COVID-19: A Phase 2b/3, Randomized, Observer-Blinded, Placebo-Controlled, Multicenter Clinical Study Evaluating the Efficacy and Safety of Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in Adults 18 Years of Age and Older
Phase: PHASE2
Conditions: Covid19, SARS-CoV-2
Sponsor: CureVac

Protocol Number: CV-NCOV-004 
 
Official Title: COVID-19: A Phase 2b/3, Randomized, Observer-Blinded, Placebo-Controlled, Multicenter 
Clinical Study Evaluating the Efficacy and Safety of Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in 
Adults 18 Years of Age and Older 
 
NCT Number: NCT04652102 
 
Document Date:  25 November 2021 

Clinical Trial Protocol 
CV-NCOV-004
CureVac AG 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 1 of 184 
 
CLINICAL TRIAL PROTOCOL 
COVID-19:  
A Phase 2b/3, Randomized, Observer-Blinded, Placebo-Controlled, Multicenter 
Clinical Study Evaluating the Efficacy and Safety of Investigational SARS-CoV-2 
mRNA Vaccine CVnCoV in Adults 18 Years of Age and Older 
Protocol Number: 
CV-NCOV-004
EudraCT Number: 
2020-003998-22  
Investigational Product: 
CV07050101 (referred to as CVnCoV) 
Trial Name: 
HERALD 
Phase: 
Phase 2b/3 
Sponsor: 
CureVac AG 
Schumannstrasse 27 
60325 Frankfurt 
Germany 
Short Title: 
Efficacy and Safety of CVnCoV in Adults 
Protocol Version: 
4.0 
Protocol Date: 
25 November 2021 
PROTOCOL VERSION HISTORY: 
Version 1.0 dated 11 November 2020 
Version 2.0 dated 17 February 2021 
Version 3.0 dated 29 March 2021 
This protocol may not be reproduced or communicated to a third party without the written 
permission of CureVac AG. 
 
 
 
 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 4 of 184 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
COVID-19: 
A 
Phase 
2b/3, 
Randomized, 
Observer-Blinded, 
Placebo-Controlled, Multicenter Clinical Study Evaluating the Efficacy 
and Safety of Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in 
Adults 18 Years of Age and Older  
Protocol Number: CV-NCOV-004 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol and all appendices, including Appendix 1 
(Responsibilities of the Investigator) and Appendix 2 (Emergency Procedures), and I will 
conduct the trial as described in compliance with this protocol, Good Clinical Practice (GCP), 
and relevant International Council on Harmonisation (ICH) guidelines. 
Once the protocol has been approved by the Independent Ethics Committee (IEC), I will not 
modify this protocol without obtaining prior approval of CureVac and of the IEC. I will submit 
the protocol modifications and/or any informed consent form modifications to CureVac and the 
IEC, and approval will be obtained before any modifications are implemented. 
I understand that all information obtained during the conduct of the trial with regard to the 
subjects’ state of health will be regarded as confidential. No subjects’ names will be disclosed. 
All subjects will be identified by assigned numbers on all electronic case report forms (eCRFs) 
and laboratory samples. Clinical information may be reviewed by CureVac or its 
representatives or regulatory agencies. Agreement must be obtained from the subject before 
disclosure of subject information to a third party. 
Information developed in this clinical trial may be disclosed by CureVac to other clinical 
Investigators, regulatory agencies, or other health authorities as required. 
Investigator Signatory 
 
 
Name 
 
Address 
 
Signature 
 
Date 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 5 of 184 
SAE Hotline and Medical Monitor Contacts 
SAE Hotline 
SAE reporting to PRA by fax or email within 24 hours after discovery: 
Site Location 
Email  
(Primary Reporting Method) 
Fax Number 
(Secondary Reporting Method) 
Europe 
 
 
Latin America 
 
 
Medical Monitors 
The Medical Monitoring team will provide 24/7 (24 hours per day and 7 days a week) on-call medical 
coverage to address trial-related questions from sites or Investigators, such as questions regarding 
eligibility requirements, the acceptability of concomitant medication or whether a subject should 
remain in the trial or needs to be discontinued. 
Medical Monitor Lead:  
 
 
 
 
 
Medical Monitoring Support Center: 
Phone: 
 
 
Fax: 
 
 
Email: 
 
 
 
 
 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 6 of 184 
TABLE OF CONTENTS 
LIST OF TABLES ..........................................................................................................10 
LIST OF FIGURES ........................................................................................................10 
LIST OF ABBREVIATIONS ...........................................................................................11 
PROTOCOL AMENDMENT RATIONALE......................................................................14 
1 
SYNOPSIS ....................................................................................................................15 
2 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES .............................................32 
3 
INTRODUCTION ...........................................................................................................47 
3.1 
Background ........................................................................................................47 
3.1.1 Coronaviruses.........................................................................................47 
3.1.2 COVID-19  ..............................................................................................49 
3.1.3 Development of CVnCoV ........................................................................49 
3.1.4 HERALD Phase 2b/3 Results .................................................................50 
3.1.5 CVnCoV and Authorized/Licensed SARS-CoV-2 Vaccines .....................50 
3.1.6 Trial Rationale.........................................................................................51 
3.2 
Risk/Benefit Assessment ....................................................................................52 
3.2.1 Known Potential Risks ............................................................................52 
3.2.2 Known Potential Benefits ........................................................................55 
3.2.3 Assessment of Potential Risks and Benefits ...........................................55 
4 
TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...............................................56 
4.1 
Objectives ..........................................................................................................56 
Objectives for the Randomized Observer-blinded Phase ...................................56 
4.1.1 Primary Objectives ..................................................................................56 
4.1.2 Secondary Objectives .............................................................................56 
4.1.3 Exploratory Objectives ............................................................................57 
4.1.4 Objectives for the Open-label Phase .......................................................58 
4.2 
Endpoints ...........................................................................................................58 
4.2.1 Primary Endpoints ..................................................................................58 
4.2.2 Secondary Endpoints ..............................................................................59 
4.2.3 Exploratory Endpoints .............................................................................60 
4.2.4 Open-label Endpoints .............................................................................61 
4.3 
Estimands ..........................................................................................................61 
5 
TRIAL DESIGN .............................................................................................................69 
5.1 
Overall Design....................................................................................................69 
5.1.1 Randomized Observer-blinded Phase 2b Design and Objectives ...........69 
5.1.2 Randomized Observer-blinded Phase 3 Design and Objectives .............70 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 7 of 184 
5.1.3 Open-label Phase Design and Objectives ...............................................72 
5.2 
Scientific Rationale for Trial Design ....................................................................73 
5.3 
Justification for Dose ..........................................................................................75 
5.4 
End of Trial Definition .........................................................................................75 
5.5 
Stopping/Pausing Rules for Safety .....................................................................75 
5.5.1 Individual Subject Stopping Rules ...........................................................75 
5.5.2 Pausing of the Trial .................................................................................75 
6 
TRIAL POPULATION ....................................................................................................77 
6.1 
Inclusion Criteria for All Subjects ........................................................................77 
6.2 
Exclusion Criteria for All Subjects .......................................................................78 
6.3 
Roll-over Criteria for the Open-label Phase ........................................................79 
6.3.1 Cohort A: CVnCoV-AV ............................................................................79 
6.3.2 Cohort B: CVnCoV only ..........................................................................79 
6.4 
Vaccine Delay Recommendations ......................................................................79 
6.5 
Failure to Meet Eligibility Criteria ........................................................................80 
7 
TRIAL VACCINE ...........................................................................................................81 
7.1 
Trial Vaccine Administration ...............................................................................81 
7.1.1 Description of the Trial Vaccines .............................................................81 
7.1.2 Dosing and Administration ......................................................................81 
7.2 
Preparation/Handling/Storage/Accountability .....................................................82 
7.2.1 CVnCoV Preparation ..............................................................................82 
7.2.2 CVnCoV Product Storage and Stability ...................................................82 
7.2.3 Placebo Control (Normal Saline) .............................................................82 
7.2.4 Accountability .........................................................................................82 
7.3 
Randomization and Blinding ...............................................................................83 
7.3.1 Randomization (Randomized Observer-blinded Phase only) ..................83 
7.3.2 Blinding (Randomized Observer-blinded Phase only) .............................83 
7.3.3 Unblinding ...............................................................................................84 
7.4 
Vaccine Compliance ..........................................................................................85 
7.5 
Misuse and Overdose ........................................................................................85 
7.6 
Concomitant Therapy and Vaccines ...................................................................85 
7.6.1 Permitted Medications/Vaccines During the Trial ....................................85 
7.6.2 Prohibited Medications/Vaccines During the Trial ...................................86 
7.7 
Therapy Leading to Discontinuation ...................................................................86 
7.8 
Treatment After the End of Trial .........................................................................87 
8 
DISCONTINUATION/WITHDRAWAL CRITERIA...........................................................88 
8.1 
Discontinuation of Trial Vaccine Administration ..................................................88 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 8 of 184 
8.2 
Withdrawal from the Trial ...................................................................................89 
8.3 
Trial Termination ................................................................................................89 
8.4 
Lost to Follow-Up ...............................................................................................90 
9 
TRIAL ASSESSMENTS AND PROCEDURES ..............................................................91 
9.1 
Schedule of Trial Assessments and Procedures ................................................91 
9.1.1 Phase 2b: Immunogenicity Subset ..........................................................92 
9.1.2 Phase 2b: Non-Immunogenicity Subjects .............................................. 101 
9.1.3 Randomized Observer-blinded Phase 3 Subjects ................................. 109 
9.1.4 Open-label Phase ................................................................................. 115 
9.2 
Efficacy Assessments ...................................................................................... 117 
9.2.1 COVID-19 Cases .................................................................................. 117 
9.2.2 Asymptomatic Cases of SARS-CoV-2 Infection (Randomized Observer-
blinded Phase only) .............................................................................. 123 
9.3 
Safety Assessments ......................................................................................... 123 
9.3.1 Safety Assessments for Subjects in the Randomized Observer-blinded 
Phase ................................................................................................... 123 
9.3.2 Safety Assessments for Subjects in the Open-label Phase ................... 124 
9.3.3 Adverse Events ..................................................................................... 124 
9.3.4 Pregnancies .......................................................................................... 128 
9.3.5 Safety Laboratory Assessments ........................................................... 128 
9.3.6 Vital Signs and Physical Examination ................................................... 128 
9.3.7 Medical and Surgical History ................................................................. 129 
9.3.8 Monitoring Committees ......................................................................... 129 
9.4 
Immunogenicity Assessments (Randomized Observer-blinded Phase only) .... 130 
9.4.1 Antibody Responses to CVnCoV Vaccination (RBD of S Protein and 
Viral Neutralizing Antibodies) ................................................................ 130 
9.4.2 Antibody Responses to SARS-CoV-2 (N Protein) ................................. 130 
9.4.3 Antibody Responses to CVnCoV Vaccination in Subjects Who Develop 
a Case of COVID-19 ............................................................................. 131 
9.4.4 Cell-mediated Immunity ........................................................................ 131 
9.5 
Testing for SARS-CoV-2 Infection .................................................................... 131 
9.5.1 Virological Confirmation of COVID-19  .................................................. 131 
9.5.2 Confirmation of a Positive Test for SARS-CoV-2 Infection Performed 
Outside of the Site ................................................................................ 132 
10 STATISTICAL CONSIDERATIONS ............................................................................. 133 
10.1 
Sample Size Determination .............................................................................. 133 
10.1.1 Primary Efficacy Objective .................................................................... 133 
10.1.2 Key Secondary Efficacy Objectives ....................................................... 133 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 9 of 184 
10.2 
Populations for Analyses .................................................................................. 134 
10.2.1 Safety Analysis Set (SAS) .................................................................... 134 
10.2.2 Safety Analysis Sets 2 (SAS 2, SASsol) ............................................... 134 
10.2.3 Efficacy Analysis Set (EAS) .................................................................. 135 
10.2.4 Per Protocol Efficacy Set (PPE) ............................................................ 135 
10.2.5 Per Protocol Immunogenicity Set (PPI) ................................................. 135 
10.3 
Statistical Analyses .......................................................................................... 137 
10.3.1 General Considerations ........................................................................ 137 
10.3.2 Demographic, Medical History, and Other Baseline Characteristics ...... 137 
10.3.3 Trial Vaccine Administration .................................................................. 137 
10.3.4 Concomitant Medication and Vaccinations ............................................ 137 
10.3.5 Efficacy Analyses .................................................................................. 137 
10.3.6 Secondary and Exploratory Immunogenicity Analysis ........................... 140 
10.3.7 Safety Analysis ..................................................................................... 141 
10.3.8 Interim Analysis .................................................................................... 141 
10.3.9 Missing Data and Discontinuation ......................................................... 143 
11 QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 144 
11.1 
Electronic Case Report Forms ......................................................................... 144 
11.2 
Audit and Inspection ......................................................................................... 144 
11.3 
Monitoring ........................................................................................................ 144 
11.4 
Data Management and Coding ......................................................................... 145 
12 ETHICS ....................................................................................................................... 146 
12.1 
Institutional Review Board/Independent Ethics Committee ............................... 146 
12.2 
Regulatory Authorities ...................................................................................... 146 
12.3 
Ethical Conduct of the Trial .............................................................................. 146 
12.4 
Informed Consent ............................................................................................. 146 
13 DATA HANDLING AND RECORD KEEPING .............................................................. 148 
13.1 
Data Protection ................................................................................................ 148 
13.2 
Amendments to the Protocol ............................................................................ 149 
13.3 
Biological Samples and Record Retention ........................................................ 149 
13.3.1 Biological Samples Retention and Destruction ...................................... 149 
13.3.2 Retention of Trial Records .................................................................... 149 
13.4 
Clinical Trial Report .......................................................................................... 150 
13.5 
Publication Policy ............................................................................................. 150 
14 REFERENCES ............................................................................................................ 151 
15 APPENDICES ............................................................................................................. 154 
Appendix 1 Responsibilities of the Investigator ............................................................ 155 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 10 of 184 
Appendix 2 Emergency Procedures............................................................................. 156 
Appendix 3 Definition of Severe COVID-19  ................................................................ 157 
Appendix 4 Definition of Moderate and Mild COVID-19  .............................................. 158 
Appendix 5 Safety and SARS-CoV-2 Tests ................................................................. 159 
Appendix 6 Flow Diagram for COVID-19 Case Interview ............................................. 160 
Appendix 7 SARS-CoV-2 Testing Outcome ................................................................. 162 
Appendix 8 Potential Immune-Mediated Diseases ....................................................... 163 
Appendix 9 Adverse Events of Special Interest (AESIs) for SARS-CoV-2 Vaccines .... 165 
Appendix 10 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................. 166 
Appendix 11 Protocol Amendment History................................................................... 174 
 
LIST OF TABLES 
Table 1 
Schedule of Trial Assessments and Procedures for Phase 2b - 
Immunogenicity Subset ................................................................................33 
Table 2 
Schedule of Trial Assessments and Procedures for Phase 2b - Non-
Immunogenicity Subjects .............................................................................37 
Table 3 
Schedule of Trial Assessments and Procedures for Phase 3 .......................40 
Table 4 
Schedule of Trial Assessments and Procedures for the Open-label Phase: 
Cohort A: CVnCoV-AV .................................................................................43 
Table 5 
Schedule of Trial Assessments and Procedures for the Open-label Phase: 
Cohort B: CVnCoV only ...............................................................................45 
Table 6 
Reporting Period by Type of Adverse Event ............................................... 125 
Table 7 
Intensity Grading* for Solicited Local Adverse Events ................................ 126 
Table 8 
Intensity Grading* for Solicited Systemic Adverse Events .......................... 127 
Table 9 
Primary and Supportive Populations for the Analysis of Each Endpoint ..... 136 
Table 10 
Two Stage Group Sequential Design with Interim Analyses at 56 and 
111 Cases and Final Analysis at 160 Cases .............................................. 143 
  
LIST OF FIGURES 
Figure 1 
Overview of HERALD Trial CV-NCOV-004 ..................................................32 
Figure 2 
Genome Organization of SARS-CoV-2 Compared with Other 
Betacoronaviruses .......................................................................................48 
Figure 3 
Trial Timeline – HERALD Trial CV-NCOV-004 .............................................72 
 
 
 
 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 11 of 184 
LIST OF ABBREVIATIONS 
ADE 
Antibody-dependent enhancement 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ARDS 
Acute respiratory distress syndrome 
AV 
Authorized/licensed vaccines for preventing COVID-19 
BMI 
Body mass index 
BoD 
Burden of disease 
CI 
Confidence interval 
CMI 
Cell-mediated immunity 
CoV 
Coronavirus 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CTL 
Cytotoxic T lymphocyte 
CVnCoV 
Investigational SARS-CoV-2 mRNA vaccine 
DSMB 
Data and Safety Monitoring Board 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
E 
Envelope 
EAS 
Efficacy Analysis Set 
eCDC 
European Centre for Disease Prevention and Control 
eCRF 
Electronic case report form 
eDiary 
Electronic Diary 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOT 
End of Trial 
FC 
Fold change 
FDA 
United States Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMFC 
Geometric mean of the fold change 
GMT 
Geometric mean titer 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 12 of 184 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IL 
Interleukin 
IM 
Intramuscular(ly) 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
LLOQ 
Lower limit of quantification 
LNP 
Lipid nanoparticles 
M 
Membrane 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome 
mRNA 
Messenger ribonucleic acid 
N 
Nucleocapsid 
PBMC 
Peripheral blood mononuclear cell 
pIMD 
Potential immune-mediated disease 
PPE 
Per Protocol Efficacy 
PPI 
Per Protocol Immunogenicity 
PT 
Preferred Term 
RBD 
Receptor-binding domain 
RNA 
Ribonucleic acid 
RT-PCR 
Reverse transcription polymerase chain reaction 
S 
Spike 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 
SAS 
Safety Analysis Set 
SAS 2 
Safety Analysis Set 
SASsol 
Solicited adverse events Safety Analysis Set 
SOC 
System Organ Class 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 13 of 184 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
VDE 
Vaccine-dependent Disease Enhancement 
VE 
Vaccine efficacy 
VNT 
Viral neutralizing titer 
VOC 
Variant of concern 
WHO 
World Health Organization 
 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 14 of 184 
PROTOCOL AMENDMENT RATIONALE 
In view of the current availability of authorized/licensed vaccines for preventing COVID-19 
(AVs) in the countries where the trial is being conducted, multiple unblinding requests have 
been granted to trial subjects seeking access to these AVs under their country’s national 
vaccination programs, and as of 18 November 2021 nearly 80% of the trial subjects have been 
unblinded and approximately 49% have already received an AV.  
CureVac has decided to focus its COVID-19 vaccine development towards the development 
of second-generation mRNA vaccine candidates in collaboration with GSK and to withdraw its 
first-generation COVID-19 vaccine candidate, CVnCoV, from the current approval process with 
the European Medicines Agency (EMA). As the number of COVID-19 cases needed for the 
determination of efficacy (case driven design) has been achieved in the current HERALD trial, 
completion of this trial will now focus on safety monitoring. 
The purpose of this protocol amendment is: 
• 
To unblind all remaining blinded subjects and inform them of the treatment received. 
• 
To monitor safety of the following subjects remaining in the open-label phase after 
unblinding: 
o Subjects who had received CVnCoV and received/will receive an AV through 
their national vaccination program. 
o Subjects who had received CVnCoV and continue follow-up in the trial as 
initially planned, without receiving an AV. 
The trial will, therefore, shift from a randomized observer-blinded to an open-label design.  
After unblinding, subjects known to have received placebo do not require further safety 
monitoring and will be discontinued. 
A simplification of the visit and calls schedule for the follow-up of the subjects is implemented 
in order to maintain subjects who received CVnCoV until the end of the trial. Subjects 
participating in the open-label phase of the trial will continue to be evaluated for symptomatic 
COVID-19 cases, but there will no longer be any inferential efficacy analysis (only a descriptive 
summary of cases). 
A descriptive summary of the changes included in the current protocol amendment is provided 
in Appendix 11. 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
CONFIDENTIAL 
Page 15 of 184 
1 SYNOPSIS 
Name of 
Investigational 
Vaccine: 
CVnCoV 
Sponsor: 
CureVac AG 
Coordinating 
Investigator: 
 
Title of Trial: 
COVID-19: 
A 
Phase 
2b/3, 
Randomized, 
Observer-Blinded, 
Placebo-Controlled, Multicenter Clinical Study Evaluating the Efficacy and 
Safety of Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in Adults 
18 Years of Age and Older   
Rationale: 
Coronaviruses are a large family of zoonotic ribonucleic acid (RNA) viruses 
causing respiratory disease, ranging from a common cold to severe diseases 
such as Middle East respiratory syndrome (MERS) and severe acute 
respiratory syndrome (SARS) in humans. In December 2019, an outbreak of 
respiratory disease caused by a novel coronavirus strain was reported in 
Wuhan City, Hubei Province, China. The novel coronavirus was named 
“severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), while the 
disease associated with it was referred to as COVID-19 (coronavirus disease 
2019). The virus spread to different parts of China and an increasing number 
of countries worldwide and on 30 January 2020 the World Health 
Organization (WHO) announced the outbreak under International Health 
Regulations as a public health emergency of international concern (the 
WHO's highest level of alarm). On 12 March 2020, the WHO announced the 
outbreak as a pandemic.  
In view of the severity of respiratory disease caused by emerging 
coronaviruses, development of a vaccine has been undertaken by several 
pharmaceutical companies, and there are now vaccines available with 
emergency authorization/conditional marketing authorization for prevention 
of COVID-19 in several countries worldwide. CureVac AG is developing a 
novel SARS-CoV-2 vaccine referred to as CVnCoV. CVnCoV is a messenger 
RNA (mRNA)-based COVID-19 vaccine in which the mRNA is protected and 
delivered by encapsulation within lipid nanoparticles (LNPs). The mRNA 
encodes the stabilized full-length spike (S) protein from the SARS-CoV-2 
virus. Following intramuscular (IM) injection of CVnCoV, the S protein is 
translated from the mRNA stimulating an antigen-specific humoral and 
cellular immune response to the S protein. Importantly, functional viral 
neutralizing titers (VNTs) are induced following vaccination with CVnCoV.   
Phase 1 and 2a trials are being conducted to generate initial data on the 
safety, reactogenicity, and immunogenicity of 2 doses of CVnCoV, 
administered 28 days apart, to adults 18 years of age and older. In a subset 
of subjects, a booster dose at 2 or 6 months after the first dose will be 
investigated. The first-in-human (FIH) Phase 1 trial, CV-NCOV-001, is 
evaluating different dose levels of CVnCoV in seronegative and seropositive 
adults 18 to 60 years of age. Following review of the FIH data, a Phase 2a 
trial, CV-NCOV-002, was initiated and is evaluating CVnCoV at selected 
dose levels in adults ≥ 61 years of age. Following the first part of 
Trial CV-NCOV-002, expansion cohorts of 220 subjects aged 18 to 60 years 
and 220 subjects aged ≥ 61 years are being enrolled and treated to generate 
additional safety and immunogenicity data in preparation of Phase 2b/3 trials. 
Dose level selection for subsequent trials will be performed based on the 
safety and immunogenicity data from these 2 trials. In the FIH Phase 1 trial, 
a dose of 12 µg elicited the same immune response as that seen in patients 
who are recovering from having been infected with the real virus. Therefore, 
this dose was selected to be used in this trial. 

Clinical Trial Protocol 
 
CV-NCOV-004 
CureVac AG 
 
COVID-19 mRNA Vaccine 
Version 4.0 (25 November 2021) 
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The present trial CV-NCOV-004 is designed as a Phase 2b/3 pivotal efficacy 
and safety trial in adults 18 years of age and older. The trial will have a 
randomized, observer-blinded, placebo-controlled design. Subjects will be 
enrolled at multiple sites globally and will be randomized in a 1:1 ratio to 
receive a 2-dose schedule of either CVnCoV at a dose level of 12 µg mRNA 
or placebo {normal saline (0.9% NaCl)} as the control.  
The above described randomized, observer-blinded phase will be followed 
by an open-label phase. The open-label phase has been added to inform all 
subjects about the trial treatment they received and to allow follow-up of 
subjects who received at least 1 dose of CVnCoV, including those who 
decide(d) after unblinding to receive an authorized/licensed vaccine for 
preventing COVID-19 (AV) through their national vaccination program. 
Placebo subjects do not require further follow-up and will discontinue the trial. 
Trial Duration for 
Each Subject: 
Approximately 13.5 months 
Phase: 2b/3 
Objectives for the 
Randomized 
Observe-Blinded 
Phase 
 
Primary Objectives: 
Primary Efficacy Objective 
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the 
prevention of first episodes of virologically-confirmed cases of COVID-19 
of any severity in SARS-CoV-2 naïve subjects.   
Primary Safety Objectives 
• 
To evaluate the safety of CVnCoV administered as a 2-dose schedule to 
subjects 18 years of age and older.  
• 
To evaluate the reactogenicity of CVnCoV administered as a 2-dose 
schedule to subjects 18 years of age and older participating in Phase 2b 
of the trial. 
Secondary 
Objectives:  
Key Secondary Efficacy Objectives 
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the 
prevention of first episodes of virologically-confirmed moderate to severe 
cases of COVID-19 in SARS-CoV-2 naïve subjects. 
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the 
prevention of first episodes of virologically-confirmed severe cases of 
COVID-19 in SARS-CoV-2 naïve subjects.  
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the 
prevention of first episodes of virologically-confirmed cases of COVID-19 
of any severity caused by “wild type” (i.e., WT/D614G lineages A.1/B.1 
without the variant of concern [VOC] B.1.1.7 [Alpha], B.1.351 [Beta], 
B.1.429 [Epsilon]) and “UK” (B.1.1.7 [Alpha]) SARS-CoV-2 strains in 
SARS-CoV-2 naïve subjects. 
Other Secondary Efficacy Objectives 
To evaluate in SARS-CoV-2 naïve subjects: 
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed cases of COVID-19 of any severity in 
subjects ≥ 61 years of age. 
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed cases of SARS-CoV-2 infection, with 
or without symptoms.  
• 
The efficacy of a 2-dose schedule of CVnCoV in reducing the Burden of 
disease (BoD) from COVID-19.   

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• 
The efficacy of CVnCoV after the first dose in the prevention of first 
episodes of virologically-confirmed cases of COVID-19 of any severity. 
Secondary Immunogenicity Objectives 
• 
To assess antibody responses to the receptor binding domain (RBD) of 
S protein of SARS-CoV-2 after 1 and 2 doses of CVnCoV in a subset of 
subjects participating in Phase 2b of the trial.   
• 
To assess SARS-CoV-2 viral neutralizing antibody responses after 1 and 
2 doses of CVnCoV in a subset of subjects participating in Phase 2b of 
the trial.   
Exploratory 
Objectives: 
Exploratory Efficacy Objectives 
To investigate in SARS-CoV-2 naïve subjects: 
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed cases of COVID-19 of any severity 
caused by individual VOCs (see Section 9.2.1.6). 
• 
If cases of COVID-19 are milder in severity in subjects receiving a 2-dose 
schedule of CVnCoV compared to those administered placebo. 
• 
If the need for supplemental oxygenation due to COVID-19 is reduced in 
subjects receiving a 2-dose schedule of CVnCoV compared to those 
administered placebo. 
• 
If the need for mechanical ventilation due to COVID-19 is reduced in 
subjects receiving a 2-dose schedule of CVnCoV compared to those 
administered placebo. 
• 
If hospitalization due to COVID-19 is reduced in subjects receiving a 
2-dose schedule of CVnCoV compared to those administered placebo. 
• 
If mortality due to COVID-19 is reduced in subjects receiving a 2-dose 
schedule of CVnCoV compared to those administered placebo.   
• 
If all-cause mortality is reduced in subjects receiving a 2-dose schedule 
of CVnCoV compared to those administered placebo. 
• 
To investigate the cell-mediated immune response of a 2-dose schedule 
of CVnCoV from approximately 200 subjects at selected site(s). 
To investigate in SARS-CoV-2 naïve and non-naïve subjects:   
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed cases of COVID-19 of any severity in 
all subjects, regardless of SARS-CoV-2 serological status at baseline. 
• 
The efficacy of CVnCoV after the first dose in the prevention of first 
episodes of virologically-confirmed cases of COVID-19 of any severity in 
all subjects, regardless of SARS-CoV-2 serological status at baseline. 
To investigate in subjects with first episodes of virologically-confirmed 
COVID-19 during the trial:  
• 
The occurrence of second episodes of COVID-19 in subjects receiving a 
2-dose schedule of CVnCoV compared to those administered placebo. 
• 
To explore correlates of protective immunity induced by CVnCoV 
vaccination. 
Objectives for the 
Open-label Phase: 
• 
To evaluate safety in all subjects ≥ 18 years of age remaining in the trial 
after unblinding.  
Open-label Exploratory Objective: 
• 
To 
describe 
the 
number 
of 
first 
episodes 
of 
symptomatic 
virologically-confirmed cases of mild, moderate, and severe COVID-19 
as assessed by the Investigator. 
Overall Design: 
Trial CV-NCOV-004 will start with an initial Phase 2b part followed by a large 
Phase 3 efficacy part. Both Phase 2b and Phase 3 parts will be randomized, 

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observer-blinded, and placebo-controlled. Adult subjects 18 years of age or 
older will be enrolled at multiple sites globally and will receive a 2-dose 
schedule of either CVnCoV at a dose level of 12 µg mRNA or placebo {normal 
saline (0.9% NaCl)} in a 1:1 ratio. Both Phase 2b and Phase 3 parts of the 
trial are consistent in design (e.g., for COVID-19 case ascertainment and 
case definition) so that cases of COVID-19 occurring in Phase 2b can be 
pooled with those in Phase 3 for the primary analysis of vaccine efficacy (VE).  
This randomized observer-blinded phase will be followed by a Phase 3 
open-label phase. The trial will be unblinded on country/site level after receipt 
of Competent Authority/Ethics Committee approval of Protocol version 4.0. 
Randomized Observer-blinded Phase 2b Design and Objectives 
(See Table 1 and Table 2 for the Schedule of Trial Assessments and 
Procedures)   
The objective of Phase 2b is to further characterize the safety, reactogenicity, 
and immunogenicity of CVnCoV prior to initiating Phase 3. CVnCoV will be 
administered at the 12 µg dose level selected for Phase 3 investigation 
informed by the safety and immunogenicity data from the initial Phase 1 and 
2a trials. Phase 2b will be conducted in 2 age groups of adults: 18 to 60 and 
≥ 61 years of age, which represent the age range of the intended Phase 3 
trial population.   
Approximately 4,000 subjects will be enrolled and randomized in a 1:1 ratio 
to receive 2 doses of either CVnCoV or placebo, administered 28 days apart. 
Of the 4,000 subjects enrolled, approximately 800 to 1,000 (20% to 25%) will 
be ≥ 61 years of age. Phase 2b will be performed in an observer-blinded 
manner to reduce any potential bias in the safety assessments. The sample 
size of 4,000 subjects is based on generating a robust and detailed dataset 
characterizing the safety, reactogenicity, and immunogenicity of CVnCoV 
prior to entering Phase 3. Furthermore, the data generated in Phase 2b will 
be the main dataset to be submitted in support of early conditional approval 
of CVnCoV.   
In Phase 2b, the safety and reactogenicity of a 2-dose schedule of CVnCoV 
will be assessed in detail by measuring the frequency and severity of the 
following adverse events (AEs): solicited local and systemic reactions for 
7 days after each vaccination; unsolicited AEs for 28 days after each 
vaccination; medically-attended AEs through 6 months after the second trial 
vaccination; and AEs of special interest (AESIs) and serious adverse events 
(SAEs) through 1 year after the second trial vaccination. The immunogenicity 
of CVnCoV will be evaluated after 1 and 2 doses in a subset of subjects (first 
600 subjects enrolled in each of the 2 age groups; a total of 1,200 subjects 
in the Immunogenicity Subset) by measuring binding antibodies to the 
SARS-CoV-2 RBD of S protein and viral neutralizing antibodies. Antibody 
persistence will also be evaluated in this trial.  
Cases of COVID-19 occurring in Phase 2b subjects will be collected and 
pooled with those occurring in Phase 3 and the total number of cases will be 
used for the primary analysis of efficacy. Surveillance for COVID-19 cases 
will be identical in Phase 2b and Phase 3. In addition, the independent Data 
and Safety Monitoring Board (DSMB) will periodically monitor COVID-19 
cases for signals of Vaccine-dependent Disease Enhancement (VDE).   
Initiation of subject enrollment of the 2 target age groups into Phase 2b will 
be flexible. Depending on the timing of data from the Phase 1 and Phase 2a 
trials, enrollment of the 2 age groups into Phase 2b may be staggered, initially 
starting with subjects 18 to 60 years of age followed by subjects ≥ 61 years 
of age. As the older age group will comprise 20% to 25% of the total number 
of subjects in Phase 2b, the staggered start is not expected to impact overall 
enrollment of the Phase 2b cohort.  
An early safety review of the Phase 2b data will be performed by the DSMB. 
The safety review will be conducted when approximately 1,000 subjects have 

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been enrolled in Phase 2b (25% of subjects enrolled; 500 recipients of 
CVnCoV and 500 recipients of placebo) and have at least 1 week of safety 
follow-up after the first trial vaccination. If the safety profile is judged to be 
acceptable and there are no safety or tolerability concerns, it is anticipated 
that enrollment of subjects into Phase 3 can begin without interruption from 
Phase 2b. Another safety review by the DSMB will be conducted when 
approximately 1,000 Phase 2b subjects have received their second trial 
vaccination and have at least 1 week of safety follow-up. All available first 
dose safety data from the Phase 2b subjects will also be reviewed at this 
time. 
Randomized Observer-blinded Phase 3 Design and Objectives 
(See Table 3 for the Schedule of Trial Assessments and Procedures) 
The primary objective of the combined Phase 2b/3 is to demonstrate the 
efficacy of a 2-dose schedule of CVnCoV in the prevention of COVID-19 
cases of any severity. Similar to Phase 2b, Phase 3 will be conducted as a 
randomized, observer-blinded, placebo-controlled trial. Approximately 
32,500 subjects, 18 years of age or older, will be enrolled at multiple sites 
globally in Phase 3 and will receive a 2-dose schedule of either CVnCoV at 
the 12 µg dose level or placebo in a 1:1 ratio.  
Subjects will undergo active surveillance for COVID-19 (see Appendix 6A). 
During all site visits and phone calls, subjects will be reminded to contact the 
site if they have an acute illness with any symptoms clinically consistent with 
COVID-19. In addition, subjects will be messaged up to twice a week to 
provide a yes or no response to having COVID-19 symptoms. Those who 
respond “yes” will be contacted by trial staff for a follow-up interview and 
assessment, if the Investigator considers the symptoms could potentially 
indicate a COVID-19 case. If a subject is suspected of having COVID-19, 
he/she will undergo testing for SARS-CoV-2 infection with samples collected 
at the site or at a home visit. If the subject is confirmed to have COVID-19, 
all subjects will be followed until resolution of their disease.   
Due to the uncertain incidence rate of COVID-19 cases in a pandemic setting, 
the trial will be conducted as a case-driven trial based on the any severity 
COVID-19 endpoint due to the higher number of cases required. The trial will 
include 2 interim analyses and a final analysis, each of which will be triggered 
by achieving a predefined number of cases meeting the primary efficacy case 
definition. As described above, cases of COVID-19 occurring in Phase 2b will 
be pooled with those in Phase 3 for the primary analysis of VE. As such, 
subjects participating in Phase 2b will contribute to the total sample size for 
the primary analysis of VE (N=36,500).  
With an equal follow-up time of evaluable subjects in the CVnCoV and 
placebo groups, efficacy would be demonstrated at the final analysis if 
53 cases or less of 160 total cases of COVID-19 of any severity are in the 
CVnCoV group (estimated VE ≥ 50.5%). Two interim analyses for high 
efficacy or futility will be performed when 56/111 cases meeting the primary 
case definition of COVID-19 cases have been accrued and adjudicated 
(approximately 5/6.5 months after the first vaccination). If the follow-up time 
of evaluable subjects is equal in both groups, early high efficacy would be 
demonstrated if 9/32 cases or less of the 56/111 cases are in the CVnCoV 
group (estimated VE at interim ≥ 80.9/59.5%); conversely, futility would be 
reached if 25/40 cases or more are in the CVnCoV group (estimated VE at 
interim ≤ 19.4/43.7%). 
Similar to Phase 2b, subjects participating in Phase 3 will be evaluated for 
SARS-CoV-2 infection during the trial, as measured by the development of 
antibodies to the N protein of SARS-CoV-2 in seronegative subjects.  
The safety objective of Phase 3 is to generate a large-scale safety database 
that will demonstrate the safety of CVnCoV. All subjects participating in the 
Phase 2b and Phase 3 parts of the trial will have medically-attended AEs 

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collected for 6 months after the second vaccination; and AESIs (see 
Appendix 9 and Appendix 10) and SAEs collected until the End of Trial (EOT) 
visit.  
 
Open-label Phase Design and Objectives 
After unblinding, the trial will shift from a randomized observer-blinded to an 
open-label design, and the following cohorts will be defined:  
Cohort A: CVnCoV-AV (See Table 4 for the Schedule of Trial Assessments 
and Procedures): Subjects ≥ 18 years who received at least 1 dose of 
CVnCoV and choose to receive an AV are included in this cohort and will be 
recommended to procure AV as standard of care per their national 
vaccination program, if not already done. Subjects will be requested to 
remain in the trial for safety follow-up until the EOT (Day 393 of the original 
Phase 2b/3 schedule). Subjects who were individually unblinded and already 
received an AV before implementation of Protocol version 4.0 will also be 
included in this cohort. 
Cohort B: CVnCoV only (See Table 5 for the Schedule of Trial Assessments 
and Procedures): Subjects ≥ 18 years who received at least 1 dose of 
CVnCoV and choose to remain in the trial without receiving any AV will 
continue follow-up until EOT (Day 393 of the original Phase 2b/3 schedule). 
Subjects who were individually unblinded during the randomized observer-
blinded phase and who received CVnCoV but did not receive an AV before 
implementation of Protocol version 4.0 and do not intend to receive an AV 
will also be included in this cohort. Subjects who initially intend to complete 
the trial without receiving an AV and later decide to receive an AV within the 
open-label phase will be switched to Cohort A. 
Placebo subjects do not require further follow-up and will discontinue the trial. 
The open-label phase will provide additional safety data, including data from 
subjects who receive an AV after CVnCoV. COVID-19 cases will continue to 
be documented, but there will no longer be any inferential efficacy analysis 
in the open-label phase (only descriptive summary of cases). Subjects will 
undergo passive surveillance for COVID-19 (see Appendix 6B). 
Trial unblinding and transition from the randomized observer-blinded phase 
to the open-label phase will be conducted on a country/site level, depending 
on full competent authority and Ethics Committee approval of Protocol 
version 4.0 per country/site. 
Trial Visits/ 
Contacts: 
For subjects participating in Phase 2b Immunogenicity Subset (see 
Table 1):  
o 7 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 57, 
Day 120, Day 211, and Day 393.  
o 3 protocol-scheduled phone contacts (safety calls) on Day 2, Day 30, 
and Day 302. 
For subjects participating in Phase 2b non-immunogenicity (see 
Table 2):  
o 6 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 120, 
Day 211, and Day 393.  
o 4 protocol-scheduled phone contacts (safety calls) on Day 2, Day 30, 
Day 57, and Day 302. 
For subjects participating in the randomized observer-blinded Phase 3 
(see Table 3): 
o 5 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 211, 
and Day 393. 
o 3 protocol-scheduled phone contacts (safety calls) on Day 57, 
Day 120, and Day 302.  

