COVID-19: A Phase 2a, Partially Observer-blind, Multicenter, Controlled, Dose-confirmation Clinical Trial to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in Adults >60 Years of Age and 18 to 60 Years of Age
Phase: PHASE2
Conditions: Coronavirus, Covid19, SARS-CoV-2, Severe Acute Respiratory Syndrome
Sponsor: CureVac

Protocol Number: CV-NCOV-002 
 
Official Title: COVID-19: A Phase 2a, partially observer-blind, multicenter, controlled, dose-confirmation 
clinical trial to evaluate the safety, reactogenicity and immunogenicity of the investigational SARS-CoV-2 
mRNA vaccine CVnCoV in adults >60 years of age and 18 to 60 years of age 
 
NCT Number: NCT04515147 
 
Document Date:  03 December 2021 

 
 
CLINICAL TRIAL PROTOCOL 
COVID-19: 
A Phase 2a, partially observer-blind, multicenter, controlled, dose-confirmation 
clinical trial to evaluate the safety, reactogenicity and immunogenicity of the 
investigational SARS-CoV-2 mRNA vaccine CVnCoV in adults >60 years of age 
and 18 to 60 years of age 
Protocol Number: 
CV-NCOV-002 
Investigational product: 
CV07050101 (referred to as CVnCoV) 
Phase: 
Phase 2a 
Sponsor: 
CureVac AG 
Schumannstrasse 27 
60325 Frankfurt 
Germany 
Short Title: 
Safety, reactogenicity and immunogenicity of CVnCoV in 
adults 
Protocol Version: 
3.0 
Protocol Date: 
03 December 2021 
 
PROTOCOL VERSION HISTORY: 
Version 1.0 dated 23 July 2020 
Version 2.0 dated 20 October 2020 
 
This protocol may not be reproduced or communicated to a third party without the written 
permission of CureVac AG. 
 
 

Clinical Trial Protocol 
 
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PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
COVID-19: A Phase 2a, partially observer-blind, multicenter, controlled, 
dose-confirmation clinical trial to evaluate the safety, reactogenicity and 
immunogenicity of the investigational SARS-CoV-2 mRNA vaccine 
CVnCoV in adults >60 years of age and 18 to 60 years of age 
Protocol Number: 
CV-NCOV-002 
This trial will be conducted with the highest respect for the individual subjects in compliance 
with the requirements of this clinical trial protocol (and amendments), and also in compliance 
with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6 (R2) Good Clinical Practice (GCP): Revised 
and consolidated guidelines [1]. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations. 
Sponsor Signatory 
 
 
 
 
CureVac AG 
 
Signature 
 
Date 
Medical Responsible Person 
 
 
 
CureVac AG 
 
Signature 
 
Date 
Vice President Clinical Operations 
 
 
CureVac AG 
 
Signature 
 
Date 
Statistician 
 
 
 
CureVac AG 
 
 
 
Signature 
 
Date 

Clinical Trial Protocol 
 
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
COVID-19: A Phase 2a, partially observer-blind, multicenter, controlled, 
dose-confirmation clinical trial to evaluate the safety, reactogenicity and 
immunogenicity of the investigational SARS-CoV-2 mRNA vaccine 
CVnCoV in adults >60 years of age and 18 to 60 years of age 
Protocol Number: CV-NCOV-002 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol, including appendices and I will conduct the 
trial as described in compliance with this protocol, GCP, and relevant 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 
 
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SAE hotline and medical monitor contacts 
SAE Hotline 
SAE reporting to PRA Health Sciences by fax or email within 24 hours after discovery: 
SAE Fax-no.: 
 
Email: 
 
Medical Monitor 
The Medical Monitor 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. 
Name of Primary Contact: 
 
Address: 
 
Phone: 
 
Fax: 
 
Email: 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 8 
1 
SYNOPSIS ....................................................................................................................10 
2 
SCHEDULE OF ACTIVITIES ........................................................................................22 
3 
INTRODUCTION ...........................................................................................................26 
3.1 
Background ........................................................................................................26 
3.1.1 Coronaviruses.........................................................................................26 
3.1.2 COVID-19 Disease .................................................................................28 
3.2 
Trial Rationale ....................................................................................................28 
3.3 
Risk/Benefit Assessment ....................................................................................29 
3.3.1 Known Potential Risks ............................................................................29 
3.3.2 Known Potential Benefits ........................................................................31 
3.3.3 Assessment of Potential Risks and Benefits ...........................................31 
4 
TRIAL OBJECTIVES AND ENDPOINTS .......................................................................32 
4.1 
Objectives ..........................................................................................................32 
4.1.1 Primary ...................................................................................................32 
4.1.2 Secondary ..............................................................................................32 
4.1.3 Exploratory .............................................................................................32 
4.2 
Endpoints ...........................................................................................................32 
4.2.1 Primary ...................................................................................................32 
4.2.2 Secondary ..............................................................................................33 
4.2.3 Exploratory .............................................................................................33 
5 
TRIAL DESIGN .............................................................................................................35 
5.1 
Overall Design....................................................................................................35 
5.2 
Change in Dose Level ........................................................................................36 
5.3 
Expansion Cohorts .............................................................................................36 
5.4 
Stopping Rules ...................................................................................................39 
5.4.1 Individual Stopping Rules .......................................................................39 
5.4.2 Trial Suspension Rule .............................................................................39 
5.5 
Scientific Rationale for Trial Design ....................................................................39 
5.6 
Justification for Dose ..........................................................................................40 
5.7 
End of Trial Definition .........................................................................................40 
6 
TRIAL POPULATION ....................................................................................................41 
6.1 
Inclusion Criteria ................................................................................................41 
6.2 
Exclusion Criteria ...............................................................................................42 
6.3 
Vaccine Delay Recommendations ......................................................................43 
6.4 
Failure to Meet Eligibility Criteria ........................................................................44 
7 
TRIAL VACCINE ...........................................................................................................45 
7.1 
Trial Vaccine Administration ...............................................................................45 
7.1.1 Description of the Trial Vaccine ..............................................................45 
7.1.2 Description of the Active Controls ...........................................................45 
7.1.3 Dosing and Administration ......................................................................45 
7.2 
Preparation/Handling/Storage/Accountability .....................................................45 
7.2.1 Preparation .............................................................................................45 
7.2.2 Product Storage and Stability ..................................................................45 
7.2.3 Accountability .........................................................................................45 
7.3 
Randomization and Blinding ...............................................................................46 
7.3.1 Emergency Unblinding ............................................................................46 
7.3.2 Licensed/Authorized Vaccine ..................................................................47 
7.4 
Vaccine Compliance ..........................................................................................47 
7.5 
Misuse and Overdose ........................................................................................47 
7.6 
Concomitant Therapy and Vaccines ...................................................................47 
7.7 
Therapy Leading to Discontinuation ...................................................................47 
7.8 
Treatment After the End of Trial .........................................................................48 
8 
Discontinuation/Withdrawal Criteria ...............................................................................49 

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8.1 
Discontinuation of Trial Vaccine Administration ..................................................49 
8.2 
Withdrawal from the Trial ...................................................................................50 
8.3 
Trial Termination ................................................................................................50 
8.4 
Lost to Follow-Up ...............................................................................................51 
9 
TRIAL ASSESSMENTS AND PROCEDURES ..............................................................52 
9.1 
Safety Assessments ...........................................................................................52 
9.1.1 Adverse Events .......................................................................................52 
9.1.2 Pregnancies ............................................................................................55 
9.1.3 Safety Laboratory Assessments .............................................................55 
9.1.4 Vital Signs, Physical Examination, and ECG ...........................................55 
9.1.5 Medical and Surgical History ...................................................................56 
9.1.6 Safety Monitoring Committees ................................................................56 
9.2 
Immunogenicity Assessments ............................................................................56 
9.2.1 Humoral Immune Response ...................................................................57 
9.2.2 Cell-Mediated Immunity ..........................................................................57 
9.2.3 Innate Immune Response .......................................................................57 
9.3 
Laboratory Testing for COVID-19 Disease .........................................................57 
10 STATISTICAL CONSIDERATIONS ...............................................................................59 
10.1 
Sample Size Determination ................................................................................59 
10.2 
Populations for Analyses ....................................................................................62 
10.3 
Statistical Analyses ............................................................................................63 
10.3.1 General Considerations ..........................................................................63 
10.3.2 Demographic, Medical History and Other Baseline Characteristics .........63 
10.3.3 Trial Vaccine Administration ....................................................................63 
10.3.4 Concomitant Medication and Vaccinations ..............................................63 
10.3.5 Primary Analysis .....................................................................................63 
10.3.6 Missing Data ...........................................................................................65 
10.3.7 Interim Analysis ......................................................................................65 
11 QUALITY CONTROL AND QUALITY ASSURANCE .....................................................67 
11.1 
Electronic Case Report Forms ...........................................................................67 
11.2 
Audit and Inspection ...........................................................................................67 
11.3 
Monitoring ..........................................................................................................67 
11.4 
Data Management and Coding ...........................................................................68 
12 ETHICS .........................................................................................................................69 
12.1 
Independent Ethics Committee ..........................................................................69 
12.2 
Regulatory Authorities ........................................................................................69 
12.3 
Ethical Conduct of the Trial ................................................................................69 
12.4 
Informed Consent ...............................................................................................70 
13 DATA HANDLING AND RECORD KEEPING ................................................................71 
13.1 
Data Protection ..................................................................................................71 
13.2 
Clinical Trial Report ............................................................................................72 
13.3 
Publication Policy ...............................................................................................72 
14 REFERENCES ..............................................................................................................73 
15 APPENDICES ...............................................................................................................76 
 
LIST OF TABLES 
Table 1 
Schedule of Trial Assessments and Procedures ..........................................22 
Table 2 
Trial Groups and Vaccination Schedule .......................................................37 
Table 3 
Intensity Grading for Solicited Local Adverse Events ...................................53 
Table 4 
Intensity Grading for Solicited Systemic Adverse Events..............................54 
Table 5 
Sample Size .................................................................................................60 
Table 6 
Estimate of Number of Subjects with Seroconverting for nCoV Spike Protein 
Antibodies and 95% Credibility Interval ........................................................61 

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Table 7 
Probabilities (in %) for Assumed True Adverse Reaction Rates and for 
Assumed True Rates of Subjects with Seroconverting for nCoV Spike Protein 
Antibodies and Different Sample Sizes ........................................................62 
Table 8 
Protocol-Required Safety Laboratory Assessments .....................................78 
 
LIST OF FIGURES 
Figure 1 
Genome Organization of SARS-CoV-2 Compared with Other 
Betacoronaviruses .......................................................................................27 
 
LIST OF APPENDICES 
Appendix 1 
Responsibilities of the Investigator ...............................................................76 
Appendix 2 
Emergency Procedures ................................................................................77 
Appendix 3 
Safety Laboratory Assessments ...................................................................78 
Appendix 4 
COVID-19 Symptoms Log ............................................................................79 
Appendix 5 
Case Definition for COVID-19 Disease .........................................................81 
Appendix 6 
Trial Governance Considerations .................................................................82 
Appendix 7 
Protocol Changes ........................................................................................83 
Appendix 8 
Potential Immune-Mediated Diseases ..........................................................84 
Appendix 9 
Adverse Events of Special Interest for SARS-CoV-2 Vaccines ....................86 
Appendix 10 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .............................................................................87 
Appendix 11 
Biological Samples and Record Retention ...................................................94 
Appendix 12 
Protocol Amendment History ........................................................................95 
 
 
 

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LIST OF ABBREVIATIONS 
ADE 
Antibody-dependent enhancement 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANA 
Antinuclear antibody 
ARDS 
Acute respiratory distress syndrome 
BMI 
Body mass index 
CCL 
Chemokine ligand 
CEPI 
Coalition for Epidemic Preparedness Innovations 
CI 
Confidence interval 
CMI 
Cell-mediated immunity 
CoV 
Coronavirus 
CRO 
Contract research organization 
CVnCoV 
Investigational SARS-CoV-2 mRNA vaccine 
DDS 
Dose-determining set 
DSMB 
Data and safety monitoring board 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
E 
Envelope 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMT 
Geometric mean titer 
hCG 
Human chorionic gonadotropin 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICS 
Intracellular cytokine staining 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IL 
Interleukin 
IM 
Intramuscularly 
IMP 
Investigational medicinal product 
IP-10 
IFN-γ-induced protein 10 

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IRB 
Institutional Review Board 
iSRC 
Internal safety review committee 
IVRS 
Interactive voice 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 
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 
SOC 
System Organ Class 
TSH 
Thyroid-stimulating hormone 
VDE 
Vaccine-dependent disease enhancement 
WHO 
World Health Organization 

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1 SYNOPSIS 
Name of 
Investigational 
Vaccine: 
CVnCoV 
Sponsor: 
CureVac AG 
Coordinating 
Investigator: 
 
Title of Trial: 
COVID-19: A Phase 2a, partially observer-blind, multicenter, controlled, 
dose-confirmation clinical trial to evaluate the safety, reactogenicity and 
immunogenicity of the investigational SARS-CoV-2 mRNA vaccine CVnCoV 
in adults >60 years of age and 18 to 60 years of age 
Rationale: 
Coronaviruses are a large family of zoonotic 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 
is referred to as COVID-19. The virus spread to different parts of China and 
then globally, and on 12 March 2020 the World Health Organization (WHO) 
announced that the outbreak was characterized as a pandemic.  
In spite of the severity of respiratory disease caused by emerging 
coronaviruses, there is currently no licensed vaccine available for prevention 
of coronavirus-associated disease. In partnership with the Coalition for 
Epidemic Preparedness Innovations (CEPI), CureVac AG is developing a 
new SARS-CoV-2 (messenger ribonucleic acid [mRNA]) vaccine formulated 
with lipid nanoparticles (referred to as CVnCoV). The safety and 
immunogenicity of this vaccine was evaluated for the first time in humans in 
the dose-finding trial CV-NCOV-001. At this time, 6 dose levels (2, 4, 6, 8, 12, 
and 16 µg) have been tested in healthy adults 18 to 60 years of age. 
This second trial was conducted to confirm the safety and immunogenicity of 
CVnCoV at different dose levels in adults >60 years (i.e., 61 years or older) 
when administered according to a 0 (Day 1), 1-month (Day 29) primary 
vaccination schedule. The dose levels to be administered in this trial will be 
selected based on data from the CV-NCOV-001 trial. For this elderly 
population, higher dose levels than the dose levels investigated for adults 
18 to 60 years of age will be considered to address potentially reduced 
immunogenicity in the context of immunosenescence. In addition, the safety 
and immunogenicity of a booster dose of CVnCoV administered at 
approximately 2 months (Day 57) or 6 months (Day 180) after the first dose 
will be evaluated in a subgroup of subjects. 
In order to bridge to the population evaluated in Trial CV-NCOV-001, adults 
18 to 60 years will also be enrolled in this trial. 
Throughout the trial, cases of COVID-19 disease will be identified and 
documented for later potential pooling of cases across trials in the clinical 
development program, such as the CV-NCOV-004 and the CV-NCOV-005 
trials. 
Trial Duration for 
Each Subject: 
Approximately 13 months for each subject 
Phase: 2a 
Objectives: 
Primary 
• 
To evaluate the safety and reactogenicity profile after 1 and 2 dose 
administrations of CVnCoV at different dose levels. 
• 
To evaluate the humoral immune response after 1 and 2 dose 
administrations of CVnCoV. 

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Secondary 
• 
To evaluate the safety and reactogenicity profile after a booster dose 
administration of CVnCoV at different dose levels. 
• 
To evaluate the humoral immune response after a booster dose 
administration of CVnCoV at different dose levels. 
Exploratory 
• 
To evaluate the cell-mediated immune (CMI) response after 1 and 2 dose 
administrations of CVnCoV at different dose levels in a subset of 
subjects. 
• 
To evaluate the innate immune response after the first dose 
administration of CVnCoV at different dose levels in a subset of subjects. 
• 
To identify and assess cases of COVID-19 disease. 
Overall Design: 
This is a Phase 2a, partially blind, active-controlled, dose-confirmation trial to 
assess the safety and immunogenicity of provisionally selected CVnCoV 
dose levels of 6 and 12 µg in an older adult population. The design of the trial 
will allow an increase or decrease in dose based on data from 
Trial CV-NCOV-001 and the initial phase of this trial. An overview of the 
planned number of subjects to be enrolled per trial group and the vaccination 
schedule is provided in Synopsis Table 1. 
Subjects will be recruited independent of their SARS-CoV-2 serology status. 
Their serostatus will be determined retrospectively by a blood sample drawn 
at baseline and analyzed to allow post hoc stratified analyses of subjects who 
are SARS-CoV-2 seronegative or seropositive at baseline. 
Initial Phase 
Subjects will be enrolled in 3 cohorts divided into 6 groups:  
• 
6 µg dose level cohorts 
o 
Group 1 (observer-blind): CVnCoV 6 µg on Day 1 and 6 µg on Day 29 
(in subjects 18 to 60 years of age) 
o 
Group 2 (observer-blind): CVnCoV 6 µg on Day 1 and 6 µg on Day 29 
(in subjects >60 years of age [i.e., 61 years or older]) 
• 
12 µg dose level cohorts 
o 
Group 3 (observer-blind): CVnCoV 12 µg on Day 1 and 12 µg on 
Day 29 (in subjects 18 to 60 years of age) 
o 
Group 4 (observer-blind): CVnCoV 12 µg on Day 1 and 12 µg on 
Day 29 (in subjects >60 years of age [i.e., 61 years or older]) 
• 
Active control cohort 
o 
Group 5 (observer-blind): licensed hepatitis A vaccine on Day 1 and 
on Day 29 (in subjects 18 to 60 years of age) 
o 
Group 6 (observer-blind): licensed pneumococcal vaccine on Day 1 
and on Day 29 (in subjects >60 years of age [i.e., 61 years or older]) 
A subgroup of subjects in Group 3 will receive a booster dose of CVnCoV on 
Day 180 and a subgroup of subjects in Group 4 will receive a booster dose of 
CVnCoV on Day 57 or Day 180, each in an open-label manner. 
The 6 µg and 12 µg groups will be enrolled sequentially, i.e., enrollment in the 
12 µg groups will only be initiated once Groups 1 and 2 have been fully 
enrolled.  
Group 2 (subjects >60 years, 6 µg) will be initiated in 4 sentinel subjects. 
These subjects should be vaccinated at least 60 minutes apart. Safety and 
reactogenicity data reported during an observation period of at least 24 hours 
after vaccination will be collected and reviewed by an internal safety review 
committee (iSRC). In this review, the iSRC will review all available safety 
data, but focus specifically on Grade 3 adverse reactions. Based on this 
review, the iSRC will decide on continuation of enrollment of subjects at this 
dose level. In a next step, 8 additional sentinel subjects will be enrolled. 
Safety and reactogenicity data reported during an observation period of at 
least 24 hours after vaccination will be collected and reviewed by the iSRC. 

