Clinical trial NCT04449276
Conditions: Severe Acute Respiratory Syndrome Coronavirus SARS-CoV-2 COVID-19
Keywords: Safety Reactogenicity Immunogenicity Vaccine CEPI
Sponsor: CureVac
Start date: 2020-06-18; Completion date: 2021-12-21
Enrollment: 280 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study aims to evaluate the safety and reactogenicity profile after 1 and 2 dose administrations of CVnCoV at different dose levels.

Detailed description:
Funded by Coalition for Epidemic Preparedness Innovations (CEPI).

This clinical trial information was submitted voluntarily under the applicable law and, therefore, certain submission deadlines may not apply. (That is, clinical trial information for this applicable clinical trial was submitted under section 402(j)(4)(A) of the Public Health Service Act and 42 CFR 11.60 and is not subject to the deadlines established by sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 11.24 and 11.44.).

Arms: arm 1: Participants will be vaccinated with CVnCoV at escalating dose levels on Day 1 and Day 29. Safety data will inform the decision to continue enrolling at the current dose level, or to proceed to dose escalation. Initially, dose levels of 2, 4 and 8 μg will be evaluated.

Dose levels of 2, 4, 6, 8 and 12µg will be evaluated with potential increase to dose levels up to 20 μg. arm 2: Participants will be given placebo on Day 1 and Day 29.
Interventions: intervention 1: CVnCoV Vaccine intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive an intramuscular injection by needle in the deltoid area. intervention 2: Participants will receive an intramuscular injection by needle in the deltoid area.

Protocol documents:
Prot_000.pdf: 
Protocol Number:  CV-NCOV-001 
 
Official Title:  A Phase 1, partially blind, placebo-controlled, dose-escalation, 
first-in-human, clinical trial to evaluate the safety, reactogenicity and 
immunogenicity after 1 and 2 doses of the investigational SARS-CoV2 mRNA vaccine CVnCoV 
administered intramuscularly in healthy adults. 
 
NCT Number: NCT04449276 
 
Document Date:  24-Jul-2020 


 
 
 
CLINICAL TRIAL PROTOCOL 
COVID-19: 
A Phase 1, partially blind, placebo-controlled, dose-escalation, first-in-human, 
clinical trial to evaluate the safety, reactogenicity and immunogenicity after 
1 and 2 doses of the investigational SARS-CoV-2 mRNA vaccine CVnCoV 
administered intramuscularly in healthy adults 
Protocol Number: 
CV-NCOV-001 
EudraCT Number: 
2020-001286-36 
Investigational product: 
CV07050101 (referred to as CVnCoV) 
Phase: 
Phase 1 
Sponsor: 
CureVac AG 
Schumannstrasse 27 
60325 Frankfurt 
Germany 
Short Title: 
Safety, reactogenicity and immunogenicity of CVnCoV in 
healthy adults 
Protocol Version: 
3.0 
Protocol Date: 
24 July 2020 
 
PROTOCOL VERSION HISTORY: 
Version 1.0 dated 28 May 2020 
Version 2.0 dated 12 June 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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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
COVID-19: A Phase 1, partially blind, placebo-controlled, dose-
escalation, first-in-human, clinical trial to evaluate the safety, 
reactogenicity and immunogenicity after 1 and 2 doses of the 
investigational SARS-CoV-2 mRNA vaccine CVnCoV administered 
intramuscularly in healthy adults 
Protocol Number: CV-NCOV-001 
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, Good Clinical Practice (GCP), and relevant 
International Council on Harmonization (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 


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SAE hotline and medical monitor contacts 
SAE Hotline 
SAE reporting to PRA 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. 
Europe 
 
Name of primary Contact: 
Address: 
Phone: 
Fax: 
Email: 
 
 
 


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TABLE OF CONTENTS 
LIST OF TABLES ........................................................................................................... 7 
LIST OF FIGURES ......................................................................................................... 7 
LIST OF APPENDICES .................................................................................................. 7 
LIST OF ABBREVIATIONS ............................................................................................ 8 
1 
SYNOPSIS ....................................................................................................................10 
2 
SCHEDULE OF ACTIVITIES ........................................................................................25 
3 
INTRODUCTION ...........................................................................................................28 
3.1 
Background ........................................................................................................28 
3.1.1 Coronaviruses.........................................................................................28 
3.1.2 COVID-19 Disease .................................................................................30 
3.2 
Trial Rationale ....................................................................................................30 
3.3 
Risk/Benefit Assessment ....................................................................................31 
3.3.1 Known Potential Risks ............................................................................31 
3.3.2 Known Potential Benefits ........................................................................33 
3.3.3 Assessment of Potential Risks and Benefits ...........................................33 
4 
TRIAL OBJECTIVES AND ENDPOINTS .......................................................................34 
4.1 
Objectives ..........................................................................................................34 
4.2 
Endpoints ...........................................................................................................34 
5 
TRIAL DESIGN .............................................................................................................37 
5.1 
Overall Design....................................................................................................37 
5.2 
Dose Escalation Steps .......................................................................................37 
5.3 
Adaptations to the Trial ......................................................................................44 
5.4 
Stopping Rules ...................................................................................................44 
5.4.1 Individual Stopping Rules .......................................................................44 
5.4.2 Trial Suspension Rule .............................................................................45 
5.5 
Scientific Rationale for Trial Design ....................................................................45 
5.6 
Justification for Dose ..........................................................................................46 
5.7 
End of Trial Definition .........................................................................................47 
6 
TRIAL POPULATION ....................................................................................................48 
6.1 
Inclusion Criteria For All Subjects .......................................................................48 
6.2 
Exclusion Criteria ...............................................................................................49 
6.3 
Vaccine Delay Recommendations ......................................................................50 
6.4 
Failure to Meet Eligibility Criteria ........................................................................51 
7 
TRIAL VACCINE ...........................................................................................................52 
7.1 
Trial Vaccine Administration ...............................................................................52 
7.1.1 Description of the Trial Vaccines .............................................................52 
7.1.2 Dosing and Administration ......................................................................52 
7.2 
Preparation/Handling/Storage/Accountability .....................................................52 
7.2.1 Preparation .............................................................................................52 
7.2.2 Product Storage and Stability ..................................................................52 
7.2.3 Accountability .........................................................................................53 
7.3 
Randomization and Blinding ...............................................................................53 
7.4 
Vaccine Compliance ..........................................................................................54 
7.5 
Misuse and Overdose ........................................................................................54 
7.6 
Concomitant Therapy and Vaccines ...................................................................54 
7.7 
Therapy Leading to Discontinuation ...................................................................54 
7.8 
Treatment After the End of Trial .........................................................................54 
8 
Discontinuation/Withdrawal Criteria ...............................................................................55 
8.1 
Discontinuation of Trial Vaccine Administration ..................................................55 
8.2 
Withdrawal from the Trial ...................................................................................56 
8.3 
Trial Termination ................................................................................................56 
8.4 
Lost to Follow-Up ...............................................................................................57 
9 
TRIAL ASSESSMENTS AND PROCEDURES ..............................................................58 
9.1 
Schedule of Trial Assessments and Procedures ................................................58 


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9.1.1 Visit 1: Day 1 ..........................................................................................58 
9.1.2 Visit 2: Day 2 – Only for Open-Label Sentinel Subjects ...........................60 
9.1.3 Phone Call: Day 2 – Only for Observer-Blind Placebo-Controlled Subjects
 
60 
9.1.4 Phone Call: Day 3 ...................................................................................60 
9.1.5 Visit 3: Day 8 ..........................................................................................61 
9.1.6 Visit 4: Day 15.........................................................................................61 
9.1.7 Visit 5: Day 29.........................................................................................61 
9.1.8 Visit 6: Day 30 – Only for Open-Label Sentinel Subjects .........................62 
9.1.9 Phone Call: Day 30 – Only Observer-Blind Placebo-Controlled Subjects 63 
9.1.10 Phone Call: Day 31 .................................................................................63 
9.1.11 Visit 7: Day 36.........................................................................................63 
9.1.12 Visit 8: Day 43.........................................................................................64 
9.1.13 Visit 9: Day 57.........................................................................................64 
9.1.14 Visit 10: Day 120 (Follow-up Visit) ..........................................................64 
9.1.15 Visit 11: Day 211 (Follow-up Visit) ..........................................................65 
9.1.16 End of Trial Visit: Day 393 ......................................................................65 
9.2 
Safety Assessments ...........................................................................................66 
9.2.1 Adverse Events .......................................................................................66 
9.2.2 Pregnancies ............................................................................................68 
9.2.3 Safety Laboratory Assessments .............................................................68 
9.2.4 Vital Signs, Physical Examination, and ECG ...........................................69 
9.2.5 Medical and Surgical History ...................................................................69 
9.2.6 Safety Monitoring Committees ................................................................69 
9.3 
Immunogenicity Assessments ............................................................................70 
9.3.1 Humoral Immune Response ...................................................................70 
9.3.2 Innate Immune Response – Only for Open-Label Sentinel Subjects .......70 
9.3.3 Cell-Mediated Immunity ..........................................................................71 
9.4 
Laboratory Testing for COVID-19 Disease .........................................................71 
10 STATISTICAL CONSIDERATIONS ...............................................................................73 
10.1 
Sample Size Determination ................................................................................73 
10.2 
Populations for Analyses ....................................................................................74 
10.3 
Statistical Analyses ............................................................................................75 
10.3.1 General Considerations ..........................................................................75 
10.3.2 Demographic, Medical History and Other Baseline Characteristics .........75 
10.3.3 Trial Vaccine Administration ....................................................................76 
10.3.4 Concomitant Medication and Vaccinations ..............................................76 
10.3.5 Primary Analysis .....................................................................................76 
10.3.6 Secondary and Exploratory Analysis .......................................................80 
10.3.7 Missing Data ...........................................................................................80 
10.3.8 Interim Analysis ......................................................................................81 
11 QUALITY CONTROL AND QUALITY ASSURANCE .....................................................82 
11.1 
Electronic Case Report Forms ...........................................................................82 
11.2 
Audit and Inspection ...........................................................................................82 
11.3 
Monitoring ..........................................................................................................82 
11.4 
Data Management and Coding ...........................................................................83 
12 ETHICS .........................................................................................................................84 
12.1 
Independent Ethics Committee ..........................................................................84 
12.2 
Regulatory Authorities ........................................................................................84 
12.3 
Ethical Conduct of the Trial ................................................................................84 
12.4 
Informed Consent ...............................................................................................84 
13 DATA HANDLING AND RECORD KEEPING ................................................................86 
13.1 
Data Protection ..................................................................................................86 
13.2 
Clinical Trial Report ............................................................................................87 
13.3 
Publication Policy ...............................................................................................87 
14 REFERENCES ..............................................................................................................88 


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15 APPENDICES ...............................................................................................................91 
 
LIST OF TABLES 
Table 1 
Schedule of Trial Assessments and Procedures ..........................................25 
Table 2 
Provisional dose levels during dose escalation ............................................41 
Table 3 
Intensity Grading* for Solicited Local Adverse Events ..................................66 
Table 4 
Intensity Grading* for Solicited Systemic Adverse Events ............................67 
Table 5 
Estimate rate of subjects with Grade 3 adverse reaction(s) and 95% 
credibility interval per dose level ...................................................................73 
Table 6 
Probabilities that the rate of Grade 3 adverse reactions is <33% is ≥80% for 
given ‘true’ adverse reactions rates during dose escalation ..........................74 
Table 7 
Distribution of subjects .................................................................................74 
Table 8 
Summary of prior distribution .......................................................................78 
Table 9 
Prior probabilities of Grade 3 adverse reaction at selected doses ................78 
Table 10 
Protocol-Required Safety Laboratory Assessments .....................................93 
Table 11 
Escalation from 2µg to 4µg: Escalate to 4µg if not more than 4 in 12 subjects 
experience a Grade 3 adverse reaction. .......................................................97 
Table 12 
Escalation from 4µg to 8µg: Only borderline scenarios are provided with 
maximum number of Grade 3 adverse reactions at 4µg which just allow to 
escalate. 3 to 4 adverse reactions at 4µg support escalation to 8µg 
depending on the outcome on previous dose levels. ....................................97 
Table 13 
Confirmation of 8µg: Scenarios represent the situations with the maximum 
number of Grade 3 adverse reactions at 8µg which still allow to confirm the 
highest dose level. 3 to 5 adverse reactions at 8µg support confirmation of 
safety of 8 µg depending on the outcome in previous dose levels. ...............98 
Table 14 
Assumed True Dose-Tolerance Scenarios ...................................................99 
Table 15 
Hypothetical Data Scenarios ........................................................................99 
LIST OF FIGURES 
Figure 1 
Genome organization of SARS-CoV-2* compared with other 
betacoronaviruses ........................................................................................29 
Figure 2 
Overview of staggered enrollment and dose escalation ...............................39 
Figure 3 
Prior medians and 95% credibility intervals ..................................................78 
LIST OF APPENDICES 
Appendix 1 
Responsibilities of the Investigator ...............................................................91 
Appendix 2 
Emergency Procedures ................................................................................92 
Appendix 3 
Safety Laboratory Assessments ...................................................................93 
Appendix 4 
COVID-19 Symptoms Log ............................................................................94 
Appendix 5 
Case Definition for COVID-19 Disease .........................................................96 
Appendix 6 
Statistical Appendix Including Model Performance and Data Scenarios .......97 
Appendix 7 
Trial Governance Considerations ............................................................... 100 
Appendix 8 
Protocol Changes ...................................................................................... 101 
Appendix 9 
Potential Immune-Mediated Diseases ........................................................ 102 
Appendix 10 
Adverse Events of Special Interest for SARS-CoV-2 Vaccines .................. 104 
Appendix 11 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................... 105 
Appendix 12 
Biological Samples and Record Retention ................................................. 112 
Appendix 13 
Protocol Amendment History ...................................................................... 113 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANA 
Antinuclear antibody 
ARI 
Acute respiratory infection 
BLRM 
Bayesian logistic regression model 
BMI 
Body mass index 
CCL 
Chemokine ligand 
CEPI 
Coalition for Epidemic Preparedness Innovations 
CMI 
Cell-mediated immunity 
CoV 
Coronavirus 
CRO 
Contract research organization 
CTL 
Cytotoxic T lymphocyte 
CVnCoV 
Investigational SARS-CoV-2 mRNA vaccine 
DDS 
Dose-determining set 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
DSMB 
Data and safety monitoring board 
E 
Envelope 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EWOC 
Escalation with overdose control 
FDA 
US Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GMT 
Geometric mean titer 
hCG 
Human chorionic gonadotropin 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICS 
Intracellular cytokine staining 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IL 
Interleukin 


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IM 
Intramuscularly 
IMP 
Investigational medicinal product 
IP-10 
IFN-γ-induced protein 10 
IRB 
Institutional Review Board 
iSRC 
Internal safety review committee 
IUD 
Intrauterine device 
IUS 
Intrauterine systems 
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 
PCR 
Polymerase chain reaction 
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 
SOP 
Standard operating procedure 
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 1, partially blind, placebo-controlled, dose-escalation, 
first-in-human, clinical trial to evaluate the safety, reactogenicity and 
immunogenicity after 1 and 2 doses of the investigational SARS-CoV-2 
mRNA vaccine CVnCoV administered intramuscularly in healthy adults. 
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 has spread to different parts of China 
and an increasing number of countries worldwide 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 (mRNA) vaccine formulated with lipid nanoparticles 
(referred to as CVnCoV). This first-in-human (FIH) Phase 1 trial will evaluate 
the safety, reactogenicity and immunogenicity of CVnCoV at different dose 
levels using an adaptive dose-finding design. This will allow dose escalation 
or de-escalation using predefined safety criteria and select the CVnCoV dose 
for further clinical development. 
Throughout the trial, cases of COVID-19 disease will be identified and 
documented for later pooling of cases across trials in the clinical development 
program. 
Trial Duration for 
Each Subject: 
Approximately 13 months for each subject. 
Phase: 1 
Objectives: 
All objectives will be analyzed in all subjects, in those subjects retrospectively 
SARS-CoV-2 seronegative at baseline, and in those subjects retrospectively 
SARS-CoV-2 seropositive at baseline. 
Primary 
• 
To evaluate the safety and reactogenicity profile after 1 and 2 dose 
administrations of CVnCoV at different dose levels. 
Secondary 
• 
To evaluate the humoral immune response after 1 and 2 dose 
administrations of CVnCoV at different dose levels. 
Exploratory 
• 
To evaluate the cell-mediated immune response after 1 and 2 dose 
administrations of CVnCoV at different dose levels in all subjects from the 
assigned site(s). 


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• 
To evaluate the innate immune response after 1 and 2 dose 
administrations of CVnCoV at different dose levels in all open-label 
sentinel subjects. 
• 
To identify and assess cases of COVID-19 disease. 
• 
To describe the rate of asymptomatic infections with SARS-CoV-2. 
Overall Design: 
This FIH trial will evaluate the safety, reactogenicity and immunogenicity of 
different dose levels of CVnCoV using an adaptive dose-finding design to 
determine the CVnCoV dose for further clinical development. Due to the 
adaptive design of the trial, the actual number of subjects enrolled might be 
lower or higher than the target numbers. 
Subjects will be enrolled in 2 age categories (18-40 years and 41-60 years) 
with an equal distribution across each category. The trial will include subjects 
with no history of COVID-19 disease as well as subjects with SARS-CoV-2 
positive serology. The SARS-CoV-2 serology status at baseline will be 
evaluated retrospectively to allow separate analyses of subjects 
retrospectively SARS-CoV-2 seronegative at baseline and subjects 
retrospectively SARS-CoV-2 seropositive at baseline. To ensure the 
open-label sentinel subjects in each dose level are seronegative, the 
SARS-CoV-2 serological status will be determined prior to enrollment during 
eligibility assessment in these subjects. Additionally, assessment of 
SARS-CoV-2 serological status may also be performed in the observer-blind 
placebo-controlled part of the trial, to identify subjects with SARS-CoV-2 
positive serology. 
Three provisional CVnCoV dose levels (2, 4 and 8µg) will be evaluated as 
indicated in Synopsis Table 1. To ensure the safety of the subjects, specified 
safety data will be reviewed on a predefined schedule by an internal safety 
review committee (iSRC) with oversight provided by an independent data 
safety monitoring board (DSMB). All subjects will be administered a second 
vaccine dose on Day 29 with the same dose level or placebo as administered 
on Day 1. 
Additional potential dose levels that could be assessed are 1, 3 and 6µg, 
depending on the reactogenicity/safety findings after vaccination with 
respectively 2, 4 and 8µg dose levels; as well as 12, 16 and/or 20µg. 
A schematic overview of the design is provided in Synopsis Figure 1.  
 