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After trial unblinding: 
Subjects of the placebo treatment arm will be notified of the trial treatment 
they received by a Subject Information Letter and will be withdrawn after an 
EOT phone call. Subjects of the CVnCoV treatment arm will be notified of the 
trial treatment they received at the next planned trial visit/phone call. 
For subjects participating in the Open-label Phase: 
Cohort A: CVnCoV-AV (Table 4) and Cohort B: CVnCoV only (Table 5): 
o Phone calls or clinic visits will be performed after trial unblinding on 
Day 302 and Day 393/EOT of the original Phase 2b/3 schedule. 
Collection of Blood 
Samples: 
The maximum total volume of blood taken over the trial period from any 
subject is 304 mL. 
Safety 
Assessments: 
The safety and reactogenicity of a 2-dose schedule of CVnCoV will be 
assessed by measuring the frequency and severity of the following AEs as 
described below.   
Safety assessments specific for subjects in Phase 2b: 
• 
Reactogenicity will be assessed daily on each vaccination day and 
the following 7 days by collection of solicited local AEs (injection site 
pain, redness, swelling, and itching) and solicited systemic AEs 
(fever, 
headache, 
fatigue, 
chills, 
myalgia, 
arthralgia, 
nausea/vomiting, and diarrhea) using electronic diaries (eDiaries). In 
addition, other indicators of safety will be collected (e.g., body 
temperature). 
• 
eDiaries will be used for collection of unsolicited AEs on each 
vaccination day and the following 28 days. 
Safety assessments for all subjects in Phase 2b and Phase 3: 
• 
Medically-attended AEs will be collected through 6 months after the 
second trial vaccination. 
• 
AESIs will be collected throughout the trial. AESIs to be monitored 
include potential immune-mediated diseases (pIMDs), AESIs for 
SARS-CoV-2 vaccines, and non-serious intercurrent medical 
conditions that may affect the immune response to vaccination.   
• 
SAEs will be collected throughout the trial.  
• 
AEs leading to vaccine withdrawal or trial discontinuation will be 
collected throughout the trial. 
Safety assessments for subjects in the Open-label Phase: 
• 
AESIs will be collected until EOT (Day 393 of the original Phase 2b/3 
schedule). AESIs to be monitored include pIMDs and AESIs for 
SARS--CoV-2 vaccines.   
• 
SAEs will be collected until EOT (Day 393 of the original Phase 2b/3 
schedule).  
• 
AEs leading to trial discontinuation will be collected until EOT (Day 
393 of the original Phase 2b/3 schedule).  
Testing for 
COVID-19: 
During the randomized observer-blinded phase of the trial, subjects clinically 
suspected of having COVID-19 will undergo testing for the SARS-CoV-2 virus 
as described below. Sample collection for the tests may be performed at the 
site or at a home visit by trial staff. Ideally, samples should be collected within 
5 days of symptom onset.  
• 
Subjects with a clinical suspicion of COVID-19 will undergo testing for 
SARS-CoV-2 infection using a rapid antigen test performed at the site 

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with the results provided to the subject. Nasopharyngeal swabs will be 
used to collect samples for the rapid antigen test. 
• 
Regardless of the result of the rapid antigen test, a nasopharyngeal swab 
sample collected at the same time will be sent to a central laboratory to 
perform a SARS-CoV-2 specific RT-PCR test. The RT-PCR test result 
will be considered definitive. 
o 
If the RT-PCR test is negative, but COVID-19 is still suspected based 
on the subject’s exposure history and clinical presentation, another 
nasopharyngeal swab sample should be taken as soon as feasible 
and sent to the central laboratory for RT-PCR testing. The RT-PCR 
retest result will be considered definitive.   
• 
In the open-label phase, subjects should report diagnosis of symptomatic 
COVID-19 positive cases to the site. For countries/sites with limited 
access to COVID-19 testing, subjects with clinical symptoms still can call 
the sites and be invited for testing on site at the investigator discretion in 
the best interest of the subject. A nasopharyngeal swab sample will be 
collected and sent to a central laboratory to perform a SARS-CoV-2 
specific RT-PCR test only if the result of the rapid antigen test is positive. 
COVID-19 Case 
Detection and Case 
Definition for 
Primary Efficacy 
Analysis: 
Case Detection: 
• 
For the randomized observer-blinded phase: During all site visits and 
phone calls, subjects will be reminded to contact the site if they have any 
1 or more of the following symptoms*: 
o Fever or chills 
o Shortness of breath or 
difficulty breathing 
o New loss of taste or smell 
o Cough 
o Fatigue  
o Muscle or body aches 
o Headache  
o Sore throat 
o Congestion or runny nose 
o Nausea or vomiting 
o Diarrhea   
*FDA Guidance for Industry, Development and Licensure of Vaccines to Prevent 
COVID-19, June 2020.   
• 
In addition, subjects will be messaged up to twice a week to provide a 
yes or no response to having COVID-19 symptoms. Those who respond 
“yes” will be contacted by trial staff for follow-up information, if the 
Investigator considers the symptoms could potentially indicate a 
COVID-19 case, using the definition applicable for the trial phase 
(randomized observer-blind versus open-label). 
• 
Based on a phone interview, if the subject is suspected of having 
COVID-19 illness, he/she will undergo RT-PCR testing for SARS-CoV-2 
infection as described above. If the subject is confirmed to have 
COVID-19, all subjects will be followed until resolution of their disease, 
even if the initial presentation is considered as mild. Information on 
clinical signs/symptoms and duration, treatments and outcome of the 
disease will be documented by trial staff and recorded in the electronic 
case report form (eCRF).   
• 
For the open-label phase: In order to decrease the burden for the trial 
subjects during the open-label phase, when only subjects having 
received CVnCoV (followed or not by AV) are still under follow-up, a more 

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restrictive definition will be used for case detection. Subjects will be 
reminded to contact the site if they have any of the following symptoms: 
o Cough 
o Fever (≥ 37.8 ºC) 
o Shortness of breath  
o Sudden onset of anosmia, 
ageusia or dysgeusia (new 
loss of taste or smell).  
• 
During this phase of the trial, subjects are asked to report symptomatic 
COVID-19 positive cases (detected independent of the study 
procedures) to site, or can be tested as part of the study procedures if 
the subject has limited access to testing. 
 
Definition of Virologically-Confirmed COVID-19 Case: 
For the randomized observer-blinded phase, a virologically-confirmed 
case of COVID-19 is defined as a positive SARS-CoV-2 specific RT-PCR test 
in a person with clinically symptomatic disease consisting of 1 or more of the 
following symptoms (based on the same screening symptoms as above): 
o Fever or chills 
o Shortness of breath or 
difficulty breathing 
o New loss of taste or smell 
o Cough 
o Fatigue  
o Muscle or body aches 
o Headache  
o Sore throat 
o Congestion or runny nose 
o Nausea or vomiting 
o Diarrhea   
This definition is intended to capture all severities of virologically-confirmed 
clinically symptomatic cases of COVID-19. As such, different disease 
severities defined for COVID-19 (e.g., mild or severe disease) will be a subset 
of these cases. 
For the open-label phase, a virologically-confirmed case of COVID-19 is 
defined as a positive SARS-CoV-2 specific RT-PCR test in a person with 
clinically symptomatic disease. 
 
Definition of Virologically-Confirmed COVID-19 Case for Primary 
Efficacy Analysis (Randomized Observer-blinded Phase only): 
For the primary analysis of efficacy, the case must meet the following criteria: 
• 
Must be a virologically-confirmed case of COVID-19 defined as a positive 
SARS-CoV-2 specific RT-PCR test in a person with clinically 
symptomatic COVID-19 as described above.  
• 
Symptom onset must have occurred ≥ 15 days following the second trial 
vaccination. 
• 
The subject must not have a history of virologically-confirmed COVID-19 
illness at enrollment or have developed a case of virologically-confirmed 
COVID-19 before 15 days following the second trial vaccination. 
• 
The subject must have been SARS-CoV-2 naïve at baseline and Day 43 
(defined as seronegative to N protein in the blood samples collected at 
baseline and Day 43). 
(Primary efficacy cases must be confirmed by the Adjudication Committee.)   
Planned Number of 
Subjects: 
The total enrollment for the Phase 2b/3 trial will be approximately 
36,500 subjects. The target enrollment for each phase of the trial is shown 
below:  
• 
4,000 subjects enrolled in Phase 2b. 
• 
32,500 subjects enrolled in Phase 3. 
Because this is a case-driven design, the final sample size will depend on the 
actual incidence rate of COVID-19 cases occurring during the trial. As such, 

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during the early stages of enrollment, an unblinded review of the incidence 
rate of cases will be performed by the DSMB. If the case accrual rate is lower 
or higher than expected, the DSMB may recommend an adjustment in 
sample size. If needed, another unblinded review by the DSMB may be 
performed later in the trial to further adjust the sample size.   
Criteria for 
Inclusion and 
Exclusion: 
Inclusion criteria for all subjects: 
Subjects will be enrolled in this trial only if they meet all of the following 
criteria: 
1. Male or female subjects 18 years of age or older. 
2. Be willing and able to provide written informed consent prior to 
initiation of any trial procedures. 
3. Expected compliance with protocol procedures and availability for 
clinical follow-up through the last planned visit. 
4. Females of non-childbearing potential defined as follows: surgically 
sterile (history of bilateral tubal ligation/occlusion, bilateral 
oophorectomy or hysterectomy) or postmenopausal {defined as 
amenorrhea for ≥ 12 consecutive months prior to screening (Day 1)} 
without an alternative medical cause). A follicle-stimulating hormone 
(FSH) level may be measured at the discretion of the Investigator to 
confirm postmenopausal status.  
5. Females of childbearing potential: negative pregnancy test {human 
chorionic gonadotropin (hCG)} within 24 hours prior to each trial 
vaccination on Day 1 and Day 29.   
6. Females of childbearing potential must use highly effective methods 
of birth control from 2 weeks before the first administration of the trial 
vaccine until 3 months following the last administration. The following 
methods of birth control are considered highly effective when used 
consistently and correctly: 
• 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, 
intravaginal or transdermal); 
• 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable); 
• 
Intrauterine devices; 
• 
Intrauterine hormone-releasing systems; 
• 
Bilateral tubal ligation; 
• 
Vasectomized or infertile partner; 
• 
Sexual abstinence  
{periodic abstinence (e.g., calendar, ovulation, symptothermal, 
and post-ovulation methods) and withdrawal are not acceptable}. 
 
Exclusion criteria for all subjects: 
Subjects will not be enrolled in this trial if they meet any of the following 
criteria: 
1. History of virologically-confirmed COVID-19 illness.  
2. For females: pregnancy or lactation.  
3. Use of any investigational or non-registered product (vaccine or 
drug) within 28 days preceding the administration of the first trial 
vaccine or planned use during the trial. 
4. Receipt of licensed vaccines within 28 days (for live vaccines) or 
14 days (for inactivated or any other vaccines) prior to the 
administration of the first trial vaccine. 

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5. Prior administration of any investigational SARS-CoV-2 vaccine or 
another coronavirus (SARS-CoV, MERS-CoV) vaccine or planned 
use during the trial. 
6. Any treatment with immunosuppressants or other immune-modifying 
drugs (including but not limited to anabolic steroids, corticosteroids, 
biologicals and methotrexate) for > 14 days total within 6 months 
preceding the administration of trial vaccine or planned use during 
the trial. For corticosteroid use, this means prednisone or equivalent, 
0.5 mg/kg/day for 14 days or more. The use of inhaled, topical, or 
localized 
injections 
of 
corticosteroids 
(e.g., 
for 
joint 
pain/inflammation) is permitted.  
7. Any medically diagnosed or suspected immunosuppressive or 
immunodeficient condition based on medical history and physical 
examination 
including 
known 
infection 
with 
human 
immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C 
virus (HCV); current diagnosis of or treatment for cancer including 
leukemia, lymphoma, Hodgkin disease, multiple myeloma, or 
generalized malignancy; chronic renal failure or nephrotic syndrome; 
and receipt of an organ or bone marrow transplant.  
8. History of angioedema (hereditary or idiopathic) or history of any 
anaphylactic reaction. 
9. History of pIMD. 
10. History of allergy to any component of CVnCoV vaccine.  
11. Administration of immunoglobulins or any blood products within 
3 months prior to the administration of trial vaccine or planned receipt 
during the trial. 
12. Subjects with a significant acute or chronic medical or psychiatric 
illness that, in the opinion of the Investigator, precludes trial 
participation (e.g., may increase the risk of trial participation, render 
the subject unable to meet the requirements of the trial, or may 
interfere with the subject’s trial evaluations). These include severe 
and/or uncontrolled cardiovascular disease, gastrointestinal disease, 
liver disease, renal disease, respiratory disease, endocrine disorder, 
and neurological and psychiatric illnesses. However, those with 
controlled and stable cases can be included in the trial. 
13. Subjects with impaired coagulation or any bleeding disorder in whom 
an IM injection or a blood draw is contraindicated. 
14. Foreseeable non-compliance with the trial procedures as judged by 
the Investigator. 
 
Roll-over criteria for the open-label phase: 
1. Subjects must have received at least 1 dose of CVnCoV during the 
randomized observer-blinded phase. 
2. Subjects must provide additional written informed consent to be 
eligible for the open-label phase. 
Cohort A: CVnCoV-AV:  
3. Subjects of the CVnCoV treatment arm who received or will receive 
any AV as standard of care through their national vaccination 
program.  
Cohort B: CVnCoV only: 
3. Subjects have not received any vaccination with any other 
investigational/authorized 
SARS-CoV-2 
vaccine 
or 
another 
coronavirus (SARS-CoV, MERS-CoV) vaccine.  

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Endpoints for the 
Randomized 
Observer-blinded 
Phase: 
 
Primary Endpoints: 
Primary Efficacy Endpoint 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity meeting the case definition for the 
primary efficacy analysis.  
Primary Safety Endpoints  
All safety endpoints will be analyzed in all subjects, in subjects seronegative 
at baseline, and in subjects seropositive at baseline. 
• 
Occurrence, intensity, and relationship of medically-attended AEs 
collected through 6 months after the second trial vaccination in all 
subjects. 
• 
Occurrence, intensity, and relationship of SAEs and AESIs collected 
throughout the trial in all subjects. 
• 
Occurrence of fatal SAEs throughout the trial in all subjects.  
• 
Occurrence, intensity, and duration of each solicited local AE within 
7 days after each trial vaccination in Phase 2b subjects.  
• 
Occurrence, intensity, duration of each solicited systemic AE within 
7 days after each trial vaccination in Phase 2b subjects. 
• 
Occurrence, intensity and relationship of unsolicited AEs occurring within 
28 days after each trial vaccination in Phase 2b subjects. 
• 
Occurrence of AEs leading to vaccine withdrawal or trial discontinuation 
throughout the trial in all subjects. 
Secondary 
Endpoints: 
Key Secondary Efficacy Endpoints 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) 
cases of moderate to severe COVID-19 meeting the case definition for 
the primary efficacy analysis (moderate and severe COVID-19 is defined 
in Appendix 3 and Appendix 4). 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) 
severe cases of COVID-19 meeting the case definition for the primary 
efficacy analysis (severe COVID-19 defined in Appendix 3).  
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity meeting the case definition due to 
infection with “wild type” (i.e., WT/D614G lineages A.1/B.1 without VOC 
B.1.1.7 [Alpha], B.1.351 [Beta], B.1.429 [Epsilon]) and “UK” (B.1.1.7 
[Alpha]) SARS-CoV-2 strains in SARS-CoV-2 naïve subjects. 
Other Secondary Efficacy Endpoints 
• 
In subjects ≥ 61 years of age, occurrence of first episodes of 
virologically-confirmed (RT-PCR positive) cases of COVID-19 of any 
severity meeting the case definition for the primary efficacy analysis. 
• 
Occurrence of virologically-confirmed (RT-PCR positive) SARS-CoV-2 
infection, with or without symptoms.  
If subject was symptomatic, onset of symptoms must have occurred 
≥ 15 days following the second trial vaccination; if subject was 
asymptomatic, the positive RT-PCR test must have occurred ≥ 15 days 
following the second trial vaccination.  
• 
BoD scores calculated based on first episodes of virologically-confirmed 
(RT-PCR positive) cases of COVID-19 of any severity meeting the case 
definition for the primary efficacy analysis.   

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o 
BoD #1 – no disease (not infected or asymptomatic infection) = 0; 
mild or moderate disease = 1; severe disease = 2.   
o 
BoD #2 – no disease (not infected or asymptomatic infection) = 0; 
disease without hospitalization = 1; disease with hospitalization = 2; 
death = 3.   
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity with symptom onset at any time after 
the first trial vaccination.  
Secondary Immunogenicity Endpoints (Phase 2b Immunogenicity 
Subset) 
SARS-CoV-2 RBD of S protein antibody responses  
On Days 1, 29, 43, 120, and 211: 
• 
Serum antibodies to SARS-CoV-2 RBD of S protein. 
• 
Occurrence of seroconversion to SARS-CoV-2 RBD of S protein. 
Seroconversion is defined as detectable SARS-CoV-2 RBD of S protein 
antibodies in the serum of subjects who tested seronegative at baseline. 
SARS-CoV-2 viral neutralizing antibody responses   
On Days 1, 29, 43, 120, and 211: 
• 
Serum neutralizing antibodies to SARS-CoV-2 virus, as measured by a 
viral neutralizing antibody assay. 
• 
Occurrence of seroconversion to SARS-CoV-2 virus, as measured by a 
viral neutralizing antibody assay. 
Seroconversion is defined as detectable SARS-CoV-2 viral neutralizing 
antibodies in the serum of subjects who tested seronegative at baseline. 
Exploratory 
Endpoints: 
Exploratory Efficacy Endpoints 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) 
cases of COVID-19 caused by individual VOCs (see Section 9.2.1.6). 
• 
Severity assessment of first episodes of virologically-confirmed (RT-PCR 
positive) cases of COVID-19 meeting the case definition for the primary 
efficacy analysis (COVID-19 severity definitions provided in Appendix 3 
and Appendix 4).  
The following endpoints will be analyzed as occurring ≥ 15 days following the 
second trial vaccination (full VE) and at any time after the first trial 
vaccination.   
In SARS-CoV-2 naïve subjects: 
• 
Occurrence of supplemental oxygenation due to COVID-19. 
• 
Occurrence of mechanical ventilation due to COVID-19.  
• 
Occurrence of hospitalization due to COVID-19.   
• 
Occurrence of death due to COVID-19.   
• 
Occurrence of death due to any cause.  
In SARS-CoV-2 naïve and non-naïve subjects: 
• 
In all subjects regardless of their baseline serostatus: occurrence of first 
episodes of virologically-confirmed (RT-PCR positive) cases of 
COVID-19 of any severity.  
The following endpoint will be analyzed in subjects who had a first episode of 
a virologically-confirmed (RT-PCR positive) case of COVID-19 of any severity 
meeting the case definition for the primary efficacy analysis.   
• 
Occurrence of second episodes of virologically-confirmed (RT-PCR 
positive) cases of COVID-19 of any severity. 
 
 

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Exploratory Immunogenicity Endpoints  
On Days 1, 29, 43, 120**, and 211** in peripheral blood mononuclear cells 
(PBMCs) from approximately 200*** subjects at selected site(s): 
• 
The frequency and functionality of SARS-CoV-2 RBD of S-specific T-cell 
response after antigen stimulation by intracellular cytokine staining (ICS) 
to investigate Th1 response and expression of Th2 markers. 
• 
The proportion of subjects with a detectable increase in SARS-CoV-2 
RBD of S-specific T-cell response. 
** Testing of samples collected on Day 120 and Day 211 will be done only in 
subjects categorized as T-cell responders on Day 29 and/or Day 43. 
*** First testing of samples will be performed for a subset of these subjects 
and might be extended to 200 subjects if T-cell response is detectable. 
Endpoints for the 
Open-label phase: 
• 
Occurrence, intensity, and relationship to CVnCoV of SAEs and AESIs 
collected throughout the trial until the EOT.  
• 
Occurrence of fatal SAEs throughout the trial until EOT. 
• 
Only for Cohort A: CVnCoV-AV: Occurrence of AEs leading to trial 
discontinuation after the first dose with an AV in the open-label phase 
until EOT. 
Open-label Exploratory Endpoints: 
• 
Occurrence of first episodes of symptomatic virologically-confirmed 
(RT-PCR positive) cases of COVID-19 of any severity as assessed by 
the Investigator. 
Any further modifications to endpoints in the open-label phase will be 
described in the statistical analysis plan (SAP). 
Data and Safety 
Monitoring Board: 
An independent DSMB will be convened to oversee the safety and efficacy 
of subjects participating in this trial, to assess the progress and conduct of 
the trial, to review the cumulative safety data from the trial, and to make 
recommendations to CureVac whether to continue, modify, or stop the trial. 
To ensure subject safety on an ongoing basis, a CureVac Safety Review 
Team reviews the safety data on a periodic basis. The outcome of these 
reviews and discussions are then shared with the DSMB Chair. In addition to 
safety data, the DSMB will be asked to review efficacy data at the interim 
analyses and at other time points during the trial for a continued assessment 
of the risk-benefit of the trial. As part of the risk-benefit analysis, the DSMB 
will periodically monitor COVID-19 cases for signals of VDE. The DSMB will 
also be asked to perform an unblinded review(s) of the incidence rate of 
COVID-19 cases to recommend an adjustment(s) in sample size, if needed. 
The DSMB Charter will describe in detail the composition and objectives of 
the DSMB; the responsibilities of the DSMB, CureVac and the contract 
research organization (CRO); the schedule and conduct of the DSMB 
meetings; and the datasets to be reviewed. 
Sample Size 
Justification: 
The total sample size of approximately 36,500 subjects for the combined 
Phase 2b/3 trial is based on formal statistical power calculations 
demonstrating the efficacy of CVnCoV. This trial is planned using a group 
sequential design with 2 interim analyses for high efficacy or futility using the 
O’Brien and Fleming error spending function for the primary endpoint of any 
COVID-19 cases. With an overall 2-sided alpha of 5%, 160 cases are needed 
at the final analysis for COVID-19 cases of any severity to reach 90% power 
to demonstrate that VE is above 30% (based on a margin of 30% for the 
lower bound of the confidence interval [CI] for VE), when considering the VE 
is 60%.  
The sample size is based on a test for one single proportion. Assuming an 
incidence rate of COVID-19 of 0.15% per month in placebo subjects; a VE of 
60%; an enrollment period of 3 months; and a non-evaluable rate of 20% 

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during the trial which includes ~5% seropositivity of enrollees at baseline (i.e. 
non-naïve subjects), then 36,500 subjects randomized to receive either 
CVnCoV or placebo in a 1:1 ratio will achieve the 160 cases at approximately 
9 months after the first vaccination. 
Because this is a case-driven trial design, the final sample size will depend 
on the actual incidence rate of COVID-19 cases occurring during the trial. As 
such, during the early stages of enrollment, an unblinded review of the 
incidence rate of cases will be performed by the DSMB. If the case accrual 
rate is lower or higher than expected, the DSMB may recommend an 
adjustment in sample size. If needed, another unblinded review by the DSMB 
may be performed later in the trial to further adjust the sample size.   
The sample size of ~4,000 subjects for Phase 2b is based on generating a 
robust and detailed dataset characterizing the safety, reactogenicity, and 
immunogenicity of CVnCoV prior to entering Phase 3 and for the early 
conditional approval submission.  
Analysis Sets: 
The main analysis populations are: 
Safety Analysis Set (SAS) 
The SAS will include all randomized subjects in Phase 2b or 3 who received 
at least 1 dose of CVnCoV or placebo.  
The SAS will be the primary population for the safety endpoints collected on 
all subjects and for the objectives evaluating efficacy after the first dose.  
Efficacy Analysis Set (EAS) 
The EAS will include all subjects randomized in Phase 2b and Phase 3 who: 
• 
Received both doses of trial vaccine according to the randomization 
(2 doses of CVnCoV or 2 doses of placebo). 
• 
Had not developed a virologically-confirmed case of COVID-19 before 
trial entry (based on Exclusion Criterion 1) or before 15 days following 
the second trial vaccination. 
• 
Had not stopped the trial before 15 days following the second trial 
vaccination.  
• 
Were SARS-CoV-2 naïve at baseline and Day 43 (based on 
seronegativity to N protein in the blood sample taken at baseline). 
The EAS will be the main analysis population for the primary efficacy endpoint 
and for the appropriate secondary efficacy endpoints. 
Per Protocol Efficacy Set (PPE) 
The PPE set will include EAS subjects who meet all eligibility criteria at trial 
entry and who have no major protocol deviations that would impact the 
efficacy outcomes as specified in the SAP. 
The PPE will be a supportive population for the primary and appropriate 
secondary efficacy endpoints.   
Additional populations that might be required for the analyses of the results 
from the open-label phase will be defined in an extended SAP. 
Statistical 
Methodology: 
Missing Data/Discontinuation: 
For SARS-CoV-2 RBD of S protein antibodies, concentration values marked 
as below the lower limit of quantification (LLOQ) will be set to 0.5*LLOQ for 
the purpose of geometric mean titer (GMT) computation.  
No imputation of missing values will be performed for any analysis (except 
the imputation for missing partial dates of AEs and concomitant medication).  
Currently no replacement of drop-out subjects is foreseen. 
Statistical 
Analyses: 
Analysis of Demographics and Other Baseline Characteristics: 
Data will be summarized with respect to demographic and baseline 
characteristics, medical history, immune response measurements, and all 
safety measurements using descriptive statistics (quantitative data) and 

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contingency tables (qualitative data) overall, by vaccine group, and by age 
group and vaccine group. 
Efficacy Analyses: 
In the primary efficacy analysis, VE, defined as the percent reduction in the 
frequency of any COVID-19 cases (according to the primary case definitions) 
in vaccinated subjects compared with subjects who received placebo will be 
calculated with exact 95%* CI as follows: 
VE = 1- RR = 1 - (ARV/ARP) = 1 – {p / r (1-p)} 
where 
ARV = attack rate in vaccinated group = nv/Nv = number of subjects reporting 
at least 1 COVID-19 episode in the CVnCoV group / total follow-up time of 
evaluable subjects in the CVnCoV group (number of person-month) 
ARP = attack rate in placebo group = np/Np = number of subjects reporting 
at least 1 COVID-19 episode in the placebo group / total follow-up time of 
evaluable subjects in the placebo group (number of person-month) 
RR = relative risk = ARV/ARP 
p = proportion of COVID-19 cases (according to primary case definition) 
coming from the CVnCoV group among all cases = nv/(nv+np) 
r = ratio of total follow-up time of evaluable subjects in the CVnCoV group 
over total follow-up time of evaluable subjects in the placebo group = Nv/Np 
* Level of CI may be slightly adjusted due to the sequential design (see Section 10.3.8). 
The statistical hypothesis for the primary efficacy endpoint is:  
H0A: VE ≤ 30% versus H1A: VE > 30% 
A is related to COVID-19 cases of any severity 
The trial will be successful if the lower limit of the exact 2-sided 95% (to be 
slightly adjusted to consider the sequential design) CI of the VE endpoint of 
all COVID-19 cases of any severity is > 30% for H0A or if the exact 2-sided 
95% (to be slightly adjusted to consider the sequential design) CI of the VE 
endpoint of moderate to severe COVID-19 cases is > 20%. If the interim 
analyses and the final analysis are performed after 56/111 and 160 cases 
meeting the primary efficacy case definition have been reported, respectively, 
the 1-sided α-risk to consider at time of final analysis according to 
O’Brien-Fleming type error-spending-function will be 0.02281.  
Efficacy will be demonstrated at the final analysis if 53 cases or less of the 
total 160 are in the CVnCoV group and if the follow-up time of evaluable 
subjects is equal in both groups (Nv=Np). At the first interim analysis, early 
high efficacy would be demonstrated if 9 cases or less of the 56 cases are in 
the CVnCoV group (observed efficacy ≥ 80.9%); conversely, futility would be 
reached if 25 cases or more are in the CVnCoV group if Nv=Np. 
At the second interim analysis, early high efficacy will be demonstrated if 
32 cases or less of the 111 cases are in the CVnCoV group (observed 
efficacy ≥ 59.5%); conversely, futility would be reached if 40 cases or more 
are in the CVnCoV group if Nv=Np. 
For the key secondary endpoints, no interim analysis is planned. However, 
descriptive statistic as VE and 95% CI will be presented. 
As a sensitivity analysis, the time to first-occurrence of virologically-confirmed 
COVID-19 cases (meeting the primary efficacy case definition) will also be 
analyzed. Kaplan-Meier curves will be displayed. 
Statistical testing of the 3 key secondary efficacy endpoints will be performed 
according to the conditional hierarchical testing procedure using the order 
 
 

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defined in the objectives and endpoints sections. Consequently: 
• 
Efficacy of CVnCoV in regard to moderate and severe cases will be 
demonstrated only if there is successful demonstration of the primary 
efficacy objective. 
• 
Efficacy of CVnCoV in regard to severe cases will be demonstrated only 
if there is successful demonstration of the primary efficacy objective and 
the key secondary objective on moderate and severe cases. 
• 
Efficacy of CVnCoV in regard to (RT-PCR positive) cases of “wild type” 
(i.e., WT/D614G lineages A.1/B.1 without VOC B.1.1.7 [Alpha], B.1.351 
[Beta], B.1.429 [Epsilon]) and “UK” (B.1.1.7 [Alpha]) will be demonstrated 
only if there is successful demonstration of the primary efficacy objective 
and the key secondary objectives on moderate and severe cases and 
severe cases. 
Otherwise, these endpoints will be analyzed as secondary endpoints without 
success criteria testing. 
To assess the efficacy in the prevention of severe COVID-19 and 
asymptomatic infections, similar analyses to the primary efficacy endpoint will 
be performed. Efficacy will be demonstrated if the lower limit of the exact 
2-sided 95% CI of the VE endpoint is > 10% for prevention of severe disease 
and > 0% for prevention of asymptomatic infections.  
Interim Analysis: Unblinded interim analyses for high efficacy, futility and for 
safety will be reviewed by the DSMB when 56/111 cases meeting the primary 
efficacy case definition have been reached.  
The safety and immunogenicity analyses will be performed overall and, 
for specified subsets, by baseline serology status for SARS-CoV-2. 
Safety Analyses - Solicited AEs: 
The frequencies and percentages of subjects experiencing each solicited 
local and systemic AE within 7 days after each vaccination will be presented 
by intensity and overall. The results will be tabulated by vaccine group and 
age groups. For subjects with more than 1 episode of the same AE within 
7 days after a vaccination, the maximum intensity will be used for tabulations. 
Safety Analyses - Unsolicited AEs: 
Unsolicited AEs including SAEs and AESIs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) by System Organ Class (SOC) 
and Preferred Term (PT). The frequency and percentage of subjects 
reporting each unsolicited AE within the 28 days after each vaccination and 
overall will be tabulated at the SOC and PT levels. Additional similar 
tabulations will be performed to evaluate severity and relationship to trial 
vaccine. 
Immunogenicity Analysis: 
Descriptive statistics for the immunogenicity endpoints will be provided by 
vaccine group and overall, and by vaccine group and age groups. 
GMT, Fold Change (FC) from baseline, Geometric mean of FC (GMFC) with 
their 95% CI will be computed for SARS-CoV-2 RBD of S protein antibody 
levels and for neutralizing antibodies, overall and separately in subjects 
seronegative at baseline and in subjects seropositive at baseline. 
For each readout, seroconversion rates will also be summarized at each 
blood sampling time point in subjects who are SARS-CoV-2 seronegative at 
baseline. 
 
For the open-label phase, safety analyses will be described by cohort. 
Details will be provided in an extended SAP. 
 

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2 STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES 
Figure 1 
Overview of HERALD Trial CV-NCOV-004 
 
 
AV: authorized/licensed vaccines for preventing COVID-19; i.m.: intramuscular; SoC: standard of care. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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b. Medication/vaccination history taken within 6 months prior to enrollment should be recorded to establish eligibility. 
c. A urine pregnancy test will be performed before each trial vaccination on Day 1 and Day 29 for women of childbearing potential. Where required by local laws and 
regulations, the pregnancy test will be performed in blood (3 mL). 
d. See Section 6.3 and Section 8.1 for an overview of the criteria leading to delay or cancellation of vaccine administration. In case of delay, the vaccination should take 
place within the allowed time windows, if feasible. The reasons for delay or cancellation should be documented in the subject chart. 
e. Physical examination and vital signs must be performed/measured by a qualified healthcare professional. See Section 9.3.6 for an overview of the required 
assessments. 
f. Vital signs will be measured pre- and post-vaccination prior to discharge. Subjects will be observed for at least 30 minutes following each vaccination. Vital signs must 
be within normal or clinically non-relevant abnormal ranges or have returned to pre-vaccination values for the subject to be discharged. 
g. eDiary (electronic diary) for recording of post-vaccination solicited AEs will be provided to subjects as needed. Solicited local and systemic AEs occurring on the day 
of vaccination (Day 1 and Day 29) and for the following 7 days will be recorded by the subject in the eDiary. In addition, the eDiary will serve as a memory aid for the 
subject to report unsolicited AEs occurring on the day of vaccination (Day 1 and Day 29) and for the following 28 days. The data will be reviewed with the subject by 
trial staff at the site visits on Day 29, Day 43, and Day 57. During phone calls, the subject´s general well-being will be checked and the subject should be reminded to 
complete the safety information by eDiary. If the subject reports by phone any concerning local or systemic reactions, or other AEs (e.g., on Day 2 or Day 30), these 
should be followed-up either by a phone call(s) or by an unscheduled site visit, based on the judgment of the Investigator.   
h. Medically-attended AEs will be collected through 6 months after the second trial vaccination. Medically-attended AEs are defined as AEs with medically-attended 
visits that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit 
to or from medical personnel (medical doctor) for any reason. SAEs, AESIs, AEs leading to vaccine withdrawal or trial discontinuation, and any non-serious intercurrent 
condition that may affect the immune response to vaccination will be collected through 1 year after the second trial vaccination. During all site visits and phone calls, 
trial staff will remind subjects to call the site immediately to report the following: if he/she experiences any concerning medical event; any medically-attended visits 
that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or 
from medical personnel (medical doctor) for any reason; or experience a serious medical event, have a change in overall health or be diagnosed with a new medical 
condition by a doctor. These should be reported regardless of the perceived relationship between the event and the trial vaccine. 
Medications associated with any solicited and unsolicited AE, medications for a medically-attended AE, AESI, or SAE, and any immune-suppressive/modulating 
medication will be documented in the eCRF for the time period specified in Table 6. In case any prohibited medication as defined in Section 7.6.2 was taken by the 
subject, this needs also be documented in the eCRF. 
i. 
The eDiary will serve as a memory aid for the subjects to report additional concomitant medication or changes in concomitant medication and the corresponding 
symptoms. The Investigator needs to transcribe concomitant medication and symptoms if matching the criteria outlined in Table 6 and any new concomitant medication 
or changes in concomitant medication prescribed for any underlying disease present already at Visit 1. 
j. 
During all site visits and phone calls, trial staff will remind subjects to contact the site if they have any of the symptoms suggestive of COVID-19. In addition, subjects 
will be messaged up to twice a week to provide a yes or no response to having COVID-19 symptoms. Those who respond “yes” will be contacted by trial staff for 
follow-up information if the Investigator considers the symptoms could potentially indicate a COVID-19 case and the process outlined in Section 9.2.1 should be 
followed. 
k. Blood samples should be collected prior to trial vaccination on Day 1 and Day 29.  

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l. 
Binding antibodies to the RBD (receptor-binding domain) of the S (spike) protein and to the N (nucleocapsid) protein of SARS-CoV-2 will be measured by 
immunoassay. Viral neutralizing antibodies directed against SARS-CoV-2 will be measured by a functional activity assay. The N protein is not a component of the 
CVnCoV vaccine, but is being measured to determine serostatus of subjects to the SARS-CoV-2 virus (naïve or non-naïve to SARS-CoV-2); distinguish immune 
responses elicited by infection with SARS-CoV-2 from those induced by CVnCoV vaccination; and determine the occurrence of SARS-CoV-2 infection during the trial. 
 

