
may be collected through a digital method or remote solution if allowed by country and site 
regulations. Informed consent will ideally be obtained via eConsent with a backup paper 
consent option if needed. If any institution-specific modifications to study-related procedures 
are proposed or made by the site, the consent should be reviewed by the sponsor or its 
designee or both before IRB/IEC submission. Once reviewed, the consent will be submitted 
by the investigator to the IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the study, all active participants must be reconsented using the revised 
form. 
Before recruitment and enrollment, each prospective participant will be given a full 
explanation of the study, be allowed to read the approved ICF, and have any questions 
answered. Once the investigator is assured that the participant understands the implications 
of participating in the study, the participant will be asked to give consent to participate in the 
study by signing the ICF via eConsent or a backup paper option. The authorized person 
obtaining the informed consent also documents this on the ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research (if applicable) and explain/address the exploratory 
research portion of the study. Participant medical records need to state that documented 
informed consent was obtained. 
For eConsent, the original signed version of the ICF is retained within the eConsent platform, 
and downloaded versions are provided to the participant and for the investigator records. In 
the event a backup paper consent is used, the investigator shall retain the signed original 
ICF(s) and give a copy of the signed original form to the participant. 
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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant, except as necessary for monitoring and auditing by the sponsor, 
its designee, the FDA, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Data Protection 
All personal data collected related to participants, investigators, or any person involved in the 
study, which may be included in the sponsor’s databases, shall be treated in accordance with 
local data protection law.  
Data collected must be adequate, relevant, and not excessive, in relation to the purposes for 
which they are collected. Each category of data must be properly justified and in line with the 
study objective. 
10.3 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year after the completion of the study. 
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Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the participant’s disease. 
10.4 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and Title 21 of the CFR by providing all essential documents. 
10.5 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of participants begins. 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
The investigator agrees to submit reports of SAEs to the sponsor and/or IRB/IEC according 
to the timeline and method outlined in the protocol. In addition, the investigator agrees to 
submit annual reports to the study site IRB/IEC as appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
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10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IP. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. No records 
may be transferred to another location or party without written notification to the sponsor. 
10.9 Publications and Results Disclosures 
During or after completion of the study, the data may be considered for reporting at a 
scientific meeting, publication in a scientific journal, or other public format. The procedures 
and timing for reporting at a scientific meeting, publication in a scientific journal, or other 
public format will be in accordance with GSK policy and the sponsor has final approval 
authority over all such issues. In these cases, the sponsor will be responsible for these 
activities and will work with the investigators to determine how the manuscript(s) is written 
and edited, the number and order of authors, the publication to which it will be submitted, 
and other related issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 
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11 Study Management 
The study administrative structure will include an SRT, contract research organization, third 
party vendors, laboratories, etc. 
11.1 Monitoring 
11.1.1 
Monitoring of the Study 
This study will be monitored according to an approved monitoring plan based on the 
objectives, purpose, design, and complexity of the study. The investigator will allocate 
adequate time for all monitoring visits and between visits to facilitate the requirements of the 
study and study timelines. The investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given direct access to all study-related 
documents and study-related facilities (eg, pharmacy, diagnostic laboratory), phone, fax, and 
internet and has adequate space to conduct the monitoring visit, if conducted on site. Site 
monitoring is conducted to ensure that the rights of human participants are protected, that the 
study is implemented in accordance with the protocol and/or other operating procedures, and 
that the study uses high quality data collection processes. The monitor will evaluate study 