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In this review, the iSRC will review all available safety data, but focus 
specifically on Grade 3 adverse reactions.  
The same procedure will be followed for Group 4 (subjects >60 years, 12 µg) 
and the iSRC will decide on continuation of enrollment of subjects at this dose 
level after review of the first 12 sentinel subjects.  
Subjects in the initial phase will be randomized according to a 10:1 ratio to 
receive CVnCoV or the active control in an observer-blinded manner. 
Expansion Cohorts 
Following the initial phase, a separate expansion cohort of 220 subjects aged 
18 to 60 years and 220 subjects aged >60 years (i.e., 61 years or older) will 
be enrolled to be vaccinated on Days 1 and 29. 
Expansion for subjects 18 to 60 years of age may start once the final dose for 
subjects in this age category has been selected based on the data from 
Trial CV-NCOV-001. Expansion for subjects >60 years of age may start once 
the final dose for these subjects has been selected based on data from this 
trial. 
Subjects in the expansion cohorts will be randomized according to a 10:1 ratio 
to receive either the selected dose of CVnCoV or the active control in an 
observer-blinded manner. 
Change in Dose Level 
Other possible dose levels to be administered in this trial will continuously be 
assessed based on the ongoing Trial CV-NCOV-001 in adults aged 18 to 
60 years. If the dose level of 12 µg is considered too reactogenic for adults 
aged 18 to 60 years in the CV-NCOV-001 trial, the dose level in this trial would 
be reduced from 12 µg to 8 µg. 
In case additional dose levels are investigated in this trial, such a dose level 
will be initiated in additional sentinel subjects in the same manner as 
described above.  
In case of any dose increases, the next dose level will only be given to 
subjects once initial data from the previous dose level have been reviewed 
by the iSRC. 
In case the starting dose level is not well tolerated, a decrease in the dose 
level may occur and the lower dose levels will be assessed in the same 
manner as described above.  
 

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Synopsis Table 1 
Trial Groups and Vaccination Schedule 
Cohort 
Age 
(years) 
Group 
Vaccination Schedule 
Blinding 
Primary Doses 
Booster Dose 
Day 1 
Day 29 
Day 57 
Day 180 
CVnCoV 6 µg 
18-60 
Group 1 
(n=11) 
CVnCoV 6 µg 
CVnCoV 6 µg 
- 
- 
Primary doses: 
Observer-blind 
CVnCoV 6 µg 
>60 
Group 2 
(n=12) 
CVnCoV 6 µg 
CVnCoV 6 µg 
- 
- 
Primary doses: 
Observer-blind 
CVnCoV 12 µg 
18-60 
Group 3 
(n=90) 
CVnCoV 12 µg 
CVnCoV 12 µg 
- 
CVnCoV 12 µg 
(n=30) 
Primary doses: 
Observer-blind 
Booster dose: 
Open-label 
CVnCoV 12 µg 
>60 
Group 4 
(n=90) 
CVnCoV 12 µg 
CVnCoV 12 µg 
CVnCoV 12 µg 
(n=30) 
- 
Primary doses: 
Observer-blind 
Booster dose: 
Open-label 
- 
CVnCoV 12 µg 
(n=30) 
Active control 
18-60 
Group 5  
(n=9) 
n=1 against 
Group 1 
Hepatitis A vaccine 
Hepatitis A vaccine 
- 
- 
Observer-blind 
>60 
Group 6 (n=9) 
n=1 against 
Group 2 
Pneumococcal 
vaccine 
Pneumococcal 
vaccine 
- 
- 
Observer-blind 

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Cohort 
Age 
(years) 
Group 
Vaccination Schedule 
Blinding 
Primary Doses 
Booster Dose 
Day 1 
Day 29 
Day 57 
Day 180 
Expansion 
18-60 
n=200 
CVnCoV 12 µg 
CVnCoV 12 µg 
- 
- 
Observer-blind 
n=20 
Hepatitis A vaccine 
Hepatitis A vaccine 
- 
- 
>60 
n=200 
CVnCoV 12 µg 
CVnCoV 12 µg 
- 
- 
Observer-blind 
 
n=20 
Pneumococcal 
vaccine 
Pneumococcal 
vaccine 
- 
- 
 

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Trial Visits/ 
Contacts: 
6 to 9 protocol-scheduled visits on Day 1, Day 2, Day 29, Day 43, Day 57 
(only for subjects receiving the booster dose on Day 57), Day 85 (only for 
subjects receiving the booster dose on Day 57), Day 180, Day 208 (only 
for subjects receiving the booster dose on Day 180), and Day 393 (only 
for subjects receiving the booster dose on Day 180) 
Protocol-scheduled phone contacts on Day 15, Day 30, Day 57 (not 
required for subjects receiving the booster dose on Day 57), Day 58 (only 
for subjects receiving the booster dose on Day 57), Day 181 (only for 
subjects receiving the booster dose on Day 180), and Day 393 (only for 
subjects who did not receive a booster on Day 180) 
2 protocol-scheduled prompts on Day 120 and Day 270 
Collection of 
Blood Samples: 
 The maximum total volume of blood taken over the trial period from any 
subject will be approximately 279 mL (or 435 mL for subjects in who cell-
mediated immunity and cytokines will be assessed) (Table 1).  
Safety 
Assessments: 
Reactogenicity will be assessed daily on each vaccination day and the 
following 7 days via collection of solicited local adverse events (AEs; 
injection site pain, redness, swelling, and itching) and systemic AEs 
(fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, 
and diarrhea) using diary cards (electronic or paper). In addition, other 
indicators of safety will be collected (e.g., body temperature). 
Diaries will also be used for collection of unsolicited AEs on each 
vaccination day and the following 28 days. In addition, subjects will 
receive a prompt (by e.g., a phone call or text message) to verify whether 
the subjects had any health concerns since the last visit. 
Subjects with any Grade 3 solicited or unsolicited AEs reported 
electronically by the subject will be contacted by the Investigator, and 
subjects who did not enter any diary information will be prompted and 
then contacted in case of non-response within 24 hours. Unscheduled 
visits will be performed when deemed necessary for safety assessments 
or to ensure data integrity. 
SAEs, adverse events of special interest (AESIs), and AEs leading to 
vaccine withdrawal or trial discontinuation will be collected throughout the 
trial. Non-serious intercurrent medical conditions that may affect the 
immune response to vaccination will also be collected throughout the trial. 
AESIs to be monitored throughout the trial include potential 
immune-mediated diseases (pIMDs) and COVID-19 disease.  
In case of confirmed COVID-19 disease, a disease-specific diary will be 
completed by the subject and/or the treating health care provider.  
Laboratory 
Testing for 
COVID-19 Disease: 
As a baseline assessment, a reverse transcription polymerase chain 
reaction (RT-PCR) test for SARS-CoV-2 will be performed in all subjects. 
Testing will be done for SARS-CoV-2 spike protein to evaluate vaccine-
induced immune responses as well as for SARS-CoV-2 N-antigen (not 
contained in the vaccine construct) to evaluate immune responses 
induced by natural infection. This will allow to retrospectively define the 
subject’s serology status, including the baseline status for the 
by-group/cohort analysis. 
Subjects will be prompted once or twice per week to report if the subjects 
have any of the following symptoms: cough, shortness of breath, difficulty 
breathing, fever ≥37.8°C, fatigue, myalgia, chills, wheezing, nasal 
congestion, runny nose, sore throat, headache, diarrhea, or new olfactory 

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and taste disorders. A COVID-19 symptoms log listing these symptoms 
will be provided to subjects with RT-PCR-confirmed COVID-19 disease. 
If any of these symptoms are observed, the Investigator will collect 
appropriate samples as soon as feasible and locally perform RT-PCR 
and/or serological assays as locally available to evaluate for infection with 
SARS-CoV-2. If a serological assay is performed, this should look at 
antibodies against N protein antigen, but not to antibodies against Spike 
viral antigen, as this is part of the vaccine. These assays will be repeated 
7 to 14 days after the initial assessment. 
Any subject with clinical suspicion of SARS-CoV-2 infection will undergo 
appropriate testing and referral within the local healthcare system as 
appropriate. Subjects with a confirmed acute SARS-CoV-2 infection 
during the trial should not receive any additional vaccine dose, but will be 
closely monitored for disease patterns and severity. In order to assess 
severity of disease, subjects will document disease progression on a 
symptom log and Investigators will document additional clinical 
parameters based on hospital records, if applicable. 
Planned Number 
of Subjects: 
Approximately 660 subjects will be enrolled. 
223 subjects during the initial phase of the trial: 
• 
23 subjects in the CVnCoV 6 µg cohort (Groups 1 and 2): 11 subjects 
18 to 60 years and 12 subjects >60 years (i.e., 61 years or older) 
• 
Approximately 180 subjects in the CVnCoV 12 µg cohort (Groups 3 
and 4): approximately 90 subjects 18 to 60 years and approximately 
90 subjects >60 years (i.e., 61 years or older)  
• 
Approximately 20 subjects in the active control cohort (Groups 5 and 
6): approximately 10 subjects 18 to 60 years and approximately 
10 subjects >60 years (i.e., 61 years or older) 
440 subjects during the expansion phase of the trial: 
• 
Approximately 220 subjects 18 to 60 years: 200 will receive CVnCoV 
and 20 will receive active control 
• 
Approximately 220 subjects >60 years (i.e., 61 years or older): 200 
will receive CVnCoV and 20 will receive active control  
Criteria for 
Inclusion and 
Exclusion: 
Inclusion criteria: 
Subjects will be enrolled in this trial only if they meet all of the following 
criteria: 
1. 
Healthy male and female subjects ≥18 years of age. 
A healthy subject is defined as an individual who is in good general 
health, according to the Investigator’s assessment. Chronic health 
conditions are acceptable if the condition is considered well 
controlled with treatment according to the discretion of the 
Investigator. 
2. 
Expected to be compliant with protocol procedures and available for 
clinical follow-up through the last planned visit. 
3. 
Subjects who are able to understand and willing to provide informed 
consent. 
4. 
Physical examination without clinically significant findings according 
to the Investigator’s assessment.  
5. 
Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2.  
6. 
Female subjects of childbearing potential: at the time of enrollment, 
negative human chorionic gonadotropin (hCG) pregnancy test 

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(serum) for female subjects presumed to be of childbearing potential 
on the day of enrollment. On Day 1 (pre-vaccination): negative urine 
pregnancy test (required if serum pregnancy test was performed 
more than 3 days before). 
7. 
Female subjects 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: 
o Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, 
intravaginal or transdermal); 
o Progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable); 
o Intrauterine devices; 
o Intrauterine hormone-releasing systems; 
o Bilateral tubal occlusion; 
o Vasectomized partner; 
o Sexual abstinence (periodic abstinence [e.g., calendar, ovulation, 
symptothermal and post-ovulation methods] and withdrawal are 
not acceptable). 
Male subjects should be instructed not to get their partners pregnant 
until 3 months after the last administration. 
Exclusion criteria: 
Subjects will not be enrolled in this trial if they meet any of the exclusion 
criteria. 
1. 
Use of any investigational or non-registered product (vaccine or 
drug) other than the trial vaccine within 28 days preceding the 
administration of the trial vaccine, or planned use during the trial 
period. 
2. 
Receipt of any other vaccines within 28 days prior to enrollment in 
this trial or planned receipt of any vaccine within 28 days of trial 
vaccine administration (primary dose or booster dose). 
3. 
Receipt of any investigational or licensed/authorized SARS-CoV-2 or 
other coronavirus vaccine prior to the administration of the trial 
vaccine. 
4. 
Any treatment with immunosuppressants or other immune-modifying 
drugs (including, but not limited to, corticosteroids, biologicals, and 
methotrexate) within 6 months prior to the administration of the trial 
vaccine or planned use during the trial, with the exception of 
topically-applied, inhaled, or intranasal steroids. 
5. 
Use of hormonal therapy for gender reassignment. 
6. 
Any medically diagnosed or suspected immunosuppressive or 
immunodeficient condition based on medical history and physical 
examination, including known human immunodeficiency virus 
infection, hepatitis B virus infection, and hepatitis C virus infection. 
7. 
History of immune-mediated or autoimmune disease. 
8. 
History of angioedema (known C1 inhibitor deficiency). 
9. 
History of anaphylaxis or allergy to any component of CVnCoV or 
aminoglycoside antibiotics. 
10. History of or current alcohol and/or drug abuse. 

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11. Subjects who are active smokers, were active smokers within the last 
year (including any vaping in the last year), or have a total smoking 
history ≥10 pack years. A pack year is calculated by multiplying the 
number of packs of cigarettes smoked per day by the number of 
years the person has smoked. 
12. History of virologically-confirmed SARS, MERS, or COVID-19 
disease or known exposure (without any personal protective 
equipment) to an individual with confirmed COVID-19 disease or 
SARS-CoV-2 infection within the past 2 weeks. 
13. Administration of immunoglobulins and/or any blood products within 
the 3 months preceding the administration of any dose of the trial 
vaccine. 
14. Presence or evidence of significant uncontrolled acute or chronic 
medical or psychiatric illness. Significant medical or psychiatric 
illnesses include but are not limited to: 
o Uncontrolled respiratory disease (e.g., chronic obstructive 
pulmonary disease, asthma), including use of the following 
asthma medications: intravenous corticosteroids, leukotriene 
modifiers, biologics.  
o Uncontrolled cardiovascular disease (e.g., congestive heart 
failure, cardiomyopathy, ischemic heart disease, history of stroke, 
peripheral artery disease, pulmonary embolism).  
o History of myocarditis or pericarditis as an adult. 
o Diabetes mellitus (insulin-dependent). 
o Uncontrolled neurological disorders or Guillain-Barré syndrome 
or history of seizure, except for febrile seizures during childhood.  
o Current or past malignancy, unless completely resolved without 
sequelae for >5 years. 
15. Foreseeable non-compliance with protocol, as judged by the 
Investigator. 
16. For female subjects: pregnancy or lactation. 
17. Subjects with impaired coagulation or any bleeding disorder in whom 
an intramuscular injection or a blood draw is contraindicated. This 
includes subjects on treatment with anticoagulants (e.g., vitamin K 
antagonists, novel oral anticoagulants, and heparin). Use of platelet 
aggregation inhibitors is not exclusionary.  
18. Subjects employed by the Sponsor, Investigator, or trial site, or 
relatives of research staff working on this trial. 
19. Subjects considered at the Investigator’s discretion to be at 
increased risk of exposure to COVID-19 disease. 
Endpoints: 
Any immunogenicity samples may also be used for assay validation and 
additional studies of the mechanism of action of the vaccine. 
Primary 
• 
The frequencies, intensities, and duration of solicited local AEs on 
Day 1 and Day 29 and the following 7 days by dose and group. 
• 
The frequencies, intensities, duration, and relationship to trial 
vaccination of solicited systemic AEs on Day 1 and Day 29 and the 
following 7 days by dose and group. 
• 
The occurrence, intensities and relationship to trial vaccination of 
unsolicited AEs on Day 1 and Day 29 and the following 28 days by 
dose and group. 
• 
The occurrence and relationship to trial vaccination of SAEs and 
AESIs throughout the trial. 