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g. eDiary (electronic diary) for recording of post-vaccination solicited AEs will be provided to subjects as needed. Solicited local and systemic AEs occurring on the day 
of vaccination (Day 1 and Day 29) and for the following 7 days will be recorded by the subject in the eDiary. In addition, the eDiary will serve as a memory aid for the 
subject to report unsolicited AEs occurring on the day of vaccination (Day 1 and Day 29) and for the following 28 days. The data will be reviewed with the subject by 
trial staff at the site visits on Day 29, Day 43, and Day 57. During phone calls, the subject´s general well-being will be checked and the subject should be reminded to 
complete the safety information by eDiary. If the subject reports by phone any concerning local or systemic reactions, or other AEs (e.g., on Day 2 or Day 30), these 
should be followed-up either by a phone call(s) or by an unscheduled site visit based on the judgment of the Investigator.   
h. Medically-attended AEs will be collected through 6 months after the second trial vaccination. Medically-attended AEs are defined as AEs with medically-attended 
visits that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit 
to or from medical personnel (medical doctor) for any reason. SAEs, AESIs, AEs leading to vaccine withdrawal or trial discontinuation, and any non-serious intercurrent 
condition that may affect the immune response to vaccination will be collected through 1 year after the second trial vaccination. During all site visits and phone calls, 
trial staff will remind subjects to call the site immediately to report the following: if he/she experiences any concerning medical event; any medically-attended visits 
that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or 
from medical personnel (medical doctor) for any reason; or experience a serious medical event, have a change in overall health or be diagnosed with a new medical 
condition by a doctor. These should be reported regardless of the perceived relationship between the event and the trial vaccine. 
Medications associated with any solicited and unsolicited AE, medications for a medically-attended AE, AESI, or SAE, and any immune-suppressive/modulating 
medication will be documented in the eCRF for the time period specified in Table 6. In case any prohibited medication as defined in Section 7.6.2 was taken by the 
subject, this needs also be documented in the eCRF. 
i. The eDiary will serve as a memory aid for the subjects to report additional concomitant medication or changes in concomitant medication and the corresponding 
symptoms. The Investigator needs to transcribe concomitant medication and symptoms if matching the criteria outlined in Table 6 and any new concomitant medication 
or changes in concomitant medication prescribed for any underlying disease present already at Visit 1. 
j. During all site visits and phone calls, trial staff will remind subjects to contact the site if they have any of the symptoms suggestive of COVID-19. In addition, subjects 
will be messaged up to twice a week to provide a yes or no response to having COVID-19 symptoms. Those who respond “yes” will be contacted by trial staff for 
follow-up information if the Investigator considers the symptoms could potentially indicate a COVID-19 case and the process outlined in Section 9.2.1 should be 
followed.  
k. Binding antibodies to the N (nucleocapsid) protein of SARS-CoV-2 will be measured by immunoassay. The N protein is not a component of the CVnCoV vaccine, but 
is being measured to determine serostatus of subjects to the SARS-CoV-2 virus (naïve or non-naïve to SARS-CoV-2) and the occurrence of SARS-CoV-2 infection 
during the trial. The baseline blood sample should be collected prior to trial vaccination on Day 1.  
l. Blood samples should be collected prior to trial vaccination on Day 1 and Day 29. 

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g. Medically-attended AEs will be collected through 6 months after the second trial vaccination. Medically-attended AEs are defined as adverse events with 
medically-attended visits that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise 
unscheduled visit to or from medical personnel (medical doctor) for any reason. SAEs, AESIs, AEs leading to vaccine withdrawal or trial discontinuation, and any 
non-serious intercurrent condition that may affect the immune response to vaccination will be collected through 1 year after the second trial vaccination. During all 
site visits and phone calls, trial staff will remind subjects to call the site immediately to report the following: if he/she experiences any concerning medical event; any 
medically-attended visits that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise 
unscheduled visit to or from medical personnel (medical doctor) for any reason; or experience a serious medical event, have a change in overall health or be diagnosed 
with a new medical condition by a doctor. These should be reported regardless of the perceived relationship between the event and the trial vaccine. 
Medications for a medically-attended AE, AESI, or SAE and any immune-suppressive/modulating medication will be documented in the eCRF for the time period 
specified in Table 6. In case any prohibited medication as defined in Section 7.6.2 was taken by the subject, this needs also be documented in the eCRF. 
h. The eDiary will serve as a memory aid for the subjects to report additional concomitant medication or changes in concomitant medication and the corresponding 
symptoms. The Investigator needs to transcribe concomitant medication and symptoms if matching the criteria outlined in Table 6 and any new concomitant medication 
or changes in concomitant medication prescribed for any underlying disease present already at Visit 1. 
i. During all site visits and phone calls, trial staff will remind subjects to contact the site if they have any of the symptoms suggestive of COVID-19. In addition, subjects 
will be messaged up to twice a week to provide a yes or no response to having COVID-19 symptoms. Those who respond “yes” will be contacted by trial staff for 
follow-up information if the Investigator considers the symptoms could potentially indicate a COVID-19 case and the process outlined in Section 9.2.1 should be 
followed.   
j. Binding antibodies to the N (nucleocapsid) protein of SARS-CoV-2 will be measured by immunoassay. The N protein is not a component of the CVnCoV vaccine, but 
is being measured to determine serostatus of subjects to the SARS-CoV-2 virus (naïve or non-naïve to SARS-CoV-2) and the occurrence of SARS-CoV-2 infection 
during the trial. The baseline blood sample should be collected prior to trial vaccination on Day 1.   

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b. 
Roll-over criteria for the open-label phase should be reviewed and confirmed on Clinic Visit OL-1.  
c. 
Vaccination history should be checked to establish eligibility. If the subject did not report any administration of a COVID-19 AV, he/she needs to be asked whether 
he/she received a COVID-19 AV already and, if confirmed, the AV needs to be documented in the eCRF.   
d. 
SAEs, AESIs, and AEs leading to trial discontinuation will be collected until the EOT.  
During all site visits, trial staff will remind subjects to call the site immediately to report the following: if he/she experiences any concerning medical event; or 
experiences a serious medical event, has a change in overall health, or is diagnosed with a new medical condition by a doctor. These should be reported regardless 
of the perceived relationship between the event and the trial vaccine. 
COVID-19 AV vaccination details (specific AV and vaccination dates) will be collected. 
e. 
Medications for AESIs, or SAEs, and any immune-suppressive/modulating medications will be documented in the eCRF for the time period specified Table 6. Any 
prohibited medication (as defined in Section 7.6.2) taken by the subject also needs to be documented in the eCRF. 
f. 
During all site visits/phone calls, trial staff will remind subjects to report any confirmed COVID-19 positive tests. 

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d. 
SAEs, AESIs, and AEs leading to trial discontinuation will be collected until the EOT.  
During all site visits, trial staff will remind subjects to call the site immediately to report the following: if he/she experiences any concerning medical event; or 
experiences a serious medical event, has a change in overall health, or is diagnosed with a new medical condition by a doctor. These should be reported regardless 
of the perceived relationship between the event and the trial vaccine. 
e. 
Medications for AESIs, or SAEs, and any immune-suppressive/modulating medications will be documented in the eCRF for the time period specified Table 6. Any 
prohibited medication (as defined in Section 7.6.2) taken by the subject also needs to be documented in the eCRF. 
f. 
During all site visits/phone calls, trial staff will remind subjects to report any confirmed COVID-19 positive tests. 
 
 
 

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3 INTRODUCTION 
3.1 Background 
3.1.1 Coronaviruses 
Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded ribonucleic acid 
(RNA) viruses that belong to the subfamily Coronavirinae, family Coronavirdiae, order 
Nidovirales. The virion has a nucleocapsid composed of genomic RNA and 
phosphorylated nucleocapsid (N) protein, which is buried inside phospholipid bilayers and 
covered by spike (S) proteins [2]. The membrane (M) protein (a type III transmembrane 
glycoprotein) and the envelope (E) protein are located among the S proteins in the virus 
envelope. CoVs were given their name based on a characteristic crown-like appearance. 
There are 4 genera of CoVs, namely, Alphacoronavirus (αCoV), Betacoronavirus (βCoV), 
Deltacoronavirus (δCoV) and Gammacoronavirus (γCoV) [3]. Evolutionary analyses have 
shown that bats and rodents are the gene sources of most αCoVs and βCoVs, while avian 
species are the gene sources of most δCoVs and γCoVs. CoVs have repeatedly crossed 
species barriers and some have emerged as important human pathogens, causing 
generally-mild acute respiratory illnesses known as the common cold [4].  
Prior to December 2019, when clusters of pneumonia cases with unknown etiology were 
detected in Wuhan City, Hubei Province, China, only 2 additional strains of CoVs had 
caused outbreaks of severe acute respiratory disease in humans: the severe acute 
respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome 
coronavirus (MERS-CoV). On 9 January 2020, a novel CoV, named severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), was officially identified as the cause 
of an outbreak of viral pneumonia in Wuhan. In the following weeks, the virus spread 
rapidly within China and an increasing number of countries worldwide. On 
30 January 2020 the World Health Organization (WHO) announced the outbreak under 
International Health Regulations as a public health emergency of international concern 
(the WHO's highest level of alarm) and on 12 March 2020, the WHO announced the 
outbreak as a pandemic. 
SARS-CoV-2 falls into the genus βCoV, which includes CoVs discovered in humans, bats 
and other wild animals (SARS-CoV, bat SARS-like CoV, and others). Similar to other 
βCoVs, the SARS-CoV-2 genome contains 2 flanking untranslated regions and a single 
long open reading frame encoding a polyprotein [3]. The SARS-CoV-2 genome is 
arranged in the order of 5’-replicase (orf1/ab)-structural proteins [S-E-M-N]−3’ and lacks 
the hemagglutinin-esterase gene which is characteristically found in lineage A βCoVs, as 
illustrated in Figure 2. 
High sequence similarity (> 99%) has been reported following analysis of virus isolates 
from patients with SARS-CoV-2 infection [5-8].  

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Figure 2 
Genome 
Organization 
of 
SARS-CoV-2 
Compared 
with 
Other 
Betacoronaviruses 
 
Source: Chan et al., 2020 [3] 
The S gene of SARS-CoV-2 appears to be highly divergent to other CoVs, with less than 
75% nucleotide sequence identity to all previously described SARS-CoVs, except a 93.1% 
nucleotide identity to RaTG13 [6]. The S genes of SARS-CoV-2 and RaTG13 S gene are 
longer than other SARS-CoVs. The major differences in SARS-CoV-2 are 3 short 
insertions in the N-terminal domain, and 4/5 key residues changes in the receptor-binding 
motif, in comparison with SARS-CoV. At the amino acid sequence level, the S glycoprotein 
of SARS-CoV-2 was found to have 76.3% identity and 87.3% similarity with the 
S glycoprotein of SARS-CoV [9]. 
The S2 subunit of SARS-CoV-2 was found to be highly conserved, sharing 99% sequence 
identity with those of the 2 bat SARS-like CoVs (SL-CoV ZXC21 and ZC45) and human 
SARS-CoV [3]. The S1 subunit of SARS-CoV-2 shares around 70% identity to that of the 
2 bat SARS-like CoVs and human SARS-CoV. The domain of the receptor-binding domain 
(RBD) (excluding the external subdomain) is highly conserved, but the external subdomain 
of the SARS-CoV-2 RBD (which is responsible for the direct interaction with the host 
receptor) shares only 40% amino acid identity with other SARS-related CoVs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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To date, there is no information available on the immune responses to SARS-CoV-2. An 
immunoinformatics approach predicted 5 cytotoxic T lymphocyte (CTL) epitopes, 
3 sequential B cell epitopes and 5 discontinuous B cell epitopes in the S glycoprotein [9]. 
Simulations suggested that the CTL epitopes bind the major histocompatibility complex 
class I peptide-binding grooves via multiple contacts, with continuous hydrogen bonds and 
salt bridge anchors, supporting their potential in generating immune responses. Of note, 
the simulations found only one overlapping CTL epitope between MERS-CoV and 
SARS-CoV-2 and no comparable epitopes with SARS-CoV. 
3.1.2 COVID-19  
SARS-CoV-2 is transmitted mainly through close contact and inhalation of respiratory 
droplets and aerosol particles. The mean incubation period is 4-6 days with about 95% of 
patients developing symptoms within 14 days after infection [10,11]. The most common 
symptoms of coronavirus disease 2019 (COVID-19) include fever, cough, dyspnea, and 
occasionally watery diarrhea. In an analysis of > 1000 hospitalized patients from China, 
44% initially presented with fever (although 89% developed fever at some point during 
hospitalization) and 68% with cough. Other symptoms included fatigue (23%), myalgia 
(15%), and gastrointestinal symptoms (8%) [11]. As with other systemic viral infections, a 
large spectrum of possible clinical manifestations are being reported in COVID-19 
patients, including neurological symptoms and signs, cardiac disease, and cutaneous 
lesions [12-15]. Chemosensory dysfunction, such as anosmia and dysgeusia, are 
increasingly reported.  
Data from more than 72,000 patients from China classified cases as mild (including mild 
pneumonia, 81%), severe (14%) or critical (5%) [16]. Severe and critical cases presented 
with severe pneumonia, septic shock and acute respiratory distress syndrome (ARDS). 
The critically ill patients requiring intensive care management present a large spectrum of 
complications in addition to ARDS, such as acute cardiac injury, acute renal injury, 
acro-ischemia, 
disseminated 
intravascular 
complications, 
bacterial 
or 
fungal 
superinfections [17,18]. 
In early stages of the outbreak, the reported case-fatality rate in China was 17% [19]. In 
admitted patients in Wuhan, mortality reached 25% in the middle of the epidemic. Similarly 
high death rates are recorded in those requiring intensive care: in a large retrospective 
cases series on COVID-19 confirmed patients admitted to intensive care units (Lombardy, 
Italy), mortality reached 26% [20]. The global mortality rate is estimated to be around 3% 
[21]. 
According to the 2020 WHO, the COVID-19 pandemic is causing significant loss of life, 
disrupting livelihoods, and threatening the recent advances in health and progress 
towards global sustainable development goals [22]. On 08 November 2020, according to 
WHO, > 50 million cases have been confirmed globally, including 1.25 million deaths. 
3.1.3 Development of CVnCoV 
There is currently one fully licensed vaccine for prevention of CoV-associated disease on 
the market and those who received a conditional approval are not yet available for the 
majority of the society. CureVac AG is developing a new SARS-CoV-2 messenger 
ribonucleic acid (mRNA) vaccine formulated with lipid nanoparticles (LNP), referred to as 

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CVnCoV, for the prevention of COVID-19 when administered as a 2-dose primary 
vaccination schedule.  
CVnCoV is an mRNA-based COVID-19 vaccine in which the mRNA is protected and 
delivered by encapsulation within LNPs. CVnCoV has been developed with CureVac’s 
proprietary RNActive® technology platform, which uses chemically unmodified mRNA 
molecules as the basis for vaccination. The mRNA encodes the stabilized full-length 
S protein from the SARS-CoV-2 virus. Following intramuscular (IM) injection of CVnCoV, 
the S protein is translated from the mRNA stimulating an antigen-specific humoral and 
cellular immune response to the S protein. Importantly, functional viral neutralizing titers 
(VNTs) and T-cell mediated immunity are induced following vaccination with CVnCoV.   
Phase 1 and 2a trials are generating initial data on the safety, reactogenicity, and 
immunogenicity of CVnCoV administered to adults 18 years of age and older. Available 
data from these trials are provided in the Investigator’s Brochure. 
3.1.4 HERALD Phase 2b/3 Results 
The HERALD final efficacy analysis on 25,062 subjects meeting the inclusion criteria for 
the primary analysis, including 228 confirmed adjudicated COVID-19 cases, has 
demonstrated: 
• 
An overall CVnCoV vaccine efficacy (VE) of 48% (p=0.01600, 95.826% CI 
31.0-61.4%) for all age groups against COVID-19 of any severity, including single 
non-respiratory mild symptoms. 
• 
Significant protection was also shown among subjects in the age group of 18 to 
60 years, with an efficacy of 52.5% (95% CI 36.2-64.8%) against disease of any 
severity and across the 15 identified strains; protection against moderate to severe 
disease was 77% (95% CI 51.8-90.4%).  
• 
In subjects over 60 years (21 cases, 9% of the analyzed COVID-19 cases), the 
available data did not allow a statistically significant determination of efficacy. 
Therefore, CureVac reassessed the benefit/risk by age group and advised the 
investigators to discuss administration of an AV to trial subjects ≥ 60 years. 
• 
Overall, the data confirm the favorable safety profile of CVnCoV. 
3.1.5 CVnCoV and Authorized/Licensed SARS-CoV-2 Vaccines 
To date, no clinical trial has proactively investigated or been designed to evaluate the 
administration of authorized/licensed vaccines for preventing COVID-19 (AVs) after 
vaccination with CVnCoV.  
A post-hoc analysis in September 2021, based on preliminary partially cleaned data, 
showed that > 11,200 subjects across CVnCoV trials were administered an AV through 
national vaccination programs after having received 1 or 2 doses of 12 to 20 µg CVnCoV. 
The most frequently administered vaccine after receiving CVnCoV was Comirnaty® 
(Pfizer-BioNTech). Although this set of data has certain limitations, the assessment of the 
safety database on those who received an AV after CVnCoV resulted in the following 
observations:  
• 
In those having received at least 1 dose of CVnCoV, the follow-up time after receipt 
of AV amounts to 2535.1 person-years. 

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• 
Most of the AEs following a commercial vaccine relate to the known reactogenicity 
profile of the commercial vaccines.  
• 
No concerning clusters of AEs have been observed after the administration of an 
AV. 
• 
There is no evidence that prior receipt of CVnCoV affects the likelihood of an SAE 
following any AV.  
3.1.6 Trial Rationale 
The present HERALD Trial CV-NCOV-004 is designed as a Phase 2b/3 pivotal efficacy 
and safety trial in adults 18 years of age and older. The trial will be conducted as a 
randomized, observer-blinded, placebo-controlled trial, followed by an open-label phase. 
In the randomized observer-blinded Phase 2b/3 part of the trial, subjects will be enrolled 
at multiple sites globally and will be randomized in a 1:1 ratio to receive a 2-dose schedule 
of either CVnCoV at a dose level of 12 µg or placebo {normal saline (0.9% NaCl) for 
injection} as the control.  
The objective of the Phase 2b part of the trial is to further characterize the safety, 
reactogenicity and immunogenicity of CVnCoV in the intended trial population of adults, 
18 years of age and older, at the dose level selected for Phase 3 investigation. The design 
of Phase 2b is consistent with the Phase 3 efficacy part of the trial, allowing cases of 
COVID-19 that occur in Phase 2b to be pooled with those in Phase 3 for the primary 
analysis of VE, thereby increasing the efficiency of the overall Phase 2b/3 trial. Combining 
COVID-19 cases in Phase 2b and 3 to expedite an efficacy outcome was considered to 
be justified in a pandemic setting. The detailed reactogenicity and immunogenicity data 
generated in Phase 2b will be the main dataset to be submitted in support of early 
conditional approval of CVnCoV.   
The primary objective of the combined Phase 2b/3 trial is to demonstrate the efficacy of a 
2-dose schedule of CVnCoV in the prevention of COVID-19 cases of any severity. Due to 
the uncertain incidence rate of COVID-19 cases in a pandemic setting, the trial will be 
conducted as a case-driven trial based on the any severity COVID-19 endpoint due to the 
higher number of cases required, which will include 2 interim analyses and a final analysis 
both triggered by achieving a predefined number of cases for each analysis. The safety 
objective of the trial is to generate a large-scale safety database that will demonstrate the 
safety of CVnCoV across the adult age groups of 18 to 60 and ≥ 61 years of age. 
The open-label phase has been added to inform all subjects about the trial treatment they 
received and to allow follow-up of subjects who received at least 1 dose of CVnCoV, 
including those who decide(d) after unblinding to receive an authorized/licensed vaccine 
for preventing COVID-19 (AV) through their national vaccination program. 
Placebo subjects do not require further follow-up and will discontinue the trial. 
Please refer to the Investigator’s Brochure for details on the RNActive® technology and 
information regarding the non-clinical and clinical trials of the investigational CVnCoV 
vaccine. 

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Infection of the skin/soft tissue at the puncture site, vein, or blood stream can occur, but 
are very rare with venous blood draws. Subject monitoring and aseptic techniques, such 
as using sterile disposable blood collection apparatuses and adhering to standard medical 
precautions, reduce any risk to a minimum. The amount of blood to be taken for sampling 
will not be harmful to the subject’s health.  
Updated data from the currently ongoing CVnCoV trials are available in the Investigator’s 
Brochure. 
3.2.2 Known Potential Benefits 
Subjects receiving the investigational CVnCoV vaccine may not directly benefit from this 
vaccination as it is not known if CVnCoV is effective in protecting against COVID-19. 
Subjects receiving saline placebo will not directly benefit from trial vaccination.  
Trial subjects will receive the following benefits:  
• 
Subjects participating in this trial may benefit from having regular health checks as 
part of the trial procedures (e.g., physical examination, vital signs assessment). Where 
illnesses are newly diagnosed, a referral will be made for the subject to an appropriate 
health provider.   
• 
If CVnCoV is found to be efficacious and meets regulatory approval, subjects in the 
placebo group may be offered CVnCoV as soon as feasible.   
• 
If CVnCoV is found to be efficacious, then subjects will have made a significant public 
health contribution.   
Updated information on CVnCoV vaccine is provided in Section 3.1.4. 
3.2.3 Assessment of Potential Risks and Benefits 
To minimize the risk for subjects participating in this trial, an independent DSMB will 
oversee the safety of the participating subjects throughout the trial (see Section 9.3.8.1).  
Potential important medical risks associated with CVnCoV, as specified in Section 3.2.1, 
can be managed should they occur. 

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4 TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
4.1 Objectives 
Objectives for the Randomized Observer-blinded Phase 
4.1.1 Primary Objectives 
Primary Efficacy Objective 
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed cases of COVID-19 of any severity in SARS-CoV-2 
naïve subjects.   
Primary Safety Objectives 
• 
To evaluate the safety of CVnCoV administered as a 2-dose schedule to subjects 
18 years of age and older.   
• 
To evaluate the reactogenicity of CVnCoV administered as a 2-dose schedule to 
subjects 18 years of age and older participating in Phase 2b of the trial. 
4.1.2 Secondary Objectives 
Key Secondary Efficacy Objectives 
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed moderate to severe cases of COVID-19 in 
SARS-CoV-2 naïve subjects. 
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed severe cases of COVID-19 in SARS-CoV-2 naïve 
subjects.  
• 
To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention of first 
episodes of virologically-confirmed cases of COVID-19 of any severity caused by “wild 
type” (i.e., WT/D614G lineages A.1/B.1 without the variant of concern [VOC] B.1.1.7 
[Alpha], B.1.351 [Beta], B.1.429 [Epsilon]) and “UK” (B.1.1.7 [Alpha]) SARS-CoV-2 
strains in SARS-CoV-2 naïve subjects. 
Other Secondary Efficacy Objectives   
To evaluate in SARS-CoV-2 naïve subjects: 
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first episodes of 
virologically-confirmed cases of COVID-19 of any severity in subjects ≥ 61 years of 
age. 
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first episodes of 
virologically-confirmed cases of SARS-CoV-2 infection, with or without symptoms.  
• 
The efficacy of a 2-dose schedule of CVnCoV in reducing the Burden of disease (BoD) 
from COVID-19. 

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• 
The efficacy of CVnCoV after the first dose in the prevention of first episodes of 
virologically-confirmed cases of COVID-19 of any severity.  
Secondary Immunogenicity Objectives 
• 
To assess antibody responses to the RBD of S protein of SARS-CoV-2 after 1 and 
2 doses of CVnCoV in a subset of subjects participating in Phase 2b of the trial.   
• 
To assess SARS-CoV-2 viral neutralizing antibody responses after 1 and 2 doses of 
CVnCoV in a subset of subjects participating in Phase 2b of the trial.   
4.1.3 Exploratory Objectives 
Exploratory Efficacy Objectives 
To investigate in SARS-CoV-2 naïve subjects: 
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first episodes of 
virologically-confirmed cases of COVID-19 of any severity caused by individual VOCs 
(see Section 9.2.1.6). 
• 
If cases of COVID-19 are milder in severity in subjects receiving a 2-dose schedule of 
CVnCoV compared to those administered placebo. 
• 
If the need for supplemental oxygenation due to COVID-19 is reduced in subjects 
receiving a 2-dose schedule of CVnCoV compared to those administered placebo. 
• 
If the need for mechanical ventilation due to COVID-19 is reduced in subjects receiving 
a 2-dose schedule of CVnCoV compared to those administered placebo. 
• 
If hospitalization due to COVID-19 is reduced in subjects receiving a 2-dose schedule 
of CVnCoV compared to those administered placebo. 
• 
If mortality due to COVID-19 is reduced in subjects receiving a 2-dose schedule of 
CVnCoV compared to those administered placebo.   
• 
If all-cause mortality is reduced in subjects receiving a 2-dose schedule of CVnCoV 
compared to those administered placebo. 
• 
To investigate the cell-mediated immune (CMI) response of a 2-dose schedule of 
CVnCoV from approximately 200 subjects at selected site(s). 
To investigate in SARS-CoV-2 naïve and non-naïve subjects:   
• 
The efficacy of a 2-dose schedule of CVnCoV in the prevention of first episodes of 
virologically-confirmed cases of COVID-19 of any severity in all subjects, regardless 
of SARS-CoV-2 serological status at baseline. 
• 
The efficacy of CVnCoV after the first dose in the prevention of first episodes of 
virologically-confirmed cases of COVID-19 of any severity in all subjects, regardless 
of SARS-CoV-2 serological status at baseline. 

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To investigate in subjects with first episodes of virologically-confirmed COVID-19 during 
the trial:  
• 
The occurrence of second episodes of COVID-19 in subjects receiving a 2-dose 
schedule of CVnCoV compared to those administered placebo. 
• 
To explore correlates of protective immunity induced by CVnCoV vaccination. 
4.1.4 Objectives for the Open-label Phase 
• 
To evaluate safety in all subjects ≥ 18 years of age remaining in the trial after 
unblinding.  
Open-label Exploratory Objective: 
• 
To describe the number of first episodes of symptomatic virologically-confirmed cases 
of mild, moderate, and severe COVID-19 as assessed by the Investigator. 
4.2 Endpoints 
4.2.1 Primary Endpoints 
Primary Efficacy Endpoint 
• 
Occurrence of first episodes of virologically-confirmed {reverse transcription 
polymerase chain reaction (RT-PCR) positive} cases of COVID-19 of any severity 
meeting the case definition for the primary efficacy analysis.   
Primary Safety Endpoints 
All safety endpoints will be analyzed in all subjects, in subjects seronegative at baseline, 
and in subjects seropositive at baseline. 
• 
Occurrence, intensity, and relationship of medically-attended AEs collected through 
6 months after the second trial vaccination in all subjects. 
• 
Occurrence, intensity, and relationship of SAEs and AESIs collected throughout the 
trial in all subjects. 
• 
Occurrence of fatal SAEs throughout the trial in all subjects. 
• 
Occurrence, intensity, and duration of each solicited local AE within 7 days after each 
trial vaccination in Phase 2b subjects.  
• 
Occurrence, intensity, duration of each solicited systemic AE within 7 days after each 
trial vaccination in Phase 2b subjects. 
• 
Occurrence, intensity and relationship of unsolicited AEs occurring within 28 days after 
each trial vaccination in Phase 2b subjects. 
• 
Occurrence of AEs leading to vaccine withdrawal or trial discontinuation throughout 
the trial in all subjects. 

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4.2.2 Secondary Endpoints 
Key Secondary Efficacy Endpoints 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) cases of 
moderate to severe COVID-19 meeting the case definition for the primary efficacy 
analysis (moderate and severe COVID-19 defined in Appendix 3 and Appendix 4).  
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) severe 
cases of COVID-19 meeting the case definition for the primary efficacy analysis 
(severe COVID-19 defined in Appendix 3).  
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) cases of 
COVID-19 of any severity meeting the case definition due to infection with “wild type” 
(i.e., WT/D614G lineages A.1/B.1 without VOC B.1.1.7 [Alpha], B.1.351 [Beta], 
B.1.429 [Epsilon]) and “UK” (B.1.1.7 [Alpha]) SARS-CoV-2 strains in SARS-CoV-2 
naïve subjects. 
Other Secondary Efficacy Endpoints 
• 
In subjects ≥ 61 years of age, occurrence of first episodes of virologically-confirmed 
(RT-PCR positive) cases of COVID-19 of any severity meeting the case definition for 
the primary efficacy analysis. 
• 
Occurrence of virologically-confirmed (RT-PCR positive) SARS-CoV-2 infection, with 
or without symptoms.  
If subject was symptomatic, onset of symptoms must have occurred ≥ 15 days 
following the second trial vaccination; if subject was asymptomatic, the positive 
RT-PCR test must have occurred ≥ 15 days following the second trial vaccination.   
• 
BoD scores calculated based on first episodes of virologically-confirmed (RT-PCR 
positive) cases of COVID-19 of any severity meeting the case definition for the primary 
efficacy analysis. 
o BoD #1 – no disease (not infected or asymptomatic infection) = 0; mild or moderate 
disease = 1; severe disease = 2.   
o BoD #2 – no disease (not infected or asymptomatic infection) = 0; disease without 
hospitalization = 1; disease with hospitalization = 2; death = 3.   
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) cases of 
COVID-19 of any severity with symptom onset at any time after the first trial 
vaccination.  
Secondary Immunogenicity Endpoints (Phase 2b Immunogenicity Subset) 
SARS-CoV-2 RBD of S protein antibody responses  
On Days 1, 29, 43, 120, and 211: 
• 
Serum antibodies to SARS-CoV-2 RBD of S protein. 
• 
Occurrence of seroconversion to SARS-CoV-2 RBD of S protein. 
 
 

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Seroconversion is defined as detectable SARS-CoV-2 RBD of S protein antibodies 
in the serum of subjects who tested seronegative at baseline. 
SARS-CoV-2 viral neutralizing antibody responses 
On Days 1, 29, 43, 120, and 211: 
• 
Serum viral neutralizing antibodies to SARS-CoV-2 virus, as measured by a viral 
neutralizing antibody assay. 
• 
Occurrence of seroconversion to SARS-CoV-2 virus, as measured by a viral 
neutralizing antibody assay. 
Seroconversion is defined as detectable SARS-CoV-2 viral neutralizing antibodies 
in the serum of subjects who tested seronegative at baseline. 
4.2.3 Exploratory Endpoints 
Exploratory Efficacy Endpoints 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) cases of 
COVID-19 caused by individual VOCs (see Section 9.2.1.6). 
• 
Severity assessment of first episodes of virologically-confirmed (RT-PCR positive) 
cases of COVID-19 meeting the case definition for the primary efficacy analysis 
(COVID-19 severity definitions provided in Appendix 3 and Appendix 4).  
The following endpoints will be analyzed as occurring ≥ 15 days following the second trial 
vaccination (full VE) and at any time after the first trial vaccination.   
In SARS-CoV-2 naïve subjects: 
• 
Occurrence of supplemental oxygenation due to COVID-19. 
• 
Occurrence of mechanical ventilation due to COVID-19.  
• 
Occurrence of hospitalization due to COVID-19.   
• 
Occurrence of death due to COVID-19.   
• 
Occurrence of death due to any cause.  
In SARS-CoV-2 naïve and non-naïve subjects: 
• 
In all subjects regardless of their baseline serostatus, occurrence of first episodes of 
virologically-confirmed (RT-PCR positive) cases of COVID-19 of any severity.  
The following endpoint will be analyzed in subjects who had a first episode of a 
virologically-confirmed (RT-PCR positive) case of COVID-19 of any severity meeting the 
case definition for the primary efficacy analysis.   
• 
Occurrence of second episodes of virologically-confirmed (RT-PCR positive) cases of 
COVID-19 of any severity.  

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Exploratory Immunogenicity Endpoints 
On Days 1, 29, 43, 120**, and 211** in peripheral blood mononuclear cells (PBMCs) from 
approximately 200*** subjects at selected site(s): 
• 
The frequency and functionality of SARS-CoV-2 RBD of S-specific T-cell response 
after antigen stimulation by intracellular cytokine staining (ICS) to investigate Th1 
response and expression of Th2 markers. 
• 
The proportion of subjects with a detectable increase in SARS-CoV-2 RBD of 
S-specific T-cell response. 
** Thereby, testing of samples collected on Day 120 and Day 211 will be done only in 
subjects categorized as T-cell responders on Day 29 and/or Day 43. 
*** First testing of samples will be performed for a subset of these subjects and might 
be extended to 200 subjects if T-cell response is detectable. 
4.2.4 Open-label Endpoints  
• 
Occurrence, intensity, and relationship to CVnCoV of SAEs and AESIs collected 
throughout the trial until the end of trial (EOT).  
• 
Occurrence of fatal SAEs throughout the trial until EOT. 
• 
Only for Cohort A: CVnCoV-AV: Occurrence of AEs leading to AV withdrawal or trial 
discontinuation after the first dose with an AV in the open-label phase until EOT. 
Open-label Exploratory Endpoint 
• 
Occurrence of first episodes of symptomatic virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity as assessed by the Investigator.   
Any further modifications to endpoints in the open-label phase will be described in the 
statistical analysis plan (SAP). 
4.3 Estimands 
Primary Efficacy (randomized observer-blinded phase only) 
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
• 
Occurrence 
of 
first 
episodes 
of 
virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity meeting 
the case definition for the primary efficacy 
analysis.  
In naïve evaluable subjects (complying with 
the definition of Efficacy Analysis Set [EAS]) at 
least 15 days following second vaccination: 
VE = 1- RR with exact 95% CI 
Where RR (relative risk) is the ratio of attack 
rates 
of 
COVID-19 
cases 
per 
100 person-month in the CVnCoV vaccine 
group over the placebo group. 
 

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Primary Safety (randomized observer-blinded phase only) 
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
• 
Occurrence, intensity, and relationship of 
medically-attended AEs collected through 
6 months after the second trial vaccination 
in all subjects. 
 
In subjects who received at least 1 dose of 
CVnCoV or placebo vaccine, the number and 
percentage of subjects by group reporting at 
least 1 and at each type (by SOC/PT) of:  
• 
Medically-attended AE in the 6 months 
after the last vaccination overall, by 
intensity and by causal relationship to trial 
vaccine. 
• 
SAE in the year after the last vaccination 
overall and by causal relationship to trial 
vaccine. 
• 
AESI in the year after the last vaccination 
overall, by intensity and by causal 
relationship to trial vaccine. 
• 
Fatal SAE in the year after the last 
vaccination.  
• 
Occurrence, intensity, and relationship of 
SAEs and AESIs collected through EOT 
visit in all subjects. 
 
• 
Occurrence of fatal SAEs through EOT 
visit in all subjects. 
• 
Occurrence, intensity, and duration of each 
solicited local AE within 7 days after each 
trial vaccination in Phase 2b subjects. 
 
In Phase 2b subjects who received at least 
1 dose of CVnCoV or placebo vaccine: 
The number and percentage of subjects by 
group reporting:  
• 
Each solicited local AE within 7 days (after 
each trial vaccination by intensity and 
overall) 
• 
Each solicited systemic AE within 7 days 
after each trial vaccination by intensity, by 
relationship to trial vaccine and overall.  
• 
At least 1 unsolicited AEs, at least 1 
Grade 3 
unsolicited 
AEs 
and 
each 
unsolicited AEs by SOC/PT occurring 
within 28 days after each trial vaccination 
and overall by causal relationship to trial 
vaccine and overall 
• 
At least 1 AE leading to vaccine withdrawal 
or trial discontinuation in the year after the 
last trial vaccination 
 
The mean duration in days by group with 
standard deviation of solicited AEs (within the 
solicited period, total duration). 
 
• 
Occurrence, intensity, duration of each 
solicited systemic AE within 7 days after 
each trial vaccination in Phase 2b subjects. 
 
• 
Occurrence, intensity, and relationship of 
unsolicited AEs occurring within 28 days 
after each trial vaccination in Phase 2b 
subjects. 
 
• 
Occurrence of AEs leading to vaccine 
withdrawal or trial discontinuation through 
EOT visit in all subjects. 
 

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Key Secondary Efficacy (randomized observer-blinded phase only) 
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
• 
Occurrence 
of 
first 
episodes 
of 
virologically-confirmed (RT-PCR positive) 
cases of moderate to severe COVID-19 
meeting the case definition for the primary 
efficacy analysis. 
In naïve evaluable subjects (complying with 
the definition of EAS) at least 15 days following 
second vaccination: 
VE = 1- RR with exact 95% CI 
Where RR (relative risk) is the ratio of attack 
rates 
of 
COVID-19 
cases 
per 
100 person-month in the CVnCoV vaccine 
group over the placebo group. 
 
• 
Occurrence 
of 
first 
episodes 
of 
virologically-confirmed (RT-PCR positive) 
severe cases of COVID-19 meeting the 
case definition for the primary efficacy 
analysis.  
 
In naïve evaluable subjects (complying with 
the definition of EAS) at least 15 days following 
second vaccination: 
VE = 1- RR with exact 95% CI 
Where RR is the ratio of attack rates of severe 
COVID-19 cases per 100 person-month in the 
CVnCoV vaccine group over the placebo 
group. 
 
• 
Occurrence 
of 
first 
episodes 
of 
virologically-confirmed (RT-PCR positive) 
cases 
of 
“wild 
type” 
and 
“Alpha” 
SARS-CoV-2 
strains 
in 
SARS-CoV-2 
naïve subjects. 
 
In naïve evaluable subjects (complying with 
the definition of EAS) at least 15 days following 
second vaccination: 
VE = 1- RR with exact 95% CI 
Where RR is the ratio of attack rates of 
COVID-19 cases per 100 person-month in the 
CVnCoV vaccine group over the placebo 
group. 
 
 

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Other Secondary Efficacy (randomized observer-blinded phase only) 
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
• 
In subjects ≥ 61 years of age, occurrence 
of first episodes of virologically-confirmed 
(RT-PCR positive) cases of COVID-19 of 
any severity meeting the case definition for 
the primary efficacy analysis. 
 
In naïve evaluable subjects ≥ 61 years of age 
at randomization (complying with the definition 
of EAS) at least 15 days following second 
vaccination: 
VE = 1- RR with exact 95% CI 
Where RR (relative risk) is the ratio of attack 
rates 
of 
COVID-19 
cases 
per 
100 
person-month in the CVnCoV vaccine group 
over the placebo group. 
 
• 
Occurrence 
of 
virologically-confirmed 
(RT-PCR positive) SARS-CoV-2 infection, 
with or without symptoms.  
If subject was symptomatic, onset of 
symptoms 
must 
have 
occurred 
≥ 15 days following the second trial 
vaccination; 
if 
subject 
was 
asymptomatic, the positive RT-PCR 
test must have occurred ≥ 15 days 
following the second trial vaccination.  
 
In naïve evaluable subjects (complying with 
the definition of EAS) at least 15 days following 
second trial vaccination: 
VE = 1- RR with exact 95% CI 
Where RR is the ratio of attack rates of 
virologically-confirmed 
(RT-PCR 
positive) 
SARS-CoV-2 infection per 100 person-month 
in the CVnCoV vaccine group over the placebo 
group. 
 
• 
BoD scores calculated based on first 
episodes 
of 
virologically-confirmed 
(RT-PCR positive) cases of COVID-19 of 
any severity meeting the case definition for 
the primary efficacy analysis. 
o 
BoD #1 – no disease (not infected 
or asymptomatic infection) = 0; 
mild or moderate disease = 1; 
severe disease = 2.   
o 
BoD #2 – no disease (not infected 
or asymptomatic infection) = 0; 
disease 
without 
hospitalization 
= 1; disease with hospitalization 
= 2; death = 3.   
 
In naïve evaluable subjects (complying with 
the definition of EAS) at least 15 days following 
second trial vaccination: 
VEBOD = 1- SV/SP with exact 95% CI 
Where SV denotes the ratio of mean BoD 
score in the CVnCoV group and the mean 
follow-up time (years) in the CVnCoV group 
and SP denotes the ratio of mean BoD score 
in the placebo group and the mean follow-up 
time (years) in the placebo group. 
• 
Occurrence 
of 
first 
episodes 
of 
virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity with 
symptom onset at any time after the first 
trial vaccination.  
 