processes based on PPD standards, ICH E6, and all applicable, regulatory guidelines. 
Monitoring details describing the strategy (eg, risk-based initiatives in operations and quality, 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or onsite monitoring), are provided in the monitoring 
plan. 
11.1.2 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency (eg, FDA or other regulatory agency) access to all 
study records. 
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The investigator should promptly notify the sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 
Modification of the Protocol 
Any changes in the required procedures defined in this protocol, except those necessary to 
remove an apparent, immediate hazard to the participants, must be reviewed and approved by 
the sponsor or designee. Amendments to the protocol (including emergency changes) must be 
submitted in writing to the investigator’s IRB/IEC, along with any applicable changes to the 
ICF, for approval before participants can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol or to 
local regulations or ICH GCP guidelines that may or may not result in a significant, 
additional risk to the participant or impacts the integrity of study data. 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard/safety risk to 
study participants without prior IRB/IEC approval. As soon as possible after such an 
occurrence, the implemented deviation or change, the reasons for it, and any proposed 
protocol amendments should be submitted to the IRB/IEC for review and approval, to the 
sponsor for agreement, and to the regulatory authorities, where required. 
In order to keep deviations from the protocol to a minimum, the investigator and relevant site 
personnel will be trained in all aspects of study conduct by the sponsor/sponsor 
representative. This training will occur either as part of the investigator meeting or site 
initiation. Ongoing training may also be performed throughout the study during routine site 
monitoring activities. 
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11.3 Study Termination 
Although GSK Biologicals SA has every intention of completing the study, GSK Biologicals 
SA reserves the right to discontinue the study at any time for clinical or administrative 
reasons. 
The end of the study is defined as the date on which the last participant completes the last 
visit (includes follow-up visit). 
If the study is prematurely terminated or suspended, the sponsor or investigator shall 
promptly inform the investigators, the IRB/IECs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements. The investigator shall promptly inform 
the participant and should assure appropriate participant therapy and/or follow-up. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
final data are summarized and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
reports in marketing applications (as applicable) meet the standards of the ICH harmonised 
tripartite guideline E3: Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the final report, the sponsor will provide the investigator with the 
summary of the study results. The investigator is encouraged to share a summary of the 
results with the study participants, as appropriate. The study results will be posted on 
publicly available clinical trial registers. 
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12 References 
CureVac. Second-generation COVID-19 vaccine candidate, CV2CoV, demonstrates high 
immunogenicity against virus variants in preclinical study. [Internet]. 2021 [cited 
2021 Jul 07]. Available from: https://www.curevac.com/en/2021/05/13/second-generation-
covid-19-vaccine-candidate-cv2cov-demonstrates-high-immunogenicity-against-virus-
variants-in-preclinical-study/  
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Biologics Evaluation and Research (US). Guidance for industry. Toxicity grading scale 
for healthy adult and adolescent volunteers enrolled in preventative vaccine clinical trials. 
September 2007 [cited 2021 Jul 09]. Available from: 
https://www.fda.gov/media/73679/download  
Kremsner PG, Guerrero RAA, Arana E, et al. Efficacy and Safety of the CVnCoV 
SARS-CoV-2 mRNA Vaccine Candidate: Results from Herald, a Phase 2b/3, Randomised, 
Observer-Blinded, Placebo-Controlled Clinical Trial in Ten Countries in Europe and Latin 
America. [Preprint from The Lancet]. 2021 [cited 2021 09 Sep]. Available from: 
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3911826  
Roth N, Schӧn J, Hoffmann D, et al. CV2CoV, an enhanced mRNA-based SARS-CoV-2 
vaccine candidate, supports higher protein expression and improved immunogenicity in rats. 
[Internet]. 2021 [cited 2021 Jul 07]. Available from: 
https://www.biorxiv.org/content/10.1101/2021.05.13.443734v1.full.pdf  
World Health Organization. WHO Director-General’s opening remarks at the media briefing 
on COVID-19 – 11 March 2020 [Internet]. 2020 [cited 2021 Jun 11]. Available from: 
https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-
media-briefing-on-covid-19---11-march-2020  
World Health Organization (WHO). WHO coronavirus (COVID-19) dashboard [Internet]. 
2021 [cited 2021 Jul 07]. Available from: https://covid19.who.int/  
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13 Appendices 
13.1 Appendix 1: Schedule of Events 
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Table 13-1 
Schedule of Events 
 