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On Day 29 and Day 43: 
• 
The proportion of subjects seroconverting for SARS-CoV-2 spike 
protein antibodies, as measured by enzyme-linked immunosorbent 
assay (ELISA). 
• 
Individual SARS-CoV-2 spike protein-specific antibody levels in 
serum, as measured by ELISA. 
• 
Geometric mean titers (GMTs) of serum SARS-CoV-2 spike protein 
antibodies, as measured by ELISA. 
• 
The proportion of subjects seroconverting for SARS-CoV-2 
neutralizing antibodies, as measured by an activity assay. 
• 
Individual SARS-CoV-2 neutralizing antibody levels in serum. 
• 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as measured 
by an activity assay. 
Secondary 
• 
The frequencies, intensities, and duration of solicited local AEs on the 
day of the booster administration and the following 7 days by group. 
• 
The frequencies, intensities, duration, and relationship to trial 
vaccination of solicited systemic AEs on the day of the booster 
administration and the following 7 days by group. 
• 
The occurrence, intensities and relationship to trial vaccination of 
unsolicited AEs on the day of the booster administration and the 
following 28 days by group. 
On Day 57 (only for subjects receiving the booster dose on Day 57), 
Day 85 (only for subjects receiving the booster dose on Day 57), Day 180 
(only for subjects receiving the booster dose on Day 57 or Day 180), 
Day 208 (only for subjects receiving the booster dose on Day 180), and 
Day 393 (only for subjects receiving the booster dose on Day 180): 
• 
The proportion of subjects seroconverting for SARS-CoV-2 spike 
protein antibodies, as measured by ELISA. 
• 
Individual SARS-CoV-2 spike protein-specific antibody levels in 
serum, as measured by ELISA. 
• 
GMTs of serum SARS-CoV-2 spike protein antibodies, as measured 
by ELISA. 
• 
The proportion of subjects seroconverting for SARS-CoV-2 
neutralizing antibodies, as measured by an activity assay. 
• 
Individual SARS-CoV-2 neutralizing antibody levels in serum. 
• 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as measured 
by an activity assay. 
Exploratory 
CMI response 
On Day 1, Day 29, and Day 43 in peripheral blood mononuclear cells 
(PBMCs) in a subset of subjects: 
• 
The frequency and functionality of SARS-CoV-2 spike-specific T-cell 
response after antigen stimulation. 
Intracellular cytokine staining (ICS) to investigate Th response will be 
used to investigate whether vaccination induces a Th1 shift from 

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baseline. Further T-cell immune responses may be investigated with 
other technologies like ELISpot or CyTOF. 
• 
The proportion of subjects with a detectable increase in SARS-CoV-2 
spike-specific T-cell response. 
Innate immune response 
On Day 1 and Day 2 in a subset of subjects: 
• 
Serum cytokine concentrations, including but not limited to interferon 
(IFN)-α, IFN-γ, IL-6, chemokine ligand (CCL) 2, and IFN-γ-induced 
protein 10 (IP 10). 
Evaluation of infection 
• 
Number of subjects with virologically-confirmed SARS-CoV-2 
infection as measured by RT-PCR at clinically determined time points 
throughout the trial. 
Sample Size 
Justification: 
The trial is designed to provide a reasonable precision for an estimate of 
the number of subjects with seroconverting for nCoV spike protein 
antibodies and an acceptable rate of Grade 3 adverse reactions.  
Analysis Sets: 
Safety Set 
The safety set will consist of all subjects who received at least 1 dose of 
trial vaccine and for whom any post-vaccination safety data are available. 
Immunogenicity Set 
The immunogenicity set will include all subjects who received at least 1 
dose of trial vaccine and for whom the baseline blood sample and at least 
1 additional blood sample are available for analysis. 
Statistical 
Methodology: 
Missing Data/Discontinuation 
Due to the exploratory design of the trial, no imputation of missing values 
will be done for any analysis (except the imputation for missing partial 
dates of AEs and concomitant medication). Reasons for discontinuation 
from the trial or trial vaccination will be listed and summarized. 
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 characteristics 
(age, gender), medical history, baseline immune status, and all safety 
measurements using descriptive statistics (quantitative data) and 
contingency tables (qualitative data) by dose level and group. Medical 
history will only be listed. 
Primary Safety Analyses 
Solicited AEs: 
The number and percentage of subjects with at least 1 solicited AE of any 
kind, by severity grade, for local AEs, systemic AEs, and overall, will be 
summarized, after the first vaccination, after the second vaccination, after 
the booster vaccination (if applicable), and after any vaccination. The 
results will be tabulated by dose level and group. For subjects with more 
than 1 episode of the same event, the maximum severity will be used for 
tabulations. In addition, the frequencies and severity of each solicited AE 
will be summarized for each vaccination day and the following 7 days. 
Similar tabulations will be performed for solicited systemic AEs 
considered as related to the trial vaccine. 
The duration and severity of solicited AEs will be analyzed at subject level. 
Unsolicited AEs: 
Unsolicited AEs, 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 

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subjects reporting these events will be tabulated at the SOC and PT 
levels. Additional similar tabulations will be performed to evaluate severity 
and relationship to the trial vaccine. 
Primary Immunogenicity Analysis 
Percentages of subjects seroconverting for nCoV spike protein antibodies 
and values of antibody levels, percentages of subjects seroconverting for 
nCoV-neutralizing antibodies and GMTs and percentages of immune cell 
populations and cellular responders will be summarized for each dose 
level. Antibody levels for nCoV spike protein antibodies and GMTs for 
nCoV-neutralizing antibodies will be summarized for each dose level for 
subjects previously exposed to SARS-CoV-2 as indicated by confirmed 
positive SARS-CoV-2 serology at baseline. Data will be presented after 
each vaccine dose. In addition, levels of cytokines will be summarized for 
a subset of subjects. 
 

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2 SCHEDULE OF ACTIVITIES 
Table 1 
Schedule of Trial Assessments and Procedures 
 
Primary Vaccination Period 
Booster Vaccination Period 
End of Trial 
Visit Number 
1a 
2 
Phone 
contact 
3 
Phone 
contact 
4 
Phone 
contactb 
5c 
Phone 
contactc 
6c 
Prompt 
7 
Phone 
contactd 
8d 
Prompt 
Phone 
contact 
9w 
Visit Window (days) 
n/a 
-0/ 
+0 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-2/ 
+4 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-10/ 
+10 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-0/  
+30 
-0/ 
+30 
Trial Day 
1 
2 
7e 
15 
29 
30 
43 
57 
57 
58 
85 
120 
180 
181 
208 
270 
393 
393 
Anchoring 
- 
1 
1 
1 
1 
29 
29 
29 
57 
57 
57 
29 
1 
180 
180 
180 
180 
180 
Signed informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
Review of criteria for 
delay or cancellation of 
vaccinationf 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xg 
 
 
 
 
 
Investigational vaccine 
administration (including 
30-minute observation) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xg 
 
 
 
 
 
Safety Monitoring 
Physical examinationh 
Xi 
 
 
 
X 
 
 
 
X 
 
 
 
Xg 
 
 
 
 
 
Symptom-directed 
physical examinationh 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signsh,j 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary (re)trainingk 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
Xg 
 
 
 
 
 
Diary reviewk 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 
 
 
Diary reminderk 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xg 
X 
 
 
 
 
Solicited AEsk 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xg 
X 
X 
 
 
 
Unsolicited AEsk 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Primary Vaccination Period 
Booster Vaccination Period 
End of Trial 
Visit Number 
1a 
2 
Phone 
contact 
3 
Phone 
contact 
4 
Phone 
contactb 
5c 
Phone 
contactc 
6c 
Prompt 
7 
Phone 
contactd 
8d 
Prompt 
Phone 
contact 
9w 
Visit Window (days) 
n/a 
-0/ 
+0 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-2/ 
+4 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-10/ 
+10 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-0/  
+30 
-0/ 
+30 
Trial Day 
1 
2 
7e 
15 
29 
30 
43 
57 
57 
58 
85 
120 
180 
181 
208 
270 
393 
393 
Anchoring 
- 
1 
1 
1 
1 
29 
29 
29 
57 
57 
57 
29 
1 
180 
180 
180 
180 
180 
SAEsl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intercurrent medical 
conditionsl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs leading to 
premature 
discontinuationl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AESIsl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/vaccination 
Xm 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety laboratory (~9 
mL)n 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Safety laboratory in case 
of abnormal result at 
previous visit (~9 mL)n 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
Serum pregnancy test 
(~3 mL)o 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testo 
X 
 
 
 
X 
 
 
 
Xg 
 
 
 
Xg 
 
 
 
 
 
TSH, thyroid antibodies, 
ANA (~3 mL)p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab 
collection for RT-PCR 
testingq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicityr 
ELISA (serum) (~12 
mL)s 
Xt 
 
 
 
Xt 
 
X 
 
Xt 
 
X 
 
Xt,v 
 
X 
 
 
X 
Only in subjects in the 
initial phase of the trial: 
SARS-CoV-2 
neutralizing activity 
(serum) (~12 mL) 
Xt 
 
 
 
Xt 
 
X 
 
Xt 
 
X 
 
Xt,v 
 
X 
 
 
X 

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Primary Vaccination Period 
Booster Vaccination Period 
End of Trial 
Visit Number 
1a 
2 
Phone 
contact 
3 
Phone 
contact 
4 
Phone 
contactb 
5c 
Phone 
contactc 
6c 
Prompt 
7 
Phone 
contactd 
8d 
Prompt 
Phone 
contact 
9w 
Visit Window (days) 
n/a 
-0/ 
+0 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-2/ 
+4 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-10/ 
+10 
-0/ 
+0 
-2/ 
+4 
-2/ 
+4 
-0/  
+30 
-0/ 
+30 
Trial Day 
1 
2 
7e 
15 
29 
30 
43 
57 
57 
58 
85 
120 
180 
181 
208 
270 
393 
393 
Anchoring 
- 
1 
1 
1 
1 
29 
29 
29 
57 
57 
57 
29 
1 
180 
180 
180 
180 
180 
Subset of subjects from 
each CVnCoV group at 
predefined site(s): 
Cell-mediated immunity 
(~40-64 mL)u 
Xt 
 
 
 
Xt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Subset of subjects from 
each CVnCoV group at 
predefined site(s): 
Cytokine assessment 
(serum) (~6 mL) 
Xt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum total blood 
volume (mL) 
109 
15 
 
 
73 
 
73 
 
33 
 
33 
 
33 
 
33 
 
 
33 
Trial end 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE: adverse event; AESI: adverse event of special interest; ANA: antinuclear antibody; ECG: electrocardiogram; ELISA: enzyme-linked immunosorbent assay; Ig: immunoglobulin; RT-PCR: 
reverse transcription polymerase chain reaction; SAE: serious adverse event; TSH: thyroid-stimulating hormone 
a. Procedures to establish subject eligibility may be performed within 21 days prior to trial vaccine administration. If all information to establish eligibility is available, these procedures can 
be done on the same day including the trial vaccine administration. Eligibility criteria need to be reviewed on the day of vaccination prior to trial vaccine administration. 
b. Phone contact on Day 57 is not required for subjects receiving an open-label booster vaccination on Day 57. 
c. This will only take place for subjects receiving an open-label booster vaccination on Day 57. 
d. This will only take place for subjects receiving an open-label booster vaccination on Day 180. 
e. 
Phone contact can be made on Day 7 at the site’s discretion to review the eDiary with the subject, but is not mandatory, and does not replace other scheduled phone contacts 
f. 
See Section 6.3 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. 
g. Only applicable for subjects receiving an open-label booster vaccination on Day 57/Day 180. 
h. Physical examination and vital signs must be performed/measured by a qualified healthcare professional. See Section 9.1.4 for an overview of the required assessments. 
i. 
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. 
j. 
Vital signs will be measured pre- and post-vaccination prior to discharge. Subjects will be observed for 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. 
k. Solicited and unsolicited AEs will be recorded in diaries. 
l. 
SAEs, AESIs (including COVID-19 disease), intercurrent medical conditions that may affect the immune response to vaccination, and AEs leading to trial or trial vaccine withdrawal will 
be collected throughout the trial. 
m. Immunosuppressants or other immune-modifying drugs, with the exception of topically-applied, inhaled, or intranasal steroids, taken within 6 months prior to enrollment and any other 
concomitant medication/vaccination taken within 1 month prior to enrollment should be recorded to establish eligibility. 

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n. See Appendix 3 for an overview of the safety laboratory assessments. 
o. A blood sample for serum pregnancy testing will be taken from women of childbearing potential on Day 1 prior to vaccination to establish eligibility. Urine pregnancy tests will be performed 
before each vaccination, unless the serum pregnancy test was performed less than 3 days before and yielded a negative result. 
p. A blood sample will be drawn for potential retrospective measurement of TSH, thyroid antibodies, and ANA in case of the occurrence of clinical autoimmune events during the trial (other 
autoantibodies might be investigated as well depending on the possible clinical autoimmune event). 
q. Swabs for COVID-19 disease testing will also be collected in case the subject displays symptoms of acute respiratory infection (including, but not limited to COVID-19 disease), if 
operationally possible (see Section 9.3). 
r. 
See Section 9.2 for an overview of the immunogenicity assessments. 
s. ELISA will be performed on SARS-CoV-2 spike (S) protein to investigate immune responses to vaccination and on SARS-CoV-2 nucleocapsid (N) protein to determine immune response 
to natural infection. 
t. 
Baseline blood samples on Day 1, Day 29, Day 57, and Day 180 must be collected prior to vaccination. 
u. The blood volume to be collected for cellular immune response will be 64 mL on Day 1 and 40 mL on Days 29 and 43. 
v. Only for subjects receiving 6 µg and for subjects receiving the 12 µg booster dose on Day 57 or Day 180. 
w. Only for subjects who received the booster on Day 180 and who had not received a licensed/authorized vaccine before the End of Trial visit. 
 

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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 phosphorlated 
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 09 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 then globally. On 07 January 2020, the International Health 
Regulations (2005) Emergency Committee agreed that the outbreak met the criteria for a 
Public Health Emergency of International Concern. On 12 March 2020, the World Health 
Organization (WHO) announced that the outbreak was characterized 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 1. 
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 1 
Genome Organization of SARS-CoV-2 Compared with Other 
Betacoronaviruses 
 
Source: Chan et al., 2020 [3] 
The S gene of SARS-CoV-2 appears 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 level of amino acids, 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 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 core 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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3.1.2 COVID-19 Disease 
SARS-CoV-2 is transmitted mainly through close contact and respiratory droplets. The 
mean incubation period is 4 to 6 days with about 95% of patients developing symptoms 
within 14 days after infection [10,11]. The most common symptoms of COVID-19 disease 
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 currently around 3% [21]. 
According to the 2020 World Health Statistics, 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 11 October 2020, 
according to WHO, 37 109 851 cases have been confirmed globally, including 1 070 355 
deaths [21]. 
3.2 Trial Rationale 
In partnership with the Coalition for Epidemic Preparedness Innovations (CEPI), CureVac 
AG is developing a new SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine 
formulated with lipid nanoparticles (LNP), referred to as CVnCoV, for the prevention of 
COVID-19 disease when administered as a 2-dose primary vaccination schedule. 
CVnCoV was developed with CureVac’s proprietary RNActive® technology platform, which 
uses chemically unmodified mRNA molecules as a basis for vaccination. The safety and 
immunogenicity of this vaccine was evaluated for the first time in humans in the 
dose-finding trial CV-NCOV-001.  
This second trial was conducted to confirm the safety and immunogenicity of CVnCoV at 
different dose levels in adults >60 years of age (i.e., 61 years or older) when administered 
according to a 0 (Day 1), 1-month (Day 29) primary vaccination schedule. The dose levels 
to be administered in this trial will be selected based on data from Trial CV-NCOV-001. 
For this elderly population, higher dose levels than the dose levels investigated for adults 
18 to 60 years of age will be considered to address potentially reduced immunogenicity in 

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the context of immunosenescence. In addition, the safety and immunogenicity of a booster 
dose of CVnCoV administered at approximately 2 months (Day 57) or 6 months (Day 180) 
after the first dose will be evaluated in a subgroup of subjects. 
In order to bridge to the population evaluated in Trial CV-NCOV-001, adults 18 to 60 years 
will also be enrolled in this trial. 
For further clinical development and for the expansion cohorts, the selected dose of 12 µg 
will generate comprehensive safety and immunogenicity data for CVnCoV. 
Please refer to the Investigator’s Brochure for details on the RNActive® technology, 
information regarding the non-clinical studies of the investigational CVnCoV vaccine, and 
additional information. 
3.3 Risk/Benefit Assessment 
3.3.1 Known Potential Risks 
Evidence from non-clinical studies shows that CVnCoV is well tolerated in relevant animal 
species and no safety risks have been identified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Furthermore, CureVac is consulting with external regulatory and scientific experts, 
including CEPI, to help identify the best animal models to evaluate the theoretical risk of 
VDE. To that end, animal models that best recapitulate human disease have been chosen, 
inclusive of hamster and non-human primate challenge studies, as recommended by 
Wang and colleagues [30]. These approaches are in line with those agreed upon for 
COVID-19 vaccine development by the International Coalition of Medicines Regulatory 
Authorities [31].  
 
 
During the very early stages of manufacture of CVnCoV, kanamycin is used. Although 
there is no evidence of residual kanamycin in the final investigational medicinal product 
(IMP), subjects with a previous class I allergic reaction to aminoglycosides should be 
excluded from vaccination with CVnCoV as a measure of precaution. 
 