In naïve subjects who received at least 1 dose 
of CVnCoV or placebo vaccine at any time 
after the first vaccination: 
VE = 1- RR with exact 95% CI 
Where RR is the ratio of attack rates of 
COVID-19 cases per 100 person-month in the 
CVnCoV vaccine group over the placebo 
group. 
 
 
 

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Secondary Immunogenicity (randomized observer-blinded phase only) 
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
On Days 1, 29, 43, 120, and 211: 
• 
Serum antibodies to SARS-CoV-2 RBD of 
S protein. 
• 
Occurrence 
of 
seroconversion 
to 
SARS-CoV-2 RBD of S protein. 
 
Seroconversion 
is 
defined 
as 
detectable 
SARS-CoV-2 
RBD 
of 
S protein antibodies in the serum of 
subjects who tested seronegative at 
baseline. 
 
On Days 1, 29, 43, 120, and 211: 
• 
Geometric mean of titers (GMT) with 95% 
CI of SARS-CoV-2 RBD of S protein 
antibody responses by group and by 
baseline sero-status and group. 
 
On Days 29, 43, 120, and 211 for subjects 
seropositive at baseline: 
• 
Geometric mean of Fold Change from 
baseline 
(GMFC) 
with 
95% 
CI 
of 
SARS-CoV-2 RBD of S protein antibody 
responses by group. 
 
On Days 29, 43, 120, and 211 for subjects 
seronegative at baseline: 
• 
Number and percentage with exact 
95% CI of subjects by group for who a 
seroconversion is observed (detectable 
SARS-CoV-2 RBD of S protein antibodies 
in the serum). 
SARS-CoV-2 
viral 
neutralizing 
antibody 
responses  
On Days 1, 29, 43, 120, and 211: 
• 
Serum viral neutralizing antibodies to 
SARS-CoV-2 virus. 
• 
Occurrence of seroconversion to SARS-
CoV-2 virus. 
 
Seroconversion 
is 
defined 
as 
detectable 
SARS-CoV-2 
viral 
neutralizing antibodies in the serum of 
subjects who tested seronegative at 
baseline. 
On Days 1, 29, 43, 120, and 211: 
• 
GMT 
with 
95% 
CI 
of 
neutralizing 
antibodies to SARS-CoV-2 virus by group 
and by baseline serostatus and group. 
 
On Days 29, 43, 120, and 211 for subjects 
seropositive at baseline: 
• 
GMFC with 95% CI of neutralizing 
antibodies to SARS-CoV-2 virus by group. 
 
On Days 29, 43, 120, and 211 for subjects 
seronegative at baseline: 
• 
Number and percentage with exact 
95% CI of subjects by group for who a 
seroconversion is observed (detectable 
neutralizing antibodies to SARS-CoV-2 
virus in the serum). 
 

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Exploratory Efficacy (randomized observer-blinded phase only) 
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
• 
Occurrence 
of 
first 
episodes 
of 
virologically-confirmed (RT-PCR positive) 
cases of COVID-19 caused by any other 
identified variants. 
 
In naïve evaluable subjects (complying with 
the definition of EAS) at least 15 days following 
second trial vaccination: 
VE = 1- RR with exact 95% CI 
Where RR (relative risk) is the ratio of attack 
rates 
of 
virologically-confirmed 
(RT-PCR 
positive) SARS-CoV-2 infection per 100 
person-month in the CVnCoV vaccine group 
over the placebo group. 
 
• 
Severity assessment of first episodes of 
virologically-confirmed (RT-PCR positive) 
cases of COVID-19 meeting the case 
definition for the primary efficacy analysis 
 
In naïve evaluable subjects (complying with 
the definition of EAS) who had a first episode 
of a virologically-confirmed (RT-PCR positive) 
case of COVID-19 of any severity meeting the 
case definition for the primary efficacy 
analysis: 
• 
The proportions of mild, moderate, and 
severe COVID-19 cases among all cases 
by severity group. 
 
The following endpoints will be analyzed as 
occurring ≥ 15 days following the second trial 
vaccination (full VE) and at any time after the 
first trial vaccination.   
• 
Occurrence of supplemental oxygenation 
due to COVID-19. 
• 
Occurrence of mechanical ventilation due 
to COVID-19.  
• 
Occurrence of hospitalization due to 
COVID-19.   
• 
Occurrence of death due to COVID-19.   
• 
Occurrence of death due to any cause.  
In naïve evaluable subjects (complying with 
the definition of EAS) at least 15 days following 
second vaccination AND in subjects who 
received at least 1 dose of CVnCoV or placebo 
vaccine at any time after the first trial 
vaccination: 
Number and percentages by group of subjects 
who:  
• 
Need for supplemental oxygenation due to 
COVID-19. 
• 
Need for mechanical ventilation due to 
COVID-19. 
• 
Hospitalized due to COVID-19. 
• 
Deceased due to COVID-19.  
• 
Deceased due to any cause.  
 

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• 
In all subjects regardless of their baseline 
serostatus, occurrence of first episodes of 
virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity.  
 
In subjects who received at least 1 dose of 
CVnCoV or placebo vaccine, at any time after 
the first trial vaccination: 
VE = 1- RR with exact 95% CI 
Where RR is the ratio of attack rates of 
COVID-19 cases per 100 person-month in the 
CVnCoV vaccine group over the placebo 
group. 
 
The following endpoint will be analyzed in 
subjects who had a first episode of a 
virologically-confirmed (RT-PCR positive) case 
of COVID-19 of any severity meeting the case 
definition for the primary efficacy analysis.   
• 
Occurrence 
of 
second 
episodes 
of 
virologically-confirmed (RT-PCR positive) 
cases of COVID-19 of any severity. 
In naïve evaluable subjects (complying with 
the definition of EAS) who had a first episode 
of a virologically-confirmed (RT-PCR positive) 
case of COVID-19 of any severity meeting the 
case definition for the primary efficacy 
analysis, at least 15 days following second 
vaccination: 
• 
The number and percentage of subjects 
who developed a second episode of 
COVID-19. 
 
 
Exploratory Immunogenicity (randomized observer-blinded phase only) 
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
On Days 1, 29, 43, 120**, and 211** in 
peripheral blood mononuclear cells (PBMCs) 
from up to 200*** subjects at selected site(s): 
• 
The 
frequency 
and 
functionality 
of 
SARS-CoV-2 RBD of S-specific T-cell 
response after antigen stimulation by 
intracellular cytokine staining (ICS) to 
investigate Th1 response and expression 
of Th2 markers. 
• 
The 
proportion 
of 
subjects 
with 
a 
detectable increase in SARS-CoV-2 RBD 
of S-specific T-cell response. 
** Thereby, testing of samples collected on 
Day 120 and Day 211 will be done only in 
subjects categorized as T-cell responders on 
Day 29 and/or Day 43. 
*** First testing of samples will be performed for 
a subset of these subjects and might be 
extended to 200 subjects if T-cell response is 
detectable. 
In subjects belonging to the 
Immunogenicity/Reactogenicity subset and 
selected to take part in the CMI subset: 
• 
The number and percentage of subjects 
for 
whom 
a 
SARS-CoV-2 
RBD 
of 
S-specific T-cell response is observed  
The number and percentage of subjects with a 
detectable increase in SARS-CoV-2 RBD of 
S-specific T-cell response. 
 

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Open-label Safety 
Cohort A: CVnCoV-AV  
ENDPOINTS (subject level) 
ESTIMANDS (population level) 
• 
Occurrence, intensity and relationship of 
SAEs and AESIs collected throughout the 
trial until the EOT. 
 
In subjects who received at least 1 dose of 
CVnCoV and participate in the open-label 
phase of the trial:  
• 
SAE after the first dose with an AV in the 
open-label phase until the EOT. 
• 
AESI after the first dose with an AV in the 
open-label phase until the EOT. 
• 
Fatal SAE in the open-label phase through 
EOT.  
• 
At 
least 
1 
AE 
leading 
to 
trial 
discontinuation. 
• 
Occurrence of fatal SAEs throughout the 
trial until the EOT. 
 
• 
Occurrence of AEs leading to trial 
discontinuation. 
Estimands corresponding to occurrence of virologically-confirmed (RT-PCR positive) cases of 
COVID-19 will be described in the SAP. 

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5 TRIAL DESIGN 
5.1 Overall Design 
Trial CV-NCOV-004 will start with an initial Phase 2b part followed by a large Phase 3 
efficacy part. Both Phase 2b and Phase 3 parts will be randomized, observer-blinded, and 
placebo-controlled. Adult subjects 18 years of age or older will be enrolled at multiple sites 
globally and will receive a 2-dose schedule of either CVnCoV at a dose level of 12 µg 
mRNA or placebo {normal saline (0.9% NaCl)} in a 1:1 ratio. Both Phase 2b and Phase 3 
parts of the trial are consistent in design (e.g., for COVID-19 case ascertainment and case 
definition) so that cases of COVID-19 occurring in Phase 2b can be pooled with those in 
Phase 3 for the primary analysis of VE.  
This randomized observer-blinded phase will be followed by a Phase 3 open-label phase. 
The trial will be unblinded on country/site level after receipt of Competent Authority/Ethics 
Committee approval of Protocol version 4.0 (see Figure 1). Subjects who received at least 
1 dose of CVnCoV may opt to remain in the trial to be followed-up as initially planned, or 
they may opt/may have opted to receive an AV through their national vaccination program 
after unblinding. Subjects who received placebo will be withdrawn after trial unblinding.  
5.1.1 Randomized Observer-blinded Phase 2b Design and Objectives   
(See Table 1 and Table 2 for the Schedule of Trial Assessments and Procedures).   
The objective of Phase 2b is to further characterize the safety, reactogenicity, and 
immunogenicity of CVnCoV prior to initiating Phase 3. CVnCoV will be administered at the 
12 µg dose level selected for Phase 3 investigation informed by the safety and 
immunogenicity data from the initial Phase 1 and 2a trials. Phase 2b will be conducted in 
2 age groups of adults: 18 to 60 and ≥ 61 years of age, which represent the age range of 
the intended Phase 3 trial population.   
Approximately 4,000 subjects will be enrolled and randomized in a 1:1 ratio to receive 
2 doses of either CVnCoV at a dose level of 12 µg mRNA or placebo, administered 
28 days apart. Of the 4,000 subjects enrolled, approximately 800 to 1,000 (20% to 25%) 
will be ≥ 61 years of age. Phase 2b will be performed in an observer-blinded manner to 
reduce any potential bias in the safety assessments. The sample size of 4,000 subjects is 
based on generating a robust and detailed dataset characterizing the safety, 
reactogenicity, and immunogenicity of CVnCoV prior to entering Phase 3. Furthermore, 
the data generated in Phase 2b will be the main dataset to be submitted in support of early 
conditional approval of CVnCoV.   
In Phase 2b, the safety and reactogenicity of a 2-dose schedule of CVnCoV will be 
assessed in detail by measuring the frequency and severity of the following AEs: solicited 
local and systemic reactions for 7 days after each vaccination; unsolicited AEs for 28 days 
after each vaccination; medically-attended AEs through 6 months after the second trial 
vaccination; and AESIs and SAEs through 1 year after the second trial vaccination. The 
immunogenicity of CVnCoV will be evaluated after 1 and 2 doses in a subset of subjects 
(first 600 subjects enrolled in each of the 2 age groups; a total of 1,200 subjects in the 
Immunogenicity Subset) by measuring binding antibodies to the SARS-CoV-2 RBD of 
S protein and viral neutralizing antibodies. Antibody persistence will also be evaluated in 
this trial. 

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Cases of COVID-19 occurring in Phase 2b subjects will be collected and pooled with those 
occurring in Phase 3 and the total number of cases will be used for the primary analysis 
of efficacy. In addition, the DSMB will periodically monitor COVID-19 cases for signals of 
VDE.  
Initiation of subject enrollment of the 2 target age groups into Phase 2b will be flexible. 
Depending on the timing of data from the Phase 1 and Phase 2a trials, enrollment of the 
2 age groups into Phase 2b may be staggered, initially starting with subjects 18 to 60 years 
of age followed by subjects ≥ 61 years of age. As the older age group will comprise 20% 
to 25% of the total number of subjects in Phase 2b, this staggered start is not expected to 
impact overall enrollment of the Phase 2b cohort.  
An early safety review of the Phase 2b data will be performed by the DSMB (see 
Section 9.3.8.1). The safety review will be conducted when approximately 1,000 subjects 
have been enrolled in Phase 2b (25% of subjects enrolled; 500 recipients of CVnCoV and 
500 recipients of placebo) and have at least 1 week of safety follow-up after the first trial 
vaccination. If the safety profile is judged to be acceptable and there are no safety or 
tolerability concerns, it is anticipated that enrollment of subjects into Phase 3 can begin 
without interruption from Phase 2b. Another safety review by the DSMB will be conducted 
when approximately 1,000 Phase 2b subjects have received their second trial vaccination 
and have at least 1 week of safety follow-up. All available first dose safety data from the 
Phase 2b subjects will also be reviewed at this time. 
5.1.2 Randomized Observer-blinded Phase 3 Design and Objectives 
(See Table 3 for Schedule of Assessments and Procedures) 
The primary objective of the combined Phase 2b/3 trial is to demonstrate the efficacy of a 
2-dose schedule of CVnCoV in the prevention of COVID-19 cases of any severity. Similar 
to Phase 2b, Phase 3 will be conducted as a randomized, observer-blinded, 
placebo-controlled trial. Approximately 32,500 subjects, 18 years of age or older, will be 
enrolled at multiple sites globally in Phase 3 and will receive a 2-dose schedule of either 
CVnCoV at the 12 µg dose level or placebo in a 1:1 ratio. Similar to Phase 2b, enrollment 
will target subjects ≥ 61 years of age to be approximately 20% to 25% of the Phase 3 trial 
population (6,500 to 8,125 subjects). The total enrollment of the combined Phase 2b and 
Phase 3 parts of the trial will be 36,500 subjects.  
Subjects will undergo active surveillance for COVID-19 (see Appendix 6A). During all site 
visits and phone calls, subjects will be reminded to contact the site if they have an acute 
illness with any symptoms clinically consistent with COVID-19. In addition, subjects will be 
messaged up to twice a week and will provide a yes or no response to having COVID-19 
symptoms. Those who respond “yes” will be contacted by trial staff for a follow-up 
interview and assessment, if the Investigator considers the symptoms could potentially 
indicate a COVID-19 case. If a subject is suspected of having COVID-19 illness, he/she 
will undergo testing for SARS-CoV-2 infection with samples collected at the site or at a 
home visit. If the subject is confirmed to have COVID-19, all subjects will be followed until 
resolution of their disease. If the subject is hospitalized, the subject’s progress must 
continue to be followed by the Investigator and a discharge summary obtained at the end 
of the hospitalization. Information on clinical symptoms and signs, their duration and 
severity, and treatment and outcome of the COVID-19 episode will be documented by trial 
staff and recorded in the electronic case report form (eCRF). Upon resolution, subjects 

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will continue to be followed through the trial end in the same manner as those who have 
not presented with COVID-19. A second episode of COVID-19 in a subject with prior 
disease will not be counted as a primary efficacy case, but will be counted for the 
exploratory objective assessing the reoccurrence of COVID-19 in vaccinated subjects.   
Due to the uncertain incidence rate of COVID-19 cases in a pandemic setting, the trial will 
be conducted as a case-driven trial based on the any severity COVID-19 endpoint, which 
will include 2 interim analyses and a final analysis both triggered by achieving a predefined 
number of cases for each analysis. As described above, cases of COVID-19 occurring in 
Phase 2b will be pooled with those in Phase 3 for the primary analysis of VE. As such, 
subjects participating in Phase 2b will contribute to the total sample size for the primary 
analysis of VE (N=36,500).  
For the primary analysis of efficacy, the case must meet the following criteria (moderate 
and severe COVID-19 is defined in Appendix 3 and Appendix 4): 
• 
Must be a virologically-confirmed case of COVID-19 defined as a positive 
SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19 
(see Section 9.2).  
• 
Symptom onset must have occurred ≥ 15 days following the second trial vaccination. 
• 
The subject must not have a history of virologically-confirmed COVID-19 at enrollment 
(based on Exclusion Criterion 1) or have developed a case of virologically-confirmed 
COVID-19 before 15 days following the second trial vaccination {see Section 10.2.3, 
Efficacy Analysis Set (EAS) population for more details}. 
• 
The subject must have been demonstrated to be SARS-CoV-2 naïve at baseline and 
at Day 43 (seronegative to N protein). 
Primary efficacy cases must be confirmed by the Adjudication Committee.  
This trial will utilize a group sequential design with 2 interim analyses for high efficacy or 
futility using the O’Brien and Fleming error spending function for the primary endpoint of 
virologically-confirmed COVID-19 cases of any severity. With an overall 2-sided alpha of 
5% and a total of 160 COVID-19 cases of any severity meeting the primary efficacy case 
definition at the final analysis, the trial will have an overall power of 90% to demonstrate a 
VE greater than 30% (based on a margin of 30% for the lower bound of the 
95% confidence interval [CI] for VE) when considering VE is 60%. Two interim analyses 
of high efficacy or futility will be performed once 56/111 cases meeting the primary case 
definition have been accrued and adjudicated (35/69% of final case number). These points 
were chosen based on 2 criteria: i) the robustness of 56/111 cases to support the decision 
of high efficacy or futility and ii) if high efficacy, this would shorten the duration of the trial 
and potentially allow the vaccine to be available earlier.  
Assuming an incidence rate of COVID-19 of 0.15% per month (1.5 cases/1000/month) in 
placebo subjects; a VE of 60%; and a non-evaluable rate of 20% during the trial which 
includes ~5% seropositivity of enrollees at baseline (i.e. non-naïve subjects), follow-up of 
36,500 subjects enrolled over 3 months (18,250 per vaccine group) will accrue the target 
160 COVID-19 cases of any severity approximately 9 months after the first vaccination.  

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During the early stages of enrollment, an unblinded review of the incidence rate of cases 
will be performed by the DSMB. If the case accrual rate is lower or higher than expected, 
the DSMB may recommend an adjustment in sample size. If needed, another unblinded 
review by the DSMB may be performed later in the trial to further adjust the sample size. 
The trial events are shown in the timeline below (Figure 3).   
Figure 3 
Trial Timeline – HERALD Trial CV-NCOV-004 
 
With an equal follow-up time of evaluable subjects in the CVnCoV and placebo groups, 
efficacy would be demonstrated at the final analysis if 53 cases or less of 160 total cases 
of COVID-19 are in the CVnCoV group (estimated VE ≥ 50.5%). Two interim analyses for 
high efficacy or futility will be performed when 56/111 cases meeting the primary case 
definition have been accrued and adjudicated (approximately 5/6.5 months after trial start). 
If the follow-up time of evaluable subjects is equal in both groups, early high efficacy would 
be demonstrated if 9/32 cases or less of the 56/111 cases are in the CVnCoV group 
(estimated VE at interim ≥ 80.9/59.5%); conversely, futility would be reached if 25/40 
cases or more are in the CVnCoV group (estimated VE at interim ≤ 19.4/43.7%). The 
assessment of the interim analyses will be performed by the DSMB and the outcome will 
be communicated without unblinding the Trial Team or the Sponsor. 
Similar to Phase 2b, subjects participating in Phase 3 will be evaluated for SARS-CoV-2 
infection during the trial, as measured by the development of antibodies to the N protein 
of SARS-CoV-2 in seronegative subjects. 
The safety objective of Phase 3 is to generate a large-scale safety database that will 
demonstrate the safety of CVnCoV. All subjects participating in the Phase 2b and Phase 3 
parts of the trial will have medically-attended AEs collected for 6 months after the second 
vaccination; and AESIs (see Appendix 9 and Appendix 10) and SAEs collected until the 
EOT visit.  
5.1.3   Open-label Phase Design and Objectives 
After unblinding, the trial will shift from a randomized observer-blinded to an open-label 
design, and the following cohorts will be defined:  
Cohort A: CVnCoV-AV (See Table 4 for the Schedule of Trial Assessments and 
Procedures): Subjects ≥ 18 years who received at least 1 dose of CVnCoV and choose to 
receive an AV are included in this cohort and will be recommended to procure AV as 
standard of care per their national vaccination program, if not already done. Subjects will 
be requested to remain in the trial for safety follow-up until the EOT (Day 393 of the original 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Phase 2b/3 schedule). Subjects who were individually unblinded and already received an 
AV before implementation of Protocol version 4.0 will also be included in this cohort. 
Cohort B: CVnCoV only (See Table 5 for the Schedule of Trial Assessments and 
Procedures): Subjects ≥ 18 years who received at least 1 dose of CVnCoV and choose to 
remain in the trial without receiving any AV will continue follow-up until EOT (Day 393 of 
the original Phase 2b/3 schedule). Subjects who were individually unblinded during the 
randomized observer-blinded phase and who received CVnCoV but did not receive an AV 
before implementation of Protocol version 4.0 and do not intend to receive an AV will also 
be included in this cohort. Subjects who initially intend to complete the trial without 
receiving an AV and later decide to receive an AV within the open-label phase will be 
switched to Cohort A. 
Placebo subjects do not require further follow-up and will discontinue the trial (see 
Section 9.1.4.2).  
The open-label phase will provide additional safety data, including data from subjects who 
receive an AV after CVnCoV. COVID-19 cases will continue to be documented, but there 
will no longer be any inferential efficacy analysis in the open-label phase (only descriptive 
summary of cases). Subjects will undergo passive surveillance for COVID-19 (see 
Appendix 6B). 
Trial unblinding and transition from the randomized observer-blinded to the open-label 
phase will be conducted on a country/site level, depending on full Competent Authority 
and Ethics Committee approval of Protocol version 4.0 per country/site. 
5.2 Scientific Rationale for Trial Design 
See also Sections 3.2 and 5.1. 
HERALD Trial CV-NCOV-004 will be conducted in the following parts: an initial Phase 2b 
trial followed by a large Phase 3 efficacy trial, followed by an open-label phase.  
Randomized Observer-blinded Phase 
Both Phase 2 and Phase 3 parts of the trial are consistent in design, so that cases of 
COVID-19 occurring in Phase 2 can be pooled with those in Phase 3 for the primary 
analysis of VE. Combining COVID-19 cases in Phase 2 and 3 to expedite an efficacy 
outcome was considered warranted in a pandemic setting. 
Both Phase 2b and Phase 3 will be randomized, observer-blinded, and placebo-controlled. 
The difference in appearance and presentation of the investigational CVnCoV vaccine and 
placebo requires the trial to be conducted in an observer-blinded manner, which is a 
commonly used and well-accepted method for trial blinding. The randomized, 
observer-blinded, and placebo-controlled design will reduce the risk of bias in the safety 
and efficacy outcomes of the trial (see also Section 7.3).   
As the elderly are affected most by SARS-CoV-2 and have a high risk for severe disease 
and mortality, it is critical to investigate CVnCoV in this population and therefore subjects 
≥ 61 years of age will be included in the randomized observer-blinded Phase 2b/3. 
The sample size of 4,000 subjects in Phase 2b is based on generating a robust and 
detailed dataset characterizing the safety, reactogenicity, and immunogenicity of CVnCoV 

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prior to entering Phase 3. Furthermore, the data generated in Phase 2b will be the main 
dataset to be submitted in support of early conditional approval of CVnCoV.   
The total sample size of 36,500 subjects for the combined Phase 2b/3 trial is based on 
demonstrating VE above 30% (based on a margin of 30% for the lower bound of the 
95% CI for VE) when considering VE is 60%. With a 2-sided alpha of 5% and a total of 
160 COVID-19 cases, the trial will have a 90% power to demonstrate a VE above 30%. 
Assuming an incidence rate of COVID-19 of 0.15% per month in control subjects; and a 
non-evaluable rate of 20% during the trial which includes 5% seropositivity of enrollees at 
baseline (i.e. non-naïve subjects), follow-up of 36,500 subjects enrolled over 3 months 
(18,250 per vaccine group) will accrue the target 160 COVID-19 cases approximately 
9 months after the first vaccination.  
For the primary analysis of efficacy, COVID-19 case ascertainment begins at ≥ 15 days 
following the second vaccination of CVnCoV. This time point allows the immune response 
to mature and reach its full height following the second dose. As such, case ascertainment 
starting at this time point represents the evaluation of full VE of CVnCoV against 
COVID-19.  
The safety objective of Phase 3 is to generate a large-scale safety database that will 
demonstrate the safety of CVnCoV. All subjects participating in the Phase 2b and 
observer-blinded Phase 3 parts of the trial will have medically-attended AEs collected for 
6 months after the second vaccination; and AESIs and SAEs collected for 1 year after the 
second vaccination. As such, each subject will participate in the trial for approximately 
13.5 months for the safety follow-up. 
Individuals with history of virologically-confirmed COVID-19 illness will be excluded from 
participating in this trial. However, this trial will not screen for or exclude subjects with 
history or laboratory evidence of prior SARS-CoV-2 infection, many of which might have 
been asymptomatic. Because pre-vaccination screening for prior infection is unlikely to 
occur in practice, it is important to understand vaccine safety and COVID-19 outcomes in 
in individuals with prior infection with SARS-CoV-2 virus.   
CMI will be evaluated in approximately 200 subjects: 100 who receive CVnCoV and 
100 who receive placebo. The goals of this are to identify immunological biomarkers to 
identify vaccine responders and people having a better immune response to CVnCoV, to 
better understand the biology of the immune response to CVnCoV, and to investigate the 
duration of the immune response to CVnCoV. Analysis of immunologically relevant 
genomic biomarkers will be limited to DNA sequencing of the subject’s T-cell receptor and 
human leukocyte antigen type. The purpose is not to test for any genetic disorders or to 
identify predisposition to any disease. 
Open-label Phase 
In view of the current availability of AVs in the countries where the trial is being conducted, 
multiple unblinding requests have been granted to trial subjects seeking access to these 
AVs under their country’s national vaccination programs, and as of 18 November 2021 
nearly 80% of the trial subjects have been unblinded and approximately 49% have already 
received an AV. After approval of Protocol version 4.0, all trial subjects will be unblinded 
and the trial will shift to an open-label design as described in Section 5.1.3. The open-label 

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phase will provide additional safety data, including data from subjects who receive an AV 
after CVnCoV.  
5.3 Justification for Dose 
Selection of the 12 µg mRNA dose level of CVnCoV for this trial was based on the safety, 
tolerability, and immunogenicity results from Trial CV-NCOV-001.   
In Trial CV-NCOV-001, a dose of 12 µg elicited the same immune response as that seen 
in patients who are recovering from having been infected with the real virus.  
Refer to the Investigator’s Brochure for an overview of these data. 
5.4 End of Trial Definition 
A subject is considered to have completed the trial when he/she has completed all visits, 
and procedures and tests applicable for the group to which he/she was randomized to. 
After trial unblinding, a placebo subject is considered to have completed the trial when 
he/she has completed the EOT phone call. 
End of Trial is defined as when the last subject has completed the last visit on Day 393 or 
prematurely discontinued the trial, for both the randomized observer-blinded Phase 2b/3 
and the open-label phase.  
5.5 Stopping/Pausing Rules for Safety 
5.5.1 Individual Subject Stopping Rules 
The individual subject stopping rules are met in case any of the following events occur 
after the first trial vaccination: 
• 
An allergic/anaphylactic reaction considered as related to the trial vaccine 
• 
Any SAE considered as related to the trial vaccine  
If any of these rules are met, the subject must not receive the second vaccine dose. The 
subject will be encouraged to continue participation until the end of the trial for safety.  
5.5.2 Pausing of the Trial 
The decision to pause the trial (i.e. temporary stopping of enrollment and vaccinations) 
due to a safety signal will be based on a recommendation from the DSMB in consultation 
with the Sponsor (see Section 9.3.8.1). The DSMB may recommend pausing the trial for 
a safety concern following a review of accumulating safety data presented at the regularly 
scheduled DSMB meetings or from an ongoing review of AEs, which include but are not 
limited to, suspected unexpected serious adverse reactions (SUSARs); all SAEs judged 
as related to trial vaccine; concerning SAEs (e.g., AESIs); and all life-threatening AEs and 
deaths. These events will be monitored by the DSMB on a regular basis during the trial. 
The selected AEs and procedures for the safety review are described in detail in the DSMB 
Charter.  
To ensure subject safety on an ongoing basis, a CureVac Safety Review Team reviews 
the safety data on a periodic basis. The outcome of these reviews and discussions are 
then shared with the DSMB Chair.  

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Based on the assessment of the benefit-risk ratio and biologic plausibility of a causal 
relationship of the AE(s) to the trial vaccine, the DSMB will make a recommendation to 
the Sponsor to either continue the trial as planned, modify its conduct, or pause the trial 
to allow further evaluation of the AE. If the latter, the Sponsor will make the decision to 
pause the trial in consultation with the DSMB.   
Please refer to the DSMB Charter for additional discussion of the DSMB’s role and 
responsibilities. 

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6 TRIAL POPULATION 
The criteria for enrollment are to be followed explicitly. If it is noted that a subject who does 
not meet 1 or more of the inclusion criteria and/or meets 1 or more of the exclusion criteria 
is inadvertently enrolled and dosed, the Sponsor must be contacted immediately. 
In this trial, individuals with a history of virologically-confirmed COVID-19 illness will be 
excluded from the trial. However, this trial will not screen for or exclude individuals with a 
history or laboratory evidence of prior SARS-CoV-2 infection. In addition, routine RT-PCR 
testing will not be performed at screening to exclude individuals with SARS-CoV-2 
infection at the time of enrollment. Any country specific regulation(s) will be adhered to in 
addition. 
6.1 Inclusion Criteria for All Subjects 
Subjects will be enrolled in this trial only if they meet all of the following criteria: 
1. 
Male or female subjects 18 years of age or older. 
2. 
Be willing and able to provide written informed consent prior to initiation of any trial 
procedures.  
3. 
Expected compliance with protocol procedures and availability for clinical follow-up 
through the last planned visit. 
4. 
Females of non-childbearing potential defined as follows: surgically sterile (history 
of bilateral tubal ligation/occlusion, bilateral oophorectomy or hysterectomy) or 
postmenopausal {defined as amenorrhea for ≥ 12 consecutive months prior to 
screening (Day 1) without an alternative medical cause}. A follicle-stimulating 
hormone (FSH) level may be measured at the discretion of the Investigator to 
confirm postmenopausal status.  
5. 
Females of childbearing potential: negative pregnancy test {human chorionic 
gonadotropin {hCG)} within 24 hours prior to each trial vaccination on Day 1 and 
Day 29.   
6. 
Females of childbearing potential must use highly effective methods of birth control 
from 2 weeks before the first administration of the trial vaccine until 3 months 
following the last administration. The following methods of birth control are 
considered highly effective when used consistently and correctly: 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal or transdermal); 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable or implantable); 
• 
Intrauterine devices; 
• 
Intrauterine hormone-releasing systems; 
• 
Bilateral tubal ligation; 
• 
Vasectomized partner or infertile partner; 

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• 
Sexual abstinence  
{periodic 
abstinence 
(e.g., 
calendar, 
ovulation, 
symptothermal 
and 
post-ovulation methods) and withdrawal are not acceptable}. 
Refer to the Clinical Trial Facilitation Group recommendations on contraception and 
pregnancy testing for further details [32]. 
6.2 Exclusion Criteria for All Subjects 
Subjects will not be enrolled in this trial if they meet any of the following criteria: 
1. History of virologically-confirmed COVID-19 illness.  
2. For females: pregnancy or lactation. 
3. Use of any investigational or non-registered product (vaccine or drug) within 
28 days preceding the administration of the first trial vaccine or planned use during 
the trial. 
4. Receipt of licensed vaccines within 28 days (for live vaccines) or 14 days (for 
inactivated or any other vaccines) prior to the administration of the first trial 
vaccine. 
5. Prior administration of any investigational SARS-CoV-2 vaccine or another 
coronavirus (SARS-CoV, MERS-CoV) vaccine or planned use during the trial. 
6. Any treatment with immunosuppressants or other immune-modifying drugs 
(including but not limited to anabolic steroids, corticosteroids, biologicals and 
methotrexate) for > 14 days total within 6 months preceding the administration of 
trial vaccine or planned use during the trial. For corticosteroid use, this means 
prednisone or equivalent, 0.5 mg/kg/day for 14 days or more. The use of inhaled, 
topical, or localized injections of corticosteroids (e.g., for joint pain/inflammation) 
is permitted. 
7. Any medically diagnosed or suspected immunosuppressive or immunodeficient 
condition based on medical history and physical examination including known 
infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or 
hepatitis C virus (HCV); current diagnosis of or treatment for cancer including 
leukemia, lymphoma, Hodgkin disease, multiple myeloma, or generalized 
malignancy; chronic renal failure or nephrotic syndrome; and receipt of an organ 
or bone marrow transplant.  
8. History of angioedema (hereditary or idiopathic) or history of any anaphylactic 
reaction. 
9. History of pIMD. 
10. History of allergy to any component of CVnCoV vaccine.  
11. Administration of immunoglobulins or any blood products within 3 months prior to 
the administration of trial vaccine or planned receipt during the trial. 
12. Subjects with a significant acute or chronic medical or psychiatric illness that, in 
the opinion of the Investigator, precludes trial participation (e.g., may increase the 

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risk of trial participation, render the subject unable to meet the requirements of the 
trial, or may interfere with the subject’s trial evaluations). These include severe 
and/or uncontrolled cardiovascular disease, gastrointestinal disease, liver disease, 
renal disease, respiratory disease, endocrine disorder, and neurological and 
psychiatric illnesses. However, those with controlled and stable cases can be 
included in the trial. 
13. Subjects with impaired coagulation or any bleeding disorder in whom an IM 
injection or a blood draw is contraindicated. 
14. Foreseeable non-compliance with the trial procedures as judged by the 
Investigator. 
6.3 Roll-over Criteria for the Open-label Phase 
1. 
Subjects must have received at least 1 dose of CVnCoV during the randomized 
observer-blinded phase. 
2. 
Subjects must provide additional written informed consent to be eligible for the 
open-label phase. 
6.3.1 Cohort A: CVnCoV-AV  
3. 
Subjects of the CVnCoV treatment arm who received or will receive any AV as 
standard of care through their national vaccination program. 
6.3.2 Cohort B: CVnCoV only 
3. 
Subjects have not received any vaccination with any other investigational/authorized 
SARS-CoV-2 vaccine or another coronavirus (SARS-CoV, MERS-CoV) vaccine.  
6.4 Vaccine Delay Recommendations 
After enrollment, subjects may encounter clinical circumstances that could warrant a delay 
of trial vaccine administration as described below.  
• 
Subjects with a clinically significant (≥ Grade 2) active infection or other acute disease 
(as assessed by the Investigator and COVID-19 is either not clinically suspected 
and/or SARS-CoV-2 testing is negative) or temperature ≥ 38.0°C (≥ 100.4°F), within 
3 days of intended trial vaccination on Day 1 or Day 29.   
o Trial vaccination should be delayed until the active infection or other acute disease 
has recovered to ≤ Grade 1 or the subject’s temperature has decreased to 
< 38.0°C (< 100.4°F). Following resolution of the illness, the subject may be 
rescheduled for trial vaccination based on the judgment of the Investigator.  
o Afebrile subjects with a minor illness may be vaccinated at the discretion of the 
Investigator. 
• 
For subjects who develop virologically-confirmed COVID-19 after the first trial 
vaccination but prior to the second; this second vaccination can be administered once 
the subject is 2 weeks symptom-free, and provided the dose can be administered 
within the predefined visit window. 

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• 
Receipt of a licensed non-COVID-19 vaccine within 28 days (for live vaccines) or 
14 days (for inactivated or any other vaccines) prior to or after scheduled 
administration of trial vaccine or AV. As these are recommended windows, 
rescheduling trial vaccination to be compliant with these windows should only be done 
if practical.   
6.5 Failure to Meet Eligibility Criteria 
The Investigator must account for all subjects who sign an informed consent. If the subject 
is found to be not eligible (i.e., did not meet all inclusion criteria or met 1 or more exclusion 
criteria), the Investigator should document this in the subject’s source documents. 
Re-screening, i.e., re-doing the full assessments for eligibility assessment as per Table 1, 
Table 2, and Table 3, or re-doing one assessment is allowed based on the judgment of 
the Investigator. 

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7 TRIAL VACCINE 
7.1 Trial Vaccine Administration 
7.1.1 Description of the Trial Vaccines 
CVnCoV is an investigational LNP-formulated RNActive® SARS-CoV-2 vaccine. The IMP 
is composed of the active pharmaceutical ingredient, an mRNA that encodes the stabilized 
full-length S protein, and 4 lipid components: cholesterol, 1,2-distearoyl-sn-glycero-3-
phosphocholine (DSPC), PEG-ylated lipid and a cationic lipid. It is supplied as a 
concentrate at 1 mg/mL of mRNA drug substance.  
The placebo vaccine will be sterile normal saline (0.9% NaCl) for injection.   
7.1.2 Dosing and Administration 
7.1.2.1 CVnCoV 
Subjects randomized to CVnCoV will receive 2 injections of CVnCoV at a dose level of 
12 µg mRNA, administered 28 days apart.   
Administration of CVnCoV must be performed by IM injection in the deltoid area, 
preferably in the non-dominant arm. CVnCoV is intended strictly for IM injection and must 
not be injected subcutaneously, intradermally, or intravenously. The instructions for 
injection as described in the Pharmacy Manual must be followed. 
7.1.2.2 Placebo Control (Normal Saline) 
Subjects randomized to the control arm of the trial will receive 2 doses of saline placebo 
{normal saline (0.9% NaCl) for injection}, administered 28 days apart.  
Administration of saline placebo must be performed by IM injection in the deltoid area, 
preferably in the non-dominant arm. The instructions for injection described in the 
Pharmacy Manual must be followed.   
7.1.2.3 Authorized Vaccines  
Countries participating in the HERALD trial currently have access to an AV such as 
Comirnaty® (Pfizer-BioNTech), Spikevax® (Moderna), Janssen COVID-19 Vaccine® 
(Janssen), Vaxzevria® (AstraZeneca), Convidecia® (Cansino), Sinopharm COVID-19 
vaccine, CoronaVac® (Sinovac), and Gam-COVID-Vac® (Sputnik V). 
Trial subjects have or will have access soon to an approved or authorized vaccination 
through their national vaccination programs. The type of vaccine and range of age for 
vaccination is decided by national vaccination programs, outside of the clinical trial 
procedures. 
After trial unblinding, investigators will provide subjects with information about the 
treatment they have received and currently available AVs at country level to allow subjects 
to make an informed decision. 