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Synopsis Table 1 
Provisional dose levels during dose escalation 
Number of subjects vaccinated per CVnCoV dose level (µg)* 
2µg 
4µg 
8µg 
12/16/20µg**** 
18-40 years 
41-60 years 
18-40 years 
41-60 years 
18-40 years 
41-60 years 
18-40 years 
41-60 years 
1 
- 
- 
- 
- 
- 
 
 
Post-vaccination observation for 24 
hours** 
- 
- 
- 
- 
 
 
1 
2 
- 
- 
- 
- 
 
 
Safety review of 24-hour post dose 1 
data (iSRC+DSMB Chair) 
- 
- 
- 
- 
 
 
4 
4 
- 
- 
- 
- 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
18 + 4 placebo*** 
18 + 4 placebo*** 
2 
2 
- 
- 
 
 
- 
- 
Safety review of 24-hour post dose 1 
data (iSRC+DSMB Chair) 
- 
- 
 
 
- 
- 
4 
4 
- 
- 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
18 + 4 placebo*** 
18 + 4 placebo*** 
2 
2 
 
 
- 
- 
- 
- 
Safety review of 24-hour post dose 1 
data (iSRC+DSMB Chair) 
 
 
- 
- 
- 
- 
4 
4 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
- 
- 
18 + 4 placebo*** 
18 + 4 placebo*** 
2 
2 
- 
- 
- 
- 
- 
- 
Safety review of 24-hour post dose 
1 data (iSRC+DSMB Chair) 
- 
- 
- 
- 
- 
- 
4 
4 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
- 
- 
- 
- 
18 to 60 years 
- 
- 
- 
- 
- 
- 
4***** 
Light grey shaded cells indicate the open-label sentinel groups. 
Dark grey shaded cells indicate the observer-blind placebo-controlled groups. 
* Provisional dose levels of 2, 4 and 8µg will be evaluated. Additional potential dose levels that could be assessed are 1, 3 and 6µg, depending on the reactogenicity/safety 
findings after vaccination with respectively 2, 4 and 8µg dose levels; as well as 12, 16 and/or 20µg. 
** If any Grade 3 ARs are reported within 24 hours following vaccination, the iSRC and DSMB Chair will be consulted before continuation of enrollment of the next 
open-label sentinel subjects. 
*** Including approximately 4 + 1 subjects with SARS-CoV-2 positive serology.  


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**** The next dose level will only be given to subjects once initial data from the previous dose level have been reviewed by the iSRC and DSMB, e.g., if 12µg is 
investigated, it will only be administered after review of the 8µg data (post dose 1 in 12 sentinel subjects), and if the dose level is then escalated to 16µg, it will only be 
administered after review of the 12µg data (post dose 1 in 12 sentinel subjects). 
***** Subjects with SARS-CoV-2 positive serology. 


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Synopsis Figure 1 Overview of staggered enrollment and dose escalation 
 


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 The 12, 16 and/or 20µg dose levels will only be given to subjects once initial data from the previous dose level have been reviewed by the iSRC and DSMB, not in parallel. 
 


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On the first vaccination day, the first open-label sentinel subject aged 
18-40 years confirmed to be SARS-CoV-2 seronegative will be enrolled 
and vaccinated with CVnCoV at the lowest dose level (2µg). The subject 
will be observed for 24 hours after vaccination. If any Grade 3 adverse 
reactions, defined as solicited systemic, solicited local and unsolicited 
Grade 3 adverse events (AEs) considered as related to the trial vaccine 
according to the Investigator, are reported within 24 hours following 
vaccination, the iSRC and DSMB Chair will be consulted. In case no 
safety concerns are identified, the next open-label sentinel group of 
3 subjects (1 aged 18-40 years and 2 aged 41-60 years) confirmed to be 
SARS-CoV-2 seronegative will be enrolled and vaccinated with CVnCoV 
at the lowest dose level (2µg). The 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 from these first 
4 subjects will be collected and reviewed by the iSRC and DSMB Chair. 
In this review, the iSRC and DSMB Chair will review all available safety 
data, but focus specifically on Grade 3 adverse reactions and any serious 
adverse event (SAE) considered as related to the trial vaccine according 
to the Investigator. Based on this review, the iSRC and DSMB Chair will 
decide on the subsequent vaccination of an additional open-label sentinel 
group of 8 subjects (4 aged 18-40 years and 4 aged 41-60 years, 
confirmed to be SARS-CoV-2 seronegative) with the same dose level on 
the next vaccination day (at least 36 hours after the first vaccination day).  
Safety and reactogenicity data of subjects vaccinated on the first and 
second vaccination days will then be collected for at least 60 hours 
post-vaccination from each subject and reviewed by the iSRC and the 
DSMB. Based on this review, the iSRC and DSMB will recommend on 
continuation of enrollment at the same dose level (start of randomized 
expansion in observer-blind placebo-controlled groups) and initiation of 
enrollment in the next dose level: 
• In case of continuation of enrollment at the 2µg dose level, an 
additional 44 subjects will be enrolled, including 10 subjects with 
SARS-CoV-2 positive serology. Of these 44 subjects, 36 (18 aged 
18-40 years and 18 aged 41-60 years) will receive CVnCoV at the 2µg 
dose level, including approximately 8 subjects with SARS-CoV-2 
positive serology. The other 8 subjects (4 aged 18-40 years and 
4 aged 41-60 years) will receive placebo in an observer-blind manner, 
including approximately 2 subjects with SARS-CoV-2 positive 
serology. 
• In case of dose escalation, a newly enrolled open-label sentinel 
group of 4 subjects (2 aged 18-40 years and 2 aged 41-60 years) 
confirmed to be SARS-CoV-2 seronegative will receive the next higher 
dose (4µg) or an intermediate dose depending on iSRC and DSMB 
recommendations. The subjects should be vaccinated at least 
60 minutes apart. In case of favorable outcome of the review by the 
iSRC and DSMB Chair of at least 24-hour post-vaccination data and 
a maximum number of 2 subjects with Grade 3 adverse reactions, an 
additional open-label sentinel group of 8 subjects (4 aged 18-40 years 
and 4 aged 41-60 years, confirmed to be SARS-CoV-2 seronegative) 
will receive the same dose level on the next vaccination day (at least 
36 hours after the first vaccination day within this dose level). 
For each subsequent step, continuation of enrollment within a dose level 
in a placebo-controlled observer-blind manner and dose escalation will be 
assessed by the iSRC and DSMB based on 60-hour post-vaccination 
safety data for each subject, including all available post-vaccination data 
from previously vaccinated subjects. The scheme for staggered 


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enrollment and dose escalation in Synopsis Figure 1 will be pursued if no 
safety concerns are found by the iSRC or DSMB.  
Once the open-label sentinel phase has been successfully concluded for 
a given dose level, enrollment will no longer be restricted to subjects with 
no history of COVID-19 disease or negative serology to SARS-CoV-2, but 
will also include subjects with SARS-CoV-2 positive serology. These 
subjects will be enrolled at pre-defined site(s). For each dose level, the 
iSRC will review at least 24-hour post-vaccination safety data from the 
first 4 seropositive subjects. These first 4 seropositive subjects within 
each dose level should be vaccinated at least 60 minutes apart. 
Vaccination of additional subjects at that dose level and/or vaccination of 
subjects with SARS-CoV-2 positive serology at a higher dose level will 
only proceed upon favorable outcome of this iSRC review.  
All subjects will be administered a second vaccine dose on Day 29 with 
the same dose level of CVnCoV or placebo as administered on Day 1. 
When safety data will be available at least 60 hours post dose 2 for all 
subjects within a dose level, the iSRC and DSMB will review all available 
safety (and, if available, immunogenicity) data to confirm the safety of the 
dose level after the second dose. 
Adaptations to the 
Trial: 
Depending on the safety and immunogenicity of the provisional dose 
levels, additional dose levels might be evaluated. In each case, the 
enrollment schedule will be performed as described in the design section 
above. 
For dose levels >8µg, the enrollment schedule will be performed as 
described in the design section above for the first 12 sentinel subjects. 
After a review of the post dose 1 data from these subjects, 4 subjects 
(aged 18 to 60 years) with SARS-CoV-2 positive serology will be enrolled 
to receive the same CVnCoV dose level. These 4 open-label subjects will 
have the same assessments as subjects in the observer-blind 
placebo-controlled groups and are included when reference is made to 
the observer-blind placebo-controlled groups throughout this protocol. 
In case the lowest dose of 2µg fails to meet the predefined safety criteria, 
a dose de-escalation to 1µg will be initiated. In case the 4µg dose level 
fails to meet the predefined safety criteria, a dose de-escalation to 3µg 
can be initiated. Similarly, in case the 8µg dose level fails to meet the 
predefined safety criteria, a dose de-escalation to 6µg can be initiated.  
Trial 
Visits/Contacts: 
For subjects in the open-label sentinel groups: 
• 
12 protocol-scheduled visits on Day 1, Day 2, Day 8, Day 15, Day 29, 
Day 30, Day 36, Day 43, Day 57, Day 120, Day 211 and Day 393 and 
2 protocol-scheduled telephone contacts (safety calls) on Day 3 and 
Day 31. 
For subjects in the observer-blind placebo-controlled groups: 
• 
10 protocol-scheduled visits on Day 1, Day 8, Day 15, Day 29, 
Day 36, Day 43, Day 57, Day 120, Day 211 and Day 393 and 
4 protocol-scheduled telephone contacts (safety calls) on Day 2, 
Day 3, Day 30 and Day 31. 
Collection of 
Blood Samples: 
At each protocol-scheduled visit, blood samples will be taken for safety 
and/or immunogenicity testing. The maximum total volume of blood taken 
over the trial period from each subject will be (Table 1): 
• 
625mL for subjects in the open-label sentinel groups,  
• 
540mL for subjects in the observer-blind placebo-controlled groups. 


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Safety 
Assessments: 
Reactogenicity will be assessed daily on each vaccination day and the 
following 7 days via collection of solicited local AEs (injection-site pain, 
redness, swelling, and itching) and systemic AEs (headache, fatigue, 
chills, myalgia, arthralgia, nausea/vomiting, and diarrhea) using diary 
cards. In addition, other indicators of safety will be collected (e.g., body 
temperature). 
Diary cards will also be used for collection of unsolicited AEs on each 
vaccination day and the following 28 days. 
SAEs, adverse events of special interest (AESIs) and AEs leading to 
vaccine withdrawal or trial discontinuation will 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, a disease-specific diary card will be completed by 
the subject or the treating health care provider. Non-serious intercurrent 
medical conditions that may affect the immune response to vaccination 
will also be collected throughout the trial. 
Laboratory 
Testing for 
COVID-19 Disease: 
As part of the eligibility assessment, a polymerase chain reaction (PCR) 
for SARS-CoV-2 will be performed. Additionally, for the 12 open-label 
sentinel subjects in each dose level, the SARS-CoV-2 serological status 
will be determined using site-specific diagnostics prior to enrollment to 
ensure they are seronegative. This may also be performed for subjects in 
the observer-blind placebo-controlled part of the trial to identify subjects 
with SARS-CoV-2 positive serology. 
At several pre-defined timepoints during the trial, IgM and IgG serology 
will be assessed. 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 (baseline) serology status for the group/cohorts 
analysis. 
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 should not 
receive any (additional) vaccine dose, but will be closely monitored for 
disease patterns and severity. 
Planned Number 
of Subjects: 
The target is to enroll 56 subjects per dose level for ≤8µg and 16 subjects 
per dose level for >8µg as follows: 
• 
12 subjects per dose level in the open-label sentinel groups 
• 
44 subjects per dose level in the observer-blind placebo-controlled 
groups for the provisional dose levels of 2, 4 and 8µg, and 4 
open-label subjects per dose level for >8µg 
Criteria for 
Inclusion and 
Exclusion: 
Inclusion criteria for all subjects: 
Subjects will be enrolled in this trial only if they meet all of the following 
criteria: 
1. 
Healthy male and female subjects aged 18 to 60 years inclusive. 
Healthy subject is defined as an individual who is in good general 
health, not having any mental or physical disorder requiring regular 
or frequent medication. 
2. 
Expected to be compliant with protocol procedures and available for 
clinical follow-up through the last planned visit. 


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3. 
Physical examination and laboratory results without clinically 
significant findings according to the Investigator’s assessment.  
4. 
Body mass index (BMI) ≥18.0 and ≤30.0kg/m2 (≥18.0 and 
≤32.0kg/m2 for subjects with SARS-CoV-2 positive serology). 
5. 
Females: At the time of enrollment, negative human chorionic 
gonadotropin (hCG) pregnancy test (serum) for women presumed to 
be of childbearing potential on the day of enrollment. On Day 1 
(pre-vaccination): negative urine pregnancy test (hCG), (only 
required if serum pregnancy test was performed more than 3 days 
before). 
6. 
Females of childbearing potential must use highly effective methods 
of birth control from 1 month 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 (IUDs); 
o Intrauterine hormone-releasing systems (IUSs); 
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). 
Exclusion criteria: 
Subjects will not be enrolled in this trial if they meet any of the exclusion 
criteria. 
The following criterion applies to all open-label sentinel subjects: 
1. 
Subjects with SARS-CoV-2 positive serology as confirmed by testing 
at enrollment. 
The following criteria apply to all subjects, except those with SARS-CoV-2 
positive serology: 
2. 
Subjects considered at the Investigator’s discretion to be at 
increased risk to acquire COVID-19 disease (including, but not 
limited to, health care workers with direct involvement in patient care 
or care of long-term care recipients). 
3. 
History of confirmed COVID-19 disease or known exposure to an 
individual with confirmed COVID-19 disease or SARS-CoV-2 
infection within the past 2 weeks. 


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The following criteria apply to all subjects: 
4. 
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. 
5. 
Receipt of any other vaccines within 14 days (for inactivated 
vaccines) or 28 days (for live vaccines) prior to enrollment in this trial 
or planned receipt of any vaccine within 28 days of trial vaccine 
administration. 
6. 
Receipt of any investigational SARS-CoV-2 or other coronavirus 
vaccine prior to the administration of the trial vaccine. 
7. 
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 steroids. Corticosteroids used in the context of 
COVID-19 disease of subjects with SARS-CoV-2 positive serology 
are not exclusionary. 
8. 
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. 
9. 
History of potential immune mediated disease (refer to Appendix 9). 
10. History of angioedema. 
11. Any known allergy, including allergy to any component of CVnCoV 
or aminoglycoside antibiotics. A history of hay fever or seasonal 
allergies (pollinosis) that does not require current treatment (e.g., 
anti-histamines) during the vaccination period (1 month before first 
vaccination until 1 month after last vaccination) is not exclusionary. 
12. History of or current alcohol and/or drug abuse. 
13. 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.  
14. Acute or currently active SARS-CoV-2 infection as confirmed by 
reactive PCR within 3 days of first trial vaccine administration. 
15. History of confirmed SARS or MERS. 
16. Administration of immunoglobulins (Igs) and/or any blood products 
within the 3 months preceding the administration of any dose of the 
trial vaccine. 
17. Presence or evidence of significant acute or chronic medical or 
psychiatric illness. Significant medical or psychiatric illnesses include 
but are not limited to: 
o Respiratory disease (e.g., chronic obstructive pulmonary disease, 
asthma) requiring daily medications currently or any treatment of 
respiratory disease exacerbations (e.g., asthma exacerbation) in 
the last 5 years. 
o Respiratory disease with clinically significant dyspnea in the last 
5 years (except COVID-19 disease in subjects with SARS-CoV-2 
positive serology). 
o Asthma 
medications: 
inhaled, 
oral, 
or 
intravenous 
(IV) 
corticosteroids, leukotriene modifiers, long- and short-acting beta 
agonists, theophylline, ipratropium, biologics.  


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o Significant cardiovascular disease (e.g., congestive heart failure, 
cardiomyopathy, ischemic heart disease, history of stroke, 
peripheral artery disease, pulmonary embolism) or history of 
myocarditis or pericarditis as an adult. 
o Elevated blood pressure or hypertension, even if well-controlled.  
o Diabetes mellitus type 1 or 2. 
o History of any neurological disorders or seizures including 
Guillain-Barré syndrome, with the exception of febrile seizures 
during childhood. 
o Current or past malignancy, unless completely resolved without 
sequelae for >5 years. 
18. Foreseeable non-compliance with protocol as judged by the 
Investigator. 
19. For females: pregnancy or lactation. 
20. History of any anaphylactic reactions. 
21. Subjects with impaired coagulation or any bleeding disorder in whom 
an intramuscular injection or a blood draw is contraindicated. 
22. Subjects employed by the Sponsor, Investigator or trial site, or 
relatives of research staff working on this trial. 
Endpoints: 
Primary 
• 
The frequencies of Grade 3 adverse reactions and any SAE 
considered as related to the trial vaccine within at least 24 hours after 
the first vaccination by dose level, for decisions on subsequent 
vaccination of an additional open-label sentinel group with the same 
dose level. 
• 
The frequencies of Grade 3 adverse reactions and any SAE 
considered as related to the trial vaccine within at least 60 hours after 
the first vaccination by dose level, for decisions on dose escalation 
as well as continuation of enrollment at the same dose level in the 
observer-blind placebo-controlled part of the trial. 
• 
The frequencies, intensities and duration of solicited local AEs on 
each vaccination day and the following 7 days by dose and dose 
level, for the characterization of the safety and reactogenicity profile. 
• 
The frequencies, intensities, duration and relationship to trial 
vaccination of solicited systemic AEs on each vaccination day and 
the following 7 days by dose and dose level, for the characterization 
of the safety and reactogenicity profile. 
• 
The occurrence, intensities and relationship to trial vaccination of 
unsolicited AEs on each vaccination day and the following 28 days by 
dose and dose level, for the characterization of the safety and 
reactogenicity profile. 
• 
The occurrence and relationship to trial vaccination of SAEs and 
AESIs at predefined time points throughout the trial, for the 
characterization of the safety and reactogenicity profile. 


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Secondary* 
On Day 8, Day 15, Day 29, Day 36, Day 43, Day 57, Day 120, Day 211 
and Day 393: 
• 
The proportion of subjects seroconverting for SARS-CoV-2 spike 
protein antibodies, as measured by ELISA. 
In subjects who did not get exposed to SARS-CoV-2 before the trial, 
or during the trial before the applicable sample was collected, as 
measured by ELISA to SARS-CoV-2 N-antigen, seroconversion is 
defined as an increase in titer in antibodies against SARS-CoV-2 
spike protein versus baseline. 
In subjects seropositive for SARS-CoV-2 at baseline, seroconversion 
is defined as a 2-fold increase in titer in antibodies against 
SARS-CoV-2 spike protein versus baseline. 
• 
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, in subjects who did not get 
exposed to SARS-CoV-2 before the trial or during the trial before the 
applicable sample was collected, as measured by ELISA to 
SARS-CoV-2 N-antigen. 
• 
The proportion of subjects seroconverting for SARS-CoV-2 
neutralizing antibodies, as measured by an activity assay. 
In subjects who did not get exposed to SARS-CoV-2 before the trial 
or during the trial before the applicable sample was collected, as 
measured by ELISA to SARS-CoV-2 N-antigen, seroconversion is 
defined as an increase in titer in SARS-CoV-2 neutralizing antibodies 
versus baseline.  
In subjects seropositive for SARS-CoV-2 at baseline, seroconversion 
is defined as a 2-fold increase in titer in SARS-CoV-2 neutralizing 
antibodies versus baseline. 
• 
Individual SARS-CoV-2 neutralizing antibody levels in serum. 
• 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as measured 
by an activity assay, in subjects who did not get exposed to 
SARS-CoV-2 before the trial or during the trial before the applicable 
sample was collected, as measured by ELISA to SARS-CoV-2 
N-antigen. 
* Samples may be used for assay validation and additional studies of the 
mechanism of action of the vaccine. 
Exploratory* 
Cell-mediated immune response 
On Day 29, Day 36 and Day 211** in peripheral blood mononuclear cells 
(PBMCs) from all subjects at the assigned site(s): 
• 
The frequency and functionality of SARS-CoV-2 spike-specific T-cell 
response after antigen stimulation. 
Intracellular cytokine staining (ICS) to investigate Th1 response and 
production of Th2 markers (e.g. secreted IL-5) will be used to 
investigate whether vaccination induces a Th1 shift from baseline. 
Further T-cell immune response maybe 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. 
** Testing of samples collected on Day 211 will be done only in subjects 
categorized as T-cell responders on Day 29 and/or Day 36. 