 
 
 
 
 
 
 
 
 
 
 

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In addition, a list of AEs of special interest (AESIs) to be monitored following administration 
of investigational SARS-CoV-2 vaccines has been identified by the Brighton Collaboration 
Safety Platform for Emergency vACcines (SPEAC) Project. If any suspected AESI (pIMD, 
COVID-19 disease or other AE specific to SARS-CoV-2 vaccines or the target disease) 
should occur in a subject who received CVnCoV, a diagnostic workup should be 
performed by a specialist depending on the type of suspected reaction (e.g., 
endocrinologist for suspected autoimmune thyroiditis) and this condition will be monitored 
and documented throughout the trial.  
CVnCoV has not been investigated in combination with other drugs or vaccines. Given 
the mechanism of action which relies on building up an adequate immune response, it is 
expected that immunosuppressive drugs like steroids may inhibit the desired 
pharmacological effect of the induction of a specific immune response against the 
SARS-CoV-2 S-protein. Similarly, drugs that enhance the immune response like certain 
cytokines (IFN-α, IL-2) may increase the response to the vaccines which could 
theoretically result in increased efficacy but also in an increased risk of toxicity. 
Active Controls 
Common side effects of both the hepatitis A vaccine and pneumococcal vaccine are the 
same as for every vaccine and include injection site reactions, loss of appetite, fever, and 
headache. 
3.3.2 Known Potential Benefits 
Subjects receiving the investigational CVnCoV vaccine may not directly benefit from this 
vaccination since the immune response is still being evaluated in humans. Furthermore, 
no correlate of protection or threshold of protection has been established for COVID-19 
disease. 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, 
electrocardiogram [ECG]). 
Active Controls 
Active controls were selected for this trial to offer a certain level of benefit to the subjects 
in the control groups. Subjects 18 to 60 years of age will receive the hepatitis A vaccine 
and subjects >60 years of age (i.e., 61 years or older) will receive the pneumococcal 
vaccine. These vaccines are considered to provide some benefit to subjects in the 
respective age categories. 
3.3.3 Assessment of Potential Risks and Benefits 
To minimize the risk for subjects participating in this trial, a data safety monitoring board 
(DSMB) will oversee the safety of the subjects on a specified schedule. The DSMB will 
also convene if any serious adverse events (SAEs) related to the vaccine occurs. If any 
dose levels other than those already administered in Trial CV-NCOV-001 are investigated 
in this trial, an internal safety review committee (iSRC) will review the safety and 
reactogenicity data on a continuous basis. 
Potential important medical risks associated with CVnCoV, as specified in Section 3.3.1, 
can be managed at the clinical trial sites, should they occur. 

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4 TRIAL OBJECTIVES AND ENDPOINTS 
4.1 Objectives 
All objectives will be analyzed in all subjects, in subjects retrospectively SARS-CoV-2 
seronegative at baseline, and in subjects retrospectively SARS-CoV-2 seropositive at 
baseline. 
4.1.1 Primary 
• 
To evaluate the safety and reactogenicity profile after 1 and 2 dose administrations 
of CVnCoV at different dose levels. 
• 
To evaluate the humoral immune response after 1 and 2 dose administrations of 
CVnCoV. 
4.1.2 Secondary 
• 
To evaluate the safety and reactogenicity profile after a booster dose administration 
of CVnCoV at different dose levels. 
• 
To evaluate the humoral immune response after a booster dose administration of 
CVnCoV at different dose levels. 
4.1.3 Exploratory 
• 
To evaluate the cell-mediated immune (CMI) response after 1 and 2 dose 
administrations of CVnCoV at different dose levels in a subset of subjects. 
• 
To evaluate the innate immune response after the first dose administration of 
CVnCoV at different dose levels in a subset of subjects. 
• 
To identify and assess cases of COVID-19 disease. 
4.2 Endpoints 
Any immunogenicity samples may also be used for assay validation and additional studies 
of the mechanism of action of the vaccine. 
4.2.1 Primary 
• 
The frequencies, intensities, and duration of solicited local AEs on Day 1 and Day 29 
and the following 7 days by dose and group. 
• 
The frequencies, intensities, duration, and relationship to trial vaccination of solicited 
systemic AEs on Day 1 and Day 29 and the following 7 days by dose and group. 
• 
The occurrence, intensities and relationship to trial vaccination of unsolicited AEs 
on Day 1 and Day 29 and the following 28 days by dose and group. 
• 
The occurrence and relationship to trial vaccination of SAEs and AESIs throughout 
the trial. 
On Day 29 and Day 43: 
• 
The proportion of subjects seroconverting for SARS-CoV-2 spike protein antibodies, 
as measured by ELISA. 

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• 
Individual SARS-CoV-2 spike protein-specific antibody levels in serum, as 
measured by ELISA. 
• 
Geometric mean titers (GMTs) of serum SARS-CoV-2 spike protein antibodies, as 
measured by ELISA. 
• 
The proportion of subjects seroconverting for SARS-CoV-2 neutralizing antibodies, 
as measured by an activity assay. 
• 
Individual SARS-CoV-2 neutralizing antibody levels in serum. 
• 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as measured by an activity 
assay. 
4.2.2 Secondary 
• 
The frequencies, intensities, and duration of solicited local AEs on the day of the 
booster administration and the following 7 days by group. 
• 
The frequencies, intensities, duration, and relationship to trial vaccination of solicited 
systemic AEs on the day of the booster administration and the following 7 days by 
group. 
• 
The occurrence, intensities and relationship to trial vaccination of unsolicited AEs 
on the day of the booster administration and the following 28 days by group. 
On Day 57 (only for subjects receiving the booster dose on Day 57), Day 85 (only for 
subjects receiving the booster dose on Day 57), Day 180 (only for subjects receiving the 
booster dose on Day 57 or Day 180), Day 208 (only for subjects receiving the booster 
dose on Day 180), and Day 393 (only for subjects receiving the booster dose on Day 180): 
• 
The proportion of subjects seroconverting for SARS-CoV-2 spike protein antibodies, 
as measured by ELISA. 
• 
Individual SARS-CoV-2 spike protein-specific antibody levels in serum, as 
measured by ELISA. 
• 
GMTs of serum SARS-CoV-2 spike protein antibodies, as measured by ELISA. 
• 
The proportion of subjects seroconverting for SARS-CoV-2 neutralizing antibodies, 
as measured by an activity assay. 
• 
Individual SARS-CoV-2 neutralizing antibody levels in serum. 
• 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as measured by an activity 
assay. 
4.2.3 Exploratory 
CMI response 
On Day 1, Day 29, and Day 43 in peripheral blood mononuclear cells (PBMCs) in a subset 
of subjects: 
• 
The frequency and functionality of SARS-CoV-2 spike-specific T-cell response after 
antigen stimulation. 
Intracellular cytokine staining (ICS) to investigate Th response will be used to 
investigate whether vaccination induces a Th1 shift from baseline. Further T-cell 

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immune response may be investigated with other technologies like ELISpot or 
CyTOF. 
• 
The proportion of subjects with a detectable increase in SARS-CoV-2 spike-specific 
T-cell response. 
Innate immune response 
On Day 1 and Day 2 in a subset of subjects: 
• 
Serum cytokine concentrations, including but not limited to IFN-α, IFN-γ, IL-6, 
chemokine ligand (CCL) 2, and IFN-γ-induced protein 10 (IP 10). 
Evaluation of infection 
• 
Number of subjects with virologically-confirmed SARS-CoV-2 infection as measured 
by RT-PCR at clinically determined time points throughout the trial. 

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5 TRIAL DESIGN 
5.1 Overall Design 
This is a Phase 2a, partially blind, active-controlled, dose-confirmation trial to assess the 
safety and immunogenicity of provisionally selected CVnCoV dose levels of 6 and 12 µg 
in an older adult population. The design of the trial will allow an increase or decrease in 
dose based on data from Trial CV-NCOV-001 and this trial (see Section 5.2). An overview 
of the planned number of subjects to be enrolled per trial group and the vaccination 
schedule is provided in Table 2.  
Subjects will be recruited independent of their SARS-CoV-2 serology status. Their 
serostatus will be determined retrospectively by a blood sample drawn at baseline and 
analyzed to allow post hoc stratified analyses of subjects who are SARS-CoV-2 
seronegative or seropositive at baseline. 
In the initial phase, subjects will be enrolled in 3 cohorts divided into 6 groups:  
• 
6 µg dose level cohorts 
o Group 1 (observer-blind): CVnCoV 6 µg on Day 1 and 6 µg on Day 29 (in 
subjects 18 to 60 years of age) 
o Group 2 (observer-blind): CVnCoV 6 µg on Day 1 and 6 µg on Day 29 (in 
subjects >60 years of age [i.e., 61 years or older]) 
• 
12 µg dose level cohorts 
o Group 3 (observer-blind): CVnCoV 12 µg on Day 1 and 12 µg on Day 29 
(in subjects 18 to 60 years of age) 
o Group 4 (observer-blind): CVnCoV 12 µg on Day 1 and 12 µg on Day 29 
(in subjects >60 years of age [i.e., 61 years or older]) 
• 
Active control cohort 
o Group 5 (observer-blind): licensed hepatitis A vaccine on Day 1 and on 
Day 29 (in subjects 18 to 60 years of age) 
o Group 6 (observer-blind): licensed pneumococcal vaccine on Day 1 and on 
Day 29 (in subjects >60 years of age [i.e., 61 years or older]) 
A subgroup of subjects in Group 3 will receive a booster dose of CVnCoV on Day 180 and 
a subgroup of subjects in Group 4 will receive a booster dose of CVnCoV on Day 57 or 
Day 180, each in an open-label manner.  
The 6 µg and 12 µg groups will be enrolled sequentially, i.e., enrollment in the 12 µg 
groups will only be initiated once Groups 1 and 2 have been fully enrolled. Group 2 
(subjects >60 years, for 6 µg) will be initiated in 4 sentinel subjects. These subjects should 
be vaccinated at least 60 minutes apart. Safety and reactogenicity data reported during 
an observation period of at least 24 hours after vaccination will be collected and reviewed 
by an iSRC. In this review, the iSRC will review all available safety data, but focus 
specifically on Grade 3 adverse reactions. Based on this review, the iSRC will decide on 
continuation of enrollment of subjects at this dose level. In a next step, 8 additional sentinel 
subjects will be enrolled. Safety and reactogenicity data reported during an observation 

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period of at least 24 hours after vaccination will be collected and reviewed by the iSRC. In 
this review, the iSRC will review all available safety data, but focus specifically on Grade 3 
adverse reactions. The same procedure will be followed for Group 4 (subjects >60 years, 
12 µg) and the iSRC will decide on continuation of enrollment of subjects at this dose level 
after review of the first 12 sentinel subjects. 
In the initial phase, subjects will be randomized according to a 10:1 ratio to receive 
CVnCoV or the active control in an observer-blinded manner.  
5.2 Change in Dose Level 
Other possible dose levels to be administered in this trial will continuously be assessed 
based on the ongoing Trial CV-NCOV-001 in adults aged 18 to 60 years. In case additional 
dose levels are investigated in this trial, such a dose level will be initiated in additional 
sentinel subjects in the same manner as described in Section 5.1. If the dose level of 12 µg 
is considered too reactogenic for adults aged 18 to 60 years in the CV-NCOV-001 trial, 
the dose level in this trial would be reduced from 12 µg to 8 µg. 
In case of any dose increases, the next dose level will only be given to subjects once initial 
data from the previous dose level have been reviewed by the iSRC. 
In case the starting dose level is not well tolerated, a decrease in the dose level may occur 
and the lower dose levels will be assessed in the same manner as described above.  
5.3 Expansion Cohorts 
Following the initial phase, a separate expansion cohort of 220 subjects aged 18 to 
60 years and 220 subjects aged >60 years (i.e., 61 years or older) will be enrolled to be 
vaccinated on Days 1 and 29.  
Expansion for subjects 18 to 60 years of age may start once the final dose for subjects in 
this age category has been selected based on the data from Trial CV-NCOV-001. 
Expansion for subjects >60 years of age may start once the final dose for these subjects 
has been selected based on data from this trial. 
Subjects in the expansion cohorts will be randomized according to a 10:1 ratio to receive 
either the selected dose of CVnCoV or the active control in an observer-blinded manner. 
 

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Table 2 
Trial Groups and Vaccination Schedule 
Cohort 
Age 
(years) 
Group 
 
Vaccination Schedule 
Blinding 
Primary Doses 
 
Booster Dose 
Day 1 
Day 29 
Day 57 
Day 180 
CVnCoV 6 µg 
18-60 
Group 1 
(n=11) 
CVnCoV 6 µg 
CVnCoV 6 µg 
- 
- 
Primary doses: 
Observer-blind 
CVnCoV 6 µg 
>60 
Group 2 
(n=12) 
CVnCoV 6 µg 
CVnCoV 6 µg 
- 
 
Primary doses: 
Observer-blind 
CVnCoV 12 µg 
18-60 
Group 3 
(n=90) 
CVnCoV 12 µg 
CVnCoV 12 µg 
- 
CVnCoV 12 µg 
(n=30) 
Primary doses: 
Observer-blind 
Booster dose: 
Open-label 
CVnCoV 12 µg 
>60 
Group 4 
(n=90) 
CVnCoV 12 µg 
CVnCoV 12 µg 
CVnCoV 12 µg 
(n=30) 
- 
Primary doses: 
Observer-blind 
Booster dose: 
Open-label 
- 
CVnCoV 12 µg 
(n=30) 
Active control 
18-60 
Group 5  
(n=9) 
n=1 against 
Group 1 
Hepatitis A vaccine 
Hepatitis A vaccine 
- 
- 
Observer-blind 
>60 
Group 6 
(n=9) 
n=1 against 
Group 2 
Pneumococcal 
vaccine 
Pneumococcal 
vaccine 
- 
- 
Observer-blind 

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Cohort 
Age 
(years) 
Group 
 
Vaccination Schedule 
Blinding 
Primary Doses 
 
Booster Dose 
Day 1 
Day 29 
Day 57 
Day 180 
Expansion 
18-60 
n=200 
CVnCoV 12 µg 
CVnCoV 12 µg 
- 
- 
Observer-blind 
n=20 
Hepatitis A vaccine 
Hepatitis A vaccine 
- 
- 
>60 
n=200 
CVnCoV 12 µg 
CVnCoV 12 µg 
- 
- 
Observer-blind  
n=20 
Pneumococcal 
vaccine 
Pneumococcal 
vaccine 
- 
- 
 
 

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5.4 Stopping Rules 
5.4.1 Individual Stopping Rules 
Individual stopping AE rules will be applicable during the entire trial to ensure safe 
administration of the second dose (and booster) to subjects vaccinated with the first 
vaccine dose.  
The stopping rules are met in case any of the following events occur on the day of 
vaccination or following 7 days: 
• 
An allergic/anaphylactic reaction considered as related to the trial vaccine. 
• 
Any SAE considered as related to the trial vaccine.  
• 
Any Grade 3 AE considered related to the trial vaccine, with the following exceptions: 
- 
Transient Grade 3 systemic AE (fever, headache, fatigue, chills, myalgia, 
arthralgia, nausea/vomiting, and diarrhea) considered related to the trial vaccine 
that resolved within 48 hours to Grade ≤2. 
- 
Transient Grade 3 local AE that resolved within 48 hours to Grade ≤2. 
If any of these rules are met, the subject must not receive the second vaccine dose (or 
booster). The subject will be encouraged to continue participation until the end of the trial 
for safety and immunogenicity assessments, but only relevant visits need to be conducted 
for any such subjects.  
5.4.2 Trial Suspension Rule 
A trial suspension rule will be applicable during the entire trial. This rule is met if a subject 
vaccinated with CVnCoV experiences an SAE considered related to the trial vaccine by 
the Investigator or Sponsor. 
If this rule is met, enrollment and vaccination with CVnCoV will be suspended within 
24 hours after reporting to the trial team. An ad-hoc DSMB meeting will be held to review 
all safety data per the DSMB charter. Depending on the DSMB assessment of the 
benefit-risk ratio, including the relationship of the SAE to the trial vaccine, enrollment and 
vaccination with CVnCoV might be temporarily halted and only be re-started upon 
approval by the DSMB and competent authority. 
5.5 Scientific Rationale for Trial Design 
This trial will evaluate the safety, reactogenicity, and immunogenicity of different CVnCoV 
dose levels in an elderly population (>60 years of age [i.e., 61 years or older]). As the 
elderly are affected most by SARS-CoV-2, it is critical to investigate CVnCoV in this 
population and determine an appropriate dose and regimen. 
A booster dose will be administered at approximately 2 months (Day 57) or at 6 months 
(Day 180) after the first dose of the primary regimen to address potentially reduced 
immunogenicity in the context of immunosenescence in this elderly population. 
Furthermore, a 0, 1, 6-month schedule is commonly used for licensed vaccines because 
it allows for an extended period for affinity maturation before the later boost. 
The duration of the trial is appropriate for mRNA vaccines, allowing a minimum of 
365 days of safety follow-up after the last primary dose for all subjects, to collect and 
evaluate safety data as needed.  

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The hepatitis A and pneumococcal vaccines were selected as control because hepatitis A 
and pneumococcal disease occur in the countries in which the trial is being conducted; 
subjects will therefore benefit from this control to some degree. 
5.6 Justification for Dose 
Two provisional CVnCoV dose levels (6 and 12 µg) will be evaluated. Based on favorable 
immunogenicity data and tolerable safety/reactogenicity data administered with 12 µg in 
Trial CV-NCOV-001, the DSMB endorsed the decision to implement the 12 µg dose in this 
phase 2a trial. Refer to the Investigator’s Brochure for an overview of the CVnCoV 
non-clinical data. 
Additional higher, lower, and/or intermediate dose levels might be evaluated depending 
on the outcomes of Trial CV-NCOV-001, as well as data from Trial CV-NCOV-002. 
Identification of immunogenic dose levels with lower mRNA content might be of particular 
importance for efficient vaccination in a worldwide viral outbreak setting. 
5.7 End of Trial Definition 
A subject is considered to have completed the trial when he/she has completed all visits 
applicable for the group to which he/she was randomized/assigned to at trial entry. 
End of Trial is defined as the point at which the last subject has completed the last visit or 
last phone contact. 