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7.1.2.4 Hypersensitivity Reactions to Vaccination 
CVnCoV should not be administered to subjects with a known hypersensitivity to any of 
the components of the vaccine.   
Since there is a theoretical risk of anaphylactic reactions, trial vaccine must only be 
administered if emergency equipment for the treatment of anaphylactic reactions 
(intravenous fluids, corticosteroids, H1 and H2 blocking agents, epinephrine, equipment 
for cardiopulmonary resuscitation) is readily available. All subjects must remain under 
direct supervision of personnel trained in the treatment of these reactions for at 
least 30 minutes following administration of trial vaccine. 
If anaphylaxis or severe hypersensitivity reactions occur following trial vaccine 
administration, no further doses should be given (see Sections 5.5.1 and 8.1). 
7.2 Preparation/Handling/Storage/Accountability 
Refer to the Pharmacy Manual for detailed information on the preparation, handling, 
storage, and blinding of CVnCoV and saline placebo.  
7.2.1 CVnCoV Preparation 
The concentrated CVnCoV must be diluted in the provided sterile normal saline (0.9% 
NaCl) diluent containing preservative to produce the dose solution for IM injection. This 
will be prepared by unblinded pharmacists or physicians or any other qualified persons 
according to local law. These pharmacists/qualified persons will have no other trial 
function following preparation of the blinded syringes for vaccination and will maintain the 
treatment assignments in strict confidence.  
7.2.2 CVnCoV Product Storage and Stability 
Concentrated CVnCoV will be shipped to the site frozen at below -60°C.  
Once at the site, concentrated CVnCoV should be stored frozen at below -60°C. 
7.2.3 Placebo Control (Normal Saline) 
The normal saline placebo control vaccine should be stored according to the Summary of 
Product Characteristics. Placebo will be prepared for injection by an unblinded 
pharmacist/qualified site personnel.  
7.2.4 Accountability 
It is the responsibility of the Investigator to ensure that the current and accurate records 
of trial supplies received, stored, and dispensed at the site are maintained using 
appropriate forms according to applicable regulations and guidelines. The trial supplies 
must be stored under the recommended storage conditions, locked with restricted access 
(refer to the Pharmacy Manual). Authorized personnel must dispense the vaccine at the 
trial site and in accordance with the protocol and applicable regulations and guidelines. 
IMP accountability and inventory logs must be kept up-to-date at the trial site with the 
following information: 
• 
Dates and quantities of CVnCoV received from CureVac. 

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• 
Unique subject identifier. 
• 
Date and quantity of trial vaccine dispensed to each subject. 
• 
Initials of the person preparing the dose. 
• 
Initials of the person administering the vaccine. 
These logs must be readily available for inspections and are open to regulatory inspection 
at any time. 
7.3 Randomization and Blinding 
Both Phase 2b and Phase 3 will be randomized, observer-blinded, and placebo-controlled. 
The difference in appearance of the investigational CVnCoV vaccine and placebo required 
the trial to be conducted in an observer-blinded manner, which is a well-accepted method 
for blinding.   
7.3.1 Randomization (Randomized Observer-blinded Phase only) 
Subjects 18 years of age or older will be enrolled at multiple sites globally and will be 
randomized in a 1:1 ratio to receive either CVnCoV or placebo. The randomization will be 
performed centrally and stratified by country and age group (18 to 60 and ≥ 61 years of 
age). The randomization scheme will be generated and maintained by an Independent 
Statistical group at the contract research organization (CRO), PRA. Subjects will be 
enrolled into the trial online and randomized using an interactive web response system 
(IWRS). After demographic and eligibility criteria are entered into the system, each subject 
enrolled into the trial will be assigned their treatment assignment.  
7.3.2 Blinding (Randomized Observer-blinded Phase only) 
Subjects will be randomized and vaccinated with CVnCoV or placebo in an 
observer-blinded manner (due to the difference in appearance and presentation of the 
investigational CVnCoV vaccine and placebo). The pharmacist/qualified site personnel 
who prepared the injection will not be blinded to the identity of the trial vaccine being 
administered to the subject. However, the vaccinator, Investigator and all site personnel 
involved in the conduct of the trial (including follow-up of safety and COVID-19 case 
ascertainment) will be blinded to trial vaccine and subject treatment assignments. To 
maintain the blinding of the vaccinator, the pharmacist/qualified site personnel who 
prepared the injection will provide the dose of trial vaccine to the vaccinator prefilled in a 
syringe with a label covering the liquid contents so that it is not visible. All personnel at the 
CRO and Sponsor directly involved in the conduct of the trial will also be blinded. There 
will be certain individuals at the CRO and Sponsor whose function requires them to be 
unblinded during the trial (e.g., unblinded monitoring for trial vaccine accountability in the 
pharmacy; unblinded independent statistician assisting the DSMB; review of 
immunogenicity data [see next paragraph]). These unblinded individuals will be identified 
and their responsibilities documented.   
Because the immunogenicity results would unblind the subject’s treatment assignment, 
the independent laboratory performing the assays will keep the results in strict confidence. 
An unblinded person, named at the start of the trial and independent of the conduct of the 
trial, will have the responsibility of reviewing the quality of the immunogenicity data as it is 
being generated. This person will maintain the results in strict confidence. To maintain the 

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blind, the immunogenicity data will only be merged with the clinical database following 
unblinding of the trial.  
It will be at the discretion of the DSMB members whether or not safety data reviewed at 
the DSMB meetings will be unblinded. If there are any safety concerns, the DSMB may 
request unblinding of an individual subject or a specific dataset at any time. In addition, 
the DSMB will periodically monitor COVID-19 cases by vaccine group for signals of VDE. 
At the interim analyses, the DSMB will review COVID-19 cases by vaccine group for 
efficacy or futility, and will communicate the outcome to the Sponsor in a blinded manner. 
For the submission of documents for regulatory approval during the ongoing conduct of 
Trial CV-NCOV-004 (e.g., if efficacy is demonstrated at one of the interim analyses), an 
unblinded Submission Team will be formed which will be completely independent of the 
team conducting the trial. The Submission Team will comprise individuals from the 
Sponsor and CRO, and their roles and responsibilities on the unblinded team will be 
clearly defined.   
7.3.3 Unblinding 
7.3.3.1 Emergency Unblinding (randomized observer-blinded phase only) 
Individual unblinding should only occur in emergency situations for reasons of subject 
safety when knowledge of the trial vaccine is essential for the clinical management or 
welfare of the subject. Unblinding in this situation will be based on the judgment of the 
Investigator, ideally in discussion with the Sponsor.  
In general, the identity of the trial vaccine should not affect the clinical management of any 
SAE/AE. Whenever possible, the Investigator should attempt to contact the Sponsor 
before breaking the blind to discuss the need for emergency unblinding. Once agreed, 
code-breaking will be carried out via the IWRS. 
When the blind is broken, the date, exact timing, and reason must be fully documented in 
the source documents. The Investigator should not inform other blinded trial staff of the 
identity of the IMP. 
If the code has been broken and there are no medical reasons for discontinuation, the 
subject may continue in the trial. If the subject has received at least 1 dose of trial vaccine, 
it will be the judgment of the Investigator, in consultation with the Sponsor, whether the 
subject will be vaccinated with the second dose. If the subject is discontinued from the 
trial, every effort should be made to continue safety follow-up of the subject until the end 
of the trial.  
7.3.3.2 Trial Unblinding 
Since the efficacy results from the HERALD trial are available and subjects in this trial are 
currently allowed to receive an AV, all subjects in this trial will be unblinded. Unblinding 
will be performed by country/site depending on full Competent Authority and Ethics 
Committee approval of Protocol version 4.0 per country/site. 
The CRO will provide the sites with the subject numbers potentially eligible for each cohort. 
Each subject will be informed by the Investigator of the available results and whether 
he/she received CVnCoV or placebo in the trial (see Section 9.1.4).   

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Subjects who received at least 1 dose of CVnCoV will be asked to remain in the trial to 
allow safety follow-up. Subjects who received placebo will be withdrawn after trial 
unblinding. 
7.4 Vaccine Compliance 
The Investigator must record all trial vaccinations administered in the subject’s eCRF 
page.  
7.5 Misuse and Overdose 
Definition of misuse: Situations where the trial vaccine is intentionally and 
inappropriately used not in accordance with the protocol dosing instructions or authorized 
product information. 
Definition of overdose: Administration of a quantity of the trial vaccine given per 
administration or cumulatively which is above the maximum recommended dose 
according to the protocol dosing instructions or authorized product information.  
No toxic effects are expected from current clinical and non-clinical experience. Possible 
local reactions (pain) or systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, 
nausea/vomiting and diarrhea) may be treated symptomatically with physical measures, 
paracetamol, or non-steroidal anti-inflammatory drugs. 
7.6 Concomitant Therapy and Vaccines 
Concomitant medication for underlying diseases and the underlying disease for which it is 
administered and vaccines must be recorded in the subject’s eCRF. 
For all subjects, concomitant therapies associated with an SAE or an AESI will be 
collected and recorded in the eCRF from the moment of informed consent was obtained 
through the end of the trial. Concomitant therapies associated with medically-attended 
AEs occurring from the moment of vaccination until 6 months after vaccination (in the 
randomized observer-blinded phase) will also be collected and recorded in the eCRF.  
For all subjects, concomitant therapies associated with COVID-19 will be captured in the 
eCRF for the duration of the trial. 
For subjects in the Phase 2b part, concomitant therapies associated with unsolicited AEs 
occurring from the time of vaccination through 28 days after vaccination will be collected 
and recorded in the eCRF. Concomitant therapies associated with solicited AEs occurring 
from the time of vaccination through 7 days after vaccination will also be collected and 
recorded in the eCRF. 
Throughout the entire trial, any medications/vaccines prohibited according to 
Section 7.6.2, including immunosuppressants or other immune-modifying drugs need to 
be documented, if taken by a subject. 
7.6.1 Permitted Medications/Vaccines During the Trial 
Subjects are permitted to use antipyretics and other pain medications to treat any ongoing 
condition(s) the subject may have. Antipyretics (e.g., paracetamol) or other pain 
medication may be used to treat any local and/or systemic reactions associated with trial 

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vaccination. Paracetamol taken prophylactically for potential vaccine-associated reactions 
is also permitted in this trial. For example, if a subject experiences adverse reactions 
following the first trial vaccination, paracetamol may be taken prophylactically for these 
reactions for the second trial vaccination. In this case, paracetamol (up to 1 gram dose) 
may be taken after trial vaccination and at bedtime, and then in the morning and at bedtime 
during the next day. Alternatively, a 500 mg dose of paracetamol may be taken every 
6 hours after trial vaccination for up to 36 hours. The dose and dosing schedule of 
paracetamol should be discussed with the Investigator.  
Paracetamol administered as a treatment for vaccine-associated reactions or for 
prophylaxis, along with timing of administration with respect to trial vaccination must be 
documented in the eCRF.   
AVs are allowed during the open-label Phase (Cohort A: CVnCoV-AV). AVs will be 
procured and provided to the subject as standard of care per the subject’s national 
vaccination program, outside of the clinical trial procedures. Receipt of any other 
investigational SARS-CoV-2 vaccine or other coronavirus vaccine (e.g., SARS-CoV, 
MERS-CoV, etc) is prohibited during the trial.  
Other than the prohibited medications and vaccines described in Section 6.2 and listed 
below in Section 7.6.2, medications that are required for the treatment of the subject’s 
pre-existing medical conditions are permitted. 
7.6.2 Prohibited Medications/Vaccines During the Trial 
• 
Use of any investigational or non-registered product (vaccine or drug) is prohibited 
during the trial. Treatment with an investigational COVID-19 drug will be allowed in 
case of diagnosed COVID-19, and this will be recorded as concomitant medication. 
• 
Licensed vaccines (other than that for COVID-19) should not be administered within 
28 days (for live vaccines) or 14 days (for inactivated or any other vaccines) of trial 
vaccine administration during the trial. 
• 
Receipt of any other investigational SARS-CoV-2 vaccine or other coronavirus vaccine 
(e.g., SARS-CoV, MERS-CoV, etc) is prohibited during the trial. AVs are allowed if the 
subject is eligible according to the national vaccination program. 
• 
Any treatment with immunosuppressants or other immune-modifying drugs (including 
but not limited to corticosteroids, biologicals and methotrexate) is prohibited during the 
trial. For corticosteroid use, this means prednisone or equivalent, 0.5 mg/kg/day for 
14 days or more. The use of inhaled, topical, or localized injections of corticosteroids 
(e.g., for joint pain/inflammation) is permitted. 
• 
Administration of immunoglobulins or any blood products is prohibited during the trial.   
7.7 Therapy Leading to Discontinuation 
If a subject requires therapy listed as an exclusion criterion in Section 6.2 and which 
cannot be delayed, discontinuation would be considered to ensure integrity of the trial 
data, following individual case review. Every effort should be made to continue safety 
follow-up of the subject until the end of the trial.  

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7.8 Treatment After the End of Trial 
No post-trial care will be provided. 

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8 DISCONTINUATION/WITHDRAWAL CRITERIA 
Participation in the trial is strictly voluntary. A subject has the right to withdraw from the 
trial at any time and for any reason. The Investigator has the right to withdraw a subject 
from further trial vaccine administration and/or the trial if this is considered in the subject’s 
best interest or as a result of a protocol deviation.  
For discontinuations due to an AE, every effort should be made to document the outcome 
of the event.  
Subjects who received at least 1 dose of trial vaccine will be encouraged to continue 
participation until the end of the trial for safety assessments. 
8.1 Discontinuation of Trial Vaccine Administration 
The primary reason for discontinuation of further administration of trial vaccine will be 
recorded in the subject’s eCRF according to the following categories: 
• 
Consent withdrawal by the subject. 
The reason for withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(i.e., withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category). 
• 
The subject becomes eligible to receive an authorized/licensed SARS-CoV-2 vaccine, 
requests to be unblinded, and refrains from getting the second dose of trial vaccine 
(before trial unblinding). 
• 
AE (including known side effects of the trial vaccine). 
If discontinuation is due to an AE possibly related to the trial vaccine or trial 
procedures, the subject must be followed-up by additional examinations according to 
the medical judgment of the Investigator until the condition is resolved or the 
Investigator deems further observations or examinations to be no longer medically 
indicated. 
• 
Change in the subject’s overall medical status prohibiting further participation. 
• 
Pregnancy (see Section 9.3.4).  
Any subject who, despite the requirement for adequate contraception, becomes 
pregnant during the trial will not receive further trial vaccine doses. The site should 
maintain contact with the pregnant subject and complete a “Clinical Trial Pregnancy 
Form” as soon as possible. In addition, the subject should be followed-up until the birth 
of the child, or spontaneous or voluntary termination. When pregnancy outcome 
information becomes available, the information should be captured using the same 
form. The subject should be reported as an IMP discontinuation and the reason (i.e. 
pregnancy) should be given. 
• 
Trial terminated by the Sponsor (in which case the minimum safety follow-up 
conducted at the EOT visit on Day 393 would be performed). 

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• 
Major protocol deviation. 
• 
Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
For subjects who develop virologically-confirmed COVID-19 after the first trial vaccination 
but prior to the second during the randomized observer-blinded phase; this second 
vaccination can be administered once the subject is 2 weeks symptom-free, and provided 
the dose can be administered within the predefined visit window. 
8.2 Withdrawal from the Trial 
Subjects should be withdrawn from the trial in case any of the following situations occur: 
• 
Continued participation jeopardizes the subject’s health, safety, or rights. 
• 
The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is 
unwilling to continue because of the AE. The reasons for not performing further safety 
or immunogenicity assessments should be documented. 
• 
The subject did not return to the site and multiple attempts (a minimum of 3 attempts) 
to contact the subject were unsuccessful (lost to follow-up). 
• 
The subject wishes to withdraw from the trial. The reason for withdrawal, if provided, 
should be recorded. 
• 
After trial unblinding, placebo subjects will be withdrawn from the trial. 
All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (i.e., withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category). 
Any subject who prematurely terminates participation in the randomized observer-blinded 
phase and who has received at least 1 trial vaccine dose will undergo the same 
procedures as for the EOT visit, unless such procedures are considered to pose 
unacceptable risk to the subject. 
Discontinued or withdrawn subjects will not be replaced. 
8.3 Trial Termination 
The Sponsor reserves the right to terminate the trial at any time. Possible reasons for trial 
termination include the following: 
• 
Outcome of the interim analysis may show high VE or futility.  
• 
Safety reasons: the incidence of AEs in this or any other trial using a related vaccine 
indicates a potential health risk for the subjects.  
• 
New scientific knowledge becomes known that makes the objectives of the trial no 
longer feasible/valid. 
• 
The site is unlikely to be able to recruit sufficient subjects within the agreed time frame. 

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• 
The site does not respond to trial management requests. 
• 
Repeated protocol deviations. 
• 
Unsafe or unethical practices. 
• 
Administrative decision. 
Following a trial termination decision, the Investigator must contact all subjects within a 
time period set by the Sponsor. All trial materials must be collected and relevant 
documentation completed to the greatest extent possible. 
The trial can also be terminated by the Regulatory Authority for any reason or if 
recommended by the DSMB, or at a site level by the Independent Ethics Committee or 
Institutional Review Board (IEC/IRB). The Sponsor may close an individual site 
prematurely for reasons such as poor protocol compliance or unsatisfactory recruitment 
of subjects. 
8.4 Lost to Follow-Up 
All efforts should be made to contact subjects who have not returned for the scheduled 
trial visit or who are unable to be contacted for a scheduled phone call. A minimum of 
3 attempts should be made and documented. If a subject is lost to follow-up before 
resolution of related SAEs or AEs, the Sponsor may consider further attempts to contact 
the subject in order to collect follow-up safety information. 

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9 TRIAL ASSESSMENTS AND PROCEDURES 
The trial assessments and procedures for this trial are presented in Table 1, Table 2, 
Table 3, Table 4, and Table 5. The trial assessments and procedures are discussed in 
this section.  
For subjects who are unable to come to the site for protocol-specified site visits (e.g., due 
to the public health emergency related to COVID-19), safety assessments may be 
performed using alternative methods (e.g., phone contact, virtual visit, alternative location 
for assessment).  
For further flexibility in trial conduct in the pandemic setting, home visits will be allowed to 
perform safety assessments and procedures including the collection of blood and any 
bio-samples. If site visits, phone contacts or sample collection cannot be performed within 
the protocol-defined windows, in such unique circumstances as a public health 
emergency, it will be acceptable to perform these tasks outside of these windows. In the 
pandemic setting, the protocol-defined windows for site visits and phone contacts are 
provided for guidance and will not be considered deviations, if not strictly adhered to.   
After trial unblinding, no blood samples will be collected; home visits will no longer be 
performed, and clinic visits may be replaced with phone calls if suitable to reduce contacts 
in the pandemic setting.  
An electronic diary (eDiary) will be used during the randomized observer-blinded phase of 
the trial for efficient collection of safety-related information. However, paper diaries may 
be substituted for some subjects.   
Initiation of subject enrollment of the 2 target age groups into Phase 2b will be flexible. 
Depending on the timing of data from the Phase 1 and Phase 2a trials, enrollment of the 
2 age groups into Phase 2b may be staggered, initially starting with subjects 18 to 60 years 
of age followed by subjects ≥ 61 years of age. As the older age group will comprise 20% 
to 25% of the total number of subjects in Phase 2b, this staggered start is not expected to 
impact overall enrollment of the Phase 2b cohort. 
The maximum total volume of blood taken over the trial period from any subject is 304 mL. 
9.1 Schedule of Trial Assessments and Procedures 
Refer to Table 1 (Immunogenicity Subjects) and Table 2 (Non-Immunogenicity Subjects) 
for the Schedule of Trial Assessments and Procedures for Phase 2b, Table 3 for the 
Schedule of Trial Assessments and Procedures for the randomized observer-blinded 
Phase 3, Table 4 for the Schedule of Trial Assessments and Procedures for the open-label 
phase Cohort A, and Table 5 for the Schedule of Trial Assessments and Procedures for 
the open-label phase Cohort B. 
The trial assessments and procedures apply to all subjects, independent if they had known 
SARS-CoV-2 positive serology before the trial or independent of the serology status at 
baseline as per retrospective analysis. 
Subjects participating in Phase 2b will be given a thermometer to measure body 
temperature orally and a measuring tape to determine the size of local injection site 
reactions.  

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Subjects will be instructed on how to enter the solicited AEs daily for 7 days in the eDiary. 
Subjects should be reminded to use the provided Mobile Health Platform for the eDiary as 
applicable during the randomized observer-blinded phase of the trial. 
During the conduct of the trial and interactions with subjects, any person with early warning 
signs of COVID-19 should be referred to emergency medical care immediately. These 
signs include, but are not limited to, the following: difficulty breathing, persistent pain or 
pressure in the chest, new confusion, inability to awake or stay awake, or bluish lips or 
face.   
9.1.1 Phase 2b: Immunogenicity Subset 
The Immunogenicity Subset of Phase 2b will include the first 600 subjects enrolled into 
each of the 2 age groups, 18-60 and ≥ 61 years of age, into Phase 2b. As such, the target 
total enrollment will be approximately 1,200 subjects.   
9.1.1.1 Clinic Visit 1: Day 1 - First Trial Vaccination 
Note that procedures to establish subject eligibility, recording of demographic information 
and medical history may be performed within 21 days prior to trial vaccine administration, 
i.e., spread out over more than 1 day. However, if all information is available and 
assessments and procedures can be performed, eligibility can be established on the same 
day of trial vaccine administration. All eligibility criteria must be reviewed prior to trial 
vaccine administration on Day 1.  
Pre-vaccination Procedures 
• 
Obtain signed informed consent form (ICF). 
- 
Signed informed consent must be obtained prior to the subject entering into the 
trial, and before any protocol-directed procedures are performed (see 
Section 12.4).  
• 
Review inclusion/exclusion criteria (see Section 6.1 and 6.2) and review prohibited 
medications listed as an exclusion criterion (see Section 6.2). 
• 
Randomize the subject in IWRS after confirmation of eligibility. 
• 
Record demographic and smoking information. 
• 
Record medical history. 
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6, including recurring medications for intermittent conditions, if taken within 
6 months prior to enrollment in this trial. 
• 
Perform a complete physical examination, including height and weight (see 
Section 9.3.6). If the complete physical examination to establish eligibility was 
performed within 21 days prior to trial vaccine administration, a symptom-directed 
physical examination should be performed on the day of vaccination prior to trial 
vaccine administration. 
• 
Measure vital signs (body temperature, pulse, blood pressure; see Section 9.3.6). 

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• 
Perform pregnancy test in females of childbearing potential (Appendix 5). 
• 
Collect pre-vaccination blood samples (see Table 1) for binding antibody testing to 
RBD of S protein of SARS-CoV-2 (~6 mL blood); SARS-CoV-2 viral neutralizing 
activity (~6 mL blood); and binding antibody testing to N protein of SARS-CoV-2 
(~6 mL blood).  
• 
Collect pre-vaccination blood samples for genomic biomarkers (~6 mL blood) from 
subjects at selected site(s). 
• 
Collect pre-vaccination blood samples for CMI (~32 mL blood) from subjects at 
selected site(s). 
Vaccination Procedure 
• 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for 
an overview of the criteria leading to delay or cancellation of vaccine administration. 
In case of delay, the vaccination should take place within the allowed time windows. 
The reasons for delay or cancellation should be documented in the subject’s chart. 
• 
Administer the trial vaccine. 
Post-vaccination Procedures 
• 
Observe the subject on site for at least 30 minutes following vaccination for safety 
monitoring. At the end of the observation period: 
- 
Measure vital signs (body temperature, pulse, blood pressure; see Section 9.3.6). 
- 
The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels. 
- 
Record the occurrence of any AEs following trial vaccination.   
• 
Instructions for the subject: 
- 
Instruct the subject how to measure solicited AEs and how to complete the eDiary. 
The subject should record solicited local and systemic AEs occurring on the day 
of vaccination and the following 7 days, and unsolicited AEs (i.e., the occurrence 
of all other AEs) occurring on the day of vaccination and the following 28 days. 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 

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- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
Note: Subjects without symptoms may have been tested for several reasons, for 
example, close exposure to a known person with SARS-CoV-2 infection or as part 
of their routine screening as a healthcare provider.  
• 
Complete the source documents and eCRF for this visit. 
9.1.1.2 Phone Call: Day 2 (-0/+0 day)  
The purpose of this phone contact is to inquire about the subject’s general well-being and 
to assess safety 1 day after the first trial vaccination.  
• 
During the phone call: 
- 
Review and record any newly reported safety data including solicited and 
unsolicited AEs, or other AEs (e.g., medically-attended AEs, SAEs).  
- 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
- 
If the subject reports any concerning local or systemic reactions, or other AEs (e.g., 
medically-attended AEs, SAEs), these should be followed-up either by a phone 
call(s) or by an unscheduled site visit based on the judgment of the Investigator.   
• 
Instructions for the subject: 
- 
Remind the subject to continue recording solicited and unsolicited AEs (i.e., the 
occurrence of all other AEs) in the eDiary. 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 

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- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this phone call. 
9.1.1.3 Clinic Visit 2: Day 29 - Second Trial Vaccination (-3/+7 days) 
Pre-vaccination Procedures 
• 
Review and record any newly reported safety data including solicited and unsolicited 
AEs, or other AEs (e.g., medically-attended AEs, SAEs).   
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Perform pregnancy test in females of childbearing potential (Appendix 5). 
• 
Collect pre-vaccination blood samples (see Table 1) for binding antibody testing to 
RBD of S protein of SARS-CoV-2 (~6 mL blood) and SARS-CoV-2 viral neutralizing 
activity (~6 mL blood). No testing of antibody to N protein of SARS-CoV-2 will be 
performed at this time point. 
• 
Collect pre-vaccination blood samples for genomic biomarkers (~6 mL blood) from 
subjects at selected site(s).  
• 
Collect pre-vaccination blood samples for CMI (~32 mL blood) from subjects at 
selected site(s). 
Vaccination Procedure 
• 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for 
an overview of the criteria leading to delay or cancellation of vaccine administration. 
In case of delay, the vaccination should take place within the allowed time windows. 
The reasons for delay or cancellation should be documented in the subject’s chart. 
• 
Administer the trial vaccine.  

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Post-vaccination Procedures 
• 
Observe the subject on site for at least 30 minutes following vaccination for safety 
monitoring. At the end of the observation period: 
- 
Measure vital signs (body temperature, pulse, blood pressure; see Section 9.3.6). 
- 
The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels.  
- 
Record the occurrence of any AEs following trial vaccination.  
• 
Instructions for the subject: 
- 
Re-instruct the subject how to measure solicited AEs and how to complete the 
eDiary. The subject should record solicited local and systemic AEs occurring on 
the day of vaccination and the following 7 days, and unsolicited AEs (i.e., the 
occurrence of all other AEs) occurring on the day of vaccination and the following 
28 days. 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine.   
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.   
• 
Complete the source documents and eCRF for this visit. 
9.1.1.4 Phone Call: Day 30 (-0/+0 day)  
The purpose of this phone contact is to inquire about the subject’s general well-being and 
to assess safety 1 day after the second trial vaccination.  
The assessments and procedures are identical to those performed during the phone call 
on Day 2.  

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9.1.1.5 Clinic Visit 3: Day 43 (-3/+3 days)   
• 
Review and record any newly reported safety data including solicited and unsolicited 
AEs, or other AEs (e.g., medically-attended AEs, SAEs).   
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Collect blood samples (see Table 1) for binding antibody testing to RBD of S protein 
of SARS-CoV-2 (~6 mL blood); SARS-CoV-2 viral neutralizing activity (~6 mL blood); 
and binding antibody testing to N protein of SARS-CoV-2 (~6 mL blood).  
• 
Collect blood samples for genomic biomarkers (~6 mL blood) from subjects at selected 
site(s). 
• 
Collect blood samples for CMI (~32 mL blood) from subjects at selected site(s). 
• 
Instructions for the subject: 
- 
Inform the subject that recording of solicited local and systemic reactions in the 
eDiary is complete. Remind the subject to continue recording unsolicited AEs (all 
AEs). 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported, 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this visit. 

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9.1.1.6 Clinic Visit 4: Day 57 (-3/+7 days) 
• 
Review and record any newly reported safety data including unsolicited AEs or other 
AEs (e.g., medically-attended AEs, SAEs).   
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Collect a blood sample for immunogenicity assessment (see Table 1) for binding 
antibody testing to RBD of S protein of SARS-CoV-2 (~6 mL blood) and SARS-CoV-2 
viral neutralizing activity (~6 mL blood). (No testing of binding antibody to N protein of 
SARS-CoV-2 will be performed at this time point).  
• 
Instructions for the subject: 
- 
Inform the subject that reporting of unsolicited AEs is complete.   
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this visit. 
9.1.1.7 Clinic Visit 5: Day 120 (-7/+7 days) 
• 
Review and record any newly reported AEs since the site visit on Day 57 (e.g., 
medically-attended AEs, SAEs).   

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• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Collect blood samples (see Table 1) for binding antibody testing to RBD of S protein 
of SARS-CoV-2 (~6 mL blood) and SARS-CoV-2 viral neutralizing activity (~6 mL 
blood). (No testing of binding antibody to N protein of SARS-CoV-2 will be performed 
at this time point). 
• 
Collect pre-vaccination blood samples for genomic biomarkers (~6 mL blood) from 
subjects at selected site(s).  
• 
Collect pre-vaccination blood samples for CMI (~32 mL blood) from subjects at 
selected site(s). 
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this visit. 
9.1.1.8 Clinic Visit 6: Day 211 (-7/+7 days) 
The assessments and procedures are identical to those performed during Clinic Visit 5 on 
Day 120, except for the below.   
• 
Collect blood samples (see Table 1) for binding antibody testing to RBD of S protein 
of SARS-CoV-2 (~6 mL blood); SARS-CoV-2 viral neutralizing activity (~6 mL blood); 

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and binding antibody testing to N (nucleocapsid) protein of SARS-CoV-2 (~6 mL 
blood). 
• 
Collect blood samples for genomic biomarkers (~6 mL blood) from subjects at selected 
site(s). 
Collect blood samples for CMI (~32 mL blood) from subjects at selected site(s). 
9.1.1.9 Phone Call: Day 302 (-7/+7 days)  
The purpose of this phone contact is to inquire about the subject’s general well-being and 
to assess safety since the site visit on Day 211.  
• 
During the phone call: 
o Review and record any newly reported AEs since the site visit on Day 211 (e.g., 
SAEs).   
o Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
o If the subject reports by phone any concerning AEs, these should be followed-up 
either by a phone call(s) or by an unscheduled site visit based on the judgment of 
the Investigator.   
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this phone call. 

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9.1.1.10 
End of Trial Visit: Day 393 (-0/+21 days) 
The EOT visit will be performed on Day 393, 1 year after the last trial vaccine 
administration. If possible, this visit should include subjects who prematurely discontinued 
vaccination during the trial. The following assessments should be performed:  
• 
Review and record any newly reported AEs since the phone contact on Day 302 (e.g., 
SAEs).  
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a complete physical examination, including height and weight (see 
Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Compete the eCRF for this visit. 
Inform the subjects that they have completed the trial and can now delete the eDiary app.   
9.1.2 Phase 2b: Non-Immunogenicity Subjects 
Following enrollment of subjects into the Immunogenicity Subset of Phase 2b (n=1,200), 
the remaining 2,800 subjects, 18 years of age and older, will be enrolled into Phase 2b.   
9.1.2.1 Clinic Visit 1: Day 1 – First Trial Vaccination 
Note that procedures to establish subject eligibility, recording of demographic information 
and medical history may be performed within 21 days prior to trial vaccine administration, 
i.e., spread out over more than 1 day. However, if all information is available and 
assessments and procedures can be performed, eligibility can be established on the same 
day of trial vaccine administration. All eligibility criteria must be reviewed prior to trial 
vaccine administration on Day 1.  
Pre-vaccination Procedures 
• 
Obtain the signed ICF. 
- 
Signed informed consent must be obtained prior to the subject entering into the 
trial, and before any protocol-directed procedures are performed (see 
Section 12.4). 
• 
Review inclusion/exclusion criteria (see Section 6.1 and 6.2) and review prohibited 
medications listed as an exclusion criterion (see Section 6.2). 
• 
Randomize the subject in IWRS after confirmation of eligibility. 
• 
Record demographic and smoking information. 
• 
Record medical history. 
• 
Record concomitant medication and vaccination according to instructions in 
Section 7.6, including recurring medication for intermittent conditions, if taken within 
6 months prior to enrollment in this trial. 

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• 
Perform a complete physical examination, including height and weight (see 
Section 9.3.6). If the complete physical examination to establish eligibility was 
performed within 21 days prior to trial vaccine administration, a symptom-directed 
physical examination should be performed on the day of vaccination prior to trial 
vaccine administration. 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Perform pregnancy test in females of childbearing potential (Appendix 5).   
• 
Collect pre-vaccination blood sample (see Table 2) for binding antibody testing to 
N protein of SARS-CoV-2 (~6 mL blood). 
Vaccination Procedure 
• 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for 
an overview of the criteria leading to delay or cancellation of vaccine administration. 
In case of delay, the vaccination should take place within the allowed time windows. 
The reasons for delay or cancellation should be documented in the subject chart. 
• 
Administer the trial vaccine. 
Post-vaccination Procedures 
• 
Observe the subject on site for at least 30 minutes following vaccination for safety 
monitoring. At the end of the observation period: 
- 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
- 
The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels. 
- 
Record the occurrence of any AEs following trial vaccination.   
• 
Instructions for the subject: 
- 
Instruct the subject how to measure solicited AEs and how to complete the eDiary. 
The subject should record solicited local and systemic AEs occurring on the day 
of vaccination and the following 7 days, and unsolicited AEs (i.e., the occurrence 
of all other AEs) occurring on the day of vaccination and the following 28 days. 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 

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- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
Note: Subjects without symptoms may have been tested for several reasons, for 
example, close exposure to a known person with SARS-CoV-2 infection or as part 
of their routine screening as a healthcare provider.  
• 
Complete the source documents and eCRF for this visit. 
9.1.2.2 Phone Call: Day 2 (-0/+0 day) 
The purpose of this phone contact is to inquire about the subject’s general well-being and 
to assess safety 1 day after the first trial vaccination.  
• 
During the phone call: 
- 
Review and record any newly reported safety data including solicited and 
unsolicited AEs, or other AEs (e.g., medically-attended AEs, SAEs).  
- 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
- 
If the subject reports any concerning local or systemic reactions, or other AEs (e.g., 
medically-attended AEs, SAEs), these should be followed-up either by a phone 
call(s) or by an unscheduled site visit based on the judgment of the Investigator.   
• 
Instructions for the subject: 
- 
Remind the subject to continue recording solicited and unsolicited AEs (i.e., the 
occurrence of all other AEs) in the eDiary. 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 

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- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this phone call. 
9.1.2.3 Clinic Visit 2: Day 29 – Second Trial Vaccination (-3/+7 days) 
Pre-vaccination Procedures 
• 
Review and record any newly reported safety data including solicited and unsolicited 
AEs, or other AEs (e.g., medically-attended AEs, SAEs).   
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Perform pregnancy test in females of childbearing potential (Appendix 5). 
Vaccination Procedure 
• 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for 
an overview of the criteria leading to delay or cancellation of vaccine administration. 
In case of delay, the vaccination should take place within the allowed time windows. 
The reasons for delay or cancellation should be documented in the subject chart. 
• 
Administer the trial vaccine. 
Post-vaccination Procedures 
• 
Observe the subject on site for at least 30 minutes following vaccination for safety 
monitoring. At the end of the observation period: 
- 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).  
- 
The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels. 
- 
Record the occurrence of any AEs following trial vaccination. 
• 
Instructions for the subject: 
- 
Re-instruct the subject how to measure solicited AEs and how to complete the 
eDiary. The subject should record solicited local and systemic AEs occurring on 

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the day of vaccination and the following 7 days, and unsolicited AEs (i.e. the 
occurrence of all other AEs) occurring on the day of vaccination and the following 
28 days. 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine.   
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5). 
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.   
• 
Complete the source documents and eCRF for this visit. 
9.1.2.4 Phone Call: Day 30 (0/+0 day) 
The purpose of this phone contact is to inquire about the subject’s general well-being and 
to assess safety 1 day after the second trial vaccination.   
The assessments and procedures are identical to those performed during the phone call 
on Day 2.  
9.1.2.5 Clinic Visit 3: Day 43 (-3/+3 days) 
• 
Review and record any newly reported safety data including solicited and unsolicited 
AEs, or other AEs (e.g., medically-attended AEs, SAEs).   
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 

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• 
Collect blood sample (see Table 2) for binding antibody testing to N protein of 
SARS-CoV-2 (~6 mL blood). 
• 
Instructions for the subject: 
- 
Inform the subject that recording of solicited local and systemic reactions in the 
eDiary is complete. Remind the subject to continue recording unsolicited AEs (all 
AEs). 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported, 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this visit. 
9.1.2.6 Phone Call: Day 57 (-3/+7) 
The purpose of this phone contact is to inquire about the subject’s general well-being and 
to assess safety since site visit on Day 43.   
• 
During the phone call: 
- 
Review and record any newly reported safety data including unsolicited AEs or 
other AEs (e.g., medically-attended AEs, SAEs).  
- 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
- 
If the subject reports any concerning local or systemic reactions, or other AEs (e.g., 
medically-attended AEs, SAEs), these should be followed-up either by a phone 
call(s) or by an unscheduled site visit based on the judgment of the Investigator.   