Screening 
D1 
D2a 
D8 
D15 
D29 
D85 
D180 
(EOS)  
Early 
Termination 
Visit 
Unscheduled 
Visit for 
Suspected 
COVID-19b 
Unscheduled 
COVID-19 
Convalescent 
Visitc 
Window 
D–14 to –1
0 
NA 
±1 
±3 
±3 
±5 
±7 
±7 
NA 
NA 
Visit 
1 
2 
NA 
3 
4 
5 
6 
7 
7 
NA 
NA 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Reassess study vaccine eligibilityd 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
vaccination history) 
X 
 
 
 
 
 
 
 
X 
X 
X 
Treatment assignment 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical SARS-CoV-2 serologyf 
X 
X 
 
 
 
 
X 
X 
X 
 
 
SARS-CoV-2 RT-PCR (nasal 
swab)g 
X 
X 
 
 
 
 
 
 
 
X 
 
Physical examinationh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurementsi 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical safety laboratory testsj 
X 
X 
 
X 
 
 
 
 
 
 
 
Blood sample for binding IgGf, k 
 
X 
 
X 
X 
Xi 
X 
X 
X 
 
 
Blood sample for neutralizationf, k 
 
X 
 
X 
X 
Xi 
X 
X 
X 
 
 
Blood for PBMC preparation for 
ICS (subset of participants) 
 
X 
 
 
X 
 
 
 
 
 
 
Vaccine administration 
 
X 
 
 
 
 
 
 
 
 
 
COVID-19 evaluationc 
 
 
 
 
 
 
 
 
 
 
Xl 
Initiate eDiary for solicited AEs 
 
X 
 
 
 
 
 
 
 
 
 
Site staff review of eDiary 
 
 
X 
X 
 
 
 
 
 
 
 
Adverse eventsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/vaccination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Note: Due to the ongoing pandemic, safety follow-up visits may be completed via televisits, as permitted by country regulations. In-person visits should be 
maintained in the study unless there is a public health emergency limiting access to study sites. During such an emergency or extenuating 
circumstance, televisits can be employed to keep personal access to subjects and ascertain their safety at a high level. 
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a. 
A safety follow-up telephone call to each sentinel participant will be performed on Day 2 prior to the vaccination of the next participant. 
b. 
Required for participants with suspected COVID-19.  
c. 
Required for participants with confirmed COVID-19.  
d. 
Prior to study vaccine administration, participants will be reassessed for development of any new condition that would be considered exclusionary including acute 
illness, pregnancy, or development of new risk factors for severe COVID-19 illness. Assessment will be based on pregnancy test results, participant-reported 
symptomology, vital sign measurements, and physical examination findings. (Note: Sentinel participants will be required to remain at the study site for 
approximately 4 hours after study vaccination for observation. All other participants will be required to remain at the study site for approximately 60 minutes after 
study vaccination for observation.) 
e. 
WOCBP only: A serum pregnancy test will be performed at Screening. A urine pregnancy test by dipstick will be performed prior to study vaccination. Negative 
confirmation is required prior to study vaccine administration. 
f. 
Clinical SARS-CoV-2 serology testing will be performed at Screening and on D1 to confirm the serostatus of the participant and on D85 and D180 for detection 
of SARS-CoV 2 infection during the study. On D1, the serology sample should be collected before study vaccine administration. At baseline, D85, and D180 the 
serology analysis will include N protein to monitor for undetected SARS-CoV-2 infections. Binding IgG and neutralization will only be obtained at Day 85 and 
D180 in participants who did not receive a licensed or authorized COVID-19 vaccine after Day 29.  
g. 
SARS-CoV-2 nasopharyngeal or mid-turbinate swab for RT-PCR diagnostic testing will be performed at Screening for eligibility and Day 1 for analysis (result 
not required for eligibility). The screening sample for RT-PCR testing must be obtained and tested within the 7 days before Day1. Additional swabs may be taken 
at any visit (or between visits) as clinically indicated according to institutional practice. 
h. 
A complete physical examination including height and weight will be performed at Screening. Symptom-directed physical examinations will be performed as 
clinically indicated at subsequent visits. 
i. 
Vital sign measurements (temperature, pulse rate, oxygen saturation by pulse oximetry, respiration rate, and blood pressure) should be collected before and after 
study vaccination on D1. Vital sign measurements should also be performed before any scheduled blood collection. Participants who are febrile (temperature 
≥38.0°C or ≥100.4°F) before study vaccination on D1 should be rescheduled for study vaccination within the relevant window period of Screening.  
j. 
Clinical safety laboratory testing will include hematology and serum chemistry. Screening laboratory tests may be repeated once for enrollment requirements. 
HIV 1/2, HB surface antigen, and anti-HCV testing will be performed at Screening only. Unscheduled visit may occur for the evaluation and follow-up of any AE. 
At unscheduled visits, clinical safety laboratory testing will be done as per investigator decision. 
k. 
Blood draws for immunogenicity assessments (binding IgG and neutralization) after D29 will only be obtained from participants who have not yet received a 
COVID-19 booster vaccination with an authorized or licensed product. 
l. 
Participants will be instructed to inform the investigator in the event of a positive SARS-CoV-2 diagnostic test. In this case, he/she will be invited to perform an 
unscheduled visit on site for COVID-19 evaluation according to the definitions provided in Section 6.6. All effort should be made by the investigator to ensure the 
disease assessment is performed in a timely manner versus the test results. 
m. Solicited local and systemic AEs will be collected during the 7 days after study vaccination (Days 1 to 7) via eDiaries. Unsolicited AEs will be recorded for 28 
days after study vaccination. SAEs, MAAEs, and AESIs will be collected for the duration of the study. 
 