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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. 
6.1 Inclusion Criteria 
Subjects will be enrolled in this trial only if they meet all of the following criteria: 
1. Healthy male and female subjects ≥18 years of age. 
A healthy subject is defined as an individual who is in good general health, according 
to the Investigator’s assessment. Chronic health conditions are acceptable if the 
condition is considered well controlled with treatment according to the discretion of the 
Investigator. 
2. Expected to be compliant with protocol procedures and available for clinical follow-up 
through the last planned visit. 
3. Subjects who are able to understand and willing to provide informed consent. 
4. Physical examination without clinically significant findings according to the 
Investigator’s assessment.  
5. Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2. 
6. Female subjects of childbearing potential: at the time of enrollment, negative human 
chorionic gonadotropin (hCG) pregnancy test (serum) for female subjects presumed 
to be of childbearing potential on the day of enrollment. On Day 1 (pre-vaccination): 
negative urine pregnancy test (required if serum pregnancy test was performed more 
than 3 days before). 
7. Female subjects 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 occlusion; 
• 
Vasectomized partner; 
• 
Sexual abstinence (periodic abstinence [e.g., calendar, ovulation, symptothermal 
and post-ovulation methods] and withdrawal are not acceptable). 

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Male subjects should be instructed not to get their partners pregnant until 3 months 
after the last administration. 
Refer to the Clinical Trial Facilitation Group recommendations on contraception and 
pregnancy testing for further details [32]. 
6.2 Exclusion Criteria 
Subjects will not be enrolled in this trial if they meet any of the exclusion criteria. 
1. Use of any investigational or non-registered product (vaccine or drug) other than the 
trial vaccine within 28 days preceding the administration of the trial vaccine, or planned 
use during the trial period. 
2. Receipt of any other vaccines within 28 days prior to enrollment in this trial or planned 
receipt of any vaccine within 28 days of trial vaccine administration (primary dose or 
booster dose). 
3. Receipt of any investigational or licensed/authorized SARS-CoV-2 or other 
coronavirus vaccine prior to the administration of the trial vaccine. 
4. Any treatment with immunosuppressants or other immune-modifying drugs (including, 
but not limited to, corticosteroids, biologicals, and methotrexate) within 6 months prior 
to the administration of the trial vaccine or planned use during the trial, with the 
exception of topically-applied, inhaled, or intranasal steroids. 
5. Use of hormonal therapy for gender reassignment. 
6. Any medically diagnosed or suspected immunosuppressive or immunodeficient 
condition based on medical history and physical examination, including known human 
immunodeficiency virus infection, hepatitis B virus infection, and hepatitis C virus 
infection. 
7. History of immune-mediated or autoimmune disease. 
8. History of angioedema (known C1 inhibitor deficiency). 
9. History of anaphylaxis or allergy to any component of CVnCoV or aminoglycoside 
antibiotics. 
10. History of or current alcohol and/or drug abuse. 
11. Subjects who are active smokers, were active smokers within the last year (including 
any vaping in the last year), or have a total smoking history ≥10 pack years. A pack 
year is calculated by multiplying the number of packs of cigarettes smoked per day 
by the number of years the person has smoked. 
12. History of virologically-confirmed SARS, MERS, or COVID-19 disease or known 
exposure (without any personal protective equipment) to an individual with confirmed 
COVID-19 disease or SARS-CoV-2 infection within the past 2 weeks. 
13. Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the administration of any dose of the trial vaccine. 

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14. Presence or evidence of significant uncontrolled acute or chronic medical or 
psychiatric illness. Significant medical or psychiatric illnesses include but are not 
limited to: 
• 
Uncontrolled respiratory disease (e.g., chronic obstructive pulmonary disease, 
asthma), including use of the following asthma medications: intravenous 
corticosteroids, leukotriene modifiers, biologics. 
• 
Uncontrolled 
cardiovascular 
disease 
(e.g., 
congestive 
heart 
failure, 
cardiomyopathy, ischemic heart disease, history of stroke, peripheral artery 
disease, pulmonary embolism).  
• 
History of myocarditis or pericarditis as an adult. 
• 
Diabetes mellitus (insulin-dependent). 
• 
Uncontrolled neurological disorders or Guillain-Barré syndrome or history of 
seizure, except for febrile seizures during childhood.  
• 
Current or past malignancy, unless completely resolved without sequelae for 
>5 years. 
15. Foreseeable non-compliance with protocol, as judged by the Investigator. 
16. For female subjects: pregnancy or lactation. 
17. Subjects with impaired coagulation or any bleeding disorder in whom an intramuscular 
injection or a blood draw is contraindicated. This includes subjects on treatment with 
anticoagulants (e.g., vitamin K antagonists, novel oral anticoagulants, and heparin). 
Use of platelet aggregation inhibitors is not exclusionary.  
18. Subjects employed by the Sponsor, Investigator, or trial site, or relatives of research 
staff working on this trial. 
19. Subjects considered at the Investigator’s discretion to be at increased risk of exposure 
to COVID-19 disease. 
6.3 Vaccine Delay Recommendations 
After enrollment, subjects may encounter clinical circumstances that warrant a delay of 
trial vaccine administration. These situations are listed below: 
• 
Subjects with a clinically significant (Grade ≥2) active infection or other acute disease 
(as assessed by the Investigator) or temperature >38.0°C (>100.4°F), within 3 days 
of intended trial vaccination. Further dose administration 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) for at least 3 days, if this still allows 
to vaccinate the subject as per the predefined interval. Temperature should be 
measured orally. 
• 
Subjects who took antipyretic medication within 8 hours before intended trial 
vaccination. 
In case of delay, the vaccination should take place within the allowed time windows 
specified in Table 1. 

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6.4 Failure to Meet Eligibility Criteria 
The Investigator must account for all subjects who sign an informed consent form (ICF). 
If the subject is found to be not eligible (i.e., did not meet all inclusion criteria or met one 
or more exclusion criteria), the Investigator should document this in the subject’s source 
data and electronic case report form (eCRF). 
Re-doing the full assessments for eligibility assessment as per Table 1 or re-testing (i.e., 
re-doing a single assessment) is allowed if the reason for ineligibility is a transient event.  
An example of a condition under which re-assessment may be considered includes: 
• 
Subjects who required treatment for an acute illness that resolved (e.g., a urinary 
tract infection) may be re-assessed once the illness resolved or the medical problem 
stabilized. 
An example of a condition under which re-testing may be considered includes: 
• 
Subjects who have clinical laboratory test value(s) that are not in line with the 
medical history and clinical evaluation of the subjects may be re-tested to confirm 
the value of the tests, if still allowed within the enrollment period (Day -21 to Day 1). 
If not feasible, the subject should be re-assessed for eligibility. 

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7 TRIAL VACCINE 
7.1 Trial Vaccine Administration 
7.1.1 Description of the Trial Vaccine 
CVnCoV is an investigational LNP-formulated RNActive® SARS-CoV-2 vaccine. The IMP 
is composed of the active pharmaceutical ingredient, an mRNA that encodes Wsmpv-SP, 
and 4 lipid components: cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 
PEG-ylated lipid, and a cationic lipid.  
7.1.2 Description of the Active Controls 
The active controls used in this trial will be a licensed hepatitis A vaccine and a licensed 
pneumococcal vaccine. These vaccines will be prepared, stored, handled, and 
administered in accordance with the package inserts. 
7.1.3 Dosing and Administration 
The provisional dose levels to be administered are provided in Table 2.  
Injections must be performed intramuscularly (IM) by needle 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 instruction for injection described in the trial-specific 
pharmacy manual must be followed. An intravascular injection is highly unlikely at this site 
due the lack of larger blood vessels. 
Subjects should be observed for 30 minutes following each vaccination. Since there is a 
theoretical risk of anaphylactic reactions, the 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. If anaphylaxis or severe hypersensitivity reactions occur 
following IMP administration, no further doses should be given. 
7.2 Preparation/Handling/Storage/Accountability 
7.2.1 Preparation 
Mixing of CVnCoV and 0.9% NaCl to produce dosing solutions for IM injection will occur 
according to the handling manual provided by CureVac AG.  
7.2.2 Product Storage and Stability 
CVnCoV is presented as an aqueous solution and stored below -60°C. 
7.2.3 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. 

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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. 
• 
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 
The initial phase of the trial will be conducted with 4 CVnCoV groups versus 2 active 
controls. In the initial phase, subjects will be randomized according to a 10:1 ratio to 
receive CVnCoV or the active control in an observer-blinded manner.  
Subjects in the expansion cohorts will be randomized according to a 10:1 ratio to receive 
either the selected dose of CVnCoV or the active control in an observer-blinded manner; 
200 subjects per age category will receive CVnCoV and 20 subjects will receive the active 
control.  
The Sponsor and safety monitoring committees will be unblinded for data from the 
randomized groups, but will take appropriate measures to ensure subject blinding is kept 
at site level until database lock.  
7.3.1 Emergency Unblinding 
In case of urgent medical conditions and if further treatment decisions must be based on 
the knowledge of the trial vaccine, the respective subjects might be unblinded. 
The Investigator can request individual subject unblinding by using the interactive voice 
response system (IVRS) and preferably after contacting the Sponsor. 
Individual unblinding should only occur in emergency situations for reasons of subject 
safety when knowledge of the IMP is essential for the clinical management or welfare of 
the subject. 
The identity of the IMP 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 IVRS. 
When the blind is broken, the date, exact timing and reason must be fully documented in 
the source documents and entered into the eCRF, as applicable. 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 the trial. 

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7.3.2 Licensed/Authorized Vaccine 
Since the efficacy results from Trial CV-NCOV-004 are available and all subjects in this 
trial are currently eligible to receive a licensed/authorized vaccine, all subjects in this trial 
will be unblinded.  
Each subject will be informed by the study physician of the available efficacy results from 
Trial CV-NCOV-004 and whether he/she received CVnCoV or an active control. All 
subjects will be asked to remain in the trial to allow safety follow-up. 
7.4 Vaccine Compliance 
The Investigator will record all injections (CVnCoV and active control) administered in the 
subject’s eCRF page. 
7.5 Misuse and Overdose 
Definition misuse: Situations where the trial vaccine is intentionally and inappropriately 
used not in accordance with the protocol dosing instructions or authorized product 
information. 
Definition 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) should be treated symptomatically with physical 
measures, paracetamol or non-steroidal anti-inflammatory drugs.  
7.6 Concomitant Therapy and Vaccines 
Concomitant medication and vaccines including the reason for administration must be 
recorded in the subject’s eCRF. As outlined in Section  6.3, vaccination will be delayed in 
subjects who take antipyretic medication within 8 hours before intended trial vaccination, 
however, prophylactic paracetamol can be taken after vaccination and should be 
documented in the subject’s eCRF. 
For additional information, refer to Section 6.2. 
7.7 Therapy Leading to Discontinuation 
If a subject requires therapy listed as an exclusion criterion in Section 6.2 (with the 
exception of a licensed/authorized SARS-CoV-2 vaccine) and which cannot be delayed, 
discontinuation would be considered to ensure integrity of the trial data, following 
individual case review, but safety follow-up until 12 months after the last dose of the 
primary regimen should be pursued.  
Licensed/authorized SARS-CoV-2 vaccines are allowed. Receipt of any other 
investigational SARS-CoV-2 vaccine or vaccines against any other virus from the 
coronavirus family is prohibited during the trial. 

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7.8 Treatment After the End of Trial 
This trial will investigate a prophylactic vaccine and therefore post-trial care is not 
applicable. 

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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. Assessments of solicited AEs 
and associated phone calls or electronic prompts (by e.g., text message) for the second 
(and booster) dose will not be necessary if a subject received only 1 dose. Overall, only 
relevant visits need to be conducted for any subjects who prematurely discontinue from 
trial product administration. Immunogenicity assessments may be performed at the 
Investigator’s discretion, if the subject agrees.  
8.1 Discontinuation of Trial Vaccine Administration 
The primary reason for discontinuation of further administrations of trial vaccine doses 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). 
• 
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 9.1.2).  
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. 
• 
Virologically-confirmed SARS-CoV-2 infection (as specified in Section 9.3). 
• 
Trial terminated by the Sponsor (in which case the minimum safety follow-up of 1 year 
after the last trial vaccine dose 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. 
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 trial site and multiple attempts (at least 3) 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. 
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 and who has received at least 1 trial 
vaccine dose will undergo the same procedures as for the end of trial 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: 
• 
Safety reasons: the incidence of AEs in this or any other trial using the same or 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 trial site is unlikely to be able to recruit sufficient subjects within the agreed time 
frame. 
• 
The trial 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 a regulatory authority for any reason or if recommended 
by the iSRC or DSMB, or at a site level by the Independent Ethics Committee (IEC) or 

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Institutional Review Board (IRB). The Sponsor may close an individual trial site 
prematurely for reasons such as poor protocol compliance or unsatisfactory recruitment 
of subjects. 
8.4 Lost to Follow-Up 
A minimum of 3 attempts to contact subjects who have not returned for the scheduled visit 
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 Schedule of Activities is detailed in Table 1. The trial procedures apply to all subjects, 
independent of the serology status at baseline per retrospective analysis. For each 
procedure, subjects are to be assessed by the same Investigator or site personnel 
whenever possible. 
In case subjects are not able to come to the site for protocol-specified 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).  
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. If all information to establish eligibility is available, these 
procedures can be done on the same day including the trial vaccine administration. 
Eligibility criteria need to be reviewed on the day of vaccination prior to trial vaccine 
administration. 
The maximum total volume of blood taken over the trial period from any subject will be 
approximately 279 mL (or 435 mL for subjects in who CMI and cytokines will be 
assessed). The blood volumes to be collected for each parameter are specified in Table 1. 
9.1 Safety Assessments 
9.1.1 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. 
Unscheduled visits will be performed when deemed necessary for safety assessments or 
to ensure data integrity. 
Subjects with any Grade 3 solicited or unsolicited AEs reported electronically by the 
subject will be contacted by the Investigator, and subjects who did not enter any diary 
information will be prompted and then contacted in case of non-response within 24 hours. 
9.1.1.1 Solicited Adverse Events 
Solicited local AEs (injection site pain, redness, swelling, and itching) and solicited 
systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and 
diarrhea) will be recorded on the day of vaccination and the following 7 days using a diary 
(electronic or paper).  
Temperature should be measured orally. 
Solicited AEs will be assessed on an intensity scale of absent, mild, moderate, and severe 
(Table 3 and Table 4). In case of related Grade 3 solicited or unsolicited AEs reported for 
more than 1 day in the diary, the subject will be questioned to establish the total duration 
of the AE as exactly as possible and this information will be recorded in the eCRF.  

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Solicited systemic Grade 3 AEs and unsolicited Grade 3 AEs, except for solicited injection 
site reactions, must be reported to the medical monitor without delay, on the same day of 
awareness by the site.  
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 each 
occurrence of each AE. 
Table 3 
Intensity Grading for Solicited Local Adverse Events  
AE 
Grade 
Definition 
Pain at injection 
site 
0 
Absent 
1 
Does not interfere with activity 
2 
Interferes with activity and/or repeated use of non-narcotic pain 
reliever >24 hours 
3 
Prevents daily activity and/or repeated use of narcotic pain reliever 
Redness 
0 
<2.5 cm 
1 
2.5 – 5 cm 
2 
5.1 – 10 cm 
3 
>10 cm 
Swelling 
0 
<2.5 cm 
1 
2.5 – 5 cm and does not interfere with activity 
2 
5.1 – 10 cm or interferes with activity 
3 
>10 cm or prevents daily activity 
Itching 
0 
Absent 
1 
Mild, no interference with activity  
2 
Moderate, some interference with activity 
3 
Significant, prevents activity 
Based on the United States Food and Drug Administration toxicity grading scale [33]. 