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• 
Instructions for the subject: 
- 
Inform the subject that reporting of unsolicited AEs is complete.  
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this phone call. 
9.1.2.7 Clinic Visit 4: Day 120 (-7/+7)  
• 
Review and record any newly reported AEs since the phone call on Day 57 (e.g., 
medically-attended AEs, SAEs).   
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  

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o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported, 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this visit. 
9.1.2.8 Clinic Visit 5: Day 211 (-7/+7)  
The assessments and procedures are identical to those performed during Clinic Visit 4 on 
Day 120, except for the below.   
Collect a blood sample (see Table 2) for binding antibody testing to N protein of 
SARS-CoV-2 (~6 mL blood). 
9.1.2.9 Phone Call: Day 302 (-7/+7)   
The purpose of this phone contact is to inquire about the subject’s general well-being and 
to assess safety since the site visit on Day 211.   
• 
During the phone call: 
o Review and record any newly reported AEs since the site visit on Day 211 (e.g., 
SAEs).   
o Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
o If the subject reports by phone any concerning AEs, these should be followed-up 
either by a phone call(s) or by an unscheduled site visit based on the judgment of 
the Investigator.   
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  

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o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this phone call. 
9.1.2.10 
End of Trial Clinic Visit: Day 393 (-0/+21 days) 
The EOT visit will be performed on Day 393, 1 year after the last trial vaccine 
administration. If possible, this visit should include subjects who prematurely discontinued 
vaccination during the trial. The following assessments should be performed:  
• 
Review and record any newly reported AEs since the phone contact on Day 302 (e.g., 
SAEs).  
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a complete physical examination, including height and weight (see 
Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Complete the source documents and eCRF for this visit. 
Inform the subjects that they have completed the trial and can now delete the eDiary app. 
9.1.3 Randomized Observer-blinded Phase 3 Subjects 
Approximately 32,500 subjects, 18 years of age and older, will be enrolled into Phase 3.   
9.1.3.1 Clinic Visit 1: Day 1 – First Trial Vaccination  
Note that procedures to establish subject eligibility, recording of demographic information 
and medical history may be performed within 21 days prior to trial vaccine administration, 
i.e., spread out over more than 1 day. However, if all information is available and 
assessments and procedures can be performed, eligibility can be established on the same 
day of trial vaccine administration. All eligibility criteria must be reviewed prior to trial 
vaccine administration on Day 1.  
Pre-vaccination Procedures 
• 
Obtain the signed ICF. 

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- Signed informed consent must be obtained prior to the subject entering into the trial, 
and before any protocol-directed procedures are performed (see Section 12.4). 
• 
Review inclusion/exclusion criteria (see Section 6.1 and 6.2) and review prohibited 
medications listed as an exclusion criterion (see Section 6.2). 
• 
Randomize the subject in IWRS after confirmation of eligibility. 
• 
Record demographic and smoking information. 
• 
Record medical history. 
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6, including recurring medications for intermittent conditions, if taken within 
6 months prior to enrollment in this trial. 
• 
Perform a complete physical examination, including height and weight (see 
Section 9.3.6). If the complete physical examination to establish eligibility was 
performed within 21 days prior to trial vaccine administration, a symptom-directed 
physical examination should be performed on the day of vaccination prior to trial 
vaccine administration. 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Perform pregnancy test in females of childbearing potential (Appendix 5). 
• 
Collect a pre-vaccination blood sample (see Table 3) for binding antibody testing to 
N protein of SARS-CoV-2 (~6 mL blood). 
Vaccination Procedure 
• 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for 
an overview of the criteria leading to delay or cancellation of vaccine administration. 
In case of delay, the vaccination should take place within the allowed time windows. 
The reasons for delay or cancellation should be documented in the subject chart. 
• 
Administer the trial vaccine. 
Post-vaccination Procedures 
• 
Observe the subject on site for at least 30 minutes following vaccination for safety 
monitoring. At the end of the observation period: 
- 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
- 
The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels. 
- 
Record any adverse reaction which constitutes an AESI, medically-attended AE, 
or an SAE.  
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 

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o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
Note: Subjects without symptoms may have been tested for several reasons, for 
example, close exposure to a known person with SARS-CoV-2 infection or as part 
of their routine screening as a healthcare provider).  
• 
Complete the source documents and eCRF for this visit. 
9.1.3.2 Clinic Visit 2: Day 29 - Second Trial Vaccination (-3/+7 days)  
Pre-vaccination Procedures 
• 
Review and record any newly collected safety data including medically-attended AEs 
and SAEs.  
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Perform pregnancy test in females of childbearing potential (Appendix 5). 
Vaccination Procedure 
• 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for 
an overview of the criteria leading to delay or cancellation of vaccine administration. 
In case of delay, the vaccination should take place within the allowed time windows. 
The reasons for delay or cancellation should be documented in the subject chart. 

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• 
Administer the trial vaccine. 
Post-vaccination Procedures 
• 
Observe the subject on site for at least 30 minutes following vaccination for safety 
monitoring. At the end of the observation period: 
- 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
- 
The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels. 
- 
Record any adverse reaction which constitutes an AESI, medically-attended AE, 
or an SAE.  
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this visit. 
9.1.3.3 Clinic Visit 3: Day 43 (-3/+3 days) 
• 
Review and record any newly collected safety data including medically-attended AEs 
and SAEs.  
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a symptom-directed physical examination (at the discretion of the 
Investigator; see Section 9.3.6). 

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• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Collect a blood sample (see Table 3) for binding antibody testing to N protein of 
SARS-CoV-2 (~6 mL blood). 
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning local or systemic reactions or other 
medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5).  
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this visit. 
9.1.3.4 Phone Call: Day 57 (-3/+7 days) and Day 120 (-7/+7 days)   
The purpose of these phone contacts is to inquire on the subject’s general well-being and 
to assess safety since the last phone contact or site visit.  
• 
During the phone call: 
- 
Review and record any newly reported AEs since the site visit or phone call (e.g., 
medically-attended AEs, SAEs).   
- 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
- 
If the subject reports by phone any concerning AEs, these should be followed-up 
either by a phone call(s) or by an unscheduled site visit based on the judgment of 
the Investigator.   
• 
Instructions for the subject: 
- 
Remind the subject to call the site immediately to report the following: 

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o If he/she experiences any concerning medical event.  
o Any medically-attended visits that are not routine visits for physical 
examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to contact the site immediately if he/she has any of the 
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to 
twice a week to provide a yes or no response to having COVID-19 symptoms. 
Those who respond “yes” will be contacted by trial staff for follow-up information if 
the Investigator considers the symptoms could potentially indicate a COVID-19 
case (see Section 9.2.1 and Section 9.5). 
- 
The subject should also be reminded to contact the site immediately if he/she had 
a positive SARS-CoV-2 test performed outside of the site, whether they were 
symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
• 
Complete the source documents and eCRF for this phone call. 
9.1.3.5 Clinic Visit 4: Day 211 (-7/+7 days) 
The assessments and procedures are identical to those performed during the clinical visit 
on Day 43.  
9.1.3.6 Phone Call: Day 302 (-7/+7 days) 
The purpose of this phone contact is to inquire on the subject’s general well-being and to 
assess safety since the last site visit on Day 211.   
The assessments and procedures are identical to those performed during the phone calls 
on Day 57 and Day 120, except for medically-attended AEs, which are only collected 
through 6 months after the second dose.  
9.1.3.7 End of Trial Clinic Visit: Day 393 (-0/+21 days) 
The EOT visit will be performed on Day 393, 1 year after the last trial vaccine 
administration. If possible, this visit should include subjects who prematurely discontinued 
vaccination during the trial. The following assessments should be performed:  
• 
Review and record any newly reported AEs since the phone contact on Day 302 (e.g., 
SAEs).  
• 
Record concomitant medications and vaccinations according to instructions in 
Section 7.6. 
• 
Perform a complete physical examination, including height and weight (see 
Section 9.3.6). 

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• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6). 
• 
Complete the source documents and eCRF for this visit. 
Inform the subjects that they have completed the trial and can now delete the eDiary app.  
9.1.4 Open-label Phase 
The open-label phase will start immediately after regulatory and ethical approval was 
obtained for Protocol version 4.0 on country/site level. Sites will be provided with a list of 
treatment assignments for subjects who are still blinded at the timepoint of trial unblinding. 
The eDiary app will no longer be used during the open-label phase. 
9.1.4.1 Subjects who Received CVnCoV: Cohorts A and B 
Subjects in the CVnCoV treatment arm who did not yet receive an AV will have to decide 
whether they will opt to receive an AV in addition to CVnCoV. Subjects of the CVnCoV 
treatment arm will be included in Cohort A if they received an AV after individual unblinding 
or will receive an AV after trial unblinding. Subjects will be included in Cohort B if they 
have not received and do not receive any AV until the EOT.  
Subjects who initially intend to complete the trial without receiving an AV and later decide 
to receive an AV within the open-label phase will be switched to Cohort A. 
All subjects who received CVnCoV and continue in the open-label phase will sign a new 
ICF after trial unblinding.  
The open-label phase visits should be scheduled according to the originally scheduled 
visits/phone calls in the Phase 2b/3 schedule: Day 302 (-3/+21 days) and Day 393 
(-0/+21 days). After trial unblinding, the Day 302 and Day 393 visits will be performed as 
phone calls, but a clinic visit may be performed if ICF signature cannot be done via e-mail, 
phone call, or mail. 
9.1.4.1.1 Phone Call/Clinic Visit OL-1: Day 302 of the Original Phase 2b/3 
Schedule (-3/+21 days) 
During this visit, a new ICF will be obtained. If the Day 302 phone call was already 
performed as part of the randomized observer-blinded phase before approval of Protocol 
version 4.0, the ICF will be signed at the Day 393/EOT phone call/clinic visit. 
Subjects in the CVnCoV treatment arm who already received or plan to receive an AV are 
eligible for Cohort A. The AV should be recorded in the eCRF.  
The following assessments should be performed: 
• 
Obtain the signed ICF: A new signed informed consent must be obtained after trial 
unblinding (see Section 12.4). 
• 
For Cohort A: Confirm choice for AV.  
• 
Review roll-over criteria for the open-label phase (see Section 6.3). 
• 
Record concomitant medications and vaccinations (including COVID-19 AV 
vaccination) since last visit or phone call, according to instructions in Section 7.6. 

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• 
Review and record any newly reported AEs since the last site visit or phone call (e.g., 
SAEs, AESIs, AEs leading to trial discontinuation).  
• 
If the subject reports any concerning AEs, these should be followed-up either by a 
phone call(s) or by an unscheduled site visit based on the judgment of the Investigator.   
• 
Instructions for the subjects: 
- 
Remind the subject to call the site immediately to report the following: 
o If he/she experiences any concerning medical event.  
o Experience a serious medical event, have a change in overall health or be 
diagnosed with a new medical condition by a doctor. These should be reported 
regardless of the perceived relationship between the event and the trial 
vaccine. 
- 
Remind the subject to report any confirmed COVID-19 positive test, or in case sites 
continue to perform the test, remind the subject to call the Investigator in case of 
new symptoms according to the more restrictive definition used for the open-label 
phase (see Section 9.2.1.3.1).  
• 
Complete the source documents and eCRF for this visit. 
9.1.4.1.2 End of Trial Phone Call/Clinic Visit OL-2: Day 393 of the Original Phase 
2b/3 Schedule (-0/+21 days) 
The EOT phone call/clinic visit will be performed on Day 393, approximately 1 year after 
the last CVnCoV administration.  
The following assessments should be performed: 
• 
If the Day 302 phone call was already performed as part of the randomized 
observer-blinded phase before approval of Protocol version 4.0, the ICF will be signed 
at the Day 393/EOT phone call/clinic visit. 
• 
Review and record any newly reported AEs since the last site visit or phone call (e.g., 
SAEs, AESIs).   
• 
Record concomitant medications and vaccinations (including COVID-19 AV 
vaccination for Cohort A) according to instructions in Section 7.6. 
• 
Complete the source documents and eCRF for this visit. 
Inform the subjects that they have completed the trial. 
9.1.4.2 Placebo Subjects  
Subjects of the placebo treatment arm will be notified of the trial treatment they received 
by a Subject Information Letter and they will be withdrawn after an EOT phone call. In 
case the subject needs to attend the site around the time of unblinding, a visit may be 
performed instead of the phone call. 
Before the EOT phone call, the subject’s medical records and eCRF need to be reviewed 
to identify any potential ongoing SAE or AESI.  

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At the EOT phone call, any follow-up information on SAEs and AESIs needs to be 
documented. Subjects further need to be asked for any new SAE or AESI since the last 
trial contact and if any, those need to be documented. 
The subject should be informed that the e-diary app can now be deleted and that no further 
tracking for COVID-19 is possible within the trial after the subject was withdrawn.  
The EOT phone call will be documented in the subject's medical records, and the 
End-of-Trial form in the eCRF will be completed. 
9.2 Efficacy Assessments 
9.2.1 COVID-19 Cases  
9.2.1.1 COVID-19 Cases in the Randomized Observer-blinded Phase 
COVID-19 case ascertainment will occur in identical manner in both the Phase 2b and 
Phase 3 parts of the trial. Case detection will begin with the identification of subjects 
reporting at least 1 symptom from a standardized list of symptoms consistent with 
COVID-19. Based on a phone interview with trial staff (see Appendix 6A), subjects 
suspected of having COVID-19 will undergo testing for SARS-CoV-2 infection, consisting 
of a rapid antigen test performed locally by the trial staff and a molecular-based RT-PCR 
test performed at a designated central laboratory. The testing strategy is described in 
Section 9.5 and Appendix 7. If the subject is confirmed to have COVID-19, subjects will 
be followed until resolution of their disease, even if the initial presentation is considered 
as mild. If the subject is hospitalized, the subject’s progress must continue to be followed 
by the Investigator and a medical/discharge summary must be obtained at the end of the 
hospitalization.  
The following definitions will apply: 
• 
Any SARS-CoV-2 infection: a SARS-CoV-2 infection detected by either RT-PCR or 
seroconversion to the N protein in a seronegative subject. 
• 
Subject without evidence of prior SARS-CoV-2 infection: subject is seronegative to the 
S and N proteins by immunoassay.  
• 
Subject with evidence of prior SARS-CoV-2 infection: subject is seropositive to the S 
and/or N proteins by immunoassay.  
• 
Subject with high risk of severe COVID-19: subject’s with the following conditions are 
at increased risk of severe COVID-19:  
- 
Cancer 
- 
Chronic kidney disease 
- 
Chronic obstructive pulmonary disease 
- 
Heart conditions, such as heart failure, coronary artery disease, or 
cardiomyopathies 
- 
Immunocompromised state (weakened immune system) from solid organ 
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- 
Obesity (body mass index [BMI] ≥ 30 kg/m2 but < 40 kg/m2) 
- 
Severe obesity (BMI ≥ 40 kg/m2) 
- 
Pregnancy 
- 
Sickle cell disease 
- 
Smoking 
- 
Type 2 diabetes mellitus 
9.2.1.2 COVID-19 Cases in the Open-label Phase 
COVID-19 case ascertainment stopped on 18 June 2021 (cut-off date for the final efficacy 
analysis) and will not occur during the open-label phase.  
During the open-label phase, subjects will undergo passive surveillance for COVID-19 
(see Appendix 6B). If beneficial for the subject, rapid testing and RT-PCR test may be 
performed based on European Centre for Disease Prevention and Control (eCDC) case 
definition (see Section 9.2.1.3.1) at the investigator discretion. The testing strategy is 
described in Section 9.5 and Appendix 7. 
9.2.1.3 Case Detection  
9.2.1.3.1 Routine Surveillance for COVID-19  
Randomized observer-blinded phase: 
During all site visits and phone calls, subjects will be reminded to contact the site if they 
have any of the following symptoms*: 
o Fever or chills 
o Shortness of breath or 
difficulty breathing 
o New loss of taste or smell 
o Cough 
o Fatigue  
o Muscle or body aches 
o Headache  
o Sore throat 
o Congestion or runny nose 
o Nausea or vomiting 
o Diarrhea   
* FDA Development and Licensure of Vaccines to Prevent COVID-19 guidance [33]. 
Subjects will also be messaged up to twice a week to provide a yes or no response to 
having COVID-19 symptoms. For both of the trial vaccinations, messaging will not begin 
until 4 days after vaccination to avoid confusing vaccine-associated reactions occurring 
during this time period (e.g., fever, chills, headache, fatigue, myalgia) with potential 
COVID-19 symptoms.   
Those who report symptoms either at the site visit or by phone call, or respond “yes” to 
having symptoms by messaging, will be contacted by trial staff for a follow-up phone 
interview if the Investigator considers the symptoms could potentially indicate a COVID-19 
case. The trial staff will use a scripted interview (in which he/she has been trained on) to 
collect information about the subject’s medical condition, which will be used to determine 
the probability of the subject having COVID-19. The interview script is provided in 
Appendix 6A. If the subject is suspected of having COVID-19 illness, he/she will undergo 
testing for SARS-CoV-2 infection (see next section). If suspicion is low, then a subsequent 

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phone call(s) will be performed to assess whether the subject’s illness and symptoms have 
progressed and if the suspicion of COVID-19 has reached a sufficient level to test the 
subject. Based on clinical judgment, phone contact may be made as frequently as daily. 
All symptomatic subjects will be provided a thermometer and oxygen saturation monitor 
for home use. Trial staff will instruct subjects to take their oral body temperature and 
oxygen saturation levels at least 3 to 4 times per day, or whenever they feel symptomatic.  
The testing strategy for SARS-CoV-2 infection is presented in Section 9.5 and Appendix 7. 
Testing will consist of 2 tests: a rapid antigen test performed locally by the trial staff and a 
molecular-based RT-PCR test performed at a designated central laboratory. Depending 
on the Investigator and his/her facility and trial staff, nasopharyngeal swab samples for 
testing will be collected either at the site or at a home visit. The visit to the site or home 
visit by trial staff will be considered an “Illness Visit” and documented as such in the eCRF.   
If the subject is virologically-confirmed to have COVID-19 by a positive RT-PCR test, 
subjects will be followed until resolution of their disease, even if the initial presentation is 
considered as mild. If the subject is hospitalized, the subject’s progress must continue to 
be followed by the Investigator and a discharge summary must be obtained at the end of 
the hospitalization. Information on clinical symptoms and signs, their duration and severity, 
and treatment and outcome of the COVID-19 episode will be documented by trial staff and 
recorded in the eCRF.  
Upon resolution, subjects will continue to be followed in the same manner as those who 
have not presented with COVID-19 (i.e. they will return to routine case surveillance). A 
second episode of COVID-19 in a subject with prior disease will not be counted as a 
primary efficacy case, but will be included in the exploratory objective assessing the 
occurrence of second episodes of COVID-19 in vaccinated subjects.  
If the subject is not virologically-confirmed by RT-PCR testing, he/she will return to routine 
surveillance for COVID-19 as a subject who is naïve to SARS-CoV-2 infection (unless 
determined otherwise by a seropositive test to the N protein).  
Open-label phase: 
In order to decrease the burden for the trial subjects during the open-label phase, when 
only subjects having received CVnCoV (followed or not by AV) are still under follow-up, a 
more restrictive definition will be used for case detection. Subjects will be reminded to 
contact the site if they have any of the of the following symptoms: 
o cough 
o fever (≥ 37.8 ºC) 
o shortness of breath 
o sudden onset of anosmia, ageusia or dysgeusia (new loss of taste or smell). 
During this phase of the trial, subjects are asked to report symptomatic COVID-19 positive 
cases (detected independent of the study procedures) to site, or can be tested as part of 
the study procedures if the subject has limited access to testing. 
Subjects who report symptoms consistent with the eCDC criteria either at the site visit or 
by phone call will be contacted by trial staff for a follow-up phone interview if the 
Investigator considers the symptoms could potentially indicate a COVID-19 case, using 
the definition applicable for the OL phase. The trial staff will use a scripted interview (in 
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condition, which will be used to determine the probability of the subject having COVID-19. 
The interview script is provided in Appendix 6B. If the subject is suspected of having 
COVID-19, he/she will undergo testing for symptomatic COVID-19 (see next section). If 
suspicion is low, then a subsequent phone call(s) will be performed to assess whether the 
subject’s illness and symptoms have progressed and if the suspicion of COVID-19 has 
reached a sufficient level to test the subject. Based on clinical judgment, phone contact 
may be made as frequently as daily.  
The testing strategy for symptomatic COVID-19 is presented in Section 9.5 and 
Appendix 7. Testing will consist of 2 tests: a rapid antigen test performed locally by the 
trial staff and a molecular-based RT-PCR test performed at a designated central 
laboratory. Depending on the Investigator and his/her facility and trial staff, 
nasopharyngeal swab samples for testing will be collected either at the site or at a home 
visit. The visit to the site will be considered an “Illness Visit” and documented as such in 
the eCRF.   
If the subject is virologically-confirmed to have COVID-19 by a positive RT-PCR test, 
subjects will be followed until resolution of their disease, even if the initial presentation is 
considered as mild. If the subject is hospitalized, the subject’s progress must continue to 
be followed by the Investigator and a discharge summary must be obtained at the end of 
the hospitalization. Information on clinical symptoms and signs, their duration and severity, 
and treatment and outcome of the COVID-19 episode will be documented by trial staff and 
recorded in the eCRF.  
Upon resolution, subjects will continue to be followed in the same manner as those who 
have not presented with COVID-19 (i.e. they will return to routine case surveillance).  
If the subject is not virologically-confirmed by RT-PCR testing, he/she will return to routine 
surveillance for COVID-19. 
 
9.2.1.3.2 Non-Routine Surveillance for COVID-19 (Positive Test Outside of the 
Site) 
Subjects will be reminded to contact the site immediately if he/she has a positive 
SARS-CoV-2 test performed outside of the site, and they were symptomatic (COVID-19 
illness) at the time of the test. 
If symptomatic, trial staff will use the scripted interview to collect information about the 
subject’s COVID-19 symptoms and medical condition (interview script in Appendix 6). The 
subject should be retested within 2 weeks to confirm the result. A nasopharyngeal swab 
sample should be sent to the Sponsor-designated central laboratory for RT-PCR testing; 
the RT-PCR test result will be considered definitive as a virologically-confirmed case of 
COVID-19. If the subject is confirmed to have COVID-19, subjects will be followed until 
resolution of their disease, as described above for subjects who were detected by routine 
surveillance.   
If the subject is not virologically-confirmed by RT-PCR testing, he/she will return to routine 
surveillance for COVID-19 as a subject who is naïve to SARS-CoV-2 infection (unless 
determined otherwise by a seropositive test to the N protein).  

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9.2.1.4 Definition of Virologically-confirmed COVID-19 Case 
For the randomized observer-blinded phase, a virologically-confirmed case of 
COVID-19 is defined as a positive SARS-CoV-2 specific RT-PCR test in a person with 
clinically symptomatic disease consisting of 1 or more of the following symptoms (based 
on the same screening symptoms as above): 
o Fever or chills 
o Shortness of breath or 
difficulty breathing 
o New loss of taste or smell 
o Cough 
o Fatigue  
o Muscle or body aches 
o Headache  
o Sore throat 
o Congestion or runny nose 
o Nausea or vomiting 
o Diarrhea   
This definition is intended to capture all severities of virologically-confirmed clinically 
symptomatic cases of COVID-19. As such, COVID-19 cases classified by severity (e.g., 
mild or severe) will be a subset of these cases. See Appendix 3 and Appendix 4 for clinical 
definitions of severe and mild COVID-19, respectively. 
For the open-label phase, virologically-confirmed case of COVID-19 is defined as a 
positive SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic 
disease. 
9.2.1.5 COVID-19 Case Definition for Primary Efficacy Analysis 
(Randomized Observer-blinded Phase only) 
For the primary analysis of efficacy, the case must meet the following criteria: 
• 
Must be a virologically-confirmed case of COVID-19 (of any severity) defined as a 
positive SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic 
COVID-19, as defined above in Section 9.2.1.4. 
• 
Symptom onset must have occurred ≥ 15 days following the second trial vaccination. 
• 
The subject must not have a history of virologically-confirmed COVID-19 illness at 
enrollment or have developed a case of virologically-confirmed COVID-19 before 
15 days following the second trial vaccination (see Section 10.2.3, Efficacy Analysis 
Set [EAS] for more details). 
• 
The subject must have been SARS-CoV-2 naïve at baseline and Day 43 (defined as 
seronegative to N protein in the blood samples collected at baseline and Day 43).  
The primary efficacy cases must be confirmed by the Adjudication Committee.  
Day 43 is 14 days post-second dose which allows the immune response to CVnCoV to 
mature and reach its height following the second dose. As such, COVID-19 case 
ascertainment starting the next day at ≥ 15 days represents the evaluation of full VE of 
CVnCoV against COVID-19.   
9.2.1.6 SARS-CoV-2 Genome Lineage Characterization (Randomized 
Observer-blinded Phase only) 
The characterization of SARS-CoV-2 variants in this trial will be implemented by viral 
whole genome sequencing of nasopharyngeal swab samples of subjects followed by 

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comparison with previously sequenced and typified genomes. Analysis will follow the 
methodology to assign names to lineages of SARS-CoV-2 using a dynamic nomenclature 
[34], using the software pangolin (V2) (https://cov-lineages.org/). The assignment 
algorithm uses machine learning, which offers a classification tree that has been trained 
using over approximately 60,000 SARS-CoV-2 sequences retrieved from GISAID, 
machine learning reconstruction and manual curation for all the lineages. Each base per 
genome was one-hot encoded, which makes every position informative for further 
prediction. Those models are available under cov-lineages/pangoLEARN at github 
(https://github.com/cov-lineages/pangoLEARN/tree/master/pangoLEARN).  
The characterization will be done centrally. The following phylogenetic clustering will be 
applied:  
1. “Wild type” virus: WT/D614G, lineages A.1/B.1 without the VOCs (i.e., without B.1.1.7 
[Alpha], B.1.351 [Beta], B.1.429 [Epsilon]) 
2. “UK” VOC: B.1.1.7 (Alpha)  
3. All other variants of concern. 
In this trial, the primary efficacy endpoint will be based on all strains, the “wild type” virus 
and all SARS-CoV-2 variants (as defined under numbers 1, 2, and 3 above); the key 
secondary efficacy endpoint will be based on the “wild type” virus and the UK variant 
B.1.1.7 (Alpha) (as defined under numbers 1 and 2 above); and the exploratory efficacy 
endpoint will be based on disease caused by individual variants of concern (as defined 
under numbers 2 and 3 above). 
9.2.1.7 Adjudication of COVID-19 Cases (Randomized Observer-blinded 
Phase only) 
An independent Committee of clinicians will be formed to adjudicate COVID-19 cases. 
The Committee will be blinded to the treatment assignment of the subject. The cases will 
be adjudicated by the members with respect to the following questions consistent with the 
endpoints of the trial. 
• 
Is the case a virologically-confirmed case of COVID-19 defined as a positive 
SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19 
with 1 or more of the symptoms listed above in Section 9.2.1.4.  
o Was the RT-PCR test performed at the CureVac designated central laboratory? 
• 
Was the symptom onset of the case ≥ 15 days following the second vaccination? Or 
did it occur before 15 days following the second trial vaccination?  
• 
Was the subject naïve or non-naïve to SARS-CoV-2 at baseline and Day 43? (defined 
as being seronegative or seropositive to the SARS-CoV-2 N protein).   
• 
Was the subject 18 to 60 years of age or ≥ 61 years of age?  
• 
Was the subject asymptomatic? If asymptomatic, was the RT-PCR test positive 
≥ 15 days following the second vaccination or before?  
• 
Was it a mild or severe case of COVID-19 based on the provided clinical definitions? 

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• 
Did the subject require supplemental oxygenation? What type of oxygen support did 
the subject receive? 
• 
Was the subject hospitalized? Was the subject admitted to the intensive care unit?  
• 
Did the subject die? Due to COVID-19 or other cause?   
9.2.2 Asymptomatic Cases of SARS-CoV-2 Infection (Randomized 
Observer-blinded Phase only)  
There will be no active surveillance in this trial for asymptomatic SARS-CoV-2 infections. 
Subjects will be reminded to contact the site immediately if he/she had a positive 
SARS-CoV-2 test performed outside of the site, whether they were symptomatic 
(COVID-19 illness) or asymptomatic at the time of the test. Subjects without symptoms 
may have been tested for several reasons, for example, close exposure to a known person 
with SARS-CoV-2 infection or as part of their routine screening as a healthcare provider. 
If the subject was asymptomatic, trial staff will contact the subject immediately to collect 
information about the positive SARS-CoV-2 test the subject reported. The subject should 
be retested as soon as feasible to confirm the result. A nasopharyngeal swab sample 
should be sent to the Sponsor-designated central laboratory for RT-PCR testing; a positive 
RT-PCR test result will be considered definitive as a virologically-confirmed case of 
SARS-CoV-2 infection. 
If the subject is confirmed to have SARS-CoV-2 infection, the subject will be followed by 
trial staff for at least 2 weeks for the development of any COVID-19 symptoms, to ensure 
that this is an asymptomatic infection. If the subject develops COVID-19, he/she will be 
followed-up as a COVID-19 case. If the subject is confirmed to be asymptomatic, 
information will be collected by the trial staff and documented on the appropriate eCRF 
page.   
If the subject is not virologically-confirmed by RT-PCR testing, he/she will return to routine 
surveillance for COVID-19 as a subject who is naïve to SARS-CoV-2 infection (unless 
determined otherwise by a seropositive test to the N protein).   
9.3 Safety Assessments 
9.3.1 Safety Assessments for Subjects in the Randomized 
Observer-blinded Phase 
The safety and reactogenicity of a 2-dose schedule of CVnCoV will be assessed as 
described below.   
9.3.1.1 Safety Assessments Specific for Subjects in Phase 2b 
• 
Reactogenicity will be assessed daily on each vaccination day and the following 
7 days by collection of solicited local AEs (injection site pain, redness, swelling, and 
itching) and systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, 
nausea/vomiting, and diarrhea) using eDiaries. In addition, other indicators of safety 
will be collected (e.g., body temperature). 
• 
The eDiary will also be used as a memory aid for the subject for the collection of 
unsolicited AEs on each vaccination day and the following 28 days. 

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9.3.1.2 Safety Assessments for All Subjects in Phase 2b and Phase 3 
• 
Medically-attended AEs will be collected through 6 months after the second trial 
vaccination. 
• 
AESIs will be collected throughout the trial. AESIs to be monitored include pIMDs, 
AESIs for SARS-CoV-2 vaccines, and non-serious intercurrent medical conditions that 
may affect the immune response to vaccination.   
• 
SAEs will be collected throughout the trial.  
• 
AEs leading to vaccine withdrawal or trial discontinuation will be collected throughout 
the trial. 
{If the subject does not receive their second trial vaccination, the AE follow-up time 
(6 months) will be determined based on the date scheduled for their second vaccination 
on Day 29}.  
9.3.2 Safety Assessments for Subjects in the Open-label Phase 
• 
AESIs will be collected until EOT (Day 393 of the original Phase 2b/3 schedule). AESIs 
to be monitored include pIMDs and AESIs for SARS-CoV-2 vaccines.   
• 
SAEs will be collected until EOT (Day 393 of the original Phase 2b/3 schedule).  
• 
AEs leading to trial discontinuation will be collected until EOT (Day 393 of the original 
Phase 2b/3 schedule). 
9.3.3 Adverse Events 
Definitions of AEs/SAEs, procedures for recording, evaluating, follow-up and reporting of 
AEs/SAEs/pregnancy/overdose, as well as assessments of intensity and causality of AEs, 
are provided in Appendix 10.   
In Phase 2b, any AEs occurring during the 30-minute observation period after vaccination 
will be recorded in the eCRF. In Phase 3, only those AEs occurring during the 30-minute 
observation period after vaccination which constitute an AESI, medically-attended AE, or 
an SAE will be recorded in the eCRF.  
It is important to note that COVID-19 illness and its complications/sequelae are consistent 
with the efficacy endpoints of the trial and, as such, should not be recorded as AEs. These 
data will be captured on the relevant eCRF pages for cases of COVID-19 illness that occur 
in the trial, which are expected outcomes of the trial. Only for any complications and 
sequelae of COVID-19 illness not mentioned on the COVID-19 summary form in the 
eCRF, an AE form needs to be completed. For consistency, the reporting procedure for 
COVID-19 cases in the open-label phase will remain as in the randomized 
observer-blinded phase despite the efficacy analysis is already completed. COVID-19 
illness and its complications/sequelae as well as all symptoms listed in Section 9.2.1.4 will 
not be reported according to the standard expedited process for SAEs, even though the 
event may meet the criteria for an SAE. However please note that all fatal cases resulting 
from COVID-19 and its complications/sequelae and from all other events will be reported 
as SAEs and need to be reported to the CRO within 24 hours (see section Reporting of 
SAEs in Appendix 10). 

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The reporting period for each type of AE and corresponding concomitant medication use 
is shown in Table 6. 
Table 6 
Reporting Period by Type of Adverse Event 
AE Type 
Days 1 to 
8 
Days 29 
to 36 
Days 1 to 
57 
Day 1 to 
Month 6 a 
Day 1 to 
EOT 
Solicited AEs (Phase 2b) 
X 
X 
 
 
 
Unsolicited AEs 
(Phase 2b) 
 
 
X 
 
 
Medically-attended AEs 
 
 
 
X 
 
SAE/AESI/COVID-19 fatal 
cases 
 
 
 
 
X 
Any vaccination other than 
CVnCoV 
 
 
 
 
X 
Any immune-suppressive/ 
modulating medication or 
other prohibited 
medication 
 
 
 
 
X 
Non-serious intercurrent 
medical conditions that 
may affect the immune 
response to vaccination 
 
 
 
 
X 
AE; adverse event; AESI: AE of special interest; AV: Authorized/licensed vaccines for preventing COVID-19; 
EOT: End of Trial; SAE: serious AE. 
 
9.3.3.1 Solicited Adverse Events 
An eDiary will be distributed to all subjects in Phase 2b for collection of solicited local AEs 
(injection-site pain, redness, swelling and itching) and solicited systemic AEs (fever, 
headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting and diarrhea) on the day of 
vaccination and the following 7 days. Subjects will be given a thermometer to measure 
body temperature orally and a measuring tape to determine the size of local injection site 
reactions. Subjects will be instructed on how to enter the solicited AEs daily for 7 days in 
the eDiary. 
Solicited AEs will be assessed on an intensity scale of absent, mild, moderate and severe 
(Table 7 and Table 8). By definition, all local solicited AEs are considered related to trial 
vaccination. For solicited systemic AEs, the Investigator will assess the relationship 
between trial vaccine and occurrence of each AE and make an assessment of intensity 
for each AE. 
If concerning to the subject or of prolonged duration, solicited Grade 3 AEs should be 
reported to the Investigator immediately. In case of related Grade 3 solicited AEs reported 
for more than 1 day on the eDiary, the subject will be questioned to establish the total 
duration of the AE as exactly as possible. 

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6 months after the second trial vaccination. SAEs and AESIs will be collected throughout 
the trial (see Table 6). 
Medically-attended AEs are defined as AEs with medically-attended visits that are not 
routine visits for physical examination or vaccination, such as visits for hospitalization, an 
emergency room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason. Clinic visits for COVID-19 testing resulting in negative 
test results are not considered as medically-attended visits, if there is no confirmed 
diagnosis and no prescribed concomitant medication. 
The occurrence of AEs (serious and non-serious) will be assessed by non-directive 
questioning of the subject at each visit during the reporting periods specified in Table 6. 
Subjects should be instructed to report immediately any AEs with serious symptoms, 
subjective complaints or objective changes in their well-being to the Investigator or the 
site personnel, regardless of the perceived relationship between the event and the trial 
vaccine. 
The Investigator will assess the relationship between trial vaccine and occurrence of each 
AE/SAE as well as the intensity (see Appendix 10). 
Non-serious intercurrent medical conditions that may affect the immune response to 
vaccination will also be collected throughout the trial. 
9.3.3.3 Adverse Events of Special Interest 
AESIs will be collected throughout the trial.  
The following events will be considered as AESI during this trial: 
• 
AEs with a suspected immune-medicated etiology (pIMDs, see Appendix 8). 
• 
Other AEs relevant to SARS-CoV-2 vaccine development or the target disease 
(see Appendix 9).  
9.3.4 Pregnancies 
Pregnancy is an exclusion criterion for enrollment in this trial, but subjects could potentially 
become pregnant during their active participation in this trial. Refer to Appendix 10 for 
details on the reporting and follow-up of pregnancies. 
9.3.5 Safety Laboratory Assessments 
(See Appendix 5) 
A urine sample (or blood, where required according to local laws and regulations) for 
pregnancy testing will be taken from women of childbearing potential on Day 1 prior to trial 
vaccination to establish eligibility. A urine (or blood, where required according to local laws 
and regulations) pregnancy test will also be performed before the second trial vaccination 
on Day 29 to continue to determine eligibility. 
9.3.6 Vital Signs and Physical Examination 
At all trial visits for Phase 2b (see Table 1 and Table 2) and Phase 3 (see Table 3), vital 
signs (body temperature, systolic/diastolic blood pressure, and pulse) will be recorded in 
a standardized manner after the subject has rested in the sitting position for 5 minutes. 

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At the first trial visit on Day 1 and EOT visit on Day 393 (see Table 1, Table 2, and 
Table 3), a complete physical examination will be performed, including examination of 
general appearance, eyes/ears/nose/throat, head/neck/thyroid, lymph node areas, 
cardiovascular system, lung/chest, abdomen, extremities and neurological examination, 
skin examination, and measurement of weight and height. At all other trial visits, a 
symptom-directed physical examination will be performed at the discretion of the 
Investigator and should include measurement of O2 saturation. 
9.3.7 Medical and Surgical History 
All significant findings and pre-existing conditions present in a subject prior to enrollment 
must be reported on the relevant medical history/current medical conditions screen of the 
eCRF. 
Information should be provided on medical and surgical history and concomitant medical 
conditions specifying those ongoing on Day 1. 
9.3.8 Monitoring Committees 
9.3.8.1 Data and Safety Monitoring Board (DSMB)  
An independent DSMB will be convened to i) oversee the safety of subjects participating 
in this trial, HERALD: CV-NCOV-004; ii) to assess the progress and conduct of the trial; 
iii) to review the cumulative safety data from the trial; iv) to perform an ongoing review of 
AEs of potential safety concern (see Section 5.5.2); and v) to make recommendations to 
the Sponsor whether to continue, modify, or pause the trial (see Section 5.5.2).  
To ensure subject safety on an ongoing basis, a CureVac Safety Review Team reviews 
the safety data on a periodic basis. The outcome of these reviews and discussions are 
then shared with the DSMB Chair.   
In addition to safety data, the DSMB will be asked to review efficacy data at the interim 
analyses or possibly at other time points during the trial for a continued assessment of the 
risk-benefit of the trial. As part of the risk-benefit analysis, the DSMB will periodically 
monitor COVID-19 cases for signals of VDE. The DSMB will also be asked to perform an 
unblinded review(s) of the incidence rate of COVID-19 cases to recommend an 
adjustment(s) in sample size, if needed. 
The DSMB Charter will describe in detail the composition and objectives of the DSMB; the 
responsibilities of the DSMB, CureVac, and CRO; the schedule and conduct of the DSMB 
meetings; and the datasets to be reviewed. The Charter will contain the SAP for the 
DSMB. 
9.3.8.2 Adjudication Committee 
An independent Committee of clinicians will be formed to adjudicate COVID-19 cases for 
assessment of the primary endpoint. The Committee will be blinded to the treatment 
assignment of the subject. The cases will be adjudicated by the members with respect to 
the questions presented in Section 9.2.1.7. The schedule of the meetings and approach 
to adjudication of cases will be defined in the Charter. The Committee Chair will attend 
the DSMB meetings as an ad hoc member.   