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Innate immune response 
On Day 2, Day 8, Day 29, Day 30 and Day 36 in all open-label sentinel 
subjects: 
• 
Serum cytokine concentrations, including but not limited to interferon 
(IFN)-α, IFN-γ, interleukin (IL)-6, chemokine ligand (CCL) 2 and 
IFN-γ-induced protein 10 (IP 10). 
• 
Gene expression profiling. 
* Samples may be used for assay validation and additional studies of the 
mechanism of action of the vaccine. 
Evaluation of infection 
• 
Number of subjects with virologically-confirmed SARS-CoV-2 
infection as measured by reverse transcription (RT)-PCR at clinically 
determined time points throughout the trial. 
• 
Number of subjects with asymptomatic SARS-CoV-2 infection as 
measured by retrospective serology at predefined time points. 
Safety Monitoring 
Committees: 
An iSRC will be established consisting of the Principal Investigator at 
each trial site, the Medical Monitor and medical representatives of the 
Sponsor. The iSRC and DSMB Chair will review all available safety data 
obtained during at least 24 hours post-vaccination for each open-label 
sentinel subject vaccinated on the first vaccination day per dose level, 
and assess for Grade 3 adverse reaction(s) and any SAE considered as 
related to the trial vaccine according to the Investigator. Based on this 
review, the iSRC and DSMB Chair will decide on the enrollment of the 
subjects planned on the next vaccination day within each dose level. The 
iSRC will also perform ongoing safety assessments for subjects beyond 
the first 24 hours on all available data. The iSRC will review at least 
24-hour post-vaccination safety data from the first 4 seropositive subjects 
enrolled at each dose-level. 
In addition, the iSRC together with the DSMB will review all available 
safety data obtained during at least 60 hours post-vaccination for each 
subject to recommend on continuation of enrollment at the same dose 
level and dose escalation. 
If no stopping rule is met, the DSMB Chair can decide to allow trial 
progression without obtaining a DSMB quorum. 
The DSMB may recommend additional measures including modification 
or halt of the trial. 
Sample Size 
Justification: 
This trial is designed to be primarily descriptive and hence, its sample size 
was not determined based on formal statistical power calculations. 
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 one additional blood sample are available for analysis. 
Statistical 
Methodology: 
Missing data/discontinuation: 
Due to the dose escalation and 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.  


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Statistical 
Analyses: 
Analysis of Demographics and Other Baseline Characteristics: 
Data will be summarized with respect to demographic and baseline 
characteristics, medical history, immune response measurements, and all 
safety measurements using descriptive statistics (quantitative data) and 
contingency tables (qualitative data) by dose level and arm. 
Safety Analyses 
The safety analyses will be performed for all subjects, for subjects 
retrospectively SARS-CoV-2 seronegative at baseline, and for subjects 
retrospectively SARS-CoV-2 seropositive at baseline. 
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 and 
after any vaccination. The results will be tabulated by dose level and arm. 
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 
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. 
Immunogenicity Analysis: 
Descriptive statistics for the immunogenicity endpoints will be provided by 
arm for each dose level. Data will be presented after each vaccine dose. 
Individual values and GMT of SARS-CoV-2 spike protein antibody levels 
and of SARS-CoV-2 neutralizing antibodies, percentages of immune cell 
populations and cellular responders will be summarized for each dose 
level in all subjects, in those subjects retrospectively SARS-CoV-2 
seronegative at baseline, and in those subjects retrospectively 
SARS-CoV-2 seropositive at baseline. For subjects who do not get 
exposed to SARS-CoV-2 before the trial, or 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 PCR-positive swab during the 
trial), percentages of subjects seroconverting for SARS-CoV-2 
spike-protein antibodies and SARS-CoV-2 neutralizing antibodies will be 
summarized at each dose level. In addition, for the open-label sentinel 
groups, levels of cytokines and changes in gene transcripts will be 
summarized. This analysis may also be performed separately in subjects 
retrospectively SARS-CoV-2 seronegative at baseline and subjects 
retrospectively SARS-CoV-2 seropositive at baseline. 
 


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2 SCHEDULE OF ACTIVITIES 
Table 1 
Schedule of Trial Assessments and Procedures 
 
Vaccination Period 
Follow-up 
End 
of 
Trial 
Contact Type 
Clinic 
Visit 
Clinic Visit/ 
Phone Calla 
Phone 
Call 
Clinic Visit 
Clinic Visit/ 
Phone Calla 
Phone 
Call 
Clinic Visit 
Clinic Visit 
Clinic 
Visit 
Visit Number 
1b 
2 
- 
- 
3 
4 
5 
6 
- 
- 
7 
8 
9 
10 
11 
12 
Visit Window (days) 
n/a 
-0/+0 
-0/+0 
-0/+0 
-0/+1 
-0/+1 
-0/+4 
-0/+0 
-0/+0 
-0/+0 
-0/+1 
-0/+1 
-0/+4 
±14 
±14 
-
0/+30 
Trial Day 
1 
2 
2 
3 
8 
15 
29 
30 
30 
31 
36 
43 
57 
120 
211 
393 
Anchoring 
- 
1 
1 
1 
1 
1 
1 
29 
29 
29 
29 
29 
29 
29 
29 
29 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
Review of criteria for delay or cancellation 
of vaccinationc 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Administration of CVnCoV or placebo 
(including 4h observation) 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Safety Monitoring 
Physical examinationd  
Xe 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Symptom-directed physical examinationd 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
Vital signsd,f 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary dispensingg 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Diary (re)trainingg 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
 
Diary reviewg 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Diary reminderg 
 
X 
Xh 
Xh 
X 
X 
 
X 
Xh 
Xh 
X 
X 
 
 
 
 
Diary collectiong 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Solicited AEsg 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Unsolicited AEsg 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
SAEsi 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 


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Vaccination Period 
Follow-up 
End 
of 
Trial 
Contact Type 
Clinic 
Visit 
Clinic Visit/ 
Phone Calla 
Phone 
Call 
Clinic Visit 
Clinic Visit/ 
Phone Calla 
Phone 
Call 
Clinic Visit 
Clinic Visit 
Clinic 
Visit 
Visit Number 
1b 
2 
- 
- 
3 
4 
5 
6 
- 
- 
7 
8 
9 
10 
11 
12 
Visit Window (days) 
n/a 
-0/+0 
-0/+0 
-0/+0 
-0/+1 
-0/+1 
-0/+4 
-0/+0 
-0/+0 
-0/+0 
-0/+1 
-0/+1 
-0/+4 
±14 
±14 
-
0/+30 
Trial Day 
1 
2 
2 
3 
8 
15 
29 
30 
30 
31 
36 
43 
57 
120 
211 
393 
Anchoring 
- 
1 
1 
1 
1 
1 
1 
29 
29 
29 
29 
29 
29 
29 
29 
29 
Intercurrent medical conditionsi 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
AEs leading to premature discontinuationi 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
AESIsi 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Concomitant medication/vaccination 
Xj 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Safety lab (~9mL)k 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Safety lab in case of abnormal result at 
previous visit (~9mL)k 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
Serum pregnancy test (~3mL)l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testm 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
TSH, thyroid antibodies, ANA (~3mL)n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Swab collection for PCR testingo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the open-label sentinel subjects in each 
dose level: 
Antibody diagnostics (serum) (~6mL)p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicityq 
ELISA (serum) (~12mL)r 
Xs 
 
 
 
X 
X 
Xs 
 
 
 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 neutralizing activity (serum) 
(~12mL) 
Xs 
 
 
 
X 
X 
Xs 
 
 
 
X 
X 
X 
X 
X 
X 
In all open-label sentinel subjects: 
Cytokine assessment (serum) (~6mL) 
Xs 
X 
 
 
X 
 
Xs 
X 
 
 
X 
 
 
 
 
 
In all open-label sentinel subjects: 
Gene expression profiling (PAXgene® blood 
RNA system) (~5mL) 
Xs 
X 
 
 
X 
 
Xs 
X 
 
 
X 
 
 
 
 
 
In all subjects from assigned site(s): 
Cell-mediated immunity (~40-64mL)t 
Xs 
 
 
 
 
 
Xs 
 
 
 
Xu 
 
 
 
X 
 
Maximum total blood volume (mL) 
120 
20 
- 
- 
45 
35 
85 
20 
 
- 
85 
35 
35 
35 
75 
35 
Trial end 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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AE: adverse event; AESI: adverse event of special interest; ANA: antinuclear antibody; ECG: electrocardiogram; ELISA: enzyme-linked immunosorbent assay;  
PBMC: peripheral blood mononuclear cell; PCR: polymerase chain reaction; RNA: ribonucleic acid; SAE: serious adverse event; TSH: thyroid-stimulating-hormone 
a. The Day 2 and Day 30 contacts will only be conducted as visits for subjects in the open-label sentinel groups. 
b. 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, including laboratory results, need to be reviewed on the 
day of vaccination prior to trial vaccine administration. 
c. 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. 
d. Physical examination and vital signs must be performed/measured by a qualified healthcare professional. See Section 9.2.4 for an overview of the required 
assessments. 
e. 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. 
f. Vital signs will be measured pre- and post-vaccination prior to discharge. Subjects will be observed for 4 hours following each vaccination. Vital signs must be within 
normal or clinically non-relevant abnormal ranges or have returned to pre-vaccination values for the subject to be discharged. 
g. Diaries for recording of post-vaccination solicited/unsolicited AEs. Solicited AEs occurring on the day of vaccination (Day 1 and Day 29) and for the following 7 days 
and unsolicited AEs occurring on the day of vaccination (Day 1 and Day 29) and for the following 28 days will be recorded by the subject on the diary cards.  
h. During the phone calls, the subject´s general well-being should be checked and the subject should be reminded to complete the safety information on the diary cards. 
i. 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. 
j. Concomitant medication/vaccination taken within 6 months prior to enrollment should be recorded to establish eligibility. 
k. See Appendix 3 for an overview of the safety laboratory assessments. 
l. A 3mL blood sample will be taken for pregnancy testing of women of childbearing potential. 
m. Urine pregnancy tests will be performed before each vaccination for women of childbearing potential, unless the serum pregnancy test was performed less than 
3 days before and yielded a negative result. 
n. 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). 
o. 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 9.4). 
p. Antibody diagnostics may also be performed in the observer-blind placebo-controlled part of the trial to identify subjects with SARS-CoV-2 positive serology. 
q. See Section 9.3 for an overview of the immunogenicity assessments. 
r. IgG and IgM ELISA will be performed on SARS-CoV-2 spike protein to investigate seroconversion and on SARS-CoV-2 N-antigen for determination of seronegativity 
to natural infection. 
s. Baseline blood samples on Day 1 and Day 29 must be collected on the day of vaccination prior to vaccination. 
t. The blood volume to be collected for cellular immune response will be 64mL on Day 1 and 40mL on Days 29, 36 and 211. 
u. In case Visit 7 (Day 36) cannot take place (e.g., due to a public health emergency), the blood sample for cell-medicated immunity assessment should be taken at 
Visit 8 (Day 43). 
 


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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 9 January 2020, a novel CoV, named severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), was officially identified as the cause 
of an outbreak of viral pneumonia in Wuhan. In the following weeks, the virus spread 
rapidly within China and an increasing number of countries worldwide. On 7 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 
 
* SARS-CoV-2 was initially named 2019-nCoV as indicated in the figure. 
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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To date, there is no information available on the immune responses to SARS-CoV-2. An 
immunoinformatics approach predicted 5 cytotoxic T lymphocyte (CTL) epitopes, 3 
sequential B cell epitopes and 5 discontinuous B cell epitopes in the S glycoprotein [9]. 
Simulations suggested that the CTL epitopes bind the major histocompatibility complex 
class I peptide-binding grooves via multiple contacts, with continuous hydrogen bonds and 
salt bridge anchors, supporting their potential in generating immune responses. Of note, 
the trial found only one overlapping CTL epitope between MERS-CoV and SARS-CoV-2 
and no comparable epitopes with SARS-CoV. 
3.1.2 COVID-19 Disease 
SARS-CoV-2 is transmitted mainly through close contact and respiratory droplets. The 
mean incubation period is 4-6 days with about 95% of patients developing symptoms 
within 14 days after infection [10,11]. The most common symptoms of 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 4% [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 22 July 2020, 
according to WHO, 14 765 256 cases have been confirmed globally, including 612 054 
deaths [21]. 
3.2 Trial Rationale 
In spite of the severity of respiratory disease caused by emerging CoVs, there is currently 
no licensed vaccine available for prevention of CoV-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 (LNP), referred to as CVnCoV, for the prevention of COVID-19 
disease when administered as a 2-dose primary vaccination schedule. This first-in-human 


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(FIH) Phase 1 trial will evaluate the safety, reactogenicity and immunogenicity of CVnCoV 
at different dose levels. Since it is considered critical to establish the safety and 
reactogenicity in participants with pre-existing immune responses, to allow vaccination in 
efficacy and other large future clinical trials as well as future public health vaccination 
campaigns without the need to incorporate baseline serology assessments in all 
participants or potential vaccines, the trial will also enroll previously infected subjects to 
allow evaluation of the safety and reactogenicity in the context of pre-existing immunity. 
CVnCoV has been developed with CureVac’s proprietary RNActive® technology platform, 
which uses chemically unmodified mRNA molecules as a basis for vaccination. 
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 
more detailed epidemiological 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. 
As with every vaccination and based on previous clinical experience with other RNActive® 
vaccines, local reactions, i.e., pain, redness, itching and swelling at the injection site, and 
systemic adverse events (AEs), i.e., fever, headache, fatigue, chills, myalgia, arthralgia, 
nausea/vomiting and diarrhea, are expected side effects that typically resolve within 
24 hours after the vaccination with or without corrective treatment with antipyretics [23, 
24, 25, 26]. After administration of CureVac’s Rabies mRNA investigational vaccine 
formulated with LNP (CV7202), in addition to the systemic AEs described above, a few 
subjects experienced decreased appetite, night sweats and tachycardia. 
As for every vaccine, the occurrence of allergic/anaphylactic reactions cannot be excluded 
and emergency equipment for the treatment of such reactions must be available at the 
trial site. These events are unexpected and constitute a potential important medical risk. 
So far, no allergic/anaphylactic reactions have been observed in the completed and 
ongoing clinical trials after repeated administration of protamine-formulated RNActive® 
vaccines, nor after administration of CV7202 at different dose levels (1µg, 2µg and 5µg) 
in the first-in-human (FIH) CV-7202-104 trial. 
Vaccine Dependent Disease Enhancement (VDE) describes a phenomenon in which 
pre-existing immunity is not enough to neutralize viral infection and may lead to severe 
disease progression. The risk of antibody-dependent enhancement (ADE), and more 
generally VDE, by CVnCoV is considered low. The factors that are postulated to contribute 
to VDE (based on observations in animal studies for SARS or MERS) are the use of 
inactivated virus, recombinant wild-type non-stabilized S-protein, nucleoprotein vaccines, 
alum or other adjuvants inducing a Th2 bias; by design these factors are not applicable to 
CVnCoV. 
The design rationale for the stabilized pre-fusion S-protein in CVnCoV was also based on 
the strategy used for MERS-CoV [27] and has been shown to lead to a better ratio of 
functional (virus neutralizing titers [VNT]) to binding antibodies (enzyme-linked 
immunosorbent assay [ELISA] titers) for eliciting a more protective immune response. 


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Based on its design and mode-of-action, it is expected that CVnCoV, an mRNA vaccine 
candidate expressing pre-fusion stabilized full-length S-protein, is unlikely to induce VDE. 
Furthermore, CVnCoV is inducing a balanced immune response, as observed in 
preclinical studies and documented in the Investigator’s Brochure, and previous evidence 
that RNA vaccines are triggering TLR-stimulation (TLR7) resulting in type I interferon (IFN) 
induction [28]. Indeed, current pharmacology data with CVnCoV indicate induction of 
type I IFN with no (interleukin [IL]-4 and IL-13) or very low (IL-5) induction of cytokines 
indicative of a Th2 response. Th2 response has been shown to be associated with 
enhanced disease in animal models (refer to Section 4.1.2 of the Investigator’s Brochure, 
in vivo Pharmacology Studies) [29]. While the VDE risk to subjects vaccinated with 
CVnCoV in the clinic are considered minimal, nevertheless, the potential risk for VDE will 
be evaluated in this trial designed to address the high unmet medical need due to the 
COVID-19 pandemic. As part of the clinical assessment in this trial, neutralizing antibodies 
will be determined and the induction of Th1 response will be investigated by cellular 
immunomonitoring with the specific aim to assess the risk of VDE prior to enrolling a larger 
number of subjects into Phase 2/3 clinical trials. Participants who experience COVID-19 
disease during the trial will be followed closely to ensure clinical symptoms and safety 
data are collected and disease progression can be monitored and reported. In parallel with 
this trial, animal challenge models will be evaluated before initiation of the Phase2/3 trials.  
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 and will be evaluated in 
parallel with this clinical trial, 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 (ICMRA) [31].  
Based on this information, the preclinical data package and measures to minimize 
potential VDE risk for human subjects are considered sufficient to initiate this FIH trial. 
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. 
Developmental toxicity studies have not been performed for CVnCoV. No 
histopathological alterations in the reproductive organs were identified in the local 
tolerance or repeat-dose toxicology studies in rat or rabbit, and toxicologically relevant 
levels of RNA were not detected in reproductive organs in the biodistribution study. 
Therefore, the teratogenicity risk is deemed low. However, given that human data on 
pregnancies is not available, the teratogenic risk associated with CVnCoV administration 
cannot be ruled out at this moment. For this reason, inclusion of female subjects of 
childbearing potential requires use of a highly effective contraceptive measure from 
1 month before the first administration of the trial vaccine until 3 months following the last 
administration. 
Due to the theoretical possibility of non-specific immune stimulating properties of CVnCoV, 
it cannot be excluded that pre-existing potential immune mediated diseases (pIMDs) may 
be aggravated, become clinically apparent for the first time or triggered after vaccination 


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with CVnCoV. Such reactions have been very rarely described after administration of other 
vaccines but the causal relationship between vaccination and the induction or aggravation 
of pIMDs is uncertain and is therefore a theoretical risk. These events are considered 
unexpected for CVnCoV. 
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 (interferon-α, interleukin-2) may increase the response to the vaccines which 
could theoretically result in increased efficacy but also in an increased risk of toxicity. 
3.3.2 Known Potential Benefits 
Subjects receiving the investigational CVnCoV vaccine may not directly benefit from this 
vaccination since the immune response has not yet been evaluated in humans and it is 
thus not known if the vaccine is effective in protecting against COVID-19 disease. 
Furthermore, no correlate of protection or threshold of protection has been established for 
COVID-19 disease up to now. 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]). 
3.3.3 Assessment of Potential Risks and Benefits 
To minimize the risk for subjects participating in this FIH trial, an internal safety review 
committee (iSRC) and data safety monitoring board (DSMB) will oversee the safety of the 
participating subjects on a specified schedule throughout the trial (see Section 9.2.6). All 
subjects will be closely observed on site for 4 hours after administration of each vaccine 
dose. 
Potential important medical risks associated with CVnCoV, as specified in Section 3.3.1, 
can be managed at clinical trial sites in a Phase 1 setting should they occur. 