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13.2 Appendix 2: Contraceptive Guidance and Pregnancy Information 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of IP, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
o A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement 
>40 IU/L (or mIU/mL) is required.  
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• Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
This contraception guidance is applicable to WOCBP in a heterosexual relationship (ie, this 
guidance does do not apply to participants in a same-sex relationship).  
True abstinence is 100% of time no sexual intercourse (male’s penis enters the female’s 
vagina). Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods, 
and withdrawal are not acceptable methods of contraception).  
Acceptable forms of primary contraception include monogamous relationship with a 
vasectomized partner who has been vasectomized for 180 days or more prior to the 
participant’s study vaccination, intrauterine devices, birth control pills, tubal ligation, and 
injectable/implantable/insertable hormonal birth control products.  
WOCBP must use at least 1 highly effective form of contraception for at least 30 days prior 
to study vaccination to 3 months after study vaccination. 
Collection of Pregnancy Information from Female Participants Who Become Pregnant 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the PPD paper pregnancy report form and faxed to the same fax number 
as may be used for backup SAE reports within 24 hours after site personnel learn of a 
participant's pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
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• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• Any poststudy pregnancy-related SAE considered reasonably related to the IP by the 
investigator will be reported to the sponsor as described in Section 6.1.1.3. 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. 
 
 
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13.3 Appendix 3: Bayesian Logistic Regression Model 
A Bayesian logistic regression model will be used to assess Grade 3 solicited AEs 
(Section 6.1.1.1.1) in an investigational group. The Bayesian logistic regression model is 
described by the following equation: 
logit(p(d)) = (α1 + β1*log(d/d*)) + β2 (indicator of OA) 
where 
• 
p(d) represents the probability of having a Grade 3 event at dose d, 
• 
logit(p) = ln(p/(1-p)), 
• 
d* = 12 µg is the reference dose,  
• 
α is an intercept parameter, reflecting the expected logit value at the 12 µg reference 
dose level,  
• 
β1 is a dose effect, 
• 
β2 is an age group effect. 
The prior for α1 and ln(β1) is a mixture of 2 bivariate normal distributions: 
1. 80% weight for α1 ≈ normal (mean=-0.8473, var=1) and ln(β1) ≈ normal 
(mean=0.2060, var=1), reflecting historical data from CVnCoV (ie, a rate of 30% at 
12 µg, and 10% at 4 µg). 
2. 20% weight for α1 ≈ normal (mean=-0.4055, var=1) and ln(β1) ≈ normal 
(mean=0.3678, var=1), reflecting an intolerable dose (ie, a rate of 40% at 12 µg and 
12% at 4 µg). 
The prior β2 is half normal (mean=0, variance=0.25, β2<0 to reflect lower reactogenicity in 
older age group [OA]). 
The covariance between priors is assumed to be zero. 
A 50% posterior probability that the rate at the next dose is greater than 30% will be used as 
a guide for the SRT recommendation on dose expansion and escalation. This will be applied 
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by dose and age group. Probabilities derived from the Bayesian model should be interpreted 
with caution when there is a low number of participants in a particular dose and age group. 
Hypothetical scenarios that illustrate posterior probability based on combined younger age 
group and older age group data is presented in Table 13-2. 
Table 13-2 
Hypothetical Data Scenarios Illustrating Posterior Probabilities 
Scenario 
Dose 
#Events 
#Participants CD – P(OD) Next Dose ND – P(TD) ND – P(OD) 
1 
2 
0 
30 
- 
- 
- 
- 
4 
0 
30 
0 
8 
0.946 
0.054 
8 
0 
30 
0 
12 
0.978 
0.022 
12 
0 
30 
0 
16 
0.997 
0.003 
16 
0 
30 
0 
20 
1.000 
0.000 
20 
0 
30 
0 
NA 
 
 
2 
2 
0 
30 
- 
- 
- 
- 
4 
4 
30 
0.050 
8 
0.764 
0.236 
8 
6 
30 
0.071 
12 
0.563 
0.437 
12 
8 
30 
0.324 
16 
0.355 
0.645* 
16 
15 
30 
0.973 
20 
0.006 
0.994* 
20 
21 
30 
1.000 
NA 
 
 
*This scenario, ND – P(OD) >0.5, would require SRT judgment to recommend proceeding with the current dose expansion 
and escalate to the next dose level. 
Abbreviations: CD = current dose; NA = not applicable; ND = next dose; P(TD) = probability of tolerable dose;  
P(OD) = probability of overdose. 
In this evaluation, the age effect was not considered in the model. 
When fitting the model on more than 15 younger adult participants, 0 events (#events) are replaced by 1 event (ie, assume 
1 event in the younger adult group); this is done to prevent results from being overinfluenced by rates of events (=0%) 
being on the boundary of the parameter space.  
 
 
 
 
 
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13.4 Appendix 4: Potential Immune-mediated Diseases 
Potential immune-mediated diseases are a subset of AEs that include autoimmune diseases 
and other inflammatory and/or neurologic disorders of interest which may or may not have 
an autoimmune etiology. Adverse events that need to be recorded and reported as pIMDs 
include those listed in Table 13-3. 
However, the investigator will exercise their medical and scientific judgment in deciding 
whether other diseases have an autoimmune origin (that is pathophysiologically involving 
systemic or organ-specific pathogenic autoantibodies) and should also be recorded as a 
pIMD. 
When there is enough evidence to make any of the diagnoses mentioned in Table 13-3, the 
AE must be reported as a pIMD. Symptoms, signs, or conditions which might (or might not) 
represent the above diagnoses, should be recorded and reported as AEs but not as pIMDs 
until the final or definitive diagnosis has been determined, and alternative diagnoses have 
been eliminated or shown to be less likely. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire will be available to investigators.  
Once a pIMD is diagnosed (serious or nonserious) in a study participant, the investigator (or 
designate) must complete, date, and sign an electronic Expedited Adverse Events Report. 
Table 13-3 
List of Potential Immune-Mediated Diseases 
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 
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(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 
 