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9.4 Immunogenicity Assessments (Randomized Observer-blinded 
Phase only) 
For Phase 2b subjects in the Immunogenicity Subset, the timing of blood sample collection 
for immunogenicity assessments post-vaccination is provided in Table 1. 
For all subjects, the timing of blood sample collection for the determination of serology 
status to natural SARS-CoV-2 infection at baseline and during the trial is provided in 
Table 1, Table 2, and Table 3. 
Because the immunogenicity results would unblind the subject’s treatment assignment, 
the laboratory performing the assays will keep the results in strict confidence. An 
unblinded person, named at the start of the trial and independent of the conduct of the 
trial, will periodically review the quality of the immunogenicity data. This person will 
maintain the results in strict confidence. 
No samples will be obtained at Day 393 after trial unblinding. The Day 57 immunogenicity 
samples in the Phase 2b Immunogenicity Subset will not be analyzed, as Day 57 data 
would not add any relevant scientific value to the already available data.  
9.4.1 Antibody Responses to CVnCoV Vaccination (RBD of S Protein and 
Viral Neutralizing Antibodies) 
Antibody responses to CVnCoV vaccination will only be evaluated in the Phase 2b part of 
the trial and only for subjects in the Immunogenicity Subset at the time points specified in 
Table 1.  
The immune response induced by vaccination with CVnCoV will be evaluated by 2 assays: 
• 
Binding antibodies to the SARS-CoV-2 RBD of the S protein measured in serum by 
immunoassay. 
• 
Viral neutralizing antibodies directed against SARS-CoV-2 measured in serum by a 
functional activity assay.  
9.4.2 Antibody Responses to SARS-CoV-2 (N Protein)  
Antibody responses to SARS-CoV-2 will be evaluated in all parts of the trial and for all 
subjects by measuring the binding antibodies to the SARS-CoV-2 N protein (virus antigen 
not contained in the vaccine construct) at the time points specified in Table 1, Table 2, 
and Table 3, and will be performed by immunoassay.  
As a measure of prior infection with SARS-CoV-2, serological status to the N protein will 
be used for the following: 
1. To determine, retrospectively, if subjects were naïve or non-naïve to SARS-CoV-2 
infection at trial entry and on Day 43.  
a. For evaluation of the efficacy of a 2-dose schedule of CVnCoV in naïve subjects, 
subjects would have to be seronegative to the N protein at baseline and Day 43.  
b. For evaluation of the efficacy after the first dose of CVnCoV in naïve subjects, 
subjects would have to be seronegative to the N protein at baseline only.  

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2. To determine if vaccination with a 2-dose schedule of CVnCoV can reduce infection 
with SARS-CoV-2 by measuring seroconversion to the N protein in seronegative 
subjects during the trial period. As described above in 1a, these subjects would have 
to be seronegative to the N protein at baseline and Day 43.   
9.4.3 Antibody Responses to CVnCoV Vaccination in Subjects Who 
Develop a Case of COVID-19   
For all cases of COVID-19 as per primary adjudication definition that occur in the 
randomized observer-blinded phase, the antibody response to trial vaccination will be 
determined in the subject’s blood samples collected on Day 1 (pre-vaccination baseline), 
Day 43, and Day 211 of the trial if available. These assays will only need to be performed 
for subjects in the Phase 2b part who are not in the Immunogenicity Subset and for Phase 
3 subjects. Subjects in the Phase 2b Immunogenicity Subset will already have these 
performed as part of the cohort. These results will be used to explore correlates of 
protective immunity induced by CVnCoV vaccination.   
9.4.4 Cell-mediated Immunity 
CMI will be evaluated in approximately 200 subjects: 100 who receive CVnCoV and 
100 who receive placebo (first testing of samples will be performed for a subset of these 
subjects and might be extended to 200 subjects if T-cell response is detectable).  
The frequency and functionality of SARS-CoV-2 RBD of S-specific T-cell response after 
antigen stimulation will be determined in PBMC in comparison to baseline. For example, 
ICS to investigate Th1 response and production of Th2 markers will be used to investigate 
whether vaccination induces a Th1 shift from the baseline. Further high profiling T-cell 
immune responses may be investigated with other technologies such as ELISpot or 
CyTOF, analysis of genomic biomarkers or any other established assays. CMI 
assessment will be performed on Day 1 (baseline), Day 29, Day 43, Day 120 and Day 211. 
Note that testing on Day 120 and Day 211 will only be performed on subjects who are 
determined as T-cell responders on Day 29 and/or Day 43. 
9.5 Testing for SARS-CoV-2 Infection 
9.5.1 Virological Confirmation of COVID-19  
See Flow Diagrams in Appendix 6 (A and B) and Appendix 7. 
9.5.1.1 Randomized Observer-blinded Phase 
During the randomized observer-blinded phase of the trial, subjects clinically suspected 
of having COVID-19 will undergo testing for the SARS-CoV-2 virus as described below. 
Sample collection for the tests may be performed at the site or at a home visit by trial staff. 
Ideally, samples should be collected within 5 days of symptom onset. The test results will 
be documented on the appropriate eCRF page.   
• 
Subjects with a clinical suspicion of COVID-19 will undergo testing for SARS-CoV-2 
infection using a rapid antigen test performed at the site with the results provided to 
the subject. Nasopharyngeal swabs will be used to collect samples for the rapid 
antigen test. 

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• 
Regardless of the result of the rapid antigen test, a nasopharyngeal swab sample 
collected at the same time will be sent to a central laboratory to perform a 
SARS-CoV-2 specific RT-PCR test. The RT-PCR test result will be considered 
definitive for SARS-CoV-2 infection. In the unlikely event that only 1 sample can be 
collected from the subject, the sample should be tested by RT-PCR at the central 
laboratory.  
o If the RT-PCR test is negative, but COVID-19 is still suspected based on the 
subject’s exposure history and clinical presentation, another nasopharyngeal swab 
sample should be taken as soon as feasible and sent to the central laboratory for 
RT-PCR testing. The RT-PCR retest result will be considered definitive for 
SARS-CoV-2 infection. 
Subjects who are negative for all testing will be considered naïve to SARS-CoV-2 
infection. In the unlikely case that a subject tests positive by the rapid antigen test but 
negative by RT-PCR, the subject will still be considered naïve without a positive 
virological confirmation by RT-PCR (unless determined otherwise by a seropositive 
test to the N protein).  
9.5.1.2 Open-label Phase 
In the open-label phase, subjects should report diagnosis of symptomatic COVID-19 
positive cases to the site. For countries/sites with limited access to COVID-19 testing, 
subjects with clinical symptoms still can call the sites and be invited for testing on site at 
the investigator discretion in the best interest of the subject. A nasopharyngeal swab 
sample will be collected and sent to a central laboratory to perform a SARS-CoV-2 specific 
RT PCR test only if the result of the rapid antigen test is positive. 
9.5.2 Confirmation of a Positive Test for SARS-CoV-2 Infection Performed 
Outside of the Site   
See Section 9.2.1.3.2 and Section 9.2.2 for follow-up of symptomatic subjects who report 
a positive test for SARS-CoV-2 infection performed outside of the site.   
For symptomatic subjects according to the eCDC criteria who report a positive test for 
SARS-CoV-2 infection which was performed outside of the site, regardless of the type of 
test, the subject should be retested within 2 weeks to confirm the result. A nasopharyngeal 
swab sample should be sent to the central laboratory for RT-PCR testing for confirmation. 
The retest result at the central laboratory will be considered definitive.   

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10 STATISTICAL CONSIDERATIONS 
10.1 Sample Size Determination 
10.1.1 Primary Efficacy Objective 
This is an event-driven trial. Sample size and power considerations are based on the 
primary objective for demonstrating efficacy of CVnCoV in the prevention of 
virologically-confirmed cases of COVID-19 of any severity meeting the primary case 
definition. A group sequential design with 2 interim analyses for cases of COVID-19 of any 
severity demonstrating a high level of efficacy or reaching futility is planned using O’Brien 
and Fleming type error-spending-function [36] and the sample size is based on the test 
for one single proportion (i.e. the proportion of cases in the CVnCoV group, among all 
cases). The group sequential design is based on the any severity COVID-19 endpoint, 
due to the higher case number required to meet this endpoint.  
With an overall 2-sided alpha of 5%, a total of 160 COVID-19 cases of any severity 
(meeting the primary efficacy case definition for COVID-19 of any severity) are needed at 
final analysis, to have a power of 90% to demonstrate the VE is above 30% based on the 
lower bound of the CI for VE, when considering the VE under the alternative hypothesis 
is 60% (i.e. equivalently to demonstrate the proportion of cases in the CVnCoV group is 
below 0.4118, based on the upper bound of the CI for proportion when considering the 
proportion under the alternative hypothesis is equal to 0.2857).  
The 2 interim analyses for high efficacy or futility of the primary objective of COVID-19 
cases of any severity will be performed once 56/111 cases have been accrued and 
adjudicated (approximately 30/60% of cases). 
Assuming an incidence rate of COVID-19 of 0.15% per month in placebo subjects, an 
overall non-evaluable rate of 20% (corresponding to subjects excluded from the EAS and 
drop-outs) and a VE of 60%, 36,500 subjects enrolled over approximately 3 months 
(18,250 per vaccine group) will accrue 160 COVID-19 cases of any severity at 
approximately 9 months after the first vaccination. A lower incidence rate, a longer 
enrollment duration, or a higher non-evaluable rate or VE will delay the acquisition of the 
160 cases and the time of final analysis. Subjects will be randomized to receive either 
CVnCoV or placebo in a 1:1 ratio, stratified by country and age group (18 to 60 and 
≥ 61 years of age).   
10.1.2 Key Secondary Efficacy Objectives 
For 
the 
key 
secondary 
efficacy 
objective 
evaluating 
the 
prevention 
of 
virologically-confirmed moderate to severe cases of COVID-19, a lower number of cases 
will be collected at the time of final analysis compared to the primary endpoint. If 1/3 of 
COVID-19 cases of any severity are moderate to severe, then 53 moderate to severe 
cases can be expected when the total number of COVID-19 cases is 160. The trial will 
then have 91.5% power to obtain a lower limit of the 95% CI of the VE above 20% when 
assuming the true VE is 70%. 
For 
the 
key 
secondary 
efficacy 
objective 
evaluating 
the 
prevention 
of 
virologically-confirmed severe cases of COVID-19, a lower number of cases will be 
collected at the time of final analysis compared to the primary endpoint. Based on an 

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analysis of a large database by Verity et al. [37], approximately 20% of COVID-19 cases 
can be clinically defined as severe or critical, the latter requiring intensive care. 
For 
the 
key 
secondary 
efficacy 
objective 
evaluating 
the 
prevention 
of 
virologically-confirmed moderate to severe cases of COVID-19, a lower number of cases 
will be collected at the time of final analysis compared to the primary endpoint. If 50% of 
COVID-19 cases of any type are “wild type” (i.e., WT/D614G lineages A.1/B.1 without 
VOC B.1.1.7 [Alpha], B.1.351 [Beta], B.1.429 [Epsilon]) and “UK” (B.1.1.7 [Alpha]), then 
80 such cases can be expected when the total number of COVID-19 cases is 160. The 
trial will then have 90.7% power to obtain a lower limit of the 95% CI of the VE above 30% 
when assuming the true VE is 70%. 
With 32 cases of severe COVID-19 (20% of 160 cases), the trial will have 81.5% power to 
obtain a lower limit of the 95% CI of the VE above 10% when assuming the true VE is 
70%. The power increases to 91% if the true VE against severe cases is 75%. With 
complete follow-up of all evaluable subjects for 1 year in this trial, it is expected that the 
additional number of COVID-19 cases accrued post-second vaccination would permit a 
more robust evaluation of CVnCoV efficacy against severe disease. This analysis will be 
presented in the SAP. 
10.2 Populations for Analyses 
In the Safety Analysis Set (SAS), Safety Analysis Set 2 (SAS 2), and the Solicited AEs 
Safety Analysis Set (SASsol), subjects will be analyzed in the group they actually received 
(as “treated”). 
Following the “intent to treat” principle in the Efficacy sets and Per-Protocol Sets, subjects 
will be analyzed in the group to which they were randomized (as “randomized”). 
Additional populations that might be required for the analyses of the results from the 
open-label phase are of exploratory nature and will be defined in an extended SAP. 
An authorized/licensed SARS-CoV-2 vaccine has become available during the trial and 
subjects can request to be unblinded. The censoring rules to avoid any bias for such 
subjects will be described in the SAP (randomized observer-blinded phase only). 
10.2.1 Safety Analysis Set (SAS) 
The SAS will include all subjects randomized in Phase 2b or 3 who received at least 1 dose 
of CVnCoV or placebo.  
The SAS will be the primary population for safety endpoints collected on all subjects (i.e., 
medically-attended AEs, AESI, AEs leading to withdrawal or trial discontinuation, and 
SAEs) and for efficacy objectives assessing efficacy after the first dose. 
10.2.2 Safety Analysis Sets 2 (SAS 2, SASsol) 
As solicited and unsolicited AEs are collected only for Phase 2b subjects, these analyses 
will then be restricted to the Phase 2b subjects.  
The SAS 2 population will include all Phase 2b subjects of the SAS and will be used for 
unsolicited AEs analysis.  

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The SASsol population will include all Phase 2b subjects of the SAS with at least 1 diary 
collection indicating the occurrence or lack of occurrence of solicited AEs and will be used 
for solicited AEs analysis. 
10.2.3 Efficacy Analysis Set (EAS) 
The EAS will include all subjects randomized in Phase 2b or Phase 3 who: 
• 
Received both doses of trial vaccine according to their randomization (2 doses of 
CVnCoV or 2 doses of placebo). 
• 
Had not developed a virologically-confirmed case of COVID-19 before trial entry 
(based on Exclusion Criterion 1) or before 15 days following the second vaccination. 
• 
Had not stopped the trial before 15 days following the second vaccination.  
• 
Were SARS-CoV-2 naïve at baseline and Day 43 (based on seronegativity to N protein 
in the blood sample taken at baseline). 
The EAS will be the primary analysis population for all efficacy endpoints (except for the 
key secondary efficacy endpoint related to seroconversion and for the efficacy endpoints 
evaluating efficacy starting after the first dose). 
10.2.4 Per Protocol Efficacy Set (PPE) 
The PPE set will include EAS subjects who meet all eligibility criteria at trial entry and who 
have no major protocol deviations that would impact the efficacy outcomes as specified in 
the SAP. 
The PPE will be a supportive population for efficacy endpoints (except for the efficacy 
secondary endpoint evaluating efficacy starting after the first dose). 
10.2.5 Per Protocol Immunogenicity Set (PPI) 
The PPI set will include all Phase 2b subjects who belong to the Immunogenicity Subset 
(IS) (i.e. ~first 600 subjects enrolled into each of the 2 age groups in Phase 2b [18-60 and 
≥ 61 years of age]) and who: 
• 
Received both doses as randomized and within the windows defined in the protocol. 
• 
Have no major protocol deviations expecting to impact the immunogenicity outcomes 
as specified in the SAP. 
• 
Have not received medical treatments (such as blood products, immunoglobulin 
therapy) that may interfere with one or both of the proposed immunogenicity 
measurements. 
• 
Have at least 1 blood sample collected starting at 14 days (Day 43) post-second 
vaccination available for analysis. 
The PPI will be the primary analysis population for SARS-CoV-2 RBD of S protein antibody 
responses and SARS-CoV-2 viral neutralizing antibody. 
Subjects to be excluded from the PPE/PPI will be identified and reviewed at the Blinded 
Data Review Meeting held before unblinding of the trial. Major protocol deviations will be 
listed and summarized. 

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compared with subjects who received placebo will be calculated with exact 95%* CI as 
follows: 
VE = 1- RR = 1 - (ARV/ARP) = 1 - {p / r (1-p)} 
where 
ARV = attack rate in vaccinated group = nv/Nv = number of subjects reporting at least 
1 COVID-19 episode in the CVnCoV group / total follow-up time of evaluable subjects in 
the CVnCoV group (number of person-month). 
ARP = attack rate in placebo group = np/Np = number of subjects reporting at least 
1 COVID-19 episode in the placebo group / total follow-up time of evaluable subjects in 
the placebo group (number of person-month). 
RR = relative risk = ARV/ARP 
p = proportion of COVID-19 cases (according to primary case definition) coming from the 
CVnCoV group among all cases = nv/(nv+np). 
r = ratio of total follow-up time of evaluable subjects in the CVnCoV group over total 
follow-up time of evaluable subjects in the placebo group = Nv/Np. 
*Level of CI may be slightly adjusted due to the sequential design (see Section 10.3.8). 
The statistical hypotheses for the primary efficacy endpoint is:  
H0A: VE ≤ 30% versus H1A: VE > 30% 
A is related to COVID-19 cases of any severity  
The trial will be successful if either the lower limit of the exact 2-sided 95% (to be slightly 
adjusted to consider the sequential design) CI of VE endpoint is > 30% for all COVID-19 
cases of any severity or if the lower limit of the exact 2-sided 95% CI of VE endpoint is > 
20% for severe to moderate COVID-19 cases.  
If the 2 interim analyses and the final analysis for COVID-19 cases of any severity are 
performed after 56/111 and 160 cases have been reported, respectively, the 1-sided α-risk 
to consider at the time of final analysis according to O’Brien-Fleming type error spending 
function will be 0.02281 and efficacy will be demonstrated at the final analysis if 53 cases 
or less over 160 are in the CVnCoV group (observed VE ≥ 50.5%). To note, the rule in 
terms of split of cases to demonstrate efficacy can slightly differ if r ≠ 1 (total follow-up time 
different in both groups). 
Sensitivity Analysis 
As a key sensitivity analysis, the time to first-occurrence of virologically-confirmed 
COVID-19 cases (according to primary case definitions) will be analyzed.  
The Kaplan-Meier curves will display the estimated probabilities of not developing 
COVID-19 and log-rank test will be performed. 
The time to first-occurrence of virologically-confirmed COVID-19 (date of symptoms onset) 
will start 15 days following the second vaccination. 

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Subjects who do not develop COVID-19 will be censored at the date of trial termination or 
cut-off date for analysis whichever comes first.  
An additional sensitivity analysis may include a Cox proportional hazards regression 
model adjusted for relevant baseline covariates specified in the SAP.   
A subgroup analysis of region (LATAM vs EUROP) on the primary endpoint will also be 
performed. 
More details on the analysis methods will be described in the SAP. 
10.3.5.2 
Secondary Efficacy Endpoints Analyses 
Statistical testing of the 3 key secondary efficacy endpoints will be performed according 
to the conditional hierarchical testing procedure using the order defined in the 
objective/endpoints sections. Consequently: 
• 
Efficacy of CVnCoV in regard to moderate and severe cases will be demonstrated only 
if there is successful demonstration of the primary efficacy objective. 
• Efficacy of CVnCoV in regard to severe cases will be demonstrated only if there is 
successful demonstration of the primary efficacy objective and the key secondary 
objective on moderate and severe cases. 
• Efficacy of CVnCoV in regard to (RT-PCR positive) cases of “wild type” (i.e., WT/D614G 
lineages A.1/B.1 without VOC B.1.1.7 [Alpha], B.1.351 [Beta], B.1.429 [Epsilon]) and 
“UK” (B.1.1.7 [Alpha]) will be demonstrated only if there is successful demonstration of 
the primary efficacy objective and the key secondary objective on moderate and severe 
cases and severe cases. 
Otherwise, these endpoints will be analyzed as exploratory endpoints without success 
criteria testing. 
To assess the efficacy in the prevention of “wild type” (i.e., WT/D614G lineages A.1/B.1 
without VOC B.1.1.7 [Alpha], B.1.351 [Beta], B.1.429 [Epsilon]) and “UK” (B.1.1.7 [Alpha]) 
cases, moderate to severe, severe disease and asymptomatic infections, similar analyses 
to those performed on the primary efficacy endpoint will be performed. The efficacy will be 
demonstrated if the lower limit of the exact 2-sided 95% CI of VE is above 30% for “wild 
type” (i.e., WT/D614G lineages A.1/B.1 without VOC B.1.1.7 [Alpha], B.1.351 [Beta], 
B.1.429 [Epsilon]) and “UK” (B.1.1.7 [Alpha]) cases, 20% for moderate to severe disease, 
10% for severe disease and above 0% for asymptomatic infections. 
Other secondary efficacy endpoints will be analyzed similarly to the primary efficacy 
endpoint but no formal testing will be performed for those endpoints. For efficacy after the 
first dose, the time to first-occurrence of virologically-confirmed COVID-19 (date of 
symptom onset) will start after the first vaccination. The BoD will be analyzed using 
2 different scoring systems. Both BoD scoring systems place more weight on efficacy 
against severe COVID-19 or severe disease as reflected by hospitalization or death. In 
addition, VE and associated CI will be calculated for each of the BoD categories. 
10.3.5.3 
Exploratory Efficacy Endpoints Analyses 
The proportions of COVID-19 cases of any severity caused by identified SARS-CoV-2 
VOCs and mild, moderate, and severe COVID-19 cases (according to primary case 
definition) among all cases will be summarized by group.  

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Description of frequencies and percentages will be provided by group for subjects who:  
• 
Need supplemental oxygenation due to COVID-19. 
• 
Need mechanical ventilation due to COVID-19. 
• 
Are hospitalized due to COVID-19. 
• 
Died due to COVID-19.  
• 
Died due to any cause.  
This will be done for events occurring ≥ 15 days following the second trial vaccination (full 
VE) and then for events occurring at any time after the first trial vaccination.  
The VE in the prevention of first episodes of virologically-confirmed cases of COVID-19 of 
any severity will be reassessed on all subjects whatever their serological status at baseline 
for cases occurring ≥ 15 days following the second trial vaccination and then for all cases 
occurring after the first dose. 
Finally, the number and percentage of subjects who developed a second episode of 
COVID-19 will be displayed by group. 
10.3.6 Secondary and Exploratory Immunogenicity Analysis 
No formal hypothesis on immunogenicity will be tested. Descriptive statistics for the 
immunogenicity endpoints will be provided for each vaccine group and overall, and by 
vaccine group and age groups. Data will be presented after each vaccine dose.  
The following analyses will be performed for antibody levels to the SARS-CoV-2 RBD of 
S protein and for neutralizing antibodies overall and separately in subjects seronegative 
at baseline and in subjects seropositive at baseline: 
• 
Geometric mean titers (GMTs) will be summarized with their 95% CI at each blood 
sampling time point.  
• 
The Fold Change (FC) from baseline will be computed for each subject and Geometric 
mean of FC (GMFC) will be displayed with their 95% CI at each blood sampling time 
point after baseline.  
Non-detectable antibodies will be arbitrary replaced by half of the detection cut-off for GMT 
and GMFC computations purpose. 
For each readout, the number and percentage of subjects SARS-CoV-2 seronegative at 
baseline for whom a seroconversion is observed will be summarized and presented at 
each blood sampling time point after baseline with exact 95% CI. Seroconversion is 
defined as detectable antibodies in the serum.  
Percentages of subjects seroconverting for SARS-CoV-2 RBD of S protein antibodies and 
SARS-CoV-2 neutralizing antibodies will be summarized. The frequency of immune cell 
populations induced by the vaccine will be summarized. Further characterization of the 
T-cell immune response may be done with other technologies like ELISpot, CyTOF and/or 
analysis of genomic biomarkers. 
Additional immunogenicity analyses including graphs will be described in the SAP as 
applicable.   

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10.3.7 Safety Analysis 
No formal statistical testing of safety data is planned. 
The descriptive safety analyses will be performed overall by vaccine group, by age group 
and vaccine group, and by serostatus and vaccine group. 
For the open-label phase, applicable descriptive analyses will also be performed by 
cohort.  
Solicited AEs: The frequencies and percentages of subjects experiencing each solicited 
local and systemic AE within 7 days after each vaccination will be presented by intensity 
and overall. For subjects with more than 1 episode of the same AE within 7 days after a 
vaccination, the maximum intensity will be used for tabulations. Similar tabulations will be 
performed for solicited systemic AEs by relationship to trial vaccination. Solicited local AEs 
will be by definition considered as related to the trial vaccine. Time to onset (in days) and 
duration (in days) will also be summarized for each solicited local and systemic AEs. 
Summary tables showing the occurrence of at least 1 local or systemic solicited AE within 
7 days after each vaccination will also be presented. 
Unsolicited AEs: Unsolicited AEs including SAEs and AESIs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) by System Organ Class (SOC) and 
Preferred Term (PT).  
The frequency and percentage of subjects reporting each unsolicited AE within the 
28 days after each vaccination and overall will be tabulated at the SOC and PT levels.  
Similar tables will be provided for: related unsolicited AEs, Grade 3 or higher unsolicited 
AEs, medically-attended AEs that occur within 6 months after the second trial vaccination, 
SAEs, related SAEs, AESIs, related AESIs, AEs leading to withdrawal or trial 
discontinuation, and SAEs resulting in death through 1 year after the second trial 
vaccination. 
When an AE occurs more than once for a subject within the 28 days post 1 vaccination, 
the maximal severity and strongest relationship to the vaccine group will be counted.  
Only AE post first vaccination will be considered in the summary tables. AE starting prior 
to the first vaccination will be recorded as medical history. 
Data listings of fatal and SAEs will be provided by subject.   
Vital signs will be summarized by descriptive statistics at each visit, including change from 
baseline, and a listing will be provided. 
10.3.8 Interim Analysis 
Two interim analyses will be performed for this trial by an unblinded independent 
statistician and reviewed by the DSMB when 56/111 cases of COVID-19 of any severity 
(meeting the primary efficacy case definition) are observed. This analysis will aim to 
assess early high efficacy or futility on the primary efficacy endpoint and will be done on 
the EAS population only. The safety data that is available at this time point will also be 
described.  
For the analysis of early demonstration of high efficacy or futility, cumulative 
O’Brien-Fleming type error spending function [36] is used to provide statistical stopping 

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rules for high efficacy (α-boundaries) and futility (β-boundaries) for the interim analysis, 
based on the information accumulated until that specific interim stage. 
At the interim stage, if the p-value for the test of the primary objective is lower than the 
α-boundary, a high level of efficacy for CVnCoV will be declared. Conversely, 
demonstration of futility will occur if the p-value is higher than the β-boundary. 
The interim analyses are planned to occur when 56/111 cases of COVID-19 of any 
severity have been observed. Table 10 below shows the boundaries for demonstrating 
high efficacy or futility, calculated on a 1-sided p-value scale using the cumulative error 
spending function. At the time of the interim analysis only descriptive statistics such as the 
point estimate of VE and respective 95% CI for key secondary objectives will be displayed, 
no formal testing will be done to protect the overall type one error at the final analyses of 
160 cases. 

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Table 10 
Two Stage Group Sequential Design with Interim Analyses at 56 
and 111 Cases and Final Analysis at 160 Cases 
*Rules in terms of split of cases to demonstrate efficacy/futility can slightly differ if the total number of evaluable 
subjects is unequal in both groups (r ≠ 1).  
If the interim analysis is performed exactly after 56/111 cases have been reported, a 
1-sided p-value lower than 0.00015/0.00707 (i.e. lower limit of the 2-sided 99.99/99.3% CI 
> 30%) will lead to the conclusion of high efficacy, while a 1-sided p-value higher than 
0.66345/0.12356 will result in the demonstration of futility. Otherwise, the final analysis 
will be performed at 160 cases. Similarly, if the number of evaluable subjects is equal in 
both groups, it means that the trial will conclude early high efficacy if 9/32 cases or less 
over 56/111 are coming from the CVnCoV group, while futility of the trial will be 
demonstrated if 25/40 cases or more are coming from the CVnCoV group. 
Of note, the actual boundaries used for decision making would depend on the exact 
number of cases occurring and reported at each analysis (interim and final). 
The boundaries will be applied in a nonbinding way as there are many other factors that 
would be part of the decision-making process.  
10.3.9 Missing Data and Discontinuation 
Analysis of vaccination variables will be done on a valid case basis, i.e., for missing 
observations, no imputation for missing data, such as last observation carried forward, will 
be applied.  
For SARS-CoV-2 RBD of S protein antibodies, concentration values marked as below the 
lower limit of quantification (LLOQ) will be set to 0.5*LLOQ.  
No imputation of missing values will be done for any analysis (except the imputation for 
missing partial dates of AEs and concomitant medication as specified in the SAP).  
Currently no replacement of drop-out subjects is foreseen. 
Reasons for discontinuation from the trial vaccine and trial will be listed and summarized. 
 
Interim Analysis 1 
Interim Analysis 2 
Final Analysis 
Number of Cases 
56 
111 
160 
Efficacy α-Boundary on 
p-value scale (1-sided) 
0.00015 
0.00707 
0.02281 
Futility β-Boundary on p-
value scale (1-sided) 
0.66345 
0.12356 
NA 
Efficacy success criteria* 
Success if ≤ 9 cases 
in CVnCoV group over  
56 cases  
(observed VE ≥ 80.9%) 
Success if ≤ 32 cases 
in CVnCoV group over 
111 cases  
(observed VE ≥ 59.5%) 
Success if ≤ 53 cases 
in CVnCoV group over 
160 cases  
(observed VE ≥ 50.5%) 
Futility* 
Futility if ≥ 25 cases 
in CVnCoV group over  
56 cases  
(observed VE ≤ 19.4%) 
Futility if ≥ 40 cases 
in CVnCoV group over 
111 cases 
(observed VE ≤ 43.7%) 
NA 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Electronic Case Report Forms 
In this trial, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications/vaccines (according to instructions in Section 7.6), medical history and 
physical assessments) will be entered into eCRFs in a timely fashion by the Investigator 
and/or the Investigator’s dedicated site staff, except for the laboratory data, which are 
transmitted to the Sponsor or designee directly. All data entered into the eCRF must be 
verifiable against source documents at the trial site, except eDiary entries of solicited AEs, 
which are automatically integrated into the eCRF. Any changes to the data entered into 
the electronic data capture system will be recorded in the audit trail. 
The Investigator will maintain adequate and accurate records for each subject entered into 
the trial. Source documents such as hospital, clinic or office charts, laboratory reports, trial 
worksheets, and signed informed consent documents are to be included in the 
Investigator’s files along with subject trial records. 
The Sponsor or the CRO will check eCRF entries against source documents according to 
the guidelines of Good Clinical Practice (GCP). The consent form will include a statement 
by which subjects allow the Sponsor or designee, as well as authorized regulatory 
agencies, to have direct access to source data that support data of the eCRF (e.g., subject 
medical files, appointment books, original laboratory records, etc.). The Sponsor or 
designee, bound by secrecy, will not disclose subject identities or personal medical 
information. 
11.2 Audit and Inspection 
The trial site also may be subject to quality assurance audits by the Sponsor or designees. 
In this circumstance, the Sponsor-designated auditor will contact the site in advance to 
arrange an auditing visit. The auditor may ask to visit the facilities where laboratory 
samples are collected, where the vaccine is stored and prepared, and any other facility 
used during the trial. In addition, there is the possibility that this trial may be inspected by 
regulatory agencies, including those of local or foreign governments. If the trial site is 
contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The Investigator and institution guarantee direct access for quality assurance 
auditors and inspectors to all trial documents and source data. 
11.3 Monitoring 
Data for each subject will be recorded in the subject’s eCRF. In accordance with GCP, 
and regulatory requirements, the trial monitor will carry out source document verification 
at regular intervals to ensure that the data collected in the eCRF are accurate and reliable. 
The frequency of monitoring visits will be determined by the rate of subject recruitment. In 
case of travel restrictions and/or prolonged lockdowns due to the COVID-19 pandemic, 
remote source data verification may be performed if allowed by country regulations and 
within the limits established (refer to the Monitoring Plan for details).  

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The compliance with the protocol will be examined with regard to inclusion and exclusion 
criteria, therapies leading to elimination and timing and availability of planned 
assessments. Protocol deviations will be monitored on an ongoing basis during the trial 
and closed before database lock. Protocol deviations will be classified as important or 
non-important. The detailed definitions of important protocol deviations leading to 
elimination of subjects from analysis will be provided in the final version of the SAP and/or 
in the final signed minutes of the data review meeting. 
The monitoring visits also provide the Sponsor with the opportunity to ensure the 
Investigators’ obligations and all applicable International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) and regulatory 
requirements are being met. 
The Investigators must permit the monitor, the IEC, the Sponsor’s and CRO’s auditors 
and representatives from regulatory authorities direct access to all trial-related documents 
and pertinent hospital or medical records for confirmation of data contained within the 
eCRF. Subject confidentiality will be protected at all times. 
An electronic medical record may be the source document; however, the trial site must 
provide a standard operating procedure (SOP) that details review and approval of data 
entries by the Principal Investigator(s) (audit trail). Furthermore, the electronic medical 
record must be compliant with the applicable regulations and with the expectations of each 
country. 
11.4 Data Management and Coding 
All data derived from the trial will remain the property of the Sponsor. The Sponsor 
assumes accountability for actions delegated to other individuals, e.g., the CRO. Data 
management of this trial will be performed by a CRO. The CRO’s responsibilities will 
include setting up a relevant database and data transfer mechanisms, along with 
appropriate validation of data and resolution of queries. Data generated within this clinical 
trial will be handled according to the data management plan and SAP or the relevant SOPs 
of the data management and biostatistics departments of the CRO. 
Trial sites will enter data in the eCRF. Access to the eCRF will be strictly password 
protected and limited to personnel directly participating in the trial. All data entered into 
the eCRF must be verifiable against source documents at the trial site, except for solicited 
AEs recorded in the eDiary (see Section 11.3). The subject’s eDiary entries of solicited 
AEs after vaccination will be considered source data and will be integrated automatically 
in the eCRF. This may include electronic source document verification. Data entered into 
the eCRF will be validated as defined in the data validation plan.  
Medical coding will use MedDRA for concomitant diseases and AEs and WHO Drug 
Dictionary for medications. 
Missing or inconsistent data will be queried to the Investigators for clarification. 
Subsequent modifications to the database will be documented. 

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12 ETHICS 
12.1 Institutional Review Board/Independent Ethics Committee 
Before initiation of the trial at the trial site, the protocol, the ICF, other written material 
given to the subjects and any other relevant trial documentation will be submitted to the 
appropriate IRB/IEC. Written approval of the trial and all relevant trial information must be 
obtained before the trial vaccine is released to the Investigators. Any necessary 
extensions or renewals of IRB/IEC approval must be obtained for changes to the trial such 
as modification of the protocol, the ICF, or other trial documentation. The written approval 
of the IRB/IEC together with the approved ICF must be filed in the trial files. 
The Investigators will report promptly to the IRB/IEC any new information that may 
adversely affect the safety of the subjects or the conduct of the trial. The Investigators will 
submit written summaries of the trial status to the IRB/IEC as required. On completion of 
the trial, the IRB/IEC will be notified that the trial has ended. 
12.2 Regulatory Authorities 
The protocol, name, and trial site of the Investigators, the votes of the IRB(s)/IEC(s), as 
well as other relevant trial documentation will be submitted to the regulatory authorities of 
the participating countries, according to local/national requirements, for review and 
approval before the beginning of the trial. On completion of the trial, the regulatory 
authorities will be notified that the trial has ended. Individual subject medical information 
obtained as a result of this trial is considered confidential.  
12.3 Ethical Conduct of the Trial 
The Investigators and all parties involved in this trial should conduct the trial in adherence 
to the ethical principles based on the current version of the Declaration of Helsinki, GCP, 
ICH guidelines, and the applicable national and local laws and regulatory requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting trial activities that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety and 
well-being of the subjects are protected, consistent with the principles that have their origin 
in the Declaration of Helsinki and that the trial data are credible.  
The Investigators and all trial staff will conduct the trial in compliance with the 
IRB(s)/IEC(s) approved version of this protocol. The rights, safety and well-being of the 
subjects are the most important considerations and prevail over the interests of science 
and society. All personnel involved in the conduct of this trial must be qualified by 
education, training, and experience to perform their assigned responsibilities.  
12.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 
The Investigators are responsible for ensuring that no subject undergoes any trial-related 
examination or activity before that subject has given written informed consent to 
participate in the trial.  

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The Investigator or designated personnel will inform the subject of the objectives, 
methods, anticipated benefits, and potential risks and inconveniences of the trial. The 
subject should be given every opportunity to ask for clarification of any points he does not 
understand and if necessary, ask for more information. At the end of the interview, the 
subject will be given ample time to consider the trial. Subjects will be required to sign and 
date the ICF. After signatures are obtained, the ICF will be kept and archived by the 
Investigator in the Investigator’s trial file. A signed and dated copy of the subject ICF will 
be provided to the subject or his/her authorized representative. 
It should be emphasized to the subject that the participation in the trial is voluntary and 
the subject may refuse to participate or discontinue from the trial at any time, without 
consequences for his/her further care or penalty or loss of benefits to which the subject is 
otherwise entitled. Subjects who refuse to give or who withdraw written informed consent 
should not be included or continue in the trial. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial, a new ICF will be approved by the IECs (and regulatory 
authorities if required). The trial subjects will be informed about this new information and 
re-consent will be obtained. 
An additional signed ICF will be obtained after unblinding from subjects who continue in 
the open-label phase. 

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13 DATA HANDLING AND RECORD KEEPING 
Essential documents are those documents that individually and collectively permit 
evaluation of the trial and quality of the data produced. After completion of the trial, all 
documents and data relating to the trial will be kept in an orderly manner by the 
Investigator in a secure trial file. This file will be available for audits by the Sponsor/CRO 
or inspections by the regulatory agencies. Essential documents should be retained for 
15 years after end of the trial. It is the responsibility of the Sponsor to inform the trial site 
of when these documents no longer need to be retained. The Investigator must contact 
the Sponsor before destroying any trial-related documentation. In addition, all subject 
medical records and other source documentation will be kept for the maximum time 
required by the hospital, institution, or medical practice and in accordance with the national 
requirements. If an Investigator moves, withdraws from the trial, or retires, the 
responsibility for maintaining the records may be transferred to another person who will 
accept responsibility. Notice of transfer must be made to and agreed by the Sponsor. 
In this trial processing of personal data will be carried out on behalf of the Sponsor by 
CRO/the data processor, governed by a contract and strictly according and subject to the 
General Data Protection Regulation (GDPR) and any applicable data protection rules and 
regulations. The Sponsor and the CRO/data processor implement appropriate technical 
and organizational measures to ensure a level of security appropriate to the risk, taking 
into account the state of the art, the costs of implementation and the nature, scope, context 
and purposes of processing as well as the risk of varying likelihood and severity for the 
rights and freedoms of natural persons. Quality control will occur at each stage of data 
handling to ensure that all data are reliable and have been processed correctly. The 
Sponsor will ensure oversight of any trial-related duties and functions carried out on its 
behalf, including trial-related duties and functions that are subcontracted to another party 
by the CRO. 
This trial will be registered on ClinicalTrials.gov in accordance with applicable laws or 
publication policy and may also be registered on other publicly accessible websites as 
necessary. 
13.1 Data Protection 
All information generated in this trial is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the trial unless prior written 
consent is gained from the Sponsor. However, authorized regulatory officials, IRB/IEC 
personnel, the Sponsor, and its authorized representatives are allowed full access to the 
records. All personal details will be treated as confidential by the Investigator and staff at 
the CRO. Prior to the processing, the Sponsor performs an assessment of the impact of 
the envisaged processing operations on the protection of personal data (according to 
Article 35 of the GDPR). 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. All 
personal identifiers according to applicable regulations (e.g., name, phone number) must 
be redacted permanently by the site personnel and replaced with the subject’s unique 
identification number in all records and data before transfer to the Sponsor (or designee). 