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4 TRIAL OBJECTIVES AND ENDPOINTS 
4.1 Objectives 
All objectives will be analyzed in all subjects, in those subjects retrospectively 
SARS-CoV-2 seronegative at baseline, and in those subjects retrospectively SARS-CoV-2 
seropositive at baseline. 
Primary objectives: 
• 
To evaluate the safety and reactogenicity profile after 1 and 2 dose administrations 
of CVnCoV at different dose levels. 
Secondary objective: 
• 
To evaluate the humoral immune response after 1 and 2 dose administrations of 
CVnCoV at different dose levels. 
Exploratory objectives: 
• 
To evaluate the cell-mediated immune response after 1 and 2 dose administrations 
of CVnCoV at different dose levels in all subjects from the assigned site(s). 
• 
To evaluate the innate immune response after 1 and 2 dose administrations of 
CVnCoV at different dose levels in all open-label sentinel subjects. 
• 
To identify and assess cases of COVID-19 disease. 
• 
To describe the rate of asymptomatic infections with SARS-CoV-2. 
4.2 Endpoints 
Primary endpoints: 
• 
The frequencies of Grade 3 adverse reactions and any serious adverse event (SAE) 
considered as related to the trial vaccine within at least 24 hours after the first 
vaccination by dose level, for decisions on subsequent vaccination of an additional 
open-label sentinel group with the same dose level. 
• 
The frequencies of Grade 3 adverse reactions and any SAE considered as related 
to the trial vaccine within at least 60 hours after the first vaccination by dose level, 
for decisions on dose escalation as well as continuation of enrollment at the same 
dose level in the observer-blind placebo-controlled part of the trial. 
• 
The frequencies, intensities and duration of solicited local AEs on each vaccination 
day and the following 7 days by dose and dose level, for the characterization of the 
safety and reactogenicity profile. 
• 
The frequencies, intensities, duration and relationship to trial vaccination of solicited 
systemic AEs on each vaccination day and the following 7 days by dose and dose 
level, for the characterization of the safety and reactogenicity profile. 
• 
The occurrence, intensities and relationship to trial vaccination of unsolicited AEs 
on each vaccination day and the following 28 days by dose and dose level, for the 
characterization of the safety and reactogenicity profile. 
• 
The occurrence and relationship to trial vaccination of SAEs and AESIs at 
predefined time points throughout the trial, for the characterization of the safety and 
reactogenicity profile. 


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Secondary endpoints*: 
On Day 8, Day 15, Day 29, Day 36, Day 43, Day 57, Day 120, Day 211 and Day 393:  
• 
The proportion of subjects seroconverting for SARS-CoV-2 spike protein antibodies, 
as measured by ELISA. 
In subjects who did not get exposed to SARS-CoV-2 before the trial, or during the 
trial before the applicable sample was collected, as measured by ELISA to 
SARS-CoV-2 N-antigen, seroconversion is defined as an increase in titer in 
antibodies against SARS-CoV-2 spike protein versus baseline. 
In subjects seropositive for SARS-CoV-2 at baseline, seroconversion is defined as 
a 2-fold increase in titer in antibodies against SARS-CoV-2 spike protein versus 
baseline. 
• 
Individual SARS-CoV-2 spike protein-specific antibody levels in serum, as 
measured by ELISA.  
• 
Geometric mean titers (GMTs) of serum SARS-CoV-2spike protein antibodies, as 
measured by ELISA, in subjects who did not get exposed to SARS-CoV-2 before 
the trial, or during the trial before the applicable sample was collected, as measured 
by ELISA to SARS-CoV-2 N-antigen. 
• 
The proportion of subjects seroconverting for SARS-CoV-2 neutralizing antibodies, 
as measured by an activity assay. 
In subjects who did not get exposed to SARS-CoV-2 before the trial, or during the 
trial before the applicable sample was collected, as measured by ELISA to 
SARS-CoV-2 N-antigen, seroconversion is defined as an increase in titer in 
SARS-CoV-2 neutralizing antibodies versus baseline.  
In subjects seropositive for SARS-CoV-2 at baseline, seroconversion is defined as 
a 2-fold increase in titer in SARS-CoV-2 neutralizing antibodies versus baseline. 
• 
Individual SARS-CoV-2 neutralizing antibody levels in serum. 
• 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as measured by an activity 
assay, in subjects who did not get exposed to SARS-CoV-2 before the trial, or during 
the trial before the applicable sample was collected, as measured by ELISA to 
SARS-CoV-2 N-antigen. 
* Samples may be used for assay validation and additional studies of the mechanism of 
action of the vaccine. 
Exploratory endpoints*: 
Cell-mediated immune response 
On Day 29, Day 36 and Day 211** in peripheral blood mononuclear cells (PBMCs) from 
all subjects at the assigned site(s): 
• 
The frequency and functionality of SARS-CoV-2 spike-specific T-cell response after 
antigen stimulation. 
Intracellular cytokine staining (ICS) to investigate Th1 response and production of 
Th2 markers (e.g. secreted IL-5) 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. 


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• 
The proportion of subjects with a detectable increase in SARS-CoV-2 spike-specific 
T-cell response. 
** Testing of samples collected on Day 211 will be done only in subjects categorized as 
T-cell responders on Day 29 and/or Day 36. 
Innate immune response 
On Day 2, Day 8, Day 29, Day 30 and Day 36 in all open-label sentinel 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). 
• 
Gene expression profiling. 
* Samples may be used for assay validation and additional studies of the mechanism of 
action of the vaccine. 
Evaluation of infection 
• 
Number of subjects with virologically-confirmed SARS-CoV-2 infection as measured 
by reverse transcription polymerase chain reaction (RT-PCR) at clinically 
determined time points throughout the trial. 
• 
Number of subjects with asymptomatic SARS-CoV-2 infection as measured by 
retrospective serology at predefined time points. 


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5 TRIAL DESIGN 
5.1 Overall Design 
This is a Phase 1, partially blind, placebo-controlled, dose escalation FIH trial of 
intramuscularly (IM) administered CVnCoV. This trial will evaluate the safety, 
reactogenicity and immunogenicity of 3 provisional CVnCoV dose levels (2, 4 and 8µg) 
using an adaptive dose-finding design. This will allow dose escalation or de-escalation 
using predefined safety criteria and select the CVnCoV dose for further clinical 
development. To ensure the safety of the subjects, specified safety data will be reviewed 
on a predefined schedule by an iSRC and a DSMB. An overview of the staggered 
enrolment and safety monitoring is provided in Figure 2.  
An adaptive 2-parameter Bayesian logistic regression model (BLRM) for dose escalation 
with overdose control (EWOC) will be used in the escalation to guide determination of the 
safety of each dose level, while decisions of dose level expansion in the sentinel groups 
of 4 subjects is based on a maximum number of 2 subjects with Grade 3 adverse 
reactions.  
Subjects will be enrolled in 2 age categories (18-40 years and 41-60 years) with an equal 
distribution across each category. The trial will include subjects with no history of 
COVID-19 disease as well as subjects with SARS-CoV-2 positive serology. The 
SARS-CoV-2 serology status at baseline will be evaluated retrospectively to allow 
separate analysis of subjects retrospectively SARS-CoV-2 seronegative at baseline and 
subjects retrospectively SARS-CoV-2 seropositive at baseline. To ensure the open-label 
sentinel subjects in each dose level are seronegative, the SARS-CoV-2 serological status 
will be determined prior to enrollment during eligibility assessment in these subjects. 
Additionally, assessment of SARS-CoV-2 serological status may also be performed in the 
observer-blind placebo-controlled part of the trial, to identify subjects with SARS-CoV-2 
positive serology. 
Due to the adaptive design of the trial, the actual number of subjects enrolled might be 
lower or higher than the target numbers. 
Throughout the trial, cases of COVID-19 disease will be identified and documented for 
later pooling of cases across trials in the clinical development program. 
5.2 Dose Escalation Steps 
The starting dose of CVnCoV is 2µg. Dose escalation steps will follow the scheme 
indicated in Table 2. In each dose escalation step, subjects will be equally distributed 
across the 2 age categories (with the exception of subjects with SARS-CoV-2 positive 
serology who receive dose levels >8µg). 
Additional potential dose levels that could be assessed are 1, 3 and 6µg, depending on 
the reactogenicity/safety findings after vaccination with respectively 2, 4 and 8µg dose 
levels; as well as 12, 16 and/or 20µg. 
All subjects will be administered a second vaccine dose on Day 29 with the same dose 
level of CVnCoV or placebo as administered on Day 1. When safety data will be available 
at least 60 hours post dose 2 for all subjects within a dose level, the iSRC and DSMB will 


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review all available safety (and, if available, immunogenicity) data to confirm the safety of 
the dose level after the second dose. 


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Figure 2 
Overview of staggered enrollment and dose escalation 
 


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The 12, 16 and/or 20µg dose levels will only be given to subjects once initial data from the previous dose level have been reviewed by the iSRC and DSMB, not in parallel. 
 


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Table 2 
Provisional dose levels during dose escalation 
Number of subjects vaccinated per CVnCoV dose level (µg)* 
2µg 
4µg 
8µg 
12/16/20µg**** 
18-40 years 
41-60 years 
18-40 years 
41-60 years 
18-40 years 
41-60 years 
18-40 years 
41-60 years 
1 
- 
- 
- 
- 
- 
 
 
Post-vaccination observation for 24 
hours** 
- 
- 
- 
- 
 
 
1 
2 
- 
- 
- 
- 
 
 
Safety review of 24-hour post dose 1 
data (iSRC+DSMB Chair) 
- 
- 
- 
- 
 
 
4 
4 
- 
- 
- 
- 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
18 + 4 placebo*** 
18 + 4 placebo*** 
2 
2 
- 
- 
 
 
- 
- 
Safety review of 24-hour post dose 1 
data (iSRC+DSMB Chair) 
- 
- 
 
 
- 
- 
4 
4 
- 
- 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
18 + 4 placebo*** 
18 + 4 placebo*** 
2 
2 
 
 
- 
- 
- 
- 
Safety review of 24-hour post dose 1 
data (iSRC+DSMB Chair) 
 
 
- 
- 
- 
- 
4 
4 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
- 
- 
18 + 4 placebo*** 
18 + 4 placebo*** 
2 
2 
- 
- 
- 
- 
- 
- 
Safety review of 24-hour post dose 
1 data (iSRC+DSMB Chair) 
- 
- 
- 
- 
- 
- 
4 
4 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
- 
- 
- 
- 
18 to 60 years 
- 
- 
- 
- 
- 
- 
4***** 
Light grey shaded cells indicate the open-label sentinel groups. 
Dark grey shaded cells indicate the observer-blind placebo-controlled groups. 
* Provisional dose levels of 2, 4 and 8µg will be evaluated. Additional potential dose levels that could be assessed are 1, 3 and 6µg, depending on the reactogenicity/safety 
findings after vaccination with respectively 2, 4 and 8µg dose levels; as well as 12, 16 and/or 20µg. 
** If any Grade 3 ARs are reported within 24 hours following vaccination, the iSRC and DSMB Chair will be consulted before continuation of enrollment of the next 
open-label sentinel subjects. 
*** Including approximately 4 + 1 subjects with SARS-CoV-2 positive serology.  


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**** The next dose level will only be given to subjects once initial data from the previous dose level have been reviewed by the iSRC and DSMB, e.g., if 12µg is 
investigated, it will only be administered after review of the 8µg data (post dose 1 in 12 sentinel subjects), and if the dose level is then escalated to 16µg, it will only be 
administered after review of the 12µg data (post dose 1 in 12 sentinel subjects). 
***** Subjects with SARS-CoV-2 positive serology. 
 


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On the first vaccination day, the first open-label sentinel subject aged 18-40 years 
confirmed to be SARS-CoV-2 seronegative will be enrolled and vaccinated with CVnCoV 
at the lowest dose level (2µg). The subject will be observed for 24 hours after vaccination. 
If any Grade 3 adverse reactions, defined as solicited systemic, solicited local and 
unsolicited Grade 3 adverse events (AEs) considered as related to the trial vaccine 
according to the Investigator, are reported within 24 hours following vaccination, the iSRC 
and DSMB Chair will be consulted. In case no safety concerns are identified, the next 
open-label sentinel group of 3 subjects (1 aged 18-40 years and 2 aged 41-60 years) 
confirmed to be SARS-CoV-2 seronegative will be enrolled and vaccinated with CVnCoV 
at the lowest dose level (2µg). The 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 from these first 4 subjects will be collected and reviewed by the 
iSRC and DSMB Chair. In this review, the iSRC and DSMB Chair will review all available 
safety data, but focus specifically on Grade 3 adverse reactions, defined as solicited 
systemic, solicited local and unsolicited Grade 3 AEs considered as related to the trial 
vaccine according to the Investigator, and any SAE considered as related to the trial 
vaccine according to the Investigator. Based on this review, the iSRC and DSMB Chair 
will decide on the subsequent vaccination of an additional open-label sentinel group of 
8 subjects (4 aged 18-40 years and 4 aged 41-60 years, confirmed to be SARS-CoV-2 
seronegative) with the same dose level on the next vaccination day (at least 36 hours after 
the first vaccination day). 
Safety and reactogenicity data of subjects vaccinated on the first and second vaccination 
days will then be collected for at least 60 hours post-vaccination from each subject and 
reviewed by the iSRC and the DSMB. Based on this review, the iSRC and DSMB will 
recommend on continuation of enrollment at the same dose level (start of randomized 
expansion in observer-blind placebo-controlled groups) and initiation of enrollment in the 
next dose level: 
• In case of continuation of enrollment at the 2µg dose level, an additional 
44 subjects will be enrolled, including 10 subjects with SARS-CoV-2 positive serology. 
Of these 44 subjects, 36 subjects (18 aged 18-40 years and 18 aged 41-60 years) will 
receive CVnCoV at the 2µg dose level, including approximately 8 subjects with 
SARS-CoV-2 positive serology. The other 8 subjects (4 aged 18-40 years and 4 aged 
41-60 years) will receive placebo in an observer-blind manner, including approximately 
2 subjects with SARS-CoV-2 positive serology. 
• In case of dose escalation, a newly enrolled open-label sentinel group of 4 subjects 
(2 aged 18-40 years and 2 aged 41-60 years) confirmed to be SARS-CoV-2 
seronegative will receive the next higher dose (4µg) or an intermediate dose depending 
on iSRC and DSMB recommendations guided by the BLRM. The subjects should be 
vaccinated at least 60 minutes apart. In case of favorable outcome of the review by the 
iSRC and DSMB Chair of at least 24-hour post-vaccination data and a maximum 
number of 2 subjects with Grade 3 adverse reactions, an additional open-label sentinel 
group of 8 subjects (4 aged 18-40 years and 4 aged 41-60 years, confirmed to be 
SARS-CoV-2 seronegative) will receive the same dose level on the next vaccination 
day (at least 36 hours after the first vaccination day). 
For each subsequent step, continuation of enrollment within a dose level in a 
placebo-controlled observer-blind manner and dose escalation will be assessed by the 
iSRC and DSMB based on 60-hour post-vaccination safety data for each subject, including 
all available post-vaccination data from previously vaccinated subjects. The scheme for 


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staggered enrollment and dose escalation in Figure 2 will be pursued if no safety concerns 
are found by the iSRC or DSMB. 
Once the open-label sentinel phase has been successfully concluded for a given dose 
level, enrollment will no longer be restricted to subjects with no history of COVID-19 
disease or negative serology to SARS-CoV-2, but will also include subjects with 
SARS-CoV-2 positive serology. These subjects will be enrolled at pre-defined site(s). For 
each dose level, the iSRC will review at least 24-hour post-vaccination safety data from 
the first 4 seropositive subjects. These first 4 seropositive subjects within each dose level 
should be vaccinated at least 60 minutes apart. Vaccination of additional subjects at that 
dose level and/or vaccination of subjects with SARS-CoV-2 positive serology at a higher 
dose level will only proceed upon favorable outcome of this iSRC review. 
5.3 Adaptations to the Trial 
Depending on the safety and immunogenicity of the provisional dose levels, additional 
dose levels might be evaluated. In each case, the enrollment schedule will be performed 
as described in Section 5.2. 
For dose levels >8µg, the enrollment schedule will be performed as described in 
Section 5.2 for the first 12 sentinel subjects. After a review of the post dose 1 data from 
these subjects, 4 subjects (aged 18 to 60 years) with SARS-CoV-2 positive serology will 
be enrolled to receive the same CVnCoV dose level. These 4 open-label subjects will have 
the same assessments as subjects in the observer-blind placebo-controlled groups and 
are included when reference is made to the observer-blind placebo-controlled groups 
throughout this protocol. 
In case the lowest dose of 2µg fails to meet the predefined safety criteria, a dose 
de-escalation to 1µg will be initiated. In case the 4µg dose level fails to meet the predefined 
safety criteria, a dose de-escalation to 3µg can be initiated. Similarly, in case the 8µg dose 
level fails to meet the predefined safety criteria, a dose de-escalation to 6µg can be 
initiated.  
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 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 (Days 1-8): 
• 
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 as 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 as 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. 


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If any of these rules are met, the subject must not receive the second vaccine dose. The 
subject will be encouraged to continue participation until the end of the trial for safety and 
immunogenicity assessments.  
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 as 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 of awareness by 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. 
During the observer-blind placebo-controlled phase at each dose level, if >4 subjects 
experienced Grade 3 adverse reaction(s) after administration of CVnCoV at a particular 
dose level, vaccination will be put on hold for all subjects in the applicable dose level and 
any higher dose level. 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 dose-de-escalation) with this and any higher dose level. 
5.5 Scientific Rationale for Trial Design 
This trial will evaluate the safety and reactogenicity of different CVnCoV dose levels using 
an adaptive Phase 1 dose-finding design. This will allow dose escalation or de-escalation 
using predefined safety criteria and select the CVnCoV dose for further clinical 
development. An adaptive 2-parameter BLRM for dose escalation with overdose control 
will be used in the escalation to guide determination of the safety of each dose level. The 
use of Bayesian response adaptive models for Phase 1 studies has been advocated by 
the European Medicines Agency (EMA) adopted guideline on small populations (EMA, 
2006) and by Rogatko et al., 2007 [37] and is one of the key elements of the US Food and 
Drug Administration (FDA)’s Critical Path Initiative. 
As mentioned in the FDA Adaptive Designs for Clinical Trials of Drugs and Biologics 
Guidance for Industry, an adaptive design provides a variety of advantages over non-
adaptive designs since adaptive designs allow the trial to adjust to information that was 
not available when the trial began. This advantage becomes especially important in 
exploratory Phase 1 dose-finding designs, as it improves understanding of vaccine effects. 
The adaptive design of this trial in combination with real-time safety monitoring facilitates 
dose-adjustment based on predefined vaccine reactogenicity criteria [33]. An adaptive 
design can make it possible to answer broader questions than normally feasible with a 
non-adaptive design [34,35]. The proposed design of the current trial saves sample size 
and efficiently assigns subjects to doses considered safe. This design therefore allows 
moving into further development of the CVnCoV vaccine more efficiently by allowing to 
move as per protocol to a lower dose level in case of too high reactogenicity, instead of 
having to pause and amend the trial protocol. This is of particular importance in view of 
the current pandemic situation, with a high medical need to develop a prophylactic vaccine 
to prevent COVID-19. 