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Polyglandular autoimmune 
syndrome 
• 
Includes Polyglandular autoimmune syndrome type I, II and III 
Eye disorders 
Ocular Autoimmune / Immune-
mediated disorders 
Including but not limited to: 
• 
Acute macular neuroretinopathy (also known as acute macular 
outer retinopathy) 
• 
Autoimmune / Immune-mediated retinopathy  
• 
Autoimmune / Immune-mediated uveitis, including idiopathic 
uveitis and sympathetic ophthalmia  
• 
Cogan's syndrome: an oculo-audiovestibular disease 
• 
Ocular pemphigoid 
• 
Ulcerative keratitis 
• 
Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-mediated 
pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel disease  
Including but not limited to:  
• 
Crohn’s disease  
• 
Microscopic colitis  
• 
Terminal ileitis 
• 
Ulcerative colitis  
• 
Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Musculoskeletal and connective 
tissue disorders  
Gout 
• 
Includes gouty arthritis 
Idiopathic inflammatory 
myopathies 
Including but not limited to: 
• 
Dermatomyositis 
• 
Inclusion body myositis 
• 
Immune-mediated necrotizing myopathy 
• 
Polymyositis 
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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 (eg, Cutaneous lupus 
erythematosus, Lupus nephritis, etc.) or complications such as 
shrinking lung syndrome (SLS) 
Systemic Scleroderma (Systemic 
Sclerosis) 
• 
Includes Reynolds syndrome (RS), systemic sclerosis with diffuse 
scleroderma and systemic sclerosis with limited scleroderma (also 
known as CREST syndrome) 
Neuroinflammatory/neuromuscular 
disorders 
Acute disseminated 
encephalomyelitis (ADEM) and 
other inflammatory demyelinating 
variants  
Includes the following: 
• 
Acute necrotizing myelitis 
• 
Bickerstaff's brainstem encephalitis  
• 
Disseminated necrotizing leukoencephalopathy (also known as 
Weston-Hurst syndrome, acute hemorrhagic leuko-encephalitis, or 
acute necrotizing hemorrhagic encephalomyelitis)  
• 
Myelin oligodendrocyte glycoprotein antibody-associated disease 
• 
Neuromyelitis optica (also known as Devic’s disease) 
• 
Noninfective encephalitis / encephalomyelitis / myelitis 
• 
Postimmunization encephalomyelitis  
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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 (eg, Optic neuritis) 
• 
Idiopathic nerve palsies/paresis (eg, 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 (eg, 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 
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• 
Glomerulonephritis rapidly progressive 
• 
Membranoproliferative glomerulonephritis 
• 
Membranous glomerulonephritis 
• 
Mesangioproliferative glomerulonephritis 
• 
Tubulointerstitial nephritis and uveitis syndrome 
Skin and subcutaneous tissue 
disorders 
Alopecia areata 
 
Autoimmune / Immune-mediated 
blistering dermatoses  
Including but not limited to:  
• 
Bullous Dermatitis 
• 
Bullous Pemphigoid  
• 
Dermatitis herpetiformis  
• 
Epidermolysis bullosa acquisita (EBA)  
• 
Linear IgA-mediated bullous dermatosis (LABD), also known as 
Linear IgA disease 
• 
Pemphigus  
Erythema multiforme 
 
Erythema nodosum 
 
Reactive granulomatous dermatitis  
Including but not limited to 
• 
Interstitial granulomatous dermatitis 
• 
Palisaded neutrophilic granulomatous dermatitis 
Lichen planus 
• 
Includes liquen planopilaris 
Localized Scleroderma (Morphoea) 
• 
Includes Eosinophilic fasciitis (also called Shulman syndrome) 
Psoriasis 
 
Pyoderma gangrenosum 
 
Stevens-Johnson Syndrome (SJS) 
 
Including but not limited to:  
• 
Toxic Epidermal Necrolysis (TEN)  
• 
SJS-TEN overlap 
Sweet’s syndrome 
• 
Includes Acute febrile neutrophilic dermatosis 
Vitiligo 
 