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Table 4 
Intensity Grading for Solicited Systemic Adverse Events  
Adverse Event 
Grade 
Definition 
Fever 
0 
<38°C 
1 
≥38 – 38.4°C 
2 
≥38.5 – 38.9°C 
3 
≥39°C 
Headache 
0 
Absent 
1 
Mild, no interference with activity 
2 
Moderate, some interference with activity and/or repeated use of 
non-narcotic pain reliever >24 hours 
3 
Significant; any use of narcotic pain reliever and/or prevents daily 
activity 
Fatigue 
0 
Absent 
1 
Mild, no interference with activity  
2 
Moderate, some interference with activity 
3 
Significant, prevents activity 
Chills  
0 
Absent 
1 
Mild, no interference with activity 
2 
Moderate, some interference with activity 
3 
Significant, prevents activity 
Myalgia 
0 
Absent 
1 
Mild, no interference with activity  
2 
Moderate, some interference with activity 
3 
Significant, prevents activity 
Arthralgia 
0 
Absent 
1 
Mild, no interference with activity  
2 
Moderate, some interference with activity 
3 
Significant, prevents activity 
Nausea/ 
Vomiting 
0 
Absent  
1 
Mild, no interference with activity and/or 1 – 2 episodes/ 24 hours 
2 
Moderate, some interference with activity and/or >2 episodes/ 
24 hours 
3 
Significant, prevents daily activity, requires outpatient intravenous 
hydration 
Diarrhea 
0 
Absent 
1 
2 – 3 loose stools or <400 g/24 hours 
2 
4 – 5 stools or 400 – 800 g/24 hours 
3 
6 or more watery stools or >800 g/24 hours or requires outpatient 
intravenous hydration 
Based on the United States Food and Drug Administration toxicity grading scale [33]. 
9.1.1.2 Unsolicited Adverse Events and Serious Adverse Events 
Diaries will also be used for collection of unsolicited AEs on each vaccination day and the 
following 28 days. In addition, subjects will receive a prompt (by e.g., a phone call or text 
message) to verify whether the subjects had any health concerns since the last visit. 
The occurrence of AEs (serious and non-serious) will be assessed by non-directive 
questioning of the subject at each visit. AEs volunteered by the subject during or between 
visits in the diary or detected through observation, physical examination, laboratory test, 
or other assessments during the entire trial, will be recorded in the eCRF, if they fall within 

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the reporting period. 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 each occurrence of 
each AE/SAE. 
SAEs and AEs leading to vaccine withdrawal or trial discontinuation will be collected 
throughout the trial. Non-serious intercurrent medical conditions that may affect the 
immune response to vaccination will also be collected throughout the trial. 
9.1.1.3 Adverse Events of Special Interest 
The following events will be considered as AESI during this trial: 
• 
AEs with a suspected immune-medicated etiology (pIMDs, see Appendix 8), 
• 
COVID-19 disease, 
• 
other AEs relevant to SARS-CoV-2 vaccine development or the target disease (see 
Appendix 9).  
AESIs will be collected throughout the trial. 
9.1.2 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. 
9.1.3 Safety Laboratory Assessments 
Blood samples for determination of hematology (complete blood count, including 
differential and platelets), clinical biochemistry, and coagulation will be analyzed as 
indicated in the Schedule of Activities. An overview of the safety laboratory tests is 
provided in Appendix 3. 
In addition, a blood sample for serum pregnancy testing will be taken from women of 
childbearing potential on Day 1 prior to vaccination to establish eligibility. Urine pregnancy 
tests will be performed before each vaccination, unless the serum pregnancy test was 
performed less than 3 days before and yielded a negative result. 
Laboratory data will be graded according with the United States Food and Drug 
Administration (FDA) toxicity grading scale [33]. Any institutional normal reference ranges 
should be provided to demonstrate that they are appropriate.  
9.1.4 Vital Signs, Physical Examination, and ECG 
Vital signs (body temperature, systolic/diastolic blood pressure, and heart rate) will be 
recorded in a standardized manner after the subject has rested in the sitting position for 
5 minutes.  
A complete physical examination should be performed at the time points specified in 
Table 1, except if a complete physical examination to establish eligibility was performed 
within 21 days prior to Day 1, in which case a symptom-directed physical examination can 

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be performed on Day 1 prior to the vaccine administration. The complete physical 
examination will include: general appearance, eyes/ears/nose/throat, head/neck/thyroid, 
lymph node areas, cardiovascular system, lung/chest, abdomen and genitourinary 
system, extremities and neurological examination, skin examination, and measurement of 
weight and height. 
An ECG with conventional 12-lead traces will be recorded on Day 1 for all subjects. 
Additionally, ECGs should be performed as clinically indicated. 
9.1.5 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. 
9.1.6 Safety Monitoring Committees 
If any SAE considered as related to the trial vaccine according to the Investigator occurs 
at any moment during the trial, all vaccinations will be put on hold. The DSMB will perform 
a comprehensive review of all relevant safety and reactogenicity data before making a 
decision to stop, continue, or modify vaccination (including evaluating lower doses). 
The DSMB may recommend additional measures including modification or halt of the trial. 
Group 2 (subjects >60 years, 6 µg) will be initiated in 4 sentinel subjects. These subjects 
should be vaccinated at least 60 minutes apart. Safety and reactogenicity data reported 
during an observation period of at least 24 hours after vaccination will be collected and 
reviewed by an iSRC. In this review, the iSRC will review all available safety data, but 
focus specifically on Grade 3 adverse reactions (defined as solicited systemic, solicited 
local, or unsolicited Grade 3 AEs considered as related to the trial vaccine). Based on this 
review, the iSRC will decide on continuation of enrollment of subjects at this dose level. In 
a next step, 8 additional sentinel subjects will be enrolled. Safety and reactogenicity data 
reported during an observation period of at least 24 hours after vaccination will be 
collected and reviewed by the iSRC. In this review, the iSRC will review all available safety 
data, but focus specifically on Grade 3 adverse reactions. The same procedure will be 
followed for Group 4 (subjects >60 years, 12 µg) and the iSRC will decide on continuation 
of enrollment of subjects at this dose level after review of the first 12 sentinel subjects. 
9.2 Immunogenicity Assessments 
An overview of the timing of blood sample collection for immunogenicity assessment is 
provided in Table 1. 
Unused samples may be used for assay validation and additional studies of the 
mechanism of action of the vaccine. 
If a subject receives a licensed/authorized vaccine, no further immunogenicity samples 
will be collected/analyzed after receipt of the licensed/authorized vaccine. Immunogenicity 
samples on Day 393 will only be collected from subjects who attend this visit at the site, 

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ie, subjects who received the Day 180 booster AND who had not received a 
licensed/authorized vaccine before this visit. 
9.2.1 Humoral Immune Response 
The humoral immune response elicited by the vaccine will be evaluated by measurement 
of SARS-CoV-2 spike protein-specific antibodies in serum by ELISA and SARS-CoV-2 
neutralizing antibodies in serum by an activity assay.  
In addition to evaluation of vaccine-induced immune responses, ELISA to SARS-CoV-2 
N-antigen (not contained in the vaccine construct) will be performed to determine the 
subject’s serology status to natural infection, to retrospectively identify the baseline 
serology status, and to detect and/or confirm natural infection during the trial. The 
SARS-CoV-2 N-antigen ELISA will be performed at the specified time points for humoral 
immune response testing to SARS-CoV-2 S-protein. 
Seroconversion will be defined as: 
• 
Subjects seronegative at baseline (in addition to a negative serostatus at baseline, 
such subjects would also not have been exposed to SARS-CoV-2 during the trial 
before the applicable sample was collected, as confirmed by a titer increase in 
antibodies to SARS-CoV-2 N-antigen or a RT-PCR-positive swab during the trial): an 
increase in antibody titer against SARS-CoV-2 spike protein versus baseline. 
• 
Subjects seropositive at baseline: a 2-fold increase in antibody titer against 
SARS-CoV-2 spike protein versus baseline. 
To further evaluate the humoral immune response, cross-reactivity with other viral 
antigens might be analyzed.  
9.2.2 Cell-Mediated Immunity 
CMI will only be evaluated in approximately 20 subjects per CVnCoV group at assigned 
site(s). 
The frequency and functionality of SARS-CoV-2 spike-specific T-cell response after 
antigen stimulation will be determined in PBMC in comparison to baseline. For example, 
ICS to investigate Th response will be used to investigate whether vaccination induces a 
Th1 shift from baseline. Further T-cell immune response may be investigated with other 
technologies like ELISpot or CyTOF. 
9.2.3 Innate Immune Response 
The innate immune response will only be evaluated in approximately 20 subjects per 
CVnCoV group at assigned site(s) by measuring serum cytokines, including but not limited 
to IFN-α, IFN-γ, IL-6, CCL 2, and IP 10. 
9.3 Laboratory Testing for COVID-19 Disease 
As a baseline assessment, a RT-PCR test for SARS-CoV-2 will be performed in all 
subjects. Testing will be done for SARS-CoV-2 spike protein to evaluate vaccine-induced 
immune responses as well as for SARS-CoV-2 N-antigen (not contained in the vaccine 
construct) to evaluate immune responses induced by natural infection. This will allow to 
retrospectively define the subject’s serology status, including the baseline status for the 
by-group/cohort analysis. 

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Subjects will be prompted once or twice per week to report if the subjects have any of the 
following symptoms: cough, shortness of breath, difficulty breathing, fever ≥37.8°C, 
fatigue, myalgia, chills, wheezing, nasal congestion, runny nose, sore throat, headache, 
diarrhea, or new olfactory and taste disorders. 
A COVID-19 symptoms log listing these symptoms will be provided to subjects with 
RT-PCR-confirmed COVID-19 disease (refer to Appendix 4 for an example symptom log). 
If any of these symptoms are observed, the Investigator will collect appropriate samples 
as soon as feasible and locally perform RT-PCR and/or serological assays as locally 
available to evaluate for infection with SARS-CoV-2. If a serological assay is performed, 
this should look at antibodies against N protein antigen, but not to antibodies against Spike 
viral antigen, as this is part of the vaccine. These assays will be repeated 7 to 14 days 
after the initial assessment. 
Any subject with clinical suspicion of SARS-CoV-2 infection will undergo appropriate 
testing and referral within the local healthcare system as appropriate. Subjects with 
confirmed SARS-CoV-2 infections during the trial should not receive any additional 
vaccine dose, but will be closely monitored for disease patterns and severity. In order to 
assess severity of disease, subjects will document disease progression on a symptom log 
and Investigators will document additional clinical parameters based on hospital records, 
if applicable. 
The currently available case definition for COVID-19 disease is provided in Appendix 5. 

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10 STATISTICAL CONSIDERATIONS 
Due to the exploratory nature of this trial, only descriptive statistics will be used. No 
confirmatory statistical inference will be performed.  
10.1 Sample Size Determination 
The sample size of the trial ensures that sufficient safety and immunogenicity data will be 
available for the selected CVnCoV dosage(s) prior to initiation of Phase 3 clinical trials. 
Approximately 200 subjects will be enrolled in the initial phase to investigate different dose 
levels and 20 subjects as control. Furthermore, 440 subjects will be enrolled in an 
expansion phase (400 will receive CVnCoV and 40 the active control).

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Table 5 
Sample Size 
Open-label 
Randomized 
Dose 
escalationa 
Group 1 
6 µg 
Age 18-60 
Group 2 
6 µg 
Age >60 
Group 3 
12 µg 
Age 18-60 
Group 4 
12 µg 
Age >60 
Expansion 
Age 18-60 
Expansion 
Age >60 
Total 
CVnCoV 
Group 5 
Active 
control 
Age 18-60 
Group 6 
Active 
control 
Age >60 
Expansion 
Active 
control 
Age ≥18 
4 
11 
12c 
90 
90 
200 
200 
603 
10b 
10b 
40 
a. 
Only if the dose level was previously untested. 
b. 
Includes 1 control subject from Group 1 and 1 control subject from Group 2. 
c. 
Includes the 4 subjects from the dose escalation. 

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The trial is designed to provide a reasonable precision for an estimate of the number of 
subjects with seroconverting for nCoV spike protein antibodies and an acceptable rate of 
Grade 3 adverse reactions. Table 6 provides the estimate and 95% credibility interval for 
the observed numbers of subjects with seroconverting for nCoV spike protein antibodies 
for different sample sizes assuming a Beta (1.9,0.1) prior for seroconverting for nCoV 
spike protein antibodies and a Beta (0.5,1.5) prior for Grade 3 adverse reactions. 
Table 6 
Estimate of Number of Subjects with Seroconverting for nCoV Spike 
Protein Antibodies and 95% Credibility Interval 
 
Sample Size 
 
90 
200 
603 
Rate (%) 
N 
95% CI 
N 
95% CI 
N 
95% CI 
80 
72 
80.3 
(71.7 - 87.7) 
160 
80.1 
(74.4 - 85.3) 
482 
80  
(76.7 - 83.1) 
85 
76 
84.7 
(76.7 - 91.2) 
170 
85.1 
(79.9 - 89.7) 
513 
85  
(82.2 - 87.8) 
90 
81 
90.1 
(83.3 - 95.3) 
180 
90 
(85.6 - 93.8) 
543 
90.1  
(87.6 - 92.3) 
95 
86 
95.5 
(90.5 - 98.7) 
190 
95 
(91.6 - 97.6) 
573 
95  
(93.2 - 96.6) 
100 
90 
99.9 
(98.9 - 100) 
200 
100 
(99.5 - 100) 
603 
100  
(99.8 - 100) 
CI: credibility interval; N: subjects with seroconverting for nCoV spike protein antibodies 
 
Table 7 provides probabilities (in %) that the following 2 conditions are simultaneously met 
for assumed true adverse reaction rates and for assumed true rates with seroconverting 
for nCoV spike protein antibodies and for different sample sizes: 
• 
there is a ≥80% probability that the true rate of Grade 3 AR(s) is ≤33%, and 
• 
there is a ≥90% probability that the true rate of subjects seroconverting for nCoV spike 
protein antibodies>95%. 
For example, for a sample size of 200, assuming a true adverse reaction rate of 20% and 
a true rate of subjects seroconverting for nCoV spike protein antibodies of 97.5%, the 
2 conditions are met with a probability of 76%. 

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Table 7 
Probabilities (in %) for Assumed True Adverse Reaction Rates and for 
Assumed True Rates of Subjects with Seroconverting for nCoV Spike 
Protein Antibodies and Different Sample Sizes 
 
Sample Size 
90 
200 
603 
True rate of subjects with 
seroconverting for nCoV 
spike protein antibodies (%) 
True rate of subjects with 
seroconverting for nCoV 
spike protein antibodies (%) 
True rate of subjects with 
seroconverting for nCoV 
spike protein antibodies (%) 
True adverse 
reaction rate (%) 
95 
97.5 
100 
95 
97.5 
100 
95 
97.5 
100 
5 
17 
61 
100 
12 
76 
100 
10 
98 
100 
10 
17 
61 
100 
12 
76 
100 
10 
98 
100 
15 
17 
61 
100 
12 
76 
100 
10 
98 
100 
20 
16 
60 
98 
12 
76 
100 
10 
98 
100 
25 
14 
51 
83 
12 
73 
96 
10 
98 
100 
30 
8 
28 
46 
7 
41 
54 
8 
78 
79 
35 
2 
8 
13 
1 
6 
8 
0 
3 
3 
 
10.2 Populations for Analyses 
Safety Set 
The safety set will consist of all subjects who received at least 1 dose of trial vaccine and 
for whom any post-vaccination safety data are available. 
Immunogenicity Set 
The immunogenicity set will include all subjects who received at least 1 dose of trial 
vaccine and for whom the baseline blood sample and at least 1 additional blood sample 
are available for analysis. 
In case a dose level has not been previously administered in Trial CV-NCOV-001, a 
dose-determining set (DDS) is defined and will consist of 4 additional subjects in the 
respective dose level and will be part of the safety set, who have either experienced 
Grade 3 adverse reactions or SAEs considered as related to the trial vaccine according to 
the Investigator at any time during the first 24 hours, or completed the 24-hour observation 
period without experiencing Grade 3 adverse reactions or SAEs considered as related to 
the trial vaccine according to the Investigator. The DDS will be used to confirm the safety 
on untested dose level prior to enrollment into the randomized part at the particular dose 
level. The minimum vaccination and safety evaluation requirements will have been met if 
the subject has received the planned dose of CVnCoV, has been observed for at least 
24 hours following the first vaccine administration and has completed the required safety 
evaluation. Subjects who do not meet these requirements will be regarded as ineligible for 
inclusion in the DDS. Since DDS is only used to confirm safety prior to randomization, the 
DDS is not reported in the tables but Grade 3 adverse reactions and SAEs considered as 
related to the trial vaccine according to the Investigator used for the analyses are marked 
in the listings. 