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The visit schedule follows that of the FIH trial with CureVac’s Rabies mRNA investigational 
vaccine (CV7202-104). The blood draws for immunogenicity will assess the induction and 
persistence of innate immune responses, antibody and T-cell responses induced by 
CVnCoV. Specifically, induction of antibody-responses will be analyzed 1, 2 and 4 weeks 
after the vaccination (Day 8, Day 15 and Day 29 following the first vaccination, and Day 36, 
Day 43 and Day 57 after the second vaccination, respectively). The persistence of the 
antibody response will be evaluated at Day 120, Day 211 and Day 393 (i.e., 3, 6 and 
12 months after the second vaccination). Activation of innate immunity will be assessed in 
the open-label sentinel subjects in the first week after first and second vaccination (Day 1, 
Day 2 and Day 8 and Day 29, Day 30 and Day 36, respectively). The induction of cell-
mediated immunity (CMI) will be analyzed in subjects from the assigned site(s) 1 week 
after the second vaccination (Day 36). In addition, memory responses will be analyzed in 
the follow-up period (Day 211). 
The duration of the trial is appropriate for mRNA vaccines, allowing a minimum of 
365 days of safety follow-up after the last vaccination for all subjects, to collect and 
evaluate safety data as needed.  
Given the different dose levels of CVnCoV to be administered sequentially, the initial part 
of the dose escalation will be open with regard to the CVnCoV arm assignments. Dose 
escalation is scheduled to happen rapidly as compared to what is usually permitted 
according to EU guidelines on FIH studies. This is justified by the current pandemic 
situation, where the global population is at risk for infection and, in certain cases, severe 
disease and death, with no efficacious vaccine available. Clinical data are available from 
42 subjects vaccinated with 1 or 2 doses of CureVac’s Rabies mRNA investigational 
vaccine formulated with the same LNPs. These data, as well as the fact that dose 
escalation will be performed only when re-assuring safety/reactogenicity data are 
available from the subjects vaccinated with the level below, up to minimum 24 hours 
post-vaccination, allow to implement this more rapid progression from one dose level to 
the next, as per predefined stopping and escalation rules. The 24-hour interval 
post-vaccination was chosen since data from the ongoing Rabies clinical trial have shown 
that adverse reactions, including those that will be used to decide on further vaccination 
steps, almost exclusively started within 24 hours after vaccination, usually even in the 
evening or night after vaccination. 
To reduce the risk of biased trial outcomes, the second part of the dose escalation will be 
conducted in a placebo-controlled observer-blind manner. Double-blinding is not possible 
due to the difference in appearance of the investigational vaccine and placebo. 
5.6 Justification for Dose 
Three provisional CVnCoV dose levels (2, 4 and 8 µg) will be evaluated, defined based 
on clinical data from the CV7202-104 trial with a Rabies vaccine using the same 
technology as well as non-clinical data. Refer to the Investigator’s Brochure for an 
overview of these data. 
Additional higher (12, 16 and/or 20µg), lower (1µg) and/or intermediate (3 and 6 µg) dose 
levels might be evaluated depending on the outcomes of the safety and reactogenicity 
evaluations and all available immunogenicity data. Identification of immunogenic dose 


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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 on 
Day 393. 


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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 one or more of the inclusion criteria and/or meets one or more of the exclusion 
criteria is inadvertently enrolled and dosed, the Sponsor must be contacted immediately. 
In this trial, subjects with no history of COVID-19 disease will be included as well as 
subjects with SARS-CoV-2 positive serology. 
6.1 Inclusion Criteria For All Subjects 
Subjects will be enrolled in this trial only if they meet all of the following criteria: 
1. 
Healthy male and female subjects aged 18 to 60 years inclusive. 
Healthy subject is defined as an individual who is in good general health, not having 
any mental or physical disorder requiring regular or frequent medication. 
2. 
Expected to be compliant with protocol procedures and available for clinical 
follow-up through the last planned visit. 
3. 
Physical examination and laboratory results without clinically significant findings 
according to the Investigator’s assessment. 
4. 
Body mass index (BMI) ≥18.0 and ≤30.0kg/m2 (≥18.0 and ≤32.0kg/m2 for subjects 
with SARS-CoV-2 positive serology). 
5. 
Females: At the time of enrollment, negative human chorionic gonadotropin (hCG) 
pregnancy test (serum) for women presumed to be of childbearing potential on the 
day of enrollment. On Day 1 (pre-vaccination): negative urine pregnancy test (hCG), 
(only required if the serum pregnancy test was performed more than 3 days before). 
6. 
Females of childbearing potential must use highly effective of birth control from 
1 month 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 (IUDs); 
o 
Intrauterine hormone-releasing systems (IUSs); 
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). 
Refer to the Clinical Trial Facilitation Group recommendations on contraception and 
pregnancy testing for further details [32]. 


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6.2 Exclusion Criteria 
Subjects will not be enrolled in this trial if they meet any of the exclusion criteria. 
The following criterion applies to all open-label sentinel subjects: 
1. 
Subjects with confirmed SARS-CoV-2 positive serology as confirmed by testing at 
enrollment. 
The following criteria apply to all subjects, except those with SARS-CoV-2 positive 
serology: 
2. 
Subjects considered at the Investigator’s discretion to be at increased risk to acquire 
COVID-19 disease (including, but not limited to, health care workers with direct 
involvement in patient care or care of long-term care recipients). 
3. 
History of confirmed COVID-19 disease or known exposure to an individual with 
confirmed COVID-19 disease or SARS-CoV-2 infection within the past 2 weeks. 
The following criteria apply to all subjects: 
4. 
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. 
5. 
Receipt of any other vaccines within 14 days (for inactivated vaccines) or 28 days 
(for live vaccines) prior to enrollment in this trial or planned receipt of any vaccine 
within 28 days of trial vaccine administration. 
6. 
Receipt of any investigational SARS-CoV-2 or other CoV vaccine prior to the 
administration of the trial vaccine. 
7. 
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 steroids. Corticosteroids used in the 
context of COVID-19 disease of subjects with SARS-CoV-2 positive serology are 
not exclusionary. 
8. 
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. 
9. 
History of a pIMD (refer to Appendix 9). 
10. 
History of angioedema. 
11. 
Any known allergy, including allergy to any component of CVnCoV or 
aminoglycoside antibiotics. A history of hay fever or seasonal allergies (pollinosis) 
that does not require current treatment (e.g., anti-histamines) during the vaccination 
period (1 month before first vaccination until 1 month after last vaccination) is not 
exclusionary. 
12. 
History of or current alcohol and/or drug abuse. 


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13. 
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.  
14. 
Acute or currently active SARS-CoV-2 infection as confirmed by reactive PCR within 
3 days of first trial vaccine administration. 
15. 
History of confirmed SARS or MERS. 
16. 
Administration of immunoglobulins (Igs) and/or any blood products within the 
3 months preceding the administration of any dose of the trial vaccine. 
17. 
Presence or evidence of significant acute or chronic medical or psychiatric illness. 
Significant medical or psychiatric illnesses include but are not limited to: 
- Respiratory disease (e.g., chronic obstructive pulmonary disease, asthma) 
requiring daily medications currently or any treatment of respiratory disease 
exacerbations (e.g., asthma exacerbation) in the last 5 years. 
- Respiratory disease with clinically significant dyspnea in the last 5 years (except 
COVID-19 disease in subjects with SARS-CoV-2 positive serology). 
- Asthma medications: inhaled, oral, or intravenous (IV) corticosteroids, 
leukotriene modifiers, long- and short-acting beta agonists, theophylline, 
ipratropium, biologics.  
- Significant 
cardiovascular 
disease 
(e.g., 
congestive 
heart 
failure, 
cardiomyopathy, ischemic heart disease, history of stroke, peripheral artery 
disease, pulmonary embolism) or history of myocarditis or pericarditis as an adult.  
- Elevated blood pressure or hypertension, even if well-controlled. 
- Diabetes mellitus type 1 or 2. 
- History of any neurological disorders or seizures including Guillain-Barré 
syndrome, with the exception of febrile seizures during childhood. 
- Current or past malignancy, unless completely resolved without sequelae for 
>5 years. 
18. 
Foreseeable non-compliance with protocol as judged by the Investigator. 
19. 
For females: pregnancy or lactation. 
20. 
History of any anaphylactic reactions. 
21. 
Subjects with impaired coagulation or any bleeding disorder in whom an IM injection 
or a blood draw is contraindicated. 
22. 
Subjects employed by the Sponsor, Investigator or trial site, or relatives of research 
staff working on this trial. 
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 


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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 the event that a subject meets a criterion for delay of vaccination, the subject may 
receive the trial dose once the window for delay has passed, if clinically appropriate to 
vaccinate in the judgment of the Investigator and the time windows of the protocol can be 
respected (refer to Table 1). 
There are also circumstances under which further vaccination is suspended in this trial, 
as detailed in Section 5.2 for the dose escalation steps and Section 5.4 for stopping rules. 
If these reactions occur, the subject(s) must not receive additional vaccinations but is/are 
encouraged to continue in trial participation for safety reasons, including collection of 
safety blood samples. Immunogenicity assessments may be performed also, at the 
Investigator’s discretion. 
6.4 Failure to Meet Eligibility Criteria 
The Investigator must account for all subjects who sign an informed consent. If the subject 
is found to be not eligible (i.e., did not meet all inclusion criteria or met 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 one 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 tests value meeting one or more exclusion 
criteria, which 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 Vaccines 
CVnCoV is an investigational LNP-formulated RNActive® SARS-CoV-2 vaccine. The IMP 
is composed of the active pharmaceutical ingredient, an mRNA that encodes Wsmpv-SP, 
and 4 lipid components: cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 
PEG-ylated lipid and a cationic lipid.  
The placebo administered in the control arms consists of 0.9% NaCl. 
7.1.2 Dosing and Administration 
The provisional dose levels to be administered are provided in Table 2. On the first 
vaccination day within each dose level, the 4 newly enrolled open-label sentinel subjects 
should be vaccinated at least 60 minutes apart. Also, the first 4 newly enrolled seropositive 
subjects within each dose level should be vaccinated at least 60 minutes apart. As detailed 
in Sections 5.2 and 5.3, additional higher, lower and/or intermediate dose levels may be 
evaluated depending on the outcome of the safety evaluations. 
All subjects will be administered a second vaccine dose on Day 29 with the same dose 
level or placebo as administered on Day 1. 
Injections must be performed IM by needle in the deltoid area (non-dominant arm) in all 
groups.  
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. 
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. All subjects must remain under 
direct supervision of personnel trained in the treatment of these reactions for 4 hours 
following administration of the trial IMP. 
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 
at the local pharmacy or a qualified Phase 1 unit according to the handling protocol 
provided by CureVac AG.  
7.2.2 Product Storage and Stability 
CVnCoV is presented as an aqueous solution and stored at below -60°C. 


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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. 
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 
In the initial part of dose escalation for the provisional dose levels of 2, 4 and 8µg, subjects 
will be enrolled in sentinel groups in an open manner. In the second part, subjects will be 
enrolled in placebo-controlled groups in an observer-blind manner within each dose level 
with a 4.5:1 ratio and stratified by the 2 age categories (18-40 and 41-60 years). 
Double-blinding is not possible due to the difference in appearance of the investigational 
vaccine and placebo. 
Groups with a dose level >8µg will be open-label. 
The Sponsor and safety monitoring committees will be unblinded for data from the 
placebo-controlled groups, but will take appropriate measures to ensure subject blinding 
is kept at site-level until database lock.  
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. 


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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. 
7.4 Vaccine Compliance 
The Investigator will record all injections (CVnCoV and placebo) 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. 
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 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 administration should be pursued.  
7.8 Treatment After the End of Trial 
No post-trial care will be provided. 


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8 DISCONTINUATION/WITHDRAWAL CRITERIA 
Participation in the trial is strictly voluntary. A subject has the right to withdraw from the 
trial at any time and for any reason. The Investigator has the right to withdraw a subject 
from further trial vaccine administration and/or the trial if this is considered in the subject’s 
best interest or as a result of a protocol deviation.  
For discontinuations due to an AE, every effort should be made to document the outcome 
of the event.  
Subjects who received at least 1 dose of trial vaccine will be encouraged to continue 
participation until the end of the trial for safety assessments. Assessments of solicited AEs 
and associated phone calls for the second 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 discontinued trial vaccine 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 9.2.2).  
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. 
• 
Clinical suspicion of SARS-CoV-2 infection (as specified in Section 9.4). 
• 
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). 
• 
Major protocol deviation. 


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• 
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 one 
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 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 the Regulatory Authority for any reason or if 
recommended by the iSRC or DSMB, or at a site level by the Independent Ethics 
Committee or Institutional Review Board (IEC/IRB). The Sponsor may close an individual 


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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 
For each procedure, subjects are to be assessed by the same Investigator or site 
personnel whenever possible. 
In case subjects are not be 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). This is in accordance with EMA’s “Guidance on the Management of 
Clinical Trials during the COVID-19 (Coronavirus) pandemic Version 3 (28/04/2020)”, 
which states that “Where a trial participant is unable to attend the site, other measures, 
such as home nursing, if possible given social distancing needs, or contact via phone or 
telemedicine means, may be required to identify adverse events and ensure continuous 
medical care and oversight.”. There will likely be further updates to this guidance, and the 
Sponsor will take these into consideration for decision-making during the course of the 
trial. 
Blood samples for humoral immune response assessment on Day 29, Day 43 and Day 57 
and for CMI assessment on Day 36 should be collected via a home visit within the 
protocol-specified time window. Blood sampling for immunogenicity assessment at other 
time points may be postponed to the next possible visit, in case of a public health 
emergency. If visits, phone-contacts or sample collection cannot be performed within the 
protocol-defined windows, in such extraordinary circumstances as a public health 
emergency, it will be acceptable to perform these tasks outside of these windows. 
Alternatively, electronic diaries may be used during the trial for collection of safety-related 
information, in which case systems will be adjusted accordingly. 
9.1 Schedule of Trial Assessments and Procedures 
Refer to the Schedule of Activities (Table 1). The trial procedures apply to all subjects, 
independent if they had a history of COVID-19 disease or SARS-CoV-2 positive serology 
and independent of the serology status at baseline as per retrospective analysis. 
9.1.1 Visit 1: Day 1 
Note that procedures to establish subject eligibility, recording of demographic information 
and medical history may be performed within 21 days prior to trial vaccine administration, 
i.e., spread out over more than 1 day. If all information to establish eligibility is available, 
these procedures can be done on the same day including the trial vaccine administration. 
Eligibility criteria, including laboratory results, need to be reviewed on the day of 
vaccination prior to trial vaccine administration. 
9.1.1.1 Pre-vaccination Procedures 
• 
Obtain the signed informed consent form. 
Signed informed consent must be obtained prior to the subject entering into the trial, 
and before any protocol-directed procedures are performed (see Section 12.4). 
• 
Review inclusion/exclusion criteria (see Section 6.1 and 6.2). 
• 
Record demographic information. 


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• 
Record medical history. 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions, if taken within 6 months prior to enrollment in this trial. 
• 
Perform a complete physical examination, including height and weight (see Section 
9.2.4). If the complete physical examination to establish eligibility was performed 
within 21 days prior to trial vaccine administration, a symptom-directed physical 
examination should be performed on the day of vaccination prior to trial vaccine 
administration. 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Carry out a 12-lead ECG (see Section 9.2.4). 
• 
Collect a swab sample for detection of SARS-CoV-2 infection by PCR. 
• 
Collect a blood sample for safety and immunogenicity assessment (~115mL for 
open-label sentinel subjects and ~105mL for observer-blind placebo-controlled 
subjects [see Table 1). 
• 
For the open-label sentinel subjects in each dose level: Collect a blood sample 
(~6mL) for determination of SARS-CoV-2 serology status. This may also be 
performed for subjects in the observer-blind placebo-controlled part of the trial to 
identify subjects with SARS-CoV-2 positive serology. 
9.1.1.2 Vaccination Procedures 
• 
Check inclusion/exclusion criteria (see Section 6.1 and 6.2) and review prohibited 
medications listed as an exclusion criterion (see Section 6.2). 
• 
Review criteria for delay of vaccination (see Section 6.3).  
• 
Collect a blood sample for a serum pregnancy test (hCG) (~3mL) to establish eligibility 
for female subjects of childbearing potential. 
• 
Conduct a urine pregnancy test for female subjects of childbearing potential, unless 
the serum pregnancy test to establish eligibility was performed less than 3 days 
before. 
• 
Collect a blood sample (~3mL) for potential retrospective baseline testing of 
autoantibodies (TSH, thyroid antibodies and anti-nuclear antibody [ANA] and other 
autoantibodies), in case of the occurrence of clinical autoimmune events. 
• 
Administer the trial vaccine dose according to the subject’s assignment. 
9.1.1.3 Post-vaccination Procedures 
• 
Observe the subject on site for at least 4 hours following vaccination for safety 
monitoring. 
• 
Issue the diary card and instruct the subject to record solicited AEs occurring on the 
day of vaccination and the following 7 days and unsolicited AEs occurring on the day 
of vaccination and the following 28 days.  
• 
Train the subject how to measure solicited AEs and how to complete the diaries. 
• 
Train the subject on when and how to contact the site to report acute respiratory 
infection (ARI) symptoms to detect COVID-19 like illnesses (see Section 9.4). 


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• 
Record safety data, including solicited AEs, unsolicited AEs, SAEs, intercurrent 
medical conditions that may affect the immune response to vaccination, AEs leading 
to premature discontinuation and AESIs. 
• 
At the end of the observation period: 
- Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4).  
- The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels. 
9.1.2 Visit 2: Day 2 – Only for Open-Label Sentinel Subjects  
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Review the diary card and remind the subject to continue recording solicited and 
unsolicited AEs in the diary card. 
• 
Re-train the subject how to measure solicited AEs and how to complete the diaries. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including solicited AEs, unsolicited AEs, SAEs, intercurrent 
medical conditions that may affect the immune response to vaccination, AEs leading 
to premature discontinuation and AESIs. 
• 
Collect a blood sample for safety and immunogenicity assessment (~20mL, see 
Table 1). 
9.1.3 Phone Call: Day 2 – Only for Observer-Blind Placebo-Controlled 
Subjects 
The purpose of this safety call is to inquire on the subject’s general well-being and to 
assess reactogenicity. 
• 
All Grade 3 solicited and unsolicited AEs and all SAEs reported by the subject during 
the call must be reported to the medical monitor without delay, on the same day of 
awareness by the site, to allow assessing Grade 3 adverse reactions and SAEs 
considered as related to the trial vaccine according to the Investigator in real time. 
• 
Remind the subject to continue recording solicited and unsolicited AEs in the diary 
card. 
9.1.4 Phone Call: Day 3 
The purpose of this safety call is to inquire on the subject’s general well-being and to 
assess reactogenicity. 
• 
All Grade 3 solicited and unsolicited AEs and all SAEs reported by the subject during 
the call must be reported to the medical monitor without delay, on the same day of 
awareness by the site, to allow assessing Grade 3 adverse reactions and SAEs 
considered as related to the trial vaccine according to the Investigator in real time. 