Vasculitis 
Large vessels vasculitis  
Including but not limited to: 
• 
Arteritic anterior ischemic optic neuropathy (AAION or arteritic 
AION) 
• 
Giant cell arteritis (also called temporal arteritis)  
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• 
Takayasu's arteritis  
Medium sized and/or small vessels 
vasculitis  
Including but not limited to: 
• 
Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis 
(type unspecified)  
• 
Behcet's syndrome  
• 
Buerger’s disease (thromboangiitis obliterans) 
• 
Churg–Strauss syndrome (allergic granulomatous angiitis)  
• 
Erythema induratum (also known as nodular vasculitis) 
• 
Henoch-Schonlein purpura (also known as IgA vasculitis) 
• 
Microscopic polyangiitis 
• 
Necrotizing vasculitis 
• 
Polyarteritis nodosa 
• 
Single organ cutaneous vasculitis, including leukocytoclastic 
vasculitis, hypersensitivity vasculitis and acute hemorrhagic edema 
of infancy (AHEI) 
• 
Wegener's granulomatosis  
Other (including multisystemic) 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
• 
Frequently used related terms include: “systemic capillary leak 
syndrome (SCLS)” or “Clarkson's Syndrome” 
Goodpasture syndrome 
• 
Frequently used related terms include: “pulmonary renal 
syndrome” and “anti-Glomerular Basement Membrane disease 
(anti-GBM disease)” 
Immune-mediated enhancement of 
disease 
• 
Includes vaccine-associated enhanced disease (VAED and 
VAERD). Frequently used related terms include “vaccine-mediated 
enhanced disease (VMED)”, “enhanced respiratory disease 
(ERD)”, “vaccine-associated 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 
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Susac's syndrome 
 
 
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13.5 Appendix 5: Tables for Laboratory Abnormalities 
Any clinically relevant laboratory results should be reported as an AE using the FDA toxicity 
grading tables (excerpt provided in Table 13-4). Per the FDA tables, the laboratory values 
provided in Table 13-4 serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they 
are appropriate, and laboratory results within institutional normal ranges will not be 
considered AEs. 
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Table 13-4 
Toxicity Grading for Serum Laboratory Abnormalities 
Parameter 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-Threatening 
(Grade 4) 
Hematology (Whole Blood) 
Hemoglobin (g/dL) - Female 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
<8.0 
Hemoglobin (g/dL) – Female 
Change from Baseline Value 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
>5.0 
Hemoglobin (g/dL) - Male 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
<8.5 
Hemoglobin (g/dL) - Male 
Change from Baseline Value 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
>5.0 
Platelets Decrease (cell/mm3) 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
<25,000 
WBC Increase (cell/mm3) 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
>25,000 
WBC Decrease (cell/mm3) 
2500 – 3500 
1500 – 2499 
1000 – 1499 
<1000 
Lymphocytes Decrease (cell/mm3) 
750 – 1000 
500 – 749 
250 – 499 
<250 
Neutrophils Decrease (cell/mm3) 
1500 – 2000 
1000 – 1499 