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The subject must be informed that his/her personal trial-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject who will be required to give consent for their data to be used as 
described in the informed consent. The subject must be informed that his/her medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities.  
Subjects or their legal representatives may request their medical information be given to 
their personal physician or other appropriate medical personnel responsible for their 
welfare. 
13.2 Amendments to the Protocol 
Amendments to this trial protocol may be made following the procedures specified by local 
laws and regulations. Substantial amendments to this trial protocol may be implemented 
only if the approval of the competent authorities and a favorable opinion of the IRB/IEC(s) 
have been obtained. 
Substantial amendments to the conduct of the clinical trial may arise from changes to the 
protocol or from new information relating to the scientific documents in support of the trial. 
Amendments to the trial are regarded as “substantial” where they are likely to have a 
significant impact on: 
• 
The safety, physical health, and mental integrity of the subjects. 
• 
The scientific value of the trial. 
• 
The conduct or management of the trial. 
• 
The quality or safety of any medicinal product used in the trial. 
If a new event occurs related to the conduct of the trial or the development of the IMP, 
which may affect the safety of the subjects, the Sponsor, and the Investigator will take 
appropriate safety measures to protect the subjects against any immediate hazard. The 
Sponsor will immediately inform the competent authorities and IRB(s)/IEC(s) of the new 
events and the measures taken. 
13.3 Biological Samples and Record Retention 
13.3.1 Biological Samples Retention and Destruction 
Collected specimens (blood) will be processed, stored, and frozen appropriately for 
analysis. The Sponsor has put into place a system to protect subjects’ personal 
information to ensure optimal confidentiality and defined standard processes for sample 
and data collection, storage, analysis, and destruction. Excess biological specimens may 
be further tested with regard to investigation of the vaccine effect and respective required 
assay validation. 
13.3.2 Retention of Trial Records 
Records and source documents pertaining to the conduct of the trial and the distribution 
of the IMP (e.g., ICFs, laboratory slips, vaccination inventory records, and other pertinent 
information) must be retained by the Investigator for a period of at least 15 years. 

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13.4 Clinical Trial Report 
The Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with the clinical trial report according to the applicable regulatory requirements. 
The Sponsor should ensure that this report meets the standards of the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). 
13.5 Publication Policy 
Any publication or scientific communication related to this trial can only take place once 
the manuscript has been reviewed by the Sponsor and once a written agreement between 
the Sponsor and the Investigators has been reached. The Sponsor will comply with the 
requirements for publication of trial results. In accordance with standard editorial and 
ethical practice, the Sponsor will generally support publication of multicenter trials only in 
their entirety and not as individual site data. In this case, a Coordinating Investigator will 
be designated by mutual agreement. Authorship will be determined by mutual agreement 
and in line with International Committee of Medical Journal Editors authorship 
requirements. 

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14 REFERENCES 
1. ICH Guidelines. Available at: http://www.ich.org/products/guidelines.html. Accessed 
12 December 2017. 
2. Li G, Fan Y, Lai Y, et al. Coronavirus Infections and Immune Responses. J Med Virol. 
2020 Jan 25. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25685 
3. Chan JF, Kok KH, Zhu Z, et al. Genomic characterization of the 2019 novel human-
pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting 
Wuhan. Emerg Microbes Infect. 2020 Dec;9(1):221-236. 
4. Wu P, Hao X, Lau EHY, et al. Real-time tentative assessment of the epidemiological 
characteristics of novel coronavirus infections in Wuhan, China, as at 22 January 
2020. 
Euro 
Surveill. 
2020 
Jan;25(3). 
https://www.eurosurveillance.org/content/10.2807/1560-
7917.ES.2020.25.3.2000044#r11 
5. Ren LL, Wang YM, Wu ZQ, et al. Identification of a novel coronavirus causing severe 
pneumonia in human: a descriptive study. Chin Med J (Engl). 2020 Jan 30. 
https://www.ncbi.nlm.nih.gov/pubmed/32004165 
6. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new 
coronavirus 
of 
probable 
bat 
origin. 
Nature. 
2020 
Feb 
3. 
https://www.nature.com/articles/s41586-020-2012-7_reference.pdf 
7. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel 
coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Jan 30. 
pii: 
S0140-6736(20)30251-8. 
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30251-8/fulltext 
8. Ceraolo C, Giorgi FM. Genomic variance of the 2019-nCoV coronavirus. J Med Virol. 
2020 Feb 6. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25700 
9. Baruah V, Bose S. Immunoinformatics-aided identification of T cell and B cell epitopes 
in the surface glycoprotein of 2019-nCoV. J Med Virol. 2020 Feb 5. 
https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25698 
10. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 
(COVID-19) from publicly reported confirmed cases: Estimation and application. Ann 
Intern Med. 2020 Mar 10. 
11. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection 
in China. New England Journal of Medicine. 2020 Feb 28. 
12. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with 
Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Apr 10. 
13. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 
and other coronaviruses. Brain Behav Immun. 2020 Mar 30. 
14. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. Journal of the 
European Academy of Dermatology and Venereology. [cited 2020 Apr 16]. 
https://onlinelibrary.wiley.com/doi/abs/10.1111/jdv.16387 
15. Atri D, Siddiqi HK, Lang J, et al. COVID-19 for the cardiologist: A current review of the 
virology, clinical epidemiology, cardiac and other clinical manifestations and potential 
therapeutic strategies. JACC Basic Transl Sci. 2020 Apr 10. 

Clinical Trial Protocol 
 
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Page 152 of 184 
16. Team TNCPERE. The epidemiological characteristics of an outbreak of 2019 novel 
coronavirus diseases (COVID-19) — China, 2020. CCDCW. 2020 Feb 1;2:1–10. 
17. Deng Y, Liu W, Liu K, et al. Clinical characteristics of fatal and recovered cases of 
coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin 
Med J. 2020 Mar 20. 
18. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with 
SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 
observational 
study. 
The 
Lancet 
Respiratory 
Medicine. 
2020 
Feb 
24. 
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30079-
5/abstract 
19. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) 
[cited 2020 Mar 24]. https://www.who.int/publications-detail/report-of-the-who-china-
joint-mission-on-coronavirus-disease-2019-(covid-19) 
20. Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 
1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, 
Italy. JAMA. 2020 Apr 6. https://doi.org/10.1001/jama.2020.5394 
21. WHO Director-General's opening remarks at the media briefing on COVID-19 - 3 
March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-
remarks-at-the-media-briefing-on-covid-19---3-march-2020 
22. World Health Statistics 2020: Monitoring health for the SDGs, sustainable 
development goals. Geneva: World Health Organization; 2020. Licence: CC BY-NC-
SA 
3.0 
IGO. 
https://apps.who.int/iris/bitstream/handle/10665/332070/9789240005105-
eng.pdf?ua=1 
23. Alberer M, Gnad-Vogt U, Hong HS, et al. Safety and immunogenicity of a mRNA rabies 
vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human 
phase 1 clinical trial. Lancet. 2017;390(10101):1511-1520. 
24. Kübler H, Scheel B, Gnad-Vogt U, et al. Self-adjuvanted mRNA vaccination in 
advanced prostate cancer patients: a first-in-man phase I/IIa study. Journal for 
Immunotherapy of Cancer. 2015;3:26. doi:10.1186/s40425-015-0068-y 
25. Hong HS, Koch SD, Scheel B, et al. Distinct transcriptional changes in non-small cell 
lung 
cancer 
patients 
associated 
with 
multi-antigenic 
RNActive® 
CV9201 
immunotherapy. 
Oncoimmunology. 
2016;5(12):e1249560. 
doi:10.1080/2162402X.2016.1249560 
26. Rausch S, Schwentner C, Stenzl A, Bedke J. mRNA vaccine CV9103 and CV9104 for 
the treatment of prostate cancer. Hum Vaccin Immunother. 2014;10(11):3146-52. 
27. Pallesen J, Wang N, Corbett KS, et al. Immunogenicity and structures of a rationally 
designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci USA. 2017; 
114(35):E7348-E7357. 
28. Fotin-Mleczek M, Duchardt KM, Lorenz C, et al. Messenger RNA-based vaccines with 
dual activity induce balanced TLR-7 dependent adaptive immune responses and 
provide antitumor activity. J Immunother. 2011;34(1):1-15. 
29. Graham B. S., et al. Rapid COVID-19 vaccine development; 2020; Science 
10.1126/science.abb8923. 
https://science.sciencemag.org/content/sci/early/2020/05/07/science.abb8923.full.pdf 
 

Clinical Trial Protocol 
 
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30. Wang J and Zand MS. The potential for antibody-dependent enhancement of 
SARS-CoV-2 infection: Translational implications for vaccine development. Journal of 
Clinical and Translational Science. 2020;1-4. 
31. Global regulatory workshop on COVID-19 vaccine development: Summary Report. 
International Coalition of Medicines Regulatory Authorities (ICMRA), 18 March 2020, 
https://www.pei.de/SharedDocs/Downloads/EN/newsroom-en/hp-news/icrma-
report.pdf?__blob=publicationFile&v=2. Accessed 11 Jun 2020. 
32. Clinical Trial Facilitation Group (CTFG) Recommendations related to contraception 
and pregnancy testing in clinical trials, September 2014. Available at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
33. US Department of Health and Human Services. Food and Drug Administration (FDA). 
Guidance for Industry. Development and Licensure of Vaccines to Prevent COVID-19. 
2020. 
[Available 
from: 
https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/development-and-licensure-vaccines-prevent-covid-19; 
Accessed October 2020]. 
34. Rambaut A, Holmes EC, O’Toole Á, et al. A dynamic nomenclature proposal for 
SARS-CoV-2 
lineages 
to 
assist 
genomic 
epidemiology. 
Nat 
Microbiol. 
2020;5:1403-1407. https://doi.org/10.1038/s41564-020-0770-5. 
35. US Department of Health and Human Services. Food and Drug Administration (FDA). 
Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 2007. [Available from: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegul
atoryInformation/Guidances/Vaccines/ucm091977.pdf; 'Accessed at: March 2019]. 
36. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659-63.   
37. Verity R, Okell LC, Dorigatti I et al. Estimates of the severity of coronavirus disease 
2019: a model-based analysis. Lancet Infect. Dis. 2020;20:669-77.   

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15 APPENDICES 

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Appendix 1 Responsibilities of the Investigator 
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the 
applicable local laws and regulations. 
The Investigator agrees to assume the following responsibilities: 
1. Conduct the trial in accordance with the protocol ICH-E6 (R2), and all the applicable 
local laws and regulations. 
2. Personally conduct or supervise the staff who will assist with the protocol. 
3. Ensure that trial-related procedures including trial specific (non-routine/non-standard 
panel) screening assessments are NOT performed on potential subjects, prior to the 
receipt of written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the trial are 
informed of these obligations. 
5. Secure prior approval of the trial and any changes by an appropriate IEC and 
competent authority. 
6. Ensure that the IEC will be responsible for initial review, continuing review, and 
approval of the protocol. 
7. Ensure that requirements for informed consent, as outlined in ICH-E6 (R2) 4.8 and 
local regulations, are met. 
8. Obtain valid informed consent from each subject and document the date of consent in 
the subject’s medical chart. Valid informed consent is the most current version 
approved by the IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including 
personal health information) that will take place in connection with the trial. If an ICF 
does not include such a subject authorization, then the Investigator must obtain a 
separate subject authorization form from each subject. 
9. Prepare and maintain adequate case histories of all persons entered into the trial, 
including eCRFs, hospital records, laboratory results, etc., and maintain these data for 
a minimum of 2 years following notification by the Sponsor that all investigations have 
been discontinued or that the Regulatory Authority has approved the marketing 
application. The Investigator should contact and receive written approval from the 
Sponsor before disposing of any such documents. 
10. Ensure that clinical data is entered into the eCRFs on the visit day during the staggered 
enrollment phase and within 5 days post-visit for all other visits. 
11.  Allow possible inspection and copying by the Regulatory Authority of GCP-specified 
source documents. 
12. Maintain current records of the receipt, administration, and disposition of Sponsor-
supplied vaccines, and return all unused Sponsor-supplied vaccines to the Sponsor. 
13.  In the event of an SAE, AESI or overdose notify the CRO within 24 hours via 
SAE/AESI/overdose/misuse report form signed by the Investigator. 
14.  Review and provide a signature as approval of the content of the clinical trial report 
(Coordinating Investigator only). 

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Appendix 2 Emergency Procedures 
During and after subjects’ participation in this trial, the Investigator or institution should 
ensure that adequate medical care is provided to subjects who present with any AEs, 
including clinically significant laboratory values related to the administration of the trial 
vaccine. The Investigator or institution should inform subjects when medical care is 
needed for intercurrent illness(es) of which the Investigator becomes aware. 
Emergency equipment for the immediate treatment of allergic/anaphylactic reactions 
(steroids, H1, H2 antihistaminergic agents, intravenous fluids, oxygen, epinephrine and 
equipment for cardiopulmonary resuscitation) must be available at all times for the 
treatment of these events, and trained personnel must be present at all times while 
subjects are being monitored after vaccination. 
The trial site should have immediate access to equipment and appropriately qualified staff 
for resuscitating and stabilizing subjects in an acute emergency (such as cardiac 
emergencies, anaphylaxis, cytokine release syndrome, convulsions, hypotension), and 
ready availability of intensive care unit and other hospital facilities. 

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Appendix 3 Definition of Severe COVID-19  
Severe COVID-19 cases are defined by any one of the following: 
• Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 
breaths per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea 
level* or PaO2/FIO2 < 300 mm Hg) 
* SpO2 should be adjusted according to altitude 
• Respiratory failure (defined as needing high flow-oxygen, noninvasive ventilation, 
mechanical ventilation or ECMO) 
• Evidence of shock (SBP < 90mm Hg, DBP < 60 mmHg, or requiring vasopressors) 
• Significant renal, hepatic, or neurologic dysfunction 
• Admission to ICU 
• Death  
FDA Development and Licensure of Vaccines to Prevent COVID-19 guidance [33]. 
 
 
 

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Appendix 4 Definition of Moderate and Mild COVID-19  
Moderate COVID-19 cases are defined by any one of the following: 
• Shortness of breath or difficulty breathing  
• Respiratory rate ≥ 20 to < 30 breaths per minute 
• Abnormal SpO2 but still > 93% on room air at sea level* 
*SpO2 should be adjusted according to altitude 
• Clinical or radiographic evidence of lower respiratory tract disease  
• Radiologic evidence of deep vein thrombosis (DVT)  
 
Mild COVID-19 cases are defined by the following: 
• Symptomatic AND 
• No shortness of breath or difficulty breathing AND 
• No hypoxemia (SpO2 saturation ≥ 95% on room air at sea level*) AND 
*SpO2 should be adjusted according to altitude 
• Does not meet the case definition of moderate or severe COVID-19  
 
 

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6B: Open-label Phase 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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Appendix 7 SARS-CoV-2 Testing Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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Appendix 8 Potential Immune-Mediated Diseases 
Current list of pIMDs: 
Gastrointestinal disorders:  
o Celiac disease  
o Crohn's disease  
o Ulcerative colitis  
o Ulcerative proctitis  
Liver disorders:  
o Autoimmune cholangitis  
o Autoimmune hepatitis  
o Primary biliary cirrhosis  
o Primary sclerosing cholangitis  
Metabolic diseases:  
o Addison's disease  
o Thyroiditis (including autoimmune [Hashimoto's disease] and subacute thyroiditis) 
o Diabetes mellitus type I  
o Grave's or Basedow's disease  
Musculoskeletal disorders:  
o Antisynthetase syndrome  
o Dermatomyositis  
o Juvenile chronic arthritis (including Still's disease)  
o Mixed connective tissue disorder  
o Polymyalgia rheumatic  
o Polymyositis  
o Psoriatic arthropathy  
o Relapsing polychondritis  
o Rheumatoid arthritis  
o Scleroderma, including diffuse systemic form and CREST syndrome  
o Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter's 
Syndrome) and undifferentiated spondyloarthritis  
o Systemic lupus erythematosus  
o Systemic sclerosis  
Neuro-inflammatory disorders:  
o Acute disseminated encephalomyelitis, including site specific variants (e.g., 
non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis)  
o Cranial nerve disorders, including paralyses/paresis (e.g., Bell's palsy)  
o Guillain-Barré syndrome, including Miller Fisher syndrome and other variants  
o Immune-mediated peripheral neuropathies, Parsonage-Turner syndrome and 
plexopathies, including chronic inflammatory demyelinating polyneuropathy, 
multifocal motor neuropathy, and polyneuropathies associated with monoclonal 
gammopathy  
o Multiple sclerosis  
o Narcolepsy  
o Optic neuritis  
o Transverse Myelitis  

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Skin disorders:  
o Alopecia areata  
o Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis 
herpetiformis  
o Cutaneous lupus erythematosus  
o Erythema nodosum  
o Morphoea  
o Lichen planus  
o Psoriasis  
o Sweet's syndrome  
o Vitiligo  
Vasculitides:  
o Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and 
temporal arteritis  
o Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, 
Kawasaki's disease, microscopic polyangiitis, Wegener's granulomatosis, 
Churg-Strauss syndrome (allergic granulomatous angiitis), Buerger's disease 
thromboangiitis obliterans, necrotizing vasculitis and anti-neutrophil cytoplasmic 
antibody (ANCA) positive vasculitis (type unspecified), Henoch-Schonlein purpura, 
Behcet's syndrome, leukocytoclastic vasculitis  
Others:  
o Antiphospholipid syndrome  
o Autoimmune hemolytic anemia  
o Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis 
rapidly progressive, membranous glomerulonephritis, membranoproliferative 
glomerulonephritis, and mesangioproliferative glomerulonephritis)  
o Autoimmune myocarditis/cardiomyopathy  
o Autoimmune thrombocytopenia  
o Goodpasture syndrome  
o Idiopathic pulmonary fibrosis  
o Pernicious anemia  
o Raynaud's phenomenon  
o Sarcoidosis  
o Sjögren's syndrome  
o Stevens-Johnson syndrome  
o Uveitis  
 

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Appendix 9 Adverse Events of Special Interest (AESIs) for 
SARS-CoV-2 Vaccines 
Current list of AESIs {based on Brighton Collaboration via CEPI’s Safety Platform for 
Emergency vACcines (SPEAC) Project}: 
Immunological disorders: 
o Anaphylaxis 
o Vasculitides 
o Enhanced disease following immunization 
o Multisystem inflammatory syndrome in children (MIS) and adults 
Respiratory disorders: 
o Acute Respiratory Distress Syndrome 
Cardiac disorders: 
Acute cardiac injury including: 
o Microangiopathy 
o Heart failure and cardiogenic shock 
o Stress cardiomyopathy 
o Coronary artery disease 
o Arrhythmia 
o Myocarditis, pericarditis 
Hematological disorders:  
o Thrombocytopenia 
Coagulation disorder: 
o Deep vein thrombosis 
o Pulmonary embolus 
o Cerebrovascular stroke 
o Limb ischemia 
o Hemorrhagic disease 
Renal disorders: 
o Acute kidney injury 
Gastrointestinal disorders 
o Liver injury 
o Acute pancreatitis 
Neurological disorders:  
o Generalized convulsion 
o Guillain-Barré Syndrome 
o Acute disseminated encephalomyelitis 
o Anosmia, ageusia 
o Meningoencephalitis 
Dermatologic disorder: 
o Chilblain-like lesions 
o Single organ cutaneous vasculitis 
o Erythema multiforme 
Other: 
o Serious local/systemic AR following immunization 
 

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Appendix 11 Protocol Amendment History 
The trial was initiated using protocol version 1.0. 
 
Protocol version 4.0: 25 November 2021 
This amendment was considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
None of the below changes affect the safety and well-being of subjects; the benefit-risk 
ratio remains favorable.  
Section # and Name 
Description of Important Change 
Brief Rationale 
Throughout 
The trial will be unblinded and an 
open-label phase will be added for 
follow-up of subjects who received 
CVnCoV.  
*In view of the current 
availability of 
authorized/licensed vaccines 
for preventing COVID-19 
(AVs) in the countries where 
the trial is being conducted, 
multiple unblinding requests 
have been granted to trial 
subjects seeking access to 
these AVs under their 
country’s national 
vaccination programs, and 
as of 18 November 2021 
nearly 80% of the trial 
subjects have been 
unblinded and approximately 
49% have already received 
an AV.  
This has led to the decision 
to unblind all subjects in the 
HERALD trial and continue 
safety follow-up of those who 
received CVnCoV, including 
those who received or will 
receive AV after CVnCoV.  
Throughout 
Two cohorts have been defined for 
the open-label phase:  
- 
Cohort A for subjects who 
received at least 1 dose of 
CVnCoV and received/will 
receive an AV after unblinding. 
- 
Cohort B for subjects who 
received at least 1 dose of 
CVnCoV and continue follow-
up as initially planned, without 
receiving further COVID-19 
vaccination. 
Subjects who received placebo do 
not require follow-up after 
unblinding and will discontinue the 
trial. 
Throughout 
Wording has been added to 
paragraphs and headings, or 
subheadings, to specify whether 
the paragraphs/sections are 
applicable to the randomized 
observer-blinded phase, open-label 
phase, or entire trial. 
Clarification. 
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Section # and Name 
Description of Important Change 
Brief Rationale 
Throughout 
Addition of WHO classification 
names to the SARS-CoV-2 strains. 
Update. 
Protocol approval 
signature page 
Name of Medical Responsible 
Person has been modified 
Administrative change. 
Coordinating 
Investigator signature 
Addition of a specific signature 
page for the Coordinating 
Investigator 
Administrative change. 
SAE Hotline and 
Medical Monitor 
contacts 
Display of Medical Monitors contact 
details has been modified 
To clarify that the contact 
details are for the Medical 
Monitoring Support Center 
Synopsis, 3.1.6 Trial 
Rationale, 5.2 Scientific 
Rationale for Trial 
Design 
Wording addition in the trial 
rationale regarding the open-label 
phase 
As above* described. 
Synopsis, 4.1.4 Open-
label Objectives, 4.2.4 
Open-label Endpoints 
Addition of objectives and 
endpoints for the open-label phase. 
As above* described. 
Synopsis, 4.1.2 
Secondary Objectives, 
4.2.2 Secondary 
Endpoints, 4.3 
Estimands, 5.1.1 
Randomized Observer 
blinded Phase 2b 
Design and Objectives, 
10.2.4 Efficacy Analysis 
Set for Seroconversion 
(EASS), 10.3.5.2 
Secondary Efficacy 
Endpoints Analyses 
Removal of key secondary 
objective and endpoint regarding 
seroconversion to the N protein of 
the virus. 
The result of this analysis is 
not relevant in the current 
situation for CVnCoV and 
with many subjects having 
received an AV (as above* 
described). 
Synopsis, 5.1 Overall 
Design, 5.1.3 Open-
label Design and 
Objectives 
Modification of wording and 
addition of new section in the trial 
design regarding the open-label 
phase. 
As above* described. 

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Section # and Name 
Description of Important Change 
Brief Rationale 
Synopsis, 2 Study 
schematic and Schedule 
of Activities, 9.1 
Schedule of Trial 
Assessments and 
Procedures 
Addition/modification of trial visits 
for the open-label phase, addition 
of Schedules of Assessments for 
the open-label phase (Tables 4 and 
5).  
As above* described. 
Synopsis, 4.2.1 Primary 
Endpoints, 4.3 
Estimands, 5.1.2 
Randomized Observer-
blinded Phase 3 Design 
and Objectives, 9.3.1.2 
Safety Assessments for 
All Subjects in Phase 2b 
and Phase 3, 9.3.2 
Safety Assessments for 
Subjects in the Open-
label Phase, 9.3.3.2 
Unsolicited Adverse 
Events and Serious 
Adverse Events, 9.3.3.3 
Adverse Events of 
Special Interest 
Clarification of the follow-up period 
for the randomized observer-
blinded phase of AESIs, SAEs, and 
AEs leading to withdrawal or 
discontinuation throughout the trial 
(until EOT) and addition of safety 
assessments for the open-label 
phase. 
 
As above* described. 
Synopsis, 9.2.1.2.1 
Routine Surveillance for 
COVID-19, 9.5.1 
Virological Confirmation 
of COVID-19, Appendix 
6 
Deletion of bullet about virus 
sequencing for positive RT-PCR 
tests. 
Description of COVID-19 testing 
during the open-label phase, with 
addition of Appendix 6B. 
Sequencing will not be 
performed.  
As above* described. 
Synopsis, 9.2.1.2. 
COVID-19 Cases in the 
Open-label Phase, 
9.2.1.3 Case Detection, 
9.2.1.4 Definition of 
Virologically-confirmed 
COVID-19 Case 
COVID-19 case definition for the 
open-label phase has been added 
according to the eCDC criteria. 
As above* described. 
Synopsis, 6.3 Roll-over 
Criteria for the Open-
label Phase 
Roll-over criteria for the open-label 
phase are defined.  
As above* described. 

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Section # and Name 
Description of Important Change 
Brief Rationale 
Synopsis, Tables 1 to 3, 
4.2.2 Secondary 
Endpoints (Randomized 
Observer-blinded Phase 
only),4.3 Estimands, ) 
Trial Assessments and 
Procedures, 9.4 
Immunogenicity 
Assessment 
(Randomized Observer-
blinded Phase only), 
9.4.3 Antibody 
Responses to CVnCoV 
Vaccination in Subjects 
Who Develop a Case of 
COVID-19   
No samples will be obtained at 
Day 393 after trial unblinding. The 
Day 57 immunogenicity samples 
will not be analyzed.  
Day 393 sampling has been 
removed for the open-label 
phase after unblinding. 
Day 57 data would not add 
any relevant scientific value 
to the already available data.  
 
Synopsis, 4.2.3 
Exploratory Endpoints 
(Randomized Observer-
blinded Phase only), 4.3 
Estimands, 9.4.4 Cell-
mediated Immunity 
Wording added to clarify that for 
exploratory immunogenicity 
endpoints, first testing of samples 
will be performed for a subset of 
these subjects and might be 
extended to 200 subjects if T-cell 
response is detectable. 
Clarification. 
Synopsis, 5.5.2 Pausing 
of the Trial, 9.3.8.1 Data 
Safety Monitoring Board 
Modification of the frequency of 
Safety Review Team reviews to “a 
periodic basis.” 
In case the weekly review 
may not be maintained 
during the open-label phase. 
Synopsis, 10 Statistical 
considerations 
Wording added regarding statistical 
analysis for the open-label phase, 
to be performed by cohort and to be 
defined in an extended SAP. 
As above* described. 
3.1.2 COVID-19  
Addition of aerosol particles 
(inhalation) as SARS-CoV-2 
method of transmission. 
Update. 
3.1.3 Development of 
CVnCoV 
Wording modified to indicate that 
currently there is one licensed 
vaccine. 
Update. 

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Section # and Name 
Description of Important Change 
Brief Rationale 
3.1.4 HERALD Phase 
2b/3 Results, 3.1.5 
CVnCoV and 
Authorized/ Licensed 
Sars.CoV.2 Vaccines 
New sections with results from the 
HERALD trial and data about 
administering an AV after CVnCoV. 
Update. 
3.2.1 Known Potential 
Risks 
Addition of reference to the 
Investigator Brochure for updated 
safety and immunogenicity data 
from currently ongoing CVnCoV 
trials. 
Update. 
4.3 Estimands 
Corrections made in the estimands 
table according to SAP, and 
addition of estimands for the open-
label endpoints. 
Correction and as above* 
described. 
5.4 End of Trial 
Definition 
Wording addition to account for 
placebo subjects who withdraw 
after unblinding. 
As above* described. 
7.1.2.3 Authorized 
Vaccines 
New section/wording addition to 
describe current availability of AVs 
and access for trial subjects. 
As above* described. 
7.3.3.2 Trial Unblinding 
New section to describe trial 
unblinding. 
As above* described. 
7.6.1 Permitted 
Medications/ Vaccines 
During the Trial, 7.6.2 
Prohibited Medications/ 
Vaccines During the 
Trial, 8.1 
Discontinuation of Trial 
Vaccine Administration 
Wording addition to clarify 
allowance of AVs after unblinding. 
As above* described. 
8.2 Withdrawal from the 
Trial 
Wording addition to indicate that 
after unblinding, placebo subjects 
will be withdrawn from the trial. 
As above* described. 
9 Trial Assessments 
and Procedures 
Wording addition to allow visits to 
be replaced with phone calls if 
suitable for the subject. 
As above* described. 

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Section # and Name 
Description of Important Change 
Brief Rationale 
9.1.1.10, 9.1.2.10, 
9.1.3.7. End Of trial 
Clinic Visit: Day 393  
Deletion of wording about Day 393 
samples and about participation in 
the 1-year Extension Study. 
As above* described. 
9.1.4 Open-label phase 
New section to describe procedures 
during the open-label phase. 
As above* described. 
9.2.1.3.2 Non-Routine 
Surveillance for COVID-
19 (Positive Test 
Outside of the Site), 
9.5.2 Confirmation of a 
Positive Test for SARS-
CoV-2 Infection 
Performed Outside of 
the Site   
Change of timing for confirmation 
retest to 2 weeks. 
Time window added to avoid 
retest occurring after end of 
trial. 
9.3.3 Adverse Events 
Explanation added for reporting of 
COVID-19 complications/sequelae. 
Clarification and as above* 
described. 
9.3.3.3 Adverse Events 
of Special Interest 
Deletion of sentence about 
intercurrent medical conditions. 
These are not adverse 
events of special interest and 
the sentence is already in 
previous section. 
11.3 Monitoring 
Wording added about remote 
source data verification on this trial.  
This is occurring due to the 
pandemic and should be 
noted in the protocol. 
12.4 Informed Consent 
Wording added to indicate that 
subjects continuing in the open-
label phase will sign a new ICF 
after unblinding.  
As above* described. 
Appendix 6 Flow 
Diagram for COVID-19 
Case Interview 
Addition of flowchart for the 
open-label phase. 
As above* described. 
Appendix 8 Potential 
Immune-Mediated 
Diseases 
Lists of potential immune-mediate 
diseases has been updated. 
Safety review meeting 
decision. 

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Section # and Name 
Description of Important Change 
Brief Rationale 
Appendix 9 Adverse 
Events of Special 
Interest (AESIs) for 
SARS -CoV-2 Vaccines 
Lists of AESIs has been updated. 
Safety review meeting 
decision. 
Appendix 10 Adverse 
Events: Definitions and 
Procedures for 
Recording, Evaluating, 
Follow up, and 
Reporting 
Wording added regarding events 
that do not meet the AE definition 
and aspects of pregnancy 
reporting. 
Clarification. 
 
 
Protocol version 3.0: 29 March 2021 
This amendment was considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
None of the below changes affect the safety and well-being of subjects; the benefit-risk 
ratio remains favorable.  
Section # and 
Name 
Description of Important Change 
Brief Rationale 
Throughout 
The co-primary objective (and 
corresponding endpoint) regarding 
the efficacy of CVnCoV in the 
prevention of moderate to severe 
COVID-19 was changed to a 
secondary objective. 
Subsequently, the corresponding 
statistical calculations were also 
updated. 
It is now generally accepted that 
a vaccine that protects against 
disease of any severity, will also 
(or even better) protect against 
more severe disease, therefore 
reducing the need to maintain 
this as a primary endpoint and 
thereby preserving the alpha. 
Throughout 
Addition of a key secondary efficacy 
objective (and corresponding 
endpoint) to demonstrate the efficacy 
of CVnCoV in the prevention of 
COVID-19 caused by the “wild type” 
(i.e., WT/D614G lineages A.1/B.1 
without VOC B.1.1.7, B.1.351, 
B.1.429) and “UK” (B.1.1.7) strain. 
Various strains have been 
identified since the original 
protocol and the efficacy to each 
individual strain should also be 
evaluated. 

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Section # and 
Name 
Description of Important Change 
Brief Rationale 
Throughout 
Addition of an exploratory objective 
(and corresponding endpoint) to 
demonstrate the efficacy on any other 
strains. 
Various strains have been 
identified since the original 
protocol and the efficacy to each 
individual strain should also be 
evaluated. 
Throughout 
Decrease in the number of subjects 
needed for exploratory 
immunogenicity from 400 to 200. 
These assessments will only be 
performed in 200 subjects in the 
Immunogenicity Subset from 
selected sites in Europe. 
Synopsis and 
6.2 Exclusion 
Criteria 
Addition of anabolic steroid use. 
Clarification 
Synopsis and 
9.1 Trial 
Assessments and 
Procedures 
Increase of 38 mL in maximum blood 
volume. 
Addition of a genomic biomarker 
(6 mL) and CMI (32 mL) sample 
on Day 120 for subjects in the 
Immunogenicity Subset. 
Tables 1, 2, and 3 
Addition of footnotes regarding 
concomitant medication. 
Clarification 
Tables 2 and 3 
and 9.1 Schedule 
of Trial 
Assessments and 
Procedures 
Removal of cell-mediated immune 
response and genomic biomarkers 
sampling. 
These assessments will only be 
performed in 200 subjects in the 
Immunogenicity Subset from 
selected sites in Europe. 
9.2.1.4 
SARS-CoV-2 
Genome Lineage 
Characterization 
New section to detail the different 
strains that will be investigated in this 
trial. 
To pre-specify the phylogenetic 
clustering that will be used. 
9.3.3 Adverse 
Events and 
Appendix 10 
Addition of instruction that any 
COVID-19 cases leading to death 
should be reported as SAEs and in 
accordance with SAE reporting 
procedures. 
Clarification 
Throughout 
Minor editorial and document 
formatting revisions. 
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Protocol version 2.0: 17 February 2021 
This amendment was considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
None of the below changes affect the safety and well-being of subjects; the benefit-risk 
ratio remains favorable.  
Section # and 
Name 
Description of Important Change 
Brief Rationale 
Throughout 
The 1-year Extension study was 
removed from this protocol. 
It is now considered a separate 
trial, CV-NCOV-004Ext 
Throughout 
Subjects who report to have 
COVID-19 symptoms will only be 
followed up if the Investigator 
considers the symptoms to be related 
to COVID-19. 
Clarification 
Throughout 
Guidance added for subjects who 
request to be unblinded due to being 
eligible to receive an 
authorized/licensed vaccine. 
Several vaccine candidates have 
been approved for emergency 
use since the original protocol 
Throughout 
Text regarding sample size adapted 
to apply also if the case accrual rate 
is higher than expected; in which 
case the DSMB may recommend a 
decrease in sample size. 
Clarification 
Throughout 
Instructions added not to record 
COVID-19 as an AE. 
Clarification 
Throughout 
More text added to record all AEs 
only during the defined reporting 
period for the specific type of AE. 
Clarification 
Synopsis 
Name of coordinating investigator 
was added. 
Informational 

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Section # and 
Name 
Description of Important Change 
Brief Rationale 
Synopsis, Tables 
1, 2, and 3, and 
9 Trial 
Assessments and 
Procedures 
Maximum blood volume updated 
based on changes in assessments; 
removed from the schedule of 
activities tables and added to 
Section 9. 
Editorial 
Synopsis and 
4.1.1 Primary 
Objectives 
The secondary objective regarding 
reactogenicity for the Phase 2b part 
was changed to a primary objective. 
Based on feedback from 
Regulatory Authorities 
Synopsis and 
4.2.1 Primary 
Endpoints 
Secondary safety endpoints moved to 
primary. 
To correspond with the 
objectives 
Synopsis and 6.1 
Inclusion Criteria 
All pregnancy tests to be done in 
serum (instead of urine) where 
required by local laws. 
To adhere to local laws and 
regulations 
Synopsis and 
9.5.1 Virological 
Confirmation of 
COVID-19 
Disease 
Instructions added that gene 
sequencing should be performed for 
the S protein in subjects with positive 
RT-PCR tests performed at the 
central laboratory. 
To identify mutations in this 
protein 
Tables 1, 2, and 3 
Blood volume for pregnancy tests 
added and clarification that all 
pregnancy tests should be performed 
in blood (and not urine) if required by 
local laws and regulations. 
To adhere to local laws and 
regulations 
Tables 2 and 3 
CMI and genomic biomarkers added 
as an assessment in any part of the 
trial. 
Subjects in these subsets do not 
necessarily have to be part of 
the Immunogenicity Subset 
Tables 1, 2, and 3 
and 7.6 
Concomitant 
Therapy and 
Vaccines 
Instructions added to record 
concomitant medications used to 
treat AEs during the same period as 
the reporting period for the type of 
AE. 
Clarification 

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Section # and 
Name 
Description of Important Change 
Brief Rationale 
5.2 Scientific 
Rationale for Trial 
Design and 5.2 
Justification for 
Dose 
Justification for dose and CMI 
assessments added. 
Based on feedback from 
Regulatory Authorities 
6.3 Vaccine Delay 
Recommendations 
and 8.1 
Discontinuation of 
Trial Vaccine 
Administration 
Guidance added that subjects may 
receive the second trial vaccine dose 
if they develop COVID-19 between 
the first and second doses (after 
being symptom-free for 2 weeks). 
Clarification 
9.1 Schedule of 
Trial Assessments 
and Procedures 
Minor changes made throughout the 
section. 
Clarification 
9.2.1 COVID-19 
Cases 
Definitions for SARS-CoV-2 infection 
(overall and in seronegative and 
seropositive subjects) and subjects 
with a high risk of severe COVID-19 
added. 
Clarification 
11.3 Monitoring 
Instruction that data should be 
collected for all subjects who sign an 
ICF removed. 
Data from screening failures are 
not entered in the electronic data 
capture system 
Appendix 9 
COVID-19 removed as an AESI. 
Correction 
Appendix 10 
Minor changes made for consistency 
with the body of the protocol. 
Clarification 
Throughout 
Minor editorial and document 
formatting revisions. 
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