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• 
Remind the subject to continue recording solicited and unsolicited AEs in the diary 
card. 
9.1.5 Visit 3: Day 8 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Review the diary card and remind the subject to continue recording unsolicited AEs 
in the diary card. 
• 
Re-train the subject how to complete the diaries. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including solicited AEs, unsolicited AEs, SAEs, intercurrent 
medical conditions that may affect the immune response to vaccination, AEs leading 
to premature discontinuation and AESIs. 
• 
Collect a blood sample for safety and immunogenicity assessment (~45mL for 
open-label sentinel subjects and ~35mL for observer-blind placebo-controlled 
subjects [see Table 1]). 
9.1.6 Visit 4: Day 15 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Review the diary card and remind the subject to continue recording unsolicited AEs. 
• 
Re-train the subject how to complete the diaries. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including unsolicited AEs, SAEs, intercurrent medical conditions 
that may affect the immune response to vaccination, AEs leading to premature 
discontinuation and AESIs. 
• 
Collect a blood sample for immunogenicity assessment (~24mL, see Table 1). 
• 
Collect a blood sample for safety assessment in case of an abnormal value for any of 
the safety parameters at the previous visit (~9mL, see Table 1). 
9.1.7 Visit 5: Day 29 
9.1.7.1 Pre-vaccination Procedures 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a complete physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 


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• 
Collect and review the diary card issued after Dose 1. 
• 
Collect a blood sample for immunogenicity assessment (~75mL for open-label 
sentinel subjects and ~65mL for observer-blind placebo-controlled subjects [see 
Table 1]). 
• 
Collect a blood sample for safety assessment in case of an abnormal value for any of 
the safety parameters at the previous visit (~9mL, see Table 1). 
9.1.7.2 Vaccination Procedures 
• 
Check criteria for discontinuation of trial vaccination (see Section 8.1) and review 
prohibited medications listed as an exclusion criterion (see Section 6.2). 
• 
Review criteria for delay of vaccination (see Section 6.3).  
• 
Conduct a urine pregnancy test for female subjects of childbearing potential. 
• 
Administer the trial vaccine dose according to the subject’s assignment.  
9.1.7.3 Post-vaccination Procedures 
• 
Observe the subject on site for at least 4 hours following vaccination for safety 
monitoring. 
• 
Issue the diary card and instruct the subject to record solicited AEs occurring on the 
day of vaccination and the following 7 days and unsolicited AEs occurring on the day 
of vaccination and the following 28 days.  
• 
Re-train the subject how to measure solicited AEs and how to complete the diaries. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including solicited AEs, unsolicited AEs, SAEs, intercurrent 
medical conditions that may affect the immune response to vaccination, AEs leading 
to premature discontinuation and AESIs. 
• 
At the end of the observation period: 
- Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4).  
- The subject may not be discharged until vital signs are within normal range or have 
returned to pre-vaccination levels. 
9.1.8 Visit 6: Day 30 – Only for Open-Label Sentinel Subjects  
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Review the diary card and remind the subject to continue recording solicited and 
unsolicited AEs in the diary card. 
• 
Re-train the subject how to measure solicited AEs and how to complete the diaries. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 


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• 
Record safety data, including solicited AEs, unsolicited AEs, SAEs, intercurrent 
medical conditions that may affect the immune response to vaccination, AEs leading 
to premature discontinuation and AESIs. 
• 
Collect a blood sample for safety and immunogenicity assessment (~20mL, see 
Table 1). 
9.1.9 Phone Call: Day 30 – Only Observer-Blind Placebo-Controlled 
Subjects 
The purpose of this safety call is to inquire on the subject’s general well-being and to 
assess reactogenicity. 
• 
All Grade 3 solicited and unsolicited AEs and all SAEs reported by the subject during 
the call must be reported to the medical monitor without delay, on the same day of 
awareness by the site, to allow assessing Grade 3 adverse reactions and SAEs 
considered as related to the trial vaccine according to the Investigator in real time. 
• 
Remind the subject to continue recording solicited and unsolicited AEs in the diary 
card. 
9.1.10 Phone Call: Day 31 
The purpose of this safety call is to inquire on the subject’s general well-being and to 
assess reactogenicity. 
• 
All Grade 3 solicited and unsolicited AEs and all SAEs reported by the subject during 
the call must be reported to the medical monitor without delay, on the same day of 
awareness by the site, to allow assessing Grade 3 adverse reactions and SAEs 
considered as related to the trial vaccine according to the Investigator in real time. 
• 
Remind the subject to continue recording solicited and unsolicited AEs in the diary 
card. 
9.1.11 Visit 7: Day 36 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Review the diary card and remind the subject to continue recording unsolicited AEs 
in the diary card. 
• 
Re-train the subject how to complete the diaries. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including solicited AEs, unsolicited AEs, SAEs, intercurrent 
medical conditions that may affect the immune response to vaccination, AEs leading 
to premature discontinuation and AESIs. 
• 
Collect a blood sample for safety and immunogenicity assessment (~85mL for 
open-label sentinel subjects and ~75mL for observer-blind placebo-controlled 
subjects [see Table 1]). 


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Note: In case Visit 7 (Day 36) cannot take place (e.g. due to a public health 
emergency), the blood sample for CMI assessment should be taken at Visit 8 
(Day 43). 
9.1.12 Visit 8: Day 43 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Review the diary card and remind the subject to continue recording unsolicited AEs 
in the diary card. 
• 
Re-train the subject how to complete the diaries. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including unsolicited AEs, SAEs, intercurrent medical conditions 
that may affect the immune response to vaccination, AEs leading to premature 
discontinuation and AESIs. 
• 
Collect a blood sample for immunogenicity assessment (~24mL, see Table 1). 
• 
Collect a blood sample for safety assessment in case of an abnormal value for any of 
the safety parameters at the previous visit (~9mL, see Table 1). 
9.1.13 Visit 9: Day 57 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Collect and review the diary card. 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including unsolicited AEs, SAEs, intercurrent medical conditions 
that may affect the immune response to vaccination, AEs leading to premature 
discontinuation and AESIs. 
• 
Collect a blood sample for immunogenicity assessment (~24mL, see Table 1). 
• 
Collect a blood sample for safety assessment in case of an abnormal value for any of 
the safety parameters at the previous visit (~9mL, see Table 1). 
9.1.14 Visit 10: Day 120 (Follow-up Visit) 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 


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• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including SAEs, intercurrent medical conditions that may affect 
the immune response to vaccination, AEs leading to premature discontinuation and 
AESIs. 
• 
Collect a blood sample for immunogenicity assessment (~24mL, see Table 1). 
• 
Collect a blood sample for safety assessment in case of an abnormal value for any of 
the safety parameters at the previous visit (~9mL, see Table 1). 
9.1.15 Visit 11: Day 211 (Follow-up Visit) 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a symptom-directed physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Re-train the subject on when and how to contact the site to report ARI symptoms to 
detect COVID-19 like illnesses (see Section 9.4). 
• 
Record safety data, including SAEs, intercurrent medical conditions that may affect 
the immune response to vaccination, AEs leading to premature discontinuation and 
AESIs. 
• 
Collect a blood sample for immunogenicity assessment (~64mL, see Table 1). 
• 
Collect a blood sample for safety assessment in case of an abnormal value for any of 
the safety parameters at the previous visit (~9mL, see Table 1). 
9.1.16 End of Trial Visit: Day 393 
The end of trial visit will be performed 365 days (-0/+30 days) after the last trial vaccine 
administration. This includes subjects who prematurely discontinued vaccination during 
the trial. The following assessments should be performed: 
• 
Record concomitant medication and vaccination, including recurring medication for 
intermittent conditions. 
• 
Perform a complete physical examination (see Section 9.2.4). 
• 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.2.4). 
• 
Record safety data, including SAEs, intercurrent medical conditions that may affect 
the immune response to vaccination, AEs leading to premature discontinuation and 
AESIs. 
• 
Collect a blood sample for immunogenicity assessment (~24mL, see Table 1). 
• 
Collect a blood sample for safety assessment in case of an abnormal value for any of 
the safety parameters at the previous visit (~9mL, see Table 1). 


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9.2 Safety Assessments 
9.2.1 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 11. 
9.2.1.1 Solicited Adverse Events 
Diary cards will be distributed to all subjects for collection of solicited local AEs 
(injection-site pain, redness, swelling and itching) and solicited systemic AEs (fever, 
headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting and diarrhea) on the day of 
vaccination and the following 7 days. 
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 on the diary card, 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.  
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 normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
*FDA toxicity grading scale [36]. 


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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 normal activity 
2 
Moderate, some interference with normal 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 normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
Chills  
0 
Absent 
1 
Mild, no interference with normal activity 
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
Myalgia 
0 
Absent 
1 
Mild, no interference with normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
Arthralgia 
0 
Absent 
1 
Mild, no interference with normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal 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 IV 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 
IV hydration 
*FDA toxicity grading scale [36]; IV = Intravenous. 
9.2.1.2 Unsolicited Adverse Events and Serious Adverse Events 
Unsolicited AEs occurring on the day of vaccination and the following 28 days will be 
recorded by the subject on the diary card.  
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 as subject diary card entries or detected through observation, physical examination, 
laboratory test, or other assessments during the entire trial, will be recorded in the eCRF. 
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 


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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. 
9.2.1.3 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 9), 
• 
COVID-19 disease, 
• 
other AEs relevant to SARS-CoV-2 vaccine development or the target disease (see 
Appendix 10).  
AESIs will be collected throughout the trial. 
9.2.2 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 11 for 
details on the reporting and follow-up of pregnancies. 
9.2.3 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 on Day 1 and one and 7 days after each vaccine 
dose administration (Days, 2, 8, 30 and 36) (refer to Table 1). At all other visits, safety 
laboratory assessment will only be done in case an abnormal value was observed at the 
previous visit. 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. 
On Day 1, the total blood drawn for safety laboratory assessment is ~15mL for all subjects. 
Blood will be taken for potential retrospective baseline measurement of TSH, thyroid 
antibodies and ANA in case of the occurrence of (a) clinical autoimmune event(s) during 
the trial (other autoantibodies might be investigated as well depending on the possible 
clinical autoimmune event). 
Laboratory data will be graded according with the FDA toxicity grading scale [36]. These 
guidelines however are dependent upon institutional normal parameters. Institutional 
normal reference ranges should be provided to demonstrate that they are appropriate.  


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9.2.4 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.  
At specific trial visits (see Table 1), a complete physical examination will be performed, 
including examination of general appearance, eyes/ears/nose/throat, head/neck/thyroid, 
lymph node areas, cardiovascular system, lung/chest, abdomen and genitourinary 
system, extremities and neurological examination, skin examination, measurement of 
weight and height. At all other trial visits, a symptom-directed physical examination may 
be performed. 
An ECG with conventional 12-lead traces will be recorded on Day 1 for all subjects. 
Additionally, ECGs should be performed as clinically indicated. 
9.2.5 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. 
9.2.6 Safety Monitoring Committees 
Specified safety data will be reviewed by an iSRC and an external and independent 
DSMB. The iSRC will consist of the Principal Investigator at each trial site, the Medical 
Monitor and medical representatives of the Sponsor. Details on the composition, 
objectives, and role and responsibilities of the iSRC and DSMB will be described in 
separate charters, agreed with the respective committee members and Sponsor. The 
charters will also define and document the content of the safety and/or immunogenicity 
summaries, and general procedures (including communications). The iSRC and DSMB 
review will be based on unblinded data.  
The iSRC and DSMB Chair will review all available safety data obtained during at least 
24 hours post-vaccination for each open-label sentinel subject vaccinated on the first 
vaccination day per dose level, and assess for Grade 3 adverse reaction(s) and any SAE 
considered as related to the trial vaccine according to the Investigator. Based on this 
review, the iSRC and DSMB Chair will decide on the enrollment of the subjects planned 
on the next vaccination day within each dose level. For each dose level, the iSRC will 
review at least 24-hour post-vaccination safety data from the first 4 seropositive subjects. 
Vaccination of additional seropositive subjects at that dose level and/or vaccination of 
subjects with SARS-CoV-2 positive serology at a higher dose level will only proceed upon 
favorable outcome of this iSRC review. The iSRC will also perform ongoing safety 
assessments for subjects beyond the first 24 hours on all available data. 
In addition, the iSRC together with the DSMB will review all available safety data obtained 
during at least 60 hours post-vaccination for each subject to recommend on continuation 
of enrollment at the same dose level and dose escalation. If no stopping rule is met, the 
DSMB Chair can decide to allow trial progression without obtaining a DSMB quorum. 


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During the observer-blind placebo-controlled phase at each dose level, if >4 subjects 
experienced Grade 3 adverse reaction(s) after administration of CVnCoV at a particular 
dose level, vaccination will be put on hold for all subjects in the applicable dose level and 
any higher dose level. 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 dose-de-escalation) with this and any higher dose level. 
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 dose-de-escalation). 
If a stopping rule or trial suspension rule is limited to subjects with SARS-CoV-2 positive 
serology, vaccination will only be put on hold for subjects with SARS-CoV-2 positive 
serology. 
The DSMB may recommend additional measures including modification or halt of the trial. 
After completion of vaccination for all subjects, the DSMB will continue to review safety 
data every 3 months, or more frequently if needed based on the safety data. 
9.3 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. 
9.3.1 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.  
The humoral immune response will be evaluated on Day 1, Day 8, Day 15, Day 29, 
Day 36, Day 43, Day 57, Day 120, Day 211 and Day 393. 
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 time points mentioned above for 
humoral immune response testing to SARS-CoV-2 S-protein. 
To further evaluate the humoral immune response, cross-reactivity with other viral 
antigens might be analyzed.  
9.3.2 Innate Immune Response – Only for Open-Label Sentinel Subjects  
The innate immune response will only be evaluated in subjects in the open-label sentinel 
groups. 


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Measurement of serum cytokines, including but not limited to IFN-α, IFN-γ, IL-6, CCL2 and 
IP-10, will be performed on Day 1, Day 2, Day 8, Day 29, Day 30 and Day 36. 
In addition, gene expression changes will be determined using the PAXgene® blood RNA 
system by transcriptome profiling on Day 1, Day 2, Day 8, Day 29, Day 30 and Day 36. 
9.3.3 Cell-Mediated Immunity 
CMI will only be evaluated in subjects from the 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, 
intracellular cytokine staining (ICS) to investigate Th1 response and production of Th2 
markers (e.g. secreted IL-5) will be used to investigate whether vaccination induces a Th1 
shift from baseline. Further T-cell immune response maybe investigated with other 
technologies like ELISpot or CyTOF. 
CMI assessment will be performed on Day 1 (baseline), Day 29, Day 36 and Day 211. 
Note that testing on Day 211 will only be performed on subjects who are determined as 
T-cell responders on Day 29 and/or Day 36. 
9.4 Laboratory Testing for COVID-19 Disease 
As part of the eligibility assessment, PCR for SARS-CoV-2 will be performed. Additionally, 
for the 12 open-label sentinel subjects in each dose level, the SARS-CoV-2 serological 
status will be determined using site-specific diagnostics prior to enrollment to ensure they 
are seronegative. This may also be performed for subjects in the observer-blind 
placebo-controlled part of the trial to identify subjects with SARS-CoV-2 positive serology. 
At several pre-defined timepoints during the trial, IgM and IgG serology will be assessed. 
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 identify the subject’s (baseline) serology status for the group/cohorts 
analysis. 
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 should not receive any (additional) vaccine dose, but 
will be closely monitored for disease patterns and severity. 
Subjects will be instructed to contact the site if they observe 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 
PCR-confirmed COVID-19 disease (refer to Appendix 4 for an example symptom log). 
If the subject displays symptoms of ARI (including, but not limited to COVID-19 disease), 
the Investigator will collect appropriate specimens as soon as feasible and perform PCR 
and serological assays at the discretion of the Investigator or treating physician to 
establish laboratory measures of infection with SARS-CoV-2. Each of those assays will 


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be repeated 7-14 days after the initial assessment as well. 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 
This trial is designed to estimate the probability that the true rate of adverse reactions for 
each dose lies in an acceptable safety range (see Section 10.3.5.1) and to describe the 
safety profile of CVnCoV. Hence, its sample size was not determined based on formal 
statistical power calculations. 
During the trial, a minimum of 12 subjects evaluable for the dose determining set (DDS-2, 
as defined in Section 10.2) will be vaccinated per dose level until completion of the dose 
escalation. After completion of the open-label sentinel phase, subjects will be enrolled in 
placebo-controlled groups in an observer-blind manner within each dose level with a 4.5:1 
ratio and stratified by the 2 age categories (18-40 and 41-60 years). For an overview of 
the distribution of subjects, refer to Figure 2. 
It is estimated that approximately 56 subjects per dose level will be enrolled, including 
48 CVnCoV and 8 placebo recipients, for ≤8µg and 16 subjects per dose level, all CVnCoV 
recipients, for >8µg. The actual number of subjects will depend on the number of dose 
levels/groups that are tested.  
The trial is designed to provide, by combining data from the open-label sentinel and the 
observer-blind placebo-controlled phases, a reasonable precision for the rate of subjects 
with Grade 3 adverse reaction(s). Table 5 provides the estimate and 95% credibility 
interval for given observed numbers of subjects for a sample size of 48 subjects per dose 
level (assuming a Beta (0.5,0.5) prior distribution). 
Table 5 
Estimate rate of subjects with Grade 3 adverse reaction(s) and 95% 
credibility interval per dose level 
N subjects with Grade 3 
adverse reaction(s) 
Estimate (95% credibility 
interval) in % 
Probability adverse 
reaction rate <33% 
0 
1 (0 - 5.1) 
100 
2 
5.1 (0.9 - 12.7) 
100 
4 
9.2 (2.9 - 18.6) 
100 
6 
13.3 (5.4 - 24) 
99.9 
8 
17.3 (8.2 - 29) 
99.4 
10 
21.4 (11.2 - 33.8) 
96.7 
12 
25.5 (14.5 - 38.5) 
88.2 
14 
29.6 (17.8 - 43) 
71.,0 
16 
33.7 (21.3 - 47.3) 
47.3 
18 
37.8 (24.9 - 51.6) 
25.1 
20 
41.8 (28.5 - 55.8) 
10.2 
N = Number of subjects 
Table 6 provides probabilities (in %) that the following condition is met for assumed true 
rates of adverse reactions and a sample size of 48 subjects per arm: There is a ≥80% 
probability that the true rate of Grade 3 adverse reaction(s) is <33%. 


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For example, assuming a true adverse reactions rate of 20%, the condition is met with a 
probability of 91.6%. 
Table 6 
Probabilities that the rate of Grade 3 adverse reactions is <33% is ≥80% 
for given ‘true’ adverse reactions rates during dose escalation 
True rate of adverse reactions 
Probability (%) 
0.05 
100 
0.1 
100 
0.15 
99.1 
0.2 
91.6 
0.25 
69.8 
0.3 
39.7 
0.35 
16.1 
The number of placebo subjects is chosen to have a minimum number of subjects to 
descriptively evaluate the onset and the level of humoral immune response taking into 
account that there are 2 age groups, 2 possible SARS-CoV-2 status at baseline, 3 different 
doses levels and a placebo group (Table 7). A total of 24 placebo subjects, of whom 18 are 
expected to have a SARS-CoV-2 negative serology before the trial start, will provide a 
reasonable number in the placebo group to differentiate between each of the age groups 
receiving CVnCoV individually and all subjects on a dose level versus all placebo 
recipients. 
Despite the small sample size for the placebo group within a dose level, a pooled within‐
trial analysis of all placebo recipients could provide a sufficient number to assess 
differences between CVnCoV and placebo recipients by providing anchoring information 
on ‘no dose’ for regression analyses. With the given number, an exploratory t-test might 
be conducted assuming a large vaccination effect, which cannot be quantified yet. As the 
effect is unknown since this is the FIH trial, no assumptions and power analyses were 
conducted. This trial will however allow to generate a hypothesis for the Phase 2/3 trials. 
Table 7 
Distribution of subjects 
 
Subjects with no history 
of COVID-19 
Subjects with SARS-Cov-2 
positive serology  
CVnCoV 
Placebo 
CVnCoV 
Placebo 
2/4/8μg: 18-40 years 
20 
9 
4 
3 
2/4/8μg: 41-60 years 
20 
9 
4 
3 
2/4/8μg: all age 
groups 
40 
18 
8 
6 
In addition, even in the absence of statistical power, the inclusion of blinding and placebo 
subjects can reduce biases in AE reporting occurring in open‐label trials. 
10.2 Populations for Analyses 
Safety Set: 
The safety set will consist of all subjects who received at least one dose of trial vaccine 
and for whom any post-vaccination safety data are available.  


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The dose-determining set 1 (DDS-1) will consist of the first 4 subjects in a dose level 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-1 will be used for the first dose expansion decision at a 
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 dose-determining set. Since DDS-1 is only used 
during dose escalation, DDS-1 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. 
The dose-determining set 2 (DDS-2) will consist of all subjects in 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 60 hours, or 
completed the 60-hour observation period without experiencing Grade 3 adverse 
reactions or SAEs considered as related to the trial vaccine according to the Investigator. 
The DDS-2 set will be used for dose escalation decisions and for decisions to continue 
enrollment after the 60-hour safety reviews. 
Immunogenicity Set: 
The immunogenicity set will include all subjects who received at least one dose of trial 
vaccine and for whom the baseline blood sample and at least 1 additional blood sample 
are available for analysis. 
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. The safety and 
immunogenicity analyses will be done overall and by baseline serology status for 
SARS-CoV-2. 
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 from this trial may be pooled with data from potential follow-up trials, e.g. in different 
age groups. 
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 
arm. Medical history will only be listed. 