500 – 999 
<500 
Eosinophils (cell/mm3) 
650 – 1500 
1501 – 5000 
>5000 
Hypereosinophilic 
Biochemistry (Serum) 
Alkaline phosphate – increase by 
factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
> 10 x ULN 
ALT (increase by factor) 
1.1 – 2.5 × ULN 
2.6 – 5.0 × ULN 
5.1 – 10 × ULN 
>10.0 × ULN 
AST (increase by factor) 
1.1 – 2.5 × ULN 
2.6 – 5.0 × ULN 
5.1 – 10 × ULN 
>10.0 × ULN 
Bilirubin – when accompanied by 
any increase in Liver Function 
Test increase by factor 
1.1 – 1.25 × ULN 
1.26 – 1.5 × ULN 
1.51-1.75 × ULN 
> 1.75 × ULN 
Bilirubin – when Liver Function 
Test is normal; increase by factor 
1.1 – 1.5 × ULN 
1.6 – 2.0 × ULN 
2.0 – 3.0 × ULN 
> 3.0 × ULN 
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 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; ULN = upper limit of the 
normal range; WBC = white blood cells.  
Source: DHHS 2007 
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GlaxoSmithKline Biologicals SA 
CV2CoV Vaccines 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
13.6 Appendix 6: Protocol Amendment History 
The document history table for this protocol and the Protocol Amendment Summary of 
Changes Table for the current Amendment 2 is located directly before the Protocol Synopsis. 
A description of Amendment 1 is presented in this appendix. 
Amendment 1, 20 Apr 2022 
Rationale for Amendment 1: 
The main purposes of Amendment 1 are to address feedback from FDA and to correct 
omissions and minor errors noted in the original protocol. 
The summary of changes table provided here describes the important changes made in 
Amendment 1 relative to the original protocol, including the sections modified and the 
corresponding rationales. The synopsis of Amendment 1 has been modified, as needed, to 
correspond to changes in the body of the protocol. Minor editorial and grammatical 
corrections were also made. 
Throughout the document, the protocol date and version were updated to reflect Amendment 
1 and the title page was updated to reflect the protocol history.  
Summary of Important Changes from the Original Protocol to Amendment 1: 
Section Number and Name 
Description of Change 
Brief Rationale 
Title page, Protocol Approval – 
Sponsor Signatory page, page 
headers 
The abbreviated title  
“CV2 SARS-COV2-002 BST” was 
added. 
To provide a more informative 
protocol number. 
Section 2 (Study Objectives and 
Endpoints, Table 2-1) 
Section 5.9 (Study Holding Rules, 
Table 5-2)) 
Section 6.1.1.1.1 (Adverse Events) 
Section 6.1.1.5 (eDiary) 
Section 13.1 (Appendix 1: 
Schedule of Events) 
The description of the period of 
collection for solicited AEs was 
revised to read “…within the 7-day 
postvaccination period (Days 1 to 
7).” 
To correct a typographical error. 
and to provide further 
clarification regarding the 
follow-up period. 
Section 3.1 (Study Design) 
Section 3.2 (Rationale for Study 
Design) 
Section 7.8 (Safety Review Team) 
Text inserted to clarify that the SRT 
will review safety data from Days 1 
to 8 (including Day 8 laboratory 
data).  
To provide clarification 
regarding the safety data that 
will be reviewed by the SRT. 
This is consistent with the SRT 
Charter.  
Page 95