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10.3 Statistical Analyses 
10.3.1 General Considerations 
All data obtained in this trial and documented in the eCRF will be listed and summarized 
with sample statistics or frequency tables as appropriate. In all tables, listings and figures, 
the dose groups will be reported from the lowest to the highest dose and by age group. 
The safety and immunogenicity analyses will be done overall and by baseline serology 
status for SARS-CoV-2.  
The primary and secondary objectives and endpoints related to seroconversion for 
SARS-CoV-2 spike protein and SARS-CoV-2 neutralizing antibodies will, in addition to the 
immunogenicity set, be analyzed for subjects who: 
• 
Received dose 1 and dose 2 of trial vaccine. 
• 
Have baseline and Day 43 blood samples for immunogenicity assessment. 
• 
Have no major protocol deviations expected to impact the immunogenicity outcomes.  
A statistical analysis plan (SAP) will be prepared and finalized at the latest prior to 
database lock. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all trial objectives and the 
handling of missing data. 
Data on COVID-19 cases from this trial may be pooled with data from other trials 
investigating CVnCoV such as Trials CV-NCOV-004 and CV-NCOV-005. 
10.3.2 Demographic, Medical History and Other Baseline Characteristics 
Data will be summarized with respect to demographic characteristics (age, gender), 
medical history, baseline immune status, and all safety measurements using descriptive 
statistics (quantitative data) and contingency tables (qualitative data) by dose level and 
group. Medical history will only be listed. 
10.3.3 Trial Vaccine Administration 
The administrations of CVnCoV or the active control will be listed and the number of 
vaccinations will be summarized in contingency tables. 
10.3.4 Concomitant Medication and Vaccinations 
Concomitant medication/vaccination after the start of the trial vaccine will be listed and 
summarized by Anatomical Therapeutic Chemical term in contingency tables.  
10.3.5 Primary Analysis 
10.3.5.1 
Primary Safety Analysis 
The safety measurements will include: 
1. AEs (type, intensity, frequency and relationship to trial vaccination), i.e., incidence and 
severity of AEs for both solicited local (injection site pain, redness, swelling, and 
itching) and solicited systemic events (fever, headache, fatigue, chills, myalgia, 
arthralgia, nausea/vomiting, and diarrhea) occurring on the day of vaccination and the 

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following 7 days) and unsolicited events (occurring on the day of vaccination and the 
following 28 days). 
2. SAEs and AESIs throughout the trial. 
Solicited AEs: For reactogenicity assessment, for each dose level and dose in each 
phase, the number and percentage of subjects with at least 1 solicited AE of any kind, by 
severity grade, for local, systemic, and overall, will be summarized after the first 
vaccination, after the second vaccination, after the booster vaccination (if applicable), and 
after any vaccination. In addition, results from the expansion phase will be tabulated by 
group. For subjects with more than 1 episode of the same event, the maximum severity 
will be used for tabulations. In addition, for each dose level and dose in the dose escalation 
and expansion phases, the frequencies and severity of each solicited AE will be 
summarized for each vaccination day and the following 7 days. Similar tabulations will be 
performed for solicited systemic AEs considered as related to the trial vaccine. The 
duration and severity of solicited AEs will be analyzed at subject level.  
In addition, other indicators of safety (e.g., body temperature) will be collected and 
summarized. The number and percentage of subjects with Grade 3 adverse reaction(s) or 
SAEs considered as related to the trial vaccine according to the Investigator with the 95% 
credibility interval based on the Beta (0.5,0.5) prior distribution for each dose level and 
dose will be calculated and summarized.  
Unsolicited AEs: Unsolicited AEs, 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 these events 
will be tabulated at the SOC and PT levels for each dose level and dose in the dose 
escalation and expansion phases. Additional similar tabulations will be performed to 
evaluate severity and relationship to the trial vaccine. AEs that are reported as related to 
the trial vaccine will be considered trial vaccine-related; missing classifications 
concerning trial vaccine relationship will also be considered trial vaccine-related. 
Safety laboratory values will be classified into low/normal/high based on laboratory normal 
ranges. Each parameter will be presented by descriptive statistics at each visit including 
change from baseline. Shift tables normal ranges will be presented. All laboratory values 
will be listed. A separate listing for abnormal lab values will be presented. 
Vital signs will be summarized by descriptive statistics at each visit including change 
from baseline will be presented and a listing will be provided. 
10.3.5.2 
Primary Immunogenicity Analysis 
Percentages of subjects seroconverting for nCoV spike protein antibodies and values of 
antibody levels, percentages of subjects seroconverting for nCoV-neutralizing antibodies 
and GMTs and percentages of immune cell populations and cellular responders will be 
summarized for each dose level. Antibody levels for nCoV spike protein antibodies and 
GMTs for nCoV-neutralizing antibodies will be summarized for each dose level for subjects 
previously exposed to SARS-CoV-2 as indicated by confirmed positive SARS-CoV-2 
serology at baseline. Data will be presented after each vaccine dose. In addition, levels of 
cytokines will be summarized for a subset of subjects. 

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10.3.6 Missing Data 
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 nCoV spike protein antibodies, concentration values marked as below the 
lower limit of quantification (LLOQ) will be set to 0.5*LLOQ.  
Due to the exploratory design of the trial, no imputation of missing values will be done for 
any analysis (except the imputation for missing partial dates of AEs and concomitant 
medication). Reasons for discontinuation from the trial or trial vaccination will be listed and 
summarized. 
Currently no replacement for drop-out subjects is foreseen. 
For safety data, some missing or partially missing variables will be imputed as follows:  
For start date: 
• If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is 
set to missing. 
• If the AE start date year value is less than the vaccination start date year value, the AE 
started before the vaccination. Therefore: 
- 
If the AE year is lower than the vaccination year and the AE month is missing, 
the imputed AE start date is set to the mid-year point (i.e., 01JULYYYY). 
- 
If the AE year is lower than the vaccination year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (i.e., 15MONYYYY). 
• If the AE start date year value is greater than the vaccination start date year value, the 
AE started after vaccination. Therefore, if the AE year is greater than the vaccination 
year and the AE month is missing, the imputed AE start date is set to the year start 
point (i.e., 01JANYYYY). 
For resolution date: 
• If date of resolution is completely missing, it is assumed that it resolved at the date of 
the end of the AE assessment period. 
• If year is present, it is assumed that it resolved on 31 December of that year (i.e., 
31DECYYYY), or at the end of the AE assessment period if earlier. 
• If year and month are present, it is assumed that it resolved on the last day of that 
month, or at the end of the AE assessment period if earlier. 
No other safety variables will be imputed. In case the number of missing/partial dates for 
solicited local AEs, solicited systemic AEs or individual solicited AEs is higher than 
expected for the analysis of durations (in days), a sensitivity analysis will be conducted 
to assess the impact on the primary endpoint. 
10.3.7 Interim Analysis 
One or more interim analyses may be performed for this trial. The analyses will be based 
on a data snapshot. As this trial is of exploratory nature and no inferential statistics are 
planned, no adjustment for multiple testing will be done. Depending on the evolving state 

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of the current pandemic and the public health need, an early analysis may be performed, 
and a study report based on interim data may be written to engage with collaborators 
and/or regulators. 

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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, medical history, and physical assessments) will be entered onto 
eCRFs in a timely fashion by the Investigator and/or the Investigator’s dedicated site staff. 
All data entered into the eCRF must be verifiable against source documents at the trial 
site. 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 contract research organization (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 (European Union member state local or 
competent authorities) or foreign governments (e.g., US-FDA and others). 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. Data collection must be 
completed for each subject who signs an ICF. For subjects who failed to meet the eligibility 
criteria, only demographic data and reason for failure will be documented. 
In accordance with GCP, and regulatory requirements, the trial monitor will perform 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. 
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 

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and closed before database lock. Protocol deviations will be classified as minor, major, or 
critical deviations. The detailed definitions of important protocol deviations leading to 
exclusion 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 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 the 
European Medicines Agency. 
11.4 Data Management and Coding 
All data derived from the trial will remain the property of the Sponsor. Data management 
of this trial will be performed by a CRO. The Sponsor assumes accountability for actions 
delegated to other individuals, e.g., the 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 standard 
operating procedures 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 (see Section 11.3). 
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 the MedDRA for concomitant diseases and AEs and the 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 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 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 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 IEC together with the approved ICF must be filed in the trial files. 
The Investigators will report promptly to the 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 IEC as required. On completion of the trial, the 
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 IEC(s), as well as 
other relevant trial documentation will be submitted to the regulatory authority(ies) of the 
participating country/ies, according to local/national requirements, for review and approval 
before the beginning of the trial.  
Any relevant AEs will be reported to regulatory authorities according to the processes and 
regulations of each country. 
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 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.  

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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.  
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/she 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 discontinued 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. 

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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 a 
CRO (i.e., acting as a data processor), governed by a contract and strictly according to 
and subject to the General Data Protection Regulation (GDPR) and any applicable data 
protection rules and regulations. The Sponsor and the CRO (data processor) will 
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 the subjects. 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, 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 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 ICF. 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 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 will ensure that this report meets the standards of the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). 
13.3 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 studies 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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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 
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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. 
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6. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new 
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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. 
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S0140-6736(20)30251-8. 
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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. 
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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]; 
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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. 
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. 

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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, 
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study. 
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Medicine. 
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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 Coronavirus disease (COVID-19) Weekly Epidemiological Update, 12 October 
2020. https://www.who.int/docs/default-source/coronaviruse/situation-
reports/20201012-weekly-epi-update-9.pdf 
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 
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. 

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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. Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 2007. [Available from: 
https://www.fda.gov/media/73679/download; Accessed 14 July 2020]. 
34. Chen Z, Yuan Y, Li Z, et al. Dose escalation with over-dose and under-dose controls 
in Phase I/II clinical trials. Contemp Clin Trials. 2015;43:133-41. 

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15 APPENDICES 
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 informed consent form 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 informed consent form 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. 

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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 
Safety Laboratory Assessments 
The tests detailed in Table 8 will be performed by the local laboratory.  
Additional tests may be performed at any time during the trial as determined necessary 
by the Investigator or required by local regulations. 
Table 8 
Protocol-Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
Complete blood count including differential and platelets 
Clinical 
Chemistry/Biochemistry 
Magnesium, creatinine, albumin and lactate dehydrogenase, 
C-reactive protein, gamma glutamyl transferase, blood urea 
nitrogen, 
bilirubin 
(direct/indirect), 
calcium, 
alkaline 
phosphatase, sodium, potassium, total protein, glutamic 
oxaloacetic 
transaminase/aspartate 
aminotransferase, 
glutamic pyruvic transaminase/alanine aminotransferase 
Coagulation 
Prothrombin time/international normalized ratio, activated 
partial thromboplastin time 
Pregnancy Tests 
Human chorionic gonadotropin 
The Investigator must document his review of each laboratory safety report, by signing 
and dating the report.  
 

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Appendix 4 
COVID-19 Symptoms Log 
The following table provides an example of a COVID-19 symptom log. This may be adapted according to emerging understanding of 
COVID-19 disease. 
Symptoms 
 
If yes, onset date 
(DD/MMM/YYYY) 
If yes, resolution date 
(DD/MMM/YYYY) 
Fever (≥37.8°C) 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Subjective fever (feeling feverish) 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Chills 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Muscle aches  
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Joint aches  
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Body aches 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Fatigue 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Runny nose 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Sore throat 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Altered voice (hoarseness) 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Cough(new onset or worsening of 
chronic cough) 
☐ Yes ☐ No 
If yes then: 
☐ dry 
☐ productive (with mucous 
production) 
___ /______ /______ 
___ /______ /______ 
Shortness of breath 
☐ Yes ☐ No 
If yes, then: 
☐ when exercising 
☐ at rest 
___ /______ /______ 
___ /______ /______ 
Wheezes 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Nausea or vomiting 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 

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Headache 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Abdominal pain 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Diarrhea (≥3 loose/looser than normal 
stools/24hr) 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Altered or loss of smell  
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Altered or loss of taste 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Loss of appetite 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Seizures 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Altered consciousness 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
Other, 
specify:___________________________ 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 
 

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Appendix 5 
Case Definition for COVID-19 Disease 
According to CEPI’s guidance “COVID-19 Efficacy Endpoints in Interventional Trials: What 
Constitutes an Incident Clinical Disease Case and What Triggers Diagnostic Work-Up 
Version 2.0 dated 25 June 2020”, virologically-confirmed COVID-19 disease is defined as 
follows: 
An RT-PCR-confirmed an acute illness that is clinically consistent with COVID-19 based 
on the presence of at least 1 new-onset symptom: a) persistent cough, b) dyspnea or 
tachypnea (RR >20/min), c) Low peripheral capillary oxygen saturation (SpO2 <95% on 
room air) as measured by pulse-oximetry, d) chest pain, e) Radiographic findings 
consistent with LRTD, f) fever (defined as body temperature of ≥37.8°C, irrespective of 
method), g) myalgia, h) chills, i) loss of smell or taste, j) headache, k) sore throat, 
l) diarrhea. 
There will likely be further updates to this guidance, and the Sponsor will take these into 
consideration during the course of the trial. 

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Appendix 6 
Trial Governance Considerations 
CureVac AG is the Sponsor of this trial. A CRO will coordinate the conduct of this trial. 

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Appendix 7 
Protocol Changes 
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 authority/authorities [CA(s)] and a favorable opinion 
of the 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 
investigational medicinal product, 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 CA(s) and IEC(s) of the 
new events and the measures taken. 

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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 Autoimmune thyroiditis (including Hashimoto 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 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 
Respiratory disorders: 
o Acute respiratory distress syndrome 
o COVID-19 disease 
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 
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 adverse reaction following immunization 
 

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Appendix 10 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of an Adverse Event (AE) 
Definition of an AE: 
• 
An AE is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. 
• 
An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
• 
All AEs fall into 1 of 2 categories: “non-serious” or “serious”. 
Examples of an AE include: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., not related 
to a known concomitant disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after administration of the trial vaccine even 
though it may have been present before the start of the trial. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either trial 
vaccine or a concomitant medication/vaccination. 
• 
An adverse effect of the trial vaccine or concomitant medication/vaccination. 
• 
An accident or injury. 
Events NOT Meeting the AE Definition: 
• 
Medical or surgical procedures or other therapeutic interventions themselves are 
not AEs, but the condition for which the surgery/intervention is required is an AE 
and should be documented accordingly. 
• 
Planned surgical measures and the condition(s) leading to these measures are not 
AEs, if the condition(s) was (were) known before the period of observation (see 
below) and did not worsen during trial. 
In the latter case the condition should be reported as medical history. 
• 
Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the trial that do not worsen. 
Death is not considered an AE but an outcome. 

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Definition of an SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death. 
• 
Is life-threatening. 
The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization: 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• 
Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect in the offspring of the subject. 
• 
Is an important medical event: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 

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Assessment of Intensity and Causality 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the trial and assign it to one of the following categories [34]. 
Absent (Grade 0): No AE. 
Mild (Grade 1): An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate (Grade 2): An event that causes sufficient discomfort to interfere with normal 
everyday activities. 
Severe (Grade 3): An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the trial vaccine 
and each occurrence of each AE/SAE. Causality will be determined as: 
• 
Related: There is a reasonable causal relationship between the trial vaccine 
and the AE. 
• 
Unrelated: There is no reasonable causal relationship between the trial 
vaccine and the AE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. Alternative 
causes, such as underlying disease(s), concomitant therapy or vaccination, and 
other risk factors, as well as the temporal relationship of the event to the trial 
vaccine administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure for CVnCoV in his/her 
assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the CRO. However, it is very 
important that the Investigator always makes an assessment of causality for 
every event before the initial transmission of the SAE data to the CRO. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• 
All local solicited symptoms are considered related to vaccination. 

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Recording of AEs and/or SAEs 
AE and SAE Recording 
• 
The Investigator is responsible for recording all AEs/SAEs observed during the trial 
i.e., from the time the subject gives informed consent until the end of trial visit or 
until the last follow-up visit, for the period described in Section 9.1.1. 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
SAEs need to be reported to the CRO within 24 hours (see section Reporting of 
SAEs). 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to the CRO in lieu of completion of the AE/SAE eCRF screen. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the CRO. In this case, all subject identifiers, with the exception of the 
subject number, will be redacted on the copies of the medical records before 
submission to the CRO. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
• 
AESIs and cases of overdose must be documented and medically assessed by the 
Investigator and the outcome described on the SAE/AESI/overdose/misuse report 
form. 
• 
Pregnancy must be documented and medically assessed by the Investigator and 
the outcome described on the Pregnancy Report Form which is to be sent to the 
CRO. 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
CRO to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a subject dies during participation in the trial or during the follow-up period, the 
Investigator will provide the CRO with a copy of any post-mortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the CRO within 24 hours of 
receipt of the information. 

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Reporting of AEs 
AE Reporting 
• 
It is the responsibility of the Investigator to document all AEs that occur during the 
trial in the source documents. AEs will be elicited by asking the subject a 
non-leading question, for example, ‘Have you experienced any new or changed 
symptoms since we last asked/since your last visit?’. 
• 
The Investigator must document all AEs that occur during the observation period 
set in this protocol on the screens provided in the eCRF. 
The following approach will be taken for documentation: 
All Adverse Events (whether serious or non-serious) which need to be reported must 
be documented on the “Adverse Event” screen of the eCRF. All AEs will be described 
using the sign, symptom, or medical diagnosis on the AE eCRF in standard medical 
terminology in order to avoid the use of vague, ambiguous, or colloquial expressions. 
Each AE will be defined as serious or non-serious according to the definitions in the 
section above. The Investigator will evaluate the severity of each AE and causal 
relationship of the event to the trial vaccine. 
Reporting of SAEs 
SAE Reporting 
• 
If the AE is serious, the Investigator must complete and sign, in addition to the 
“Adverse Event” screen in the eCRF, an “SAE/AESI/overdose/misuse report form” 
at the time the SAE is detected. 
• 
Email or facsimile transmission of the SAE/AESI/overdose/misuse paper report 
form is the preferred method to transmit this information to the CRO /medical 
monitor or the SAE coordinator. 
• 
This form must be marked as “initial” report and sent immediately (i.e., within 24 
hours upon becoming aware of the SAE) to the CRO. 
• 
The Investigator will document the date when any employee/co-Investigator had 
first been aware of the report and fax or e-mail all SAE reports (initial and follow-up 
reports) even if they are incomplete within 24 hours upon receipt to the safety 
department of the Sponsor or CRO. 
• 
In rare circumstances and in the absence of email or facsimile equipment, 
notification by telephone is acceptable with a copy of the SAE data collection tool 
sent by overnight mail or courier service. Initial notification via telephone does not 
replace the need for the Investigator to complete and sign the SAE report form 
within the designated reporting time frames. 
• 
The “initial SAE report” should be as complete as possible, including causality 
assessment, details of the current illness and (S)AE, the reason why the event was 
considered serious; date of onset and end date (if applicable); diagnostic 
procedures and treatment of the event; relevant medical history and concomitant 
medication and vaccinations; and action taken with the trial vaccine(s). The SAE 
report form must be signed by the Investigator or his authorized designee(s). 
• 
Investigator must inform the CRO about AESIs and cases of overdose by applying 
the same timelines and rules of SAE reporting. 