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10.3.3 Trial Vaccine Administration 
The administrations of CVnCoV or placebo 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 assumption is that the rate of subjects with Grade 3 adverse reactions will be similar 
in subjects independent of baseline serology status (seronegative or seropositive) and 
therefore similar in subjects with no history of COVID-19 disease and subjects with 
SARS-CoV-2 positive serology. Both groups will be analyzed together for the primary 
analysis of Grade 3 adverse reactions. Additional subgroup analyses will be performed for 
subjects 
retrospectively 
SARS-CoV-2 
seronegative 
at 
baseline and 
subjects 
retrospectively SARS-CoV-2 seropositive at baseline. 
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will be used for the dose escalation while decisions of 
dose level expansion in the sentinel groups of 4 subjects is based on a maximum number 
of 2 subjects with Grade 3 adverse reactions. Of note, dose escalation can also not 
proceed if any SAE considered as related to the trial vaccine according to the Investigator 
occurs. The use of Bayesian response adaptive models for Phase 1 studies has been 
advocated by the EMA adopted guideline on small populations (EMA, 2006) and by 
Rogatko et al., 2007 [37] and is one of the key elements of the FDA’s Critical Path Initiative. 
A modified 2-parameter BLRM will be used for dose escalation [38]. Standardized doses 
will be used such that one of the doses (d*) equals 1, e.g., doses are rescaled as d/d*. 
Consequently, α is equal to the odds of the probability of intolerance at d*. All information 
currently available about the dose-adverse reaction relationship of CVnCoV is 
summarized in a prior distribution. This prior distribution is then updated after each group 
of subjects with all of the adverse reactions data available in the safety set from the current 
trial. Once updated, the distribution summarizes the probability that the true rate of 
adverse reactions for each dose lies in the following categories: 
• 0% to <33%: targeted tolerance; and 
• ≥33% to 100%: intolerance. 
The EWOC principle mandates that any dose of CVnCoV that has more than a 50% 
chance of being in the intolerance category is not considered for the next dose 
administrations [38, 39]. A clinical synthesis of the available safety and reactogenicity 
information (including adverse reactions that are not Grade 3 adverse reactions), 
laboratory values and, if available, immune response information as well as the 
recommendations from the Bayesian model and the iSRC/DSMB will be used to determine 
the dose level(s) for the next group at a dose-escalation teleconference. In any case where 
there is a change in dose level to be administered to the next enrolled subjects, a new 
model will be defined using a Meta-Analytic-Predictive prior, based on the observed data. 


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The frequency of Grade 3 adverse reactions and SAEs considered as related to the trial 
vaccine according to the Investigator will be tabulated by dose level after 24 hours and 
60 hours post-vaccination and information about the Grade 3 adverse reactions and SAEs 
considered as related to the trial vaccine according to the Investigator will be listed by 
dose level. 
Bayesian Logistic Regression Model 
The objective of the design is to determine the highest dose with less than 50% risk of a 
true Grade 3 adverse reaction rate being equal to or above 33%. The dose escalation will 
be guided by a modified Bayesian 2-parameter logistic regression model with overdose 
control.  
The model is formulated as follows: 
logit(p(d)) = log(α) + β*log(d/d*), 
where logit(p) = log(p/(1-p)). p(d) represents the probability of having a Grade 3 adverse 
reaction in the first 24 hours at dose d, d* = 8µg is the reference dose, allowing for the 
interpretation of α as the odds of an adverse reaction at dose d*, and θ = (log(α), log(β)) 
with α, β >0 is the parameter vector of the model. 
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a multivariate 
normal distribution, i.e., 
π(θ) = MVN(μ, Σ) 
the multivariate normal distribution with mean vector μ and covariance matrix Σ, with 
 
Prior derivation 
Since no prior information is available, the uncertainty about the dose-tolerance 
relationship is expressed by a mixture distribution composed of a main component (a priori 
assuming 10% and 20% adverse reaction probabilities at 2µg and 8µg, respectively), a 
low tox (a priori assuming 5% and 15% adverse reaction probabilities at 2µg and 8µg, 
respectively) and a high tox component (a priori assuming 25% and 50% adverse reaction 
probabilities at 2µg and 8µg, respectively). All mixture components are attached with high 
uncertainty expressed by unit variances of the coefficients. A summary of the prior 
probabilities of Grade 3 adverse reactions at different doses, as well as the corresponding 
probability of targeted and overdosing, are shown in Table 9. Graphically, the prior 
medians with accompanying 95% credible intervals are shown in Figure 3. The uncertainty 
around the medians is large, showing the low amount of in-men information this prior 
provides. 
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Table 8 
Summary of prior distribution 
Prior 
Component 
Mixture Weight 
Mean Vector 
STD Vector 
Correlation 
Main 
0.8 
-1.386 
1 
0 
-0.536 
1 
Low tox 
0.1 
-1.735 
1 
0 
-0.136 
1 
High tox 
0.1 
0.000 
1 
0 
-0.233 
1 
-0.761 
1 
Table 9 
Prior probabilities of Grade 3 adverse reaction at selected doses 
Dose 
(µg) 
Probability of true 
adverse reaction rate in 
Mean 
STD 
Quantiles 
[0-0.33) 
[0.33-1] 
2.5% 
50% 
97.5% 
2 
0.898 
0.102 
0.133 
0.145 
0 
0.083 
0.545 
4 
0.841 
0.159 
0.179 
0.161 
0.007 
0.128 
0.615 
8 
0.708 
0.292 
0.26 
0.185 
0.034 
0.213 
0.721 
Doses in bold type meet the overdose criterion, P(overdose) < 0.20. 
* STD = standard deviation. 
Figure 3 
Prior medians and 95% credibility intervals 
 
The highest acceptable dose may be considered reached if both of the following criteria 
is fulfilled: 
1. 
The posterior probability of the true Grade 3 adverse reaction rate in the target 
interval [0%-33%) is at least 50% and the probability of being above the target is 
below 50%. 
2. 
At least 12 subjects have been vaccinated with this dose level. 


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Statistical model assessment 
The model was assessed using 2 different metrics: 
1. 
Hypothetical data scenarios: For various potential data constellations as they 
could occur in the actual trial, the maximal next doses as allowed by the model and 
by the 200% escalation limit are investigated. Data scenarios thus provide a way to 
assess the “on-trial” behavior of the model. 
2. 
Simulated operating characteristics: These illustrate for different assumed true 
dose-tolerance relationships, how often a correct dose would be declared as highest 
acceptable dose by the model. They are a way to assess the “long-run” behavior of 
the model. 
In summary, the model showed very good behavior as assessed by these metrics. More 
details can be found in Appendix 6. 
10.3.5.2 
Descriptive 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 systemic events (fever, headache, fatigue, chills, myalgia, arthralgia, 
nausea/vomiting and diarrhea) occurring on the day of vaccination and the following 
7 days) and unsolicited events (occurring on the day of vaccination and the following 
28 days). 
2. SAEs and AESIs throughout the trial. 
The descriptive safety analyses will be performed for all subjects, for subjects 
retrospectively SARS-CoV-2 seronegative at baseline, and for subjects retrospectively 
SARS-CoV-2 seropositive at baseline. 
Solicited AEs: For reactogenicity assessment, for each dose level and dose, 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 and after any vaccination. 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, 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. Additional similar 


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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 
10.3.6 Secondary and Exploratory Analysis 
Descriptive statistics for the secondary and exploratory immunogenicity endpoints will be 
provided by arm for each dose level. Data will be presented after each vaccine dose.  
Individual values and GMT of SARS-CoV-2 spike protein antibody levels and of 
SARS-CoV-2 neutralizing antibodies, percentages of immune cell populations and cellular 
responders will be summarized for each dose level in all subjects, in those subjects 
retrospectively SARS-CoV-2 seronegative at baseline, and in those subjects 
retrospectively SARS-CoV-2 seropositive at baseline. For subjects who do not get 
exposed to SARS-CoV-2 before the trial, or 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 PCR-positive swab during the trial), percentages of subjects seroconverting for 
SARS-CoV-2 spike-protein antibodies and SARS-CoV-2 neutralizing antibodies will be 
summarized at each dose level. In addition, for the open-label sentinel groups, levels of 
cytokines and changes in gene transcripts will be summarized. This analysis may also be 
performed separately in subjects retrospectively SARS-CoV-2 seronegative at baseline 
and subjects retrospectively SARS-CoV-2 seropositive at baseline. 
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. 
10.3.7 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 SARS-CoV-2 spike protein antibodies, concentration values marked as 
below the lower limit of quantification (LLOQ) will be set to 0.5*LLOQ.  
No imputation of missing values will be done for any analysis (except the imputation for 
missing partial dates of AEs and concomitant medication). Reasons for discontinuation 
from the trial or trial vaccination will be listed and summarized. 
Currently no replacement of 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. 


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• 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. 
10.3.8 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 
of the current pandemic and the public heath 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. 
Each dose escalation step is considered as an interim analysis (refer to Section 5.2 for 
the dose escalation steps). 
 


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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 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 informed consent form (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 carry out 
source document verification at regular intervals to ensure that the data collected in the 
eCRF are accurate and reliable. The frequency of monitoring visits will be determined by 
the rate of subject recruitment. 


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


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12 ETHICS 
12.1 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. 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.  
12.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 
The Investigators are responsible for ensuring that no subject undergoes any trial-related 
examination or activity before that subject has given written informed consent to 
participate in the trial.  


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The Investigator or designated personnel will inform the subject of the objectives, 
methods, anticipated benefits and potential risks and inconveniences of the trial. The 
subject should be given every opportunity to ask for clarification of any points he does not 
understand and if necessary, ask for more information. At the end of the interview, the 
subject will be given ample time to consider the trial. Subjects will be required to sign and 
date the ICF. After signatures are obtained, the ICF will be kept and archived by the 
Investigator in the Investigator’s trial file. A signed and dated copy of the subject ICF will 
be provided to the subject or his/her authorized representative. 
It should be emphasized to the subject that the participation in the trial is voluntary and 
the subject may refuse to participate or 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 Sponsor by CRO/ 
the data processor, governed by a contract and strictly according and subject to the GDPR 
and any applicable data protection rules and regulations.  The Sponsor and the CRO/data 
processor implement appropriate technical and organizational measures to ensure a level 
of security appropriate to the risk, taking into account the state of the art, the costs of 
implementation and the nature, scope, context and purposes of processing as well as the 
risk of varying likelihood and severity for the rights and freedoms of natural 
persons.  Quality control will occur at each stage of data handling to ensure that all data 
are reliable and have been processed correctly. The Sponsor will ensure oversight of any 
trial-related duties and functions carried out on its behalf, including trial-related duties and 
functions that are subcontracted to another party by the CRO. 
This trial will be registered on ClinicalTrials.gov in accordance with applicable laws or 
publication policy and may also be registered on other publicly accessible websites as 
necessary. 
13.1 Data Protection 
All information generated in this trial is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the trial unless prior written 
consent is gained from the Sponsor. However, authorized regulatory officials, 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 (acc. to Art. 35 
GDPR). 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. All 
personal identifiers according to applicable regulations (e.g., name, phone number) must 
be redacted permanently by the site personnel and replaced with the subject’s unique 
identification number in all records and data before transfer to the Sponsor (or designee). 


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The subject must be informed that his/her personal trial-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject who will be required to give consent for their data to be used as 
described in the informed consent The subject must be informed that his/her medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities.  
Subjects or their legal representatives may request their medical information be given to 
their personal physician or other appropriate medical personnel responsible for their 
welfare. 
13.2 Clinical Trial Report 
The Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with the clinical trial report according to the applicable regulatory requirements. 
The Sponsor should ensure that this report meets the standards of the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). 
13.3 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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pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting 
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16. Team TNCPERE. The epidemiological characteristics of an outbreak of 2019 novel 
coronavirus diseases (COVID-19) — China, 2020. CCDCW. 2020 Feb 1;2:1–10. 
17. Deng Y, Liu W, Liu K, et al. Clinical characteristics of fatal and recovered cases of 
coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin 
Med J. 2020 Mar 20. 
18. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with 
SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 
observational 
study. 
The 
Lancet 
Respiratory 
Medicine. 
2020 
Feb 
24; 
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30079-
5/abstract 
19. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) 
[cited 2020 Mar 24]; https://www.who.int/publications-detail/report-of-the-who-china-
joint-mission-on-coronavirus-disease-2019-(covid-19) 
20. Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 
1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, 
Italy. JAMA. 2020 Apr 6; https://doi.org/10.1001/jama.2020.5394 
21. WHO Coronavirus disease (COVID-19) situation reports. Report 184, 22 July 2020. 
https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200722-
covid-19-sitrep-184.pdf?sfvrsn=7680210a_2 
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 


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30. Wang J and Zand MS. The potential for antibody-dependent enhancement of SARS-
CoV-2 infection: Translational implications for vaccine development. Journal of Clinical 
and Translational Science. 2020;1-4. 
31. Global regulatory workshop on COVID-19 vaccine development: Summary Report. 
International Coalition of Medicines Regulatory Authorities (ICMRA), 18 March 2020, 
https://www.pei.de/SharedDocs/Downloads/EN/newsroom-en/hp-news/icrma-
report.pdf?__blob=publicationFile&v=2. Accessed 11 Jun 2020. 
32. Clinical Trial Facilitation Group (CTFG) Recommendations related to contraception 
and pregnancy testing in clinical trials, September 2014. Available at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
33. Coates S, Pohl O, Gotteland JP, et al. Efficient Design of Integrated and Adaptively 
Interlinked Protocols for Early-Phase Drug Development Programs. Ther Innov Regul 
Sci. 2020;54(1):184-194. 
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. 
35. Heyse JF, Kuter BJ, Dallas MJ, Heaton P. Evaluating the safety of a rotavirus vaccine: 
the REST of the story. Clin Trials. 2008;5(2):131-9. 
36. US Department of Health and Human Services. Food and Drug Administration (FDA). 
Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 2007. [Available from: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegul
atoryInformation/Guidances/Vaccines/ucm091977.pdf; 'Accessed at: March 2019]. 
37. Rogatko A, Schoeneck D, Jonas W, et al. Translation of innovative designs into phase 
I trials. J Clin Oncol. 2007 Nov 1;25(31):4982-6. 
38. Neuenschwander B, Branson M, Gsponer T.Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008 Jun 15;27(13):2420-39.  
39. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med. 1998 May 30;17(10):1103-20. 


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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 10 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 10 
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 
Serum/Urine 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 
___ /______ /______ 
___ /______ /______ 
Headache 
☐ Yes ☐ No 
___ /______ /______ 
___ /______ /______ 


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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 
Statistical Appendix Including Model Performance and Data 
Scenarios 
The model was assessed by 2 different metrics: hypothetical on-trial data scenarios and 
long-run operating characteristics. 
Hypothetical Data Scenarios 
Exemplary hypothetical data scenarios are shown in Table 11 to Table 13. These 
scenarios reflect potential on-trial data constellations and related escalation as allowed by 
the model and the 200% escalation limit. For each scenario, the probability of overdosing 
for the current dose, as well as the next potential dose and related probabilities of target-
dosing are shown.  
These settings illustrate the adaptive behavior of the model which takes into account all 
observed data from previous dose levels and show a reasonable behavior of the model. 
Table 11 
Escalation from 2µg to 4µg: Escalate to 4µg if not more than 4 in 12 
subjects experience a Grade 3 adverse reaction. 
Scenario 
Dose 
#AR 
#Pat 
CD - 
P(OD) 
Next 
Dose 
ND - 
P(TD) 
ND - 
P(OD) 
1 
2 
0 
12 
0.000 
4 
0.994 
0.006 
2 
2 
4 
12 
0.269 
4 
0.524 
0.476 
3 
2 
5 
12 
0.496 
2 
0.504 
0.496 
CD=Current dose  
P(OD)= Probability of overdose 
ND= Next dose 
P(TD)= Probability of target dose 
P(OD)= Probability of overdose 
Table 12 
Escalation from 4µg to 8µg: Only borderline scenarios are provided with 
maximum number of Grade 3 adverse reactions at 4µg which just allow to 
escalate. 3 to 4 adverse reactions at 4µg support escalation to 8µg 
depending on the outcome on previous dose levels. 
Scenario 
Dose 
#AR 
#Pat 
CD - 
P(OD) 
Next 
Dose 
ND - 
P(TD) 
ND - 
P(OD) 
3 
2 
0 
12 
 
 
 
 
4 
4 
12 
0.052 
8 
0.599 
0.401 
4 
2 
1 
12 
 
 
 
 
4 
4 
12 
0.106 
8 
0.568 
0.432 
5 
2 
2 
12 
 
 
 
 
4 
3 
12 
0.094 
8 
0.658 
0.342 
6 
2 
3 
12 
 
 
 
 
4 
3 
12 
0.193 
8 
0.558 
0.442 
7 
2 
4 
12 
 
 
 
 
4 
2 
12 
0.18 
8 
0.61 
0.39 


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Table 13 
Confirmation of 8µg: Scenarios represent the situations with the maximum 
number of Grade 3 adverse reactions at 8µg which still allow to confirm the 
highest dose level. 3 to 5 adverse reactions at 8µg support confirmation of 
safety of 8 µg depending on the outcome in previous dose levels. 
Scenario 
Dose 
#AR 
#Pat 
CD - 
P(OD) 
Next 
Dose 
ND - 
P(TD) 
ND - 
P(OD) 
8 
2 
0 
12 
 
 
 
 
4 
0 
12 
 
 
 
 
8 
5 
12 
0.391 
8 
0.609 
0.391 
9 
2 
0 
12 
 
 
 
 
4 
2 
12 
 
 
 
 
8 
5 
12 
0.452 
8 
0.548 
0.452 
10 
2 
0 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
4 
12 
0.328 
8 
0.672 
0.328 
11 
2 
0 
12 
 
 
 
 
4 
4 
12 
 
 
 
 
8 
4 
12 
0.402 
8 
0.598 
0.402 
12 
2 
1 
12 
 
 
 
 
4 
1 
12 
 
 
 
 
8 
5 
12 
0.321 
8 
0.679 
0.321 
13 
2 
1 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
5 
12 
0.497 
8 
0.503 
0.497 
14 
2 
1 
12 
 
 
 
 
4 
4 
12 
 
 
 
 
8 
4 
12 
0.433 
8 
0.567 
0.433 
15 
2 
2 
12 
 
 
 
 
4 
2 
12 
 
 
 
 
8 
5 
12 
0.431 
8 
0.569 
0.431 
16 
2 
2 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
4 
12 
0.375 
8 
0.625 
0.375 
17 
2 
2 
12 
 
 
 
 
4 
4 
12 
 
 
 
 
8 
4 
12 
0.484 
8 
0.516 
0.484 
18 
2 
3 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
4 
12 
0.44 
8 
0.56 
0.44 
Operating Characteristics 
Operating characteristics are a way to assess the long-run behavior of a model. Under an 
assumed true dose-tolerance curve, metrics such as the probability of recommending a 
dose with true Grade 3 adverse reaction rate in the target interval can be approximated 
via simulation. Table 14 describes 3 assumed true scenarios which were used to assess 
the operating characteristics of the model. These scenarios reflect a wide range of 
possible cases as follows: 
• 
Scenario 1 (P): aligned with prior means 


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• 
Scenario 2 (H): high-intolerance scenario 
• 
Scenario 3 (LH): low-intolerance followed by high-intolerance 
Table 14 
Assumed True Dose-Tolerance Scenarios 
Scenario 
 
 
 
 
 
Dose 
2 
4 
8 
1(P) 
P(Grade 3 adverse 
reactions) 
0.13 
0.18 
0.26 
2(H) 
0.30 
0.50 
0.60 
3(LH) 
0.15 
0.30 
0.45 
Bold numbers indicate true adverse reaction rates in the target interval [0-0.33). 
For each of these scenarios, 500 trials were simulated. It was then assessed how often a 
dose was declared safe with true Grade 3 adverse reaction rate in the targeted or over-
dose range. Furthermore, the average, minimum and maximum number of subjects per 
trial and the average number of Grade 3 adverse reactions per trial are reported. Results 
are shown in Table 15. 
Table 15 
Hypothetical Data Scenarios 
Scenario 
% of trials recommending a 
dose with true Grade 3 
adverse reaction rate in 
Stopped 
# Subjects 
# Grade 3 
adverse reactions 
 
Target dose 
Overdose 
% of trials Mean (Min - Max) Mean (Min - Max) 
1 (P) 
98.2 
0 
1.8 
33.58 (4 - 36) 
6.21 (0 - 11) 
2 (H) 
56.4 
21 
22.6 
18.79 (4 - 36) 
7.18 (3 - 15) 
3 (LH) 
74.2 
24 
1.8 
28.75 (4 - 36) 
7.66 (3 - 13) 
In Scenario 1, which reflects the case that the true dose-tolerance relationship is aligned 
with prior means, 98.2% of the simulated trials declared a dose as safe with true Grade 3 
adverse reaction rate in the targeted dose range, while 1.8% of the simulated trials were 
stopped without declaring a dose to be safe. 
In Scenario 2 (high-intolerance scenario), the starting dose has already 30% probability of 
observing at least 1 Grade 3 adverse reaction at the first dose level. This contributes to 
the increased percentage of 22.6% of all simulated trials for which the trial is stopped since 
none of the doses is considered tolerable anymore. This is an expected situation for a 
high-intolerance scenario. Despite the high intolerance probabilities assumed, only 21% 
of the simulated trials declared a dose safe with true Grade 3 adverse reaction rate in the 
overdose range. 
Scenario 3, 74.2% of the simulated trials declared a dose safe with true Grade 3 adverse 
reaction rate in the targeted dose range and in only 1.8% the trial was stopped, while in 
24% of the trials, a safe dose in the overdose range was declared. 
The mean subject numbers ranged from 18.79 subjects (high scenario) to 33.58 subjects 
(prior means scenario) and the maximum number of subjects was 36. Mean numbers of 
grade 3 ARs ranged from 6.21 to 7.66. 
In summary, the operating characteristics demonstrate a good precision of the highest 
acceptable dose determination. 