GlaxoSmithKline Biologicals SA 
CV2CoV Vaccines 
Protocol 217741 (CV2 SARS-COV2-002 BST) Amendment 2 
13 Jun 2022 
Confidential  
Section Number and Name 
Description of Change 
Brief Rationale 
Section 5.9 (Study Holding Rules, 
Table 5-2)  
Rule 1f was revised to read “any 
same or similar Grade 3 related 
unsolicited adverse events, 
including but not limited to the 
identical MedDRA high-level 
term”. 
To enhance safe conduct of the 
study and to address an FDA 
comment. 
Section 6.1.1.2.1 (Assessment of 
Severity; Table 6-1) 
For Temperature, Intensity Grade 3, 
the criterion now reads >102.0°F, 
rather than >102.1°F.  
To correct a rounding error and 
to address an FDA comment.  
Section 6.1.1.3.1 (Reporting 
Serious Adverse Events and 
Adverse Events of Special Interest) 
Added the following 1-sentence 
paragraph: If the EDC is 
unavailable and a faxed form is 
used to report an SAE or AESI, the 
site should update the EDC with 
exactly the same information 
reported on paper (by fax) as soon 
as possible after the EDC becomes 
available again. 
To clarify that the EDC must 
always be updated with SAE or 
AESI data as soon as possible 
after transmitting the same data 
by fax.  
Section 6.2 (Pregnancy Reporting) 
Section 13.2 (Appendix 2: 
Contraceptive Guidance and 
Pregnancy Information) 
Changed the heading name and 
modified the text to state that 
pregnancies are to be reported using 
paper forms faxed to the same fax 
number as may be used for backup 
SAE reports.  
To clarify procedures for 
reporting detected pregnancies.  
Section 13.1 (Appendix 1: 
Schedule of Events, Table 13-1) 
Added marks to indicate that AEs 
and concomitant 
medications/vaccinations are 
collected at an ET visit. 
To correct an omission and to 
address FDA comment. 
 
Page 96