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Determination of Expectedness, Reference Safety Information 
• 
Expectedness will be determined by the CRO according to the designated 
Reference Safety Information provided in the current Investigator’s Brochure. Any 
updates or substantial amendments will be considered accordingly. 
Observation Period 
• 
For the purpose of this trial, the period of observation for collection of AEs required 
to be reported in the eCRF extends from the time the subject gives informed 
consent until the end of the trial, for the period described in Section 9.1.1. 
• 
All AEs that occur in the course of the clinical trial regardless of the causal 
relationship should be monitored and followed up until the outcome is known or it 
is evident that no further information can be obtained. 
• 
There must be documented reasonable attempts to obtain follow-up information 
and outcome. 
• 
It is the responsibility of the Investigator to ensure that any necessary additional 
therapeutic measures and follow-up procedures are performed. 
Post-Trial Events 
• 
If the Investigator becomes aware of any SAE that occurred after the end of the 
trial but is considered to be caused by the trial vaccine(s), this must be reported to 
the CRO. 
• 
These SAEs will be processed by the CRO. Instructions for how to submit these 
SAEs will be provided in a handout in the Investigator Site File. 
Reporting of Other Events 
Reporting and Follow-up of Pregnancies 
• 
Pregnancy is an exclusion criterion for enrollment in this trial, but subjects could 
potentially become pregnant during their active participation in this trial. 
• 
Any pregnancy in a subject having received a trial vaccine must be reported to the 
CRO within 24 hours of the site learning of its occurrence, using a pregnancy 
reporting form. If the subject becomes pregnant during the trial, she will not receive 
any further doses of any Sponsor-supplied trial vaccine. The pregnancy must be 
followed to determine outcome, including spontaneous or voluntary termination, 
details of birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. This follow-up should 
occur even if the intended duration of safety follow-up for the trial has ended. 
• 
The trial site should maintain contact with pregnant subjects to obtain pregnancy 
outcome information. 
• 
Any complications during pregnancy (e.g., gestational diabetes or eclampsia) are 
to be considered as an AE; however, these complications could result in the event 
being an SAE. Spontaneous abortions, fetal death, stillbirth and congenital 
anomalies reported in the baby are always considered as SAEs. The pregnancy by 
itself will not be processed as an SAE. The Investigator will follow the subject until 
completion of the pregnancy and must assess the outcome in the shortest possible 
time but not more than 30 days within completion of the pregnancy. The 

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Investigator should notify the CRO of the outcome of the pregnancy by submitting 
a Follow-up Pregnancy Report. 
 
Reporting and Follow-up of SUSARs and Other Regulatory Reporting 
• 
Any SUSAR will be the subject of expedited reporting. 
• 
The Sponsor and/or the CRO shall ensure that all relevant information about a 
SUSAR that is fatal or life-threatening is reported to the relevant competent 
authorities and IEC(s) within 7 days after knowledge by the Sponsor of such a case 
and that relevant follow-up information is communicated within an additional 8 days. 
• 
The Sponsor will report all serious and unexpected AEs, which are judged by either 
the Investigator or the Sponsor as having a reasonable suspected causal 
relationship (suspected unexpected serious adverse reactions, SUSARs), to the 
competent authority, the concerned Independent Ethics Committee and 
Investigators according to applicable law. 
• 
Post-trial SUSARs that occur after the subject has completed the clinical trial must 
be reported by the Investigator to the Sponsor. 
 
Reporting and Follow-up of Misuse and Overdose 
• 
Drug misuse and drug overdose should always be reported in the same format (i.e., 
on SAE form) and within the same timelines as a SAE, even if they may not result 
in an adverse outcome.  
• 
When an “overdose” or “drug misuse” of the trial vaccine occurs without an AE, the 
Investigator should also complete an “SAE/AESI/overdose/misuse report form” and 
send this to the Sponsor’s safety contact. 
• 
It should be clearly stated that no AE was observed. If no SAE is associated, 
misuse/overdose will be assessed as non-serious. 
• 
In this case, there is no need to complete the “Averse Event” screen in the eCRF. 
 
Product Quality Complaints 
• 
Pharmaceutical Technical Complaints associated with the trial vaccine must be 
reported to the Sponsor immediately (refer to the pharmacy manual for details). 
• 
The same reporting timelines as for SAEs apply.  
 
 

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Appendix 11 
Biological Samples and Record Retention 
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. 
Retention of Trial Records 
Records and source documents pertaining to the conduct of the trial and the distribution 
of the investigational medicinal product (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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Appendix 12 
Protocol Amendment History 
The trial was initiated using protocol version 1.0. 
Protocol version 3.0: 03 December 2021 
This amendment also consolidates changes made in local amendments for each site 
and therefore supersedes Version 2.2 for Panama and Version 2.4 for Peru. 
Overall Rationale for the Amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
All subjects will be unblinded. 
Following the results from the final 
efficacy analysis of the pivotal trial, 
CV-NCOV-004 (HERALD), all 
subjects will be unblinded.  
Throughout 
The Day 393 visit changed to a 
phone contact for subjects who 
did not receive the Day 180 
booster. 
Only subjects who received a 
booster on Day 180 and who 
did not receive a 
licensed/authorized vaccine 
before this visit need to return 
to the site in person. 
To protect the safety of subjects 
during increasing incidence rates of 
COVID-19 cases. 
Throughout 
Clarifications added that 
immunogenicity from Day 57 
will only be evaluated as 
follows: 
Day 57: only subjects who 
receive the Day 57 booster. 
Day 85: only subjects who 
receive the Day 57 booster. 
Day 180: only subjects who 
receive the Day 57 or Day 180 
booster. 
Day 208: only subjects who 
receive the Day 180 booster. 
Day 393: only subjects who 
receive the Day 180 booster. 
Immunogenicity analyses at all time 
points for all subjects are not 
required. 
Synopsis,  
Removal of the exploratory 
objective and associated 
This will not be analyzed. 

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Section # and Name 
Description of Change 
Brief Rationale 
4.1.3 Exploratory 
Objectives,  
4.2.3 Exploratory 
Endpoints 
endpoint to describe the rate of 
asymptomatic infections. 
Synopsis Table 1, 
Table 2 Trial Groups 
and Vaccination 
Schedule 
Updated dose level to be 
administered in the expansion 
phase from “to be determined” 
to 12 µg. 
The optimal dose level for CVnCoV 
was determined to be 12 µg and 
that dose level was further 
investigated in the expansion 
phase. 
Synopsis 
In Trial Visits/Contacts, 
removal of “only for subjects 
receiving the booster dose on 
Day 180” for Day 180 visit. 
Clarification that Day 180 visit is for 
all subjects.  
Synopsis 
In Planned Number of 
Subjects, the planned number 
of subjects in the initial phase 
was increased from 220 to 
223. 
3 more subjects than initially 
planned were enrolled. 
Synopsis, 
6.1 Inclusion Criteria 
 
Addition of inclusion criterion: 
Subjects who are able to 
understand 
and 
willing 
to 
provide informed consent. 
Standard criterion used across 
trials. 
Synopsis, 
6.1 Inclusion Criteria 
Duration of the restriction on 
avoidance of partners of male 
subjects falling pregnant 
changed from the duration of 
the trial to 3 months after the 
last administration. 
A period of 13 months (the entire 
duration of the trial) is not 
necessary. 3 months is consistent 
with the period for female subjects 
to use highly effective methods of 
birth control. 
Synopsis, 
6.2 Exclusion Criteria 
Addition of “or 
licensed/authorized” to 
investigational SARS-CoV-2 
vaccines. 
Several vaccines against 
SARS-CoV-2 have since been 
licensed or authorized. 
2 Schedule of 
Activities 
Footnote added that 
immunogenicity samples on 
Day 180 are only to be 
collected from subjects who 
received the 6 µg dose or the 
booster on Day 57 or Day 180. 
This sample is no longer needed 
for other subjects. 

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Section # and Name 
Description of Change 
Brief Rationale 
2 Schedule of 
Activities 
Footnote added that 
immunogenicity samples at the 
End of Trial visit are only to be 
collected from subjects who 
received the Day 180 booster 
and had not received an 
authorized/licensed vaccine 
before the End of Trial visit. 
This sample is no longer needed 
for other subjects. 
5.6 Justification for 
Dose 
Updated to state that results 
from Trial CV-NCOV-001 
showed that 12 µg is the 
optimal dose level. 
Results from this trial have since 
become available. 
7.7 Therapy Leading 
to Discontinuation 
Text added that subjects may 
receive a licensed/authorized 
SARS-CoV-2 vaccine during 
the trial, but not any 
investigational vaccines or 
vaccines against any other 
coronavirus. 
Several licensed/authorized 
vaccines have become available 
since the start of the trial. 
9.2 Immunogenicity 
Assessments 
Instruction added to not collect 
further immunogenicity 
samples if a subject receives a 
licensed/authorized vaccine. 
Results from these samples would 
not contribute to the 
immunogenicity analyses of 
CVnCoV and collection thereof is 
therefore unnecessary. 
Table 6 
Correction in last column from 
95.2 to 93.2. 
Correction. 
10.3.1 General 
Considerations 
Additional immunogenicity 
analyses added. 
Immunogenicity data will also be 
summarized separately for subjects 
who received both primary doses, 
who have baseline as well as 
Day 43 data available, and who 
have no major protocol deviations 
which could impact the 
immunogenicity outcomes. 
Appendix 4 COVID-19 
Symptoms Log 
Change for fever criterion from 
>37.8°C to ≥37.8°C 
Correction. 
Throughout 
PCR changed to RT-PCR. 
Consistency. 

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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document 
formatting revisions and 
changes based on updated 
data. 
- 
 
Protocol version 2.0: 20 October 2020 
This amendment is 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.  
Overall Rationale for the Amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
Medical Responsible 
Person Updated 
 added as the 
Medical Responsible Person  
To account for team member 
change. 
SAE hotline and 
medical monitor 
contacts 
Contact details for medical 
monitor updated. 
To account for team member 
change. 
Synopsis, 
3.2 Trial Rationale 
Addition of 12 and 16 µg to the 
following sentence: 
At this time, 6 dose levels (2, 4, 
6, 8, 12, and 16 µg) have been 
tested in healthy adults 18 to 
60 years of age. 
Updated to include additional 
dose level tested in the ongoing 
Trial CV-NCOV-001. 
Throughout 
Revision of planned treatment 
groups. Dose in 8 µg cohort 
changed to 12 µg and groups 
within this cohort changed to:  
Group 3 (observer-blind): 
CVnCoV 12 µg on Day 1 and 12 
µg on Day 29 (in subjects 18 to 
60 years of age). 
Group 4 (observer-blind): 
CVnCoV 12 µg on Day 1 and 12 
µg on Day 29 (in subjects >60 
Increase in the dose level to be 
investigated based on the safety 
and immunogenicity data from 
Trial CV-NCOV-001. 

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Section # and Name 
Description of Change 
Brief Rationale 
years of age [i.e., 61 years or 
older]). 
Throughout 
Change in the number of 
subjects in the initial phase of 
the trial. 
Associated with the change in the 
initial groups. 
Throughout 
Addition of a booster dose of 
CVnCoV at Day 57 for a 
subgroup of subjects plus 
associated visits/contacts. 
To investigate 2 different booster 
schedules. 
2 Schedule of activities 
Updated visit numbering. 
To account for addition of a visit 
for the Day 57 booster dose and 
associated visits/contacts. 
2 Schedule of activities 
Addition of optional Phone 
Contact on Day 7. 
To facilitate review of the eDiary 
with the subject at an earlier 
timepoint. 
Synopsis, 
2 Schedule of 
Activities, 
9 Trial Assessments 
and Procedures 
Maximum total volume of blood 
taken over the trial period from 
each subject increased. 
Collection of blood samples will 
be performed at the visits on 
Day 57 and Day 85, which have 
been added for subjects who 
receive the Day 57 booster dose.  
Synopsis, 
4.2.1 Primary 
Endpoints 
Wording of primary endpoints 
revised to specify “Day 1 and 
Day 29”. 
To clarify that the primary safety 
endpoints are evaluated after the 
primary doses and the secondary 
safety endpoints after the booster 
dose. 
Synopsis, 
4.2.2 Secondary 
Endpoints 
Secondary endpoints added to 
account for the following 
secondary objective: To 
evaluate the safety and 
reactogenicity profile after a 
booster dose administration of 
CVnCoV at different dose levels. 
To clarify that the primary safety 
endpoints are evaluated after the 
primary doses and the secondary 
safety endpoints after the booster 
dose. 
Synopsis, 
5.1 Overall Design, 
7.3 Randomization 
and Blinding 
Addition of the following text: 
“Subjects in the initial phase will 
be randomized according to a 
10:1 ratio to receive CVnCoV or 
To clarify randomization ratio for 
the initial phase. 

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Section # and Name 
Description of Change 
Brief Rationale 
the active control in an observer-
blinded manner.” 
Synopsis, 
5.2 Change in Dose 
Level 
Revision of text relating to 
changes of dose level to allow 
for an increase up to 20 µg in 
the case of insufficient 
immunogenicity and a reduction 
in dose from 12 µg to 8 µg in the 
case reactogenicity is too high. 
To facilitate changes in dose 
level. 
5.5 Scientific Rationale 
for Trial Design 
Removed rationale for inclusion 
of double dose group.  
The double dose treatment group 
has been removed from the trial 
design as determined by the 
Steering Committee. 
Synopsis, 
6.1 Inclusion Criteria 
Inclusion criterion 4 revised to 
account for an increase the 
upper limit of body mass index 
to:   
Body mass index (BMI) ≥18.0 
and ≤32.0 kg/m2 
To facilitate recruitment.  
Synopsis, 
6.1 Inclusion Criteria 
Addition of the following text to 
inclusion criterion 6: 
“Male subjects should be 
instructed not to get their 
partners pregnant during the 
study.” 
Clarification 
Synopsis, 
6.2 Exclusion Criteria 
Addition of “(primary dose or 
booster dose)” to exclusion 
criterion 2: 
“Receipt of any other vaccines 
within 28 days prior to 
enrollment in this trial or planned 
receipt of any vaccine within 28 
days of trial vaccine 
administration (primary dose or 
booster dose)”. 
Clarification 
Synopsis, 
6.2 Exclusion Criteria 
Definition of pack year added to 
exclusion criterion 11. 
Clarification 

Clinical Trial Protocol 
 
CV-NCOV-002 
CureVac AG 
V3.0 (03 December 2021) 
CONFIDENTIAL 
Page 101 of 102 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, 
6.2 Exclusion Criteria 
Addition of “virologically “ to 
exclusion criterion 12: 
“History of virologically-
confirmed SARS, MERS, or 
COVID-19 disease or known 
exposure (without any personal 
protective equipment) to an 
individual with confirmed 
COVID-19 disease or 
SARS-CoV-2 infection within the 
past 2 weeks.” 
Clarification 
7.6 Concomitant 
Therapy and Vaccines 
Addition of the following text: 
“As outlined in Section 6.3, 
vaccination will be delayed in 
subjects who take antipyretic 
medication within 8 hours before 
intended trial vaccination, 
however, prophylactic 
paracetamol can be taken after 
vaccination and should be 
documented in the subject’s 
eCRF.” 
Clarification 
7.1.3 Dosing and 
Administration 
Removal of text detailing 
administration instructions for 
the double dose group. 
The double dose treatment group 
has been removed from the trial 
design as determined by the 
Steering Committee. 
9.1.1.1 Solicited 
Adverse Events 
Removed the following text: 
“For Group 4 where 2 injections 
are given in opposite arms, the 
solicited local reactions will be 
documented separately. The 
severity and relatedness for 
each separate solicited local 
reaction should be assessed 
and recorded in the eCRF.” 
The double dose treatment group 
has been removed from the trial 
design as determined by the 
Steering Committee. 

Clinical Trial Protocol 
 
CV-NCOV-002 
CureVac AG 
V3.0 (03 December 2021) 
CONFIDENTIAL 
Page 102 of 102 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, 
9.3 Laboratory Testing 
for COVID-19 Disease 
Text added to clarify procedure 
for performing RT-PCR and 
serological assays locally for 
subjects who have symptoms 
associated with COVID-19 
disease.  
Clarification 
Synopsis, 
9.3 Laboratory Testing 
for COVID-19 Disease 
Addition of the following text 
detailing which antibody tests 
should be performed in subjects 
who have symptoms associated 
with COVID-19 disease: 
“If a serological assay is 
performed, this should look at 
antibodies against N protein 
antigen, but not to antibodies 
against Spike viral antigen, as 
this is part of the vaccine.” 
Clarification 
Synopsis,  
Table 1 Trial Groups 
and Vaccination 
schedule 
Table 5 Sample size 
Changed the number of subjects 
in Group 3 and Group 4 to 
90 subjects each. 
Changed the number of subjects 
in Group 5 and Group 6 to 
9 subjects each.  
Group 3 with 90 subjects go 
against Group 5 with 9 subjects 
and Group 4 with 90 subjects will 
go against Group 6 with 
9 subjects. This will give a 10:1 
ratio. Group 1 and Group 2 were 
randomized at 10:1, but the 
blocks were not completed as this 
was not necessary from a safety 
perspective. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not been 
summarized.