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Appendix 7 
Trial Governance Considerations 
CureVac AG is the Sponsor of this trial. A CRO will organize the conduct of this trial. 


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Appendix 8 
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 9 
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 10 
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 AR following immunization 
 


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Appendix 11 
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 one of two 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 [36]. 
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 one 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 9.2.1. 
• 
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 CRF extends from the time the subject gives informed consent 
until the end of the trial, for the period described in Section 9.2.1. 
• 
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 12 
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 13 
Protocol Amendment History 
The trial was initiated using protocol version 2.0; changes made between versions 1.0 and 
2.0 are therefore not listed here. 
Protocol version 3.0: 24 July 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. The DSMB for this trial has determined that the dose-levels 
evaluated thus far have shown an acceptable safety/reactogenicity profile. 
Overall Rationale for the Amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
Title 
Addition of “COVID-19” at start 
of title 
Request of Competent Authority 
Throughout 
Addition of details for dose 
escalation to 12, 16 and/or 20µg 
To increase the dose to >8µg 
based on safety and available 
immunogenicity data after iSRC 
and DSMB review, and not only 
after immunogenicity data from 
the second dose is available. 
Synopsis, Schedule of 
Assessments, 5.1. 
Overall Design, 
9.1.1.1. 
Pre-vaccination 
Procedures and 9.4. 
Laboratory Testing for 
COVID-19 Disease 
Addition of the possibility to 
perform site-specific diagnostics 
prior to enrollment to test 
subjects’ serological status also 
in the observer-blind 
placebo-controlled part of the 
trial 
To allow the sites to conduct this 
test to identify subjects with 
SARS-CoV-2 positive serology as 
part of the protocol 
Synopsis and 5.2. 
Dose Escalation Steps 
Post-vaccination observation for 
the first subject vaccinated with 
CV-nCoV 2µg was extended 
from “until midnight” to “for 
24 hours” 
Request of Ethical Committee 


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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis and 6.1. 
Inclusion Criteria 
Addition of the following to 
criterion 4: 
Body mass index (BMI) ≥18.0 
and ≤30.0kg/m2 (≥18.0 and 
≤32.0kg/m2 for subjects with 
SARS-CoV-2 positive serology). 
To facilitate recruitment of 
subjects with SARS-CoV-2 
positive serology, who are only 
recruited after evaluation of 
reactogenicity/safety of 
seronegative sentinel subjects 
Synopsis and 6.2. 
Exclusion Criteria 
Addition of the following to 
criterion 7:  
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 
steroids. Corticosteroids used in 
the context of COVID-19 
disease of subjects with 
SARS-CoV-2 are not 
exclusionary. 
To facilitate recruitment of 
subjects with SARS-CoV-2 
positive serology, who are only 
recruited after evaluation of 
reactogenicity/safety of 
seronegative sentinel subjects. 
Those subjects may have had 
COVID-19 disease and may have 
received corticosteroids as part of 
the treatment. This should not 
lead to exclusion 
Synopsis and 6.2. 
Exclusion Criteria 
Addition of the following to 
criterion 11:  
Any known allergy, including 
allergy to any component of 
CVnCoV or aminoglycoside 
antibiotics. A history of hay fever 
or seasonal allergies (pollinosis) 
that does not require current 
treatment (e.g., anti-histamines) 
during the vaccination period 
(1 month before first vaccination 
until 1 month after last 
vaccination) is not exclusionary. 
To facilitate recruitment. Seasonal 
allergies are not seen as a risk 
factor, in particular if not requiring 
treatment 


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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis and 6.2. 
Exclusion Criteria 
Addition of the following to 
criterion 17:  
Respiratory disease with 
clinically significant dyspnea in 
the last 5 years (except 
COVID-19 disease in subjects 
with SARS-CoV-2 positive 
serology). 
To facilitate recruitment of 
subjects with SARS-CoV-2 
positive serology, who are only 
recruited after evaluation of 
reactogenicity/safety of 
seronegative sentinel subjects. 
Those subjects may have had 
COVID-19 disease which should 
not exclude them from 
participation in the trial 
8. Discontinuation/ 
Withdrawal Criteria 
Addition of the following text 
“Assessments of solicited AEs 
and associated phone calls for 
the second 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 discontinued trial 
vaccine administration.” 
Only relevant visits need to be 
conducted for any subjects who 
prematurely discontinued trial 
vaccine administration 
9.2.3. Safety 
Laboratory 
Assessments 
Removed reference to the 
Common Terminology Criteria 
for Adverse Events 
The FDA toxicity grading scale 
will be used for grading laboratory 
data 
Appendix 5 Case 
Definition for 
COVID-19 Disease 
Update of the case definition for 
COVID-19 disease 
To comply with the new Coalition 
for Epidemic Preparedness 
Innovations definition 
Throughout 
Removal of the requirement for 
“known” SARS-CoV-2 positive 
serology 
To facilitate recruitment of 
subjects with SARS-CoV-2 
positive serology 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore have not been 
summarized 
 

SAP_001.pdf: 
Protocol Number:  CV-NCOV-001 
 
Official Title:  A Phase 1, partially blind, placebo-controlled, dose-escalation, 
first-in-human, clinical trial to evaluate the safety, reactogenicity and 
immunogenicity after 1 and 2 doses of the investigational SARS-CoV2 mRNA vaccine CVnCoV 
administered intramuscularly in healthy adults. 
 
NCT Number: NCT04449276 
 
Document Date:  25-Nov-2021 


                                               Statistical Analysis Plan (SAP) 
Version Date: 25-NOV-2021  
 
Sponsor: CureVac AG 
 
Protocol no: CV-NCOV-001 
Page 1 of 47 
Strictly Confidential.  © 2021, PRA Health Sciences.  All rights reserved. 
Statistical Analysis Plan (SAP) 
Protocol Title: 
A Phase 1, partially blind, placebo-controlled, dose-escalation, 
first-in-human, clinical trial to evaluate the safety, reactogenicity and 
immunogenicity after 1 and 2 doses of the investigational SARS-CoV-
2 mRNA vaccine CVnCoV administered intramuscularly in healthy 
adults. 
Protocol Version No./Date: 
3.0/24-JUL-2020 
CRF Version No./Date: 
4.0/01-FEB-2021 
SAP Version No./Date: 
3.0/25-NOV-2021 
 
 Approvals 
Sponsor 
Sponsor Name: 
CureVac AG 
Representative/ Title: 
Signature /Date: 
 
 
Representative/ Title: 
Signature /Date: 
 
 
Representative/ Title: 
Signature /Date: 
 
 
Representative/ Title: 
Signature /Date: 
 
 
PRA 
Biostatistician / Title: 
Signature /Date: 
 
 
 (NOTE: Electronic Signatures should only be used if all parties have the ability to eSign.) 
 
 


                                               Statistical Analysis Plan (SAP) 
Version Date: 25-NOV-2021  
 
Sponsor: CureVac AG 
 
Protocol no: CV-NCOV-001 
Page 2 of 47 
Strictly Confidential.  © 2021, PRA Health Sciences.  All rights reserved. 
 Change History 
Version/Date 
Change Log 
1.0/23-JUL-2020 
Created as new 
2.0/17-SEP-2020 
Section 8.0 updated to reflect protocol version 3.0 
Section 10.4.7 Adverse Reactions added – definition added 
Section 10.4.8 Credibility Interval and related Estimate - clarification regarding 
calculation added 
Section 10.5 Retrospective SARS-CoV-2 Baseline Serology – definition added 
Section 10.6 Subjects not exposed to SARS-CoV-2 before or during the trial – 
definition added 
Section 10.7.1 Geometric mean – clarification regarding calculation added 
Section 10.7.2 Seroconversion – definition added 
Section 11.1 Interim Analyses – details for scope added 
Section 12.6.3.1 Secondary Endpoints; clarification of analysis and fold change, mean 
fold change and box plots added for ELISA IgG/IgM and VNT.  
Appendix 3 Statistical details added 
Appendix 4 Inclusion/Exclusion criteria updated 
3.0/25-NOV-2021 
Section 10.5.4 Evaluation of infection - definition added 
Section 10.6 Censoring rule for subjects unblinded due to availability of 
authorized/licensed vaccine 
Section 12.2 Important protocol deviations – process definition added 
Section 12.6.2 Adding analysis of occurrence of AEs related to SMQs. 
Section 12.6.3.1 Additional analysis for subjects receiving both doses, are 
seronegative and did not have any protocol deviations with impact to immune 
response 
 
 
 


                                               Statistical Analysis Plan (SAP) 
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 Table of Contents 
 Approvals ................................................................................................................................................ 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents .................................................................................................................................... 3 
 Purpose ................................................................................................................................................... 5 
 Scope ...................................................................................................................................................... 5 
 Introduction ............................................................................................................................................. 5 
6.1 Changes from Protocol .................................................................................................................... 5 
 Study Objectives ..................................................................................................................................... 5 
7.1 Primary objectives ............................................................................................................................ 5 
7.2 Secondary objective ......................................................................................................................... 5 
7.3 Exploratory objectives ...................................................................................................................... 5 
 Study Design ........................................................................................................................................... 6 
8.1 Overall Design ................................................................................................................................. 6 
8.1.1 Dose Escalation Steps........................................................................................................... 7 
8.2 Adaptations of the Trial .................................................................................................................. 10 
8.2.1 Stopping Rules for Second Dose ........................................................................................ 10 
8.2.2 Trial Suspension Rule .......................................................................................................... 10 
8.2.3 Justification for Dose ........................................................................................................... 11 
8.2.4 End of Trial Definition .......................................................................................................... 11 
8.3 Sample Size Considerations .......................................................................................................... 11 
8.4 Randomization ............................................................................................................................... 13 
8.5 Blinding/Unblinding ........................................................................................................................ 13 
 Study Endpoints .................................................................................................................................... 13 
9.1 Primary Endpoints .......................................................................................................................... 13 
9.2 Secondary Endpoints ..................................................................................................................... 14 
9.3 Exploratory Endpoints .................................................................................................................... 14 
9.4 Endpoint Attributes ......................................................................................................................... 15 
9.5 Population Sets .............................................................................................................................. 16 
9.5.1 Safety Set ............................................................................................................................ 16 
9.5.2 Dose-determining Set 1 (DDS-1) ......................................................................................... 16 
9.5.3 Dose-determining Set 2 (DDS-2) ......................................................................................... 17 
9.5.4 Immunogenicity Set ............................................................................................................. 17 
 Conventions and Derivations .............................................................................................................. 17 
10.1 Baseline and Change from Baseline ........................................................................................... 17 
10.2 Missing Data ................................................................................................................................ 17 
10.3 Prior and Concomitant Medications ............................................................................................. 19 
10.4 Adverse Events (AEs) .................................................................................................................. 19 
10.4.1 Solicited AEs ...................................................................................................................... 19 
10.4.2 Unsolicited Adverse Events ............................................................................................... 20 
10.4.3 Serious Adverse Events .................................................................................................... 21 
10.4.4 Adverse Events of Special Interest .................................................................................... 21 
10.4.5 Medically Attended Adverse Events .................................................................................. 21 
10.4.6 Duration Solicited Adverse Events .................................................................................... 21 
10.4.7 Adverse Reactions ............................................................................................................. 21 
10.4.8 Adverse Events Related to Standardised and Customized MedDRA Queries ................. 21 
10.4.9 Credibility Interval and related Estimate ............................................................................ 22 
10.5 Immunogenicity Assessments ..................................................................................................... 22 
10.5.1 Humoral Immune Response .............................................................................................. 22 
10.5.2 Retrospective SARS-CoV-2 Baseline Serology Status ..................................................... 22 
10.5.3 Subjects not exposed to SARS-CoV-2 during the trial ...................................................... 22 
10.5.4 Evaluation of Infection ....................................................................................................... 23 


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10.5.5 Geometric Mean ................................................................................................................ 23 
10.5.6 Seroconversion SARS-CoV-2 Spike and SARS-CoV-2 Neutralizing Antibodies .............. 23 
10.6 Censoring Rules for Subjects Unblinded and/or Treated with Alternate Licensed/Authorized 
Vaccine ................................................................................................................................................ 23 
 Interim Analyses, DSMB and iSRC ..................................................................................................... 25 
11.1 Interim Analyses .......................................................................................................................... 25 
11.2 Safety Monitoring Committees ..................................................................................................... 25 
 Statistical Methods .............................................................................................................................. 26 
12.1 Subject Disposition ...................................................................................................................... 26 
12.2 Important Protocol Deviations ...................................................................................................... 26 
12.3 Demographic and Baseline Characteristics ................................................................................. 27 
12.4 Medical History ............................................................................................................................ 27 
12.5 Trial Vaccine ................................................................................................................................ 27 
12.5.1 Trial Vaccine Exposure ...................................................................................................... 27 
12.5.2 Prior and Concomitant Medications and Vaccinations ...................................................... 27 
12.6 Primary Analysis .......................................................................................................................... 27 
12.6.1 Primary Safety Analysis for Dose Escalation Phase ......................................................... 27 
12.6.2 Primary Descriptive Safety Analysis .................................................................................. 30 
12.6.3 Secondary and Exploratory Endpoints .............................................................................. 31 
12.6.4 Laboratory Data ................................................................................................................. 33 
12.6.5 Vital Signs .......................................................................................................................... 34 
12.6.6 Physical Examinations, ECGs, and Other Observations Related to Safety ...................... 34 
 References .......................................................................................................................................... 34 
 Glossary of Abbreviations ................................................................................................................... 35 
LIST OF ABBREVIATIONS ................................................................................................................. 35 
 Appendices ......................................................................................................................................... 38 
Appendix 1 
Potential Immune-Mediated Diseases ........................................................................ 38 
Appendix 2 
Adverse Events of Special Interest for SARS-CoV-2 Vaccines .................................. 40 
Appendix 3 
Statistical Appendix Including Model Performance and Data Scenarios .................... 41 
Appendix 4 
Inclusion/Exclusion Criteria ......................................................................................... 44 
Appendix 5 List of TFLs ....................................................................................................................... 46 
Appendix 6 Identification of Protocol Deviations Leading to Exclusion from Analysis Sets ................ 46 
Appendix 7 MedDRA Terms for CMQs ................................................................................................ 46 
 


                                               Statistical Analysis Plan (SAP) 
Version Date: 25-NOV-2021  
 
Sponsor: CureVac AG 
 
Protocol no: CV-NCOV-001 
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 Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under CureVac AG Protocol CV-NCOV-001. 
 Scope 
The Statistical Analysis Plan outlines the following: 
• 
Study Objectives 
• 
Study Design 
• 
Endpoints and Assessments 
• 
Applicable Study Definitions 
• 
Analysis Sets 
• 
Statistical Methods 
• 
Conventions and Definitions 
 Introduction 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under CureVac AG Protocol CV-NCOV-001. 
The SAP should be read in conjunction with the  
• 
Study protocol version 3.0, 24-JUL-2020 
• 
Case report form (CRF) version 3.0, 09-JUL-2020  
Changes following approval of the first version of the SAP will be tracked in the SAP Change Log and a 
final version of the amended SAP will be approved prior to final database lock. Final approval of this 
document will occur prior to database lock. 
Each version of the SAP requires approval by the Sponsor. 
6.1 Changes from Protocol 
No changes. 
 Study Objectives 
All objectives will be analyzed in all subjects, in those subjects retrospectively SARS-CoV-2 seronegative 
at baseline, and in those subjects retrospectively SARS-CoV-2 seropositive at baseline. 
7.1 Primary objectives 
• 
To evaluate the safety and reactogenicity profile after 1 and 2 dose administrations of CVnCoV at 
different dose levels. 
7.2 Secondary objective 
• 
To evaluate the humoral immune response after 1 and 2 dose administrations of CVnCoV at 
different dose levels. 
7.3 Exploratory objectives 
• 
To evaluate the cell-mediated immune response after 1 and 2 dose administrations of CVnCoV at 
different dose levels in all subjects from the assigned site(s). 


                                               Statistical Analysis Plan (SAP) 
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• 
To evaluate the innate immune response after 1 and 2 dose administrations of CVnCoV at different 
dose levels in all open-label sentinel subjects. 
• 
To identify and assess cases of COVID-19 disease. 
• 
To describe the rate of asymptomatic infections with SARS-CoV-2. 
 Study Design 
8.1 Overall Design 
This is a Phase 1, partially blind, placebo-controlled, dose escalation first-in-human (FIH) trial of 
intramuscularly (IM) administered CVnCoV. This trial will evaluate the safety, reactogenicity and 
immunogenicity of 3 provisional CVnCoV dose levels (2, 4 and 8µg) using an adaptive dose-finding design. 
This will allow dose escalation or de-escalation using predefined safety criteria and select the CVnCoV 
dose for further clinical development. To ensure the safety of the subjects, specified safety data will be 
reviewed on a predefined schedule by an independent safety review committee (iSRC) and a data safety 
monitoring board (DSMB).  
 
An adaptive 2-parameter Bayesian logistic regression model (BLRM) for dose escalation with overdose 
control (EWOC) will be used in the escalation to guide determination of the safety of each dose level, while 
decisions of dose level expansion in the sentinel groups of 4 subjects is based on a maximum number of 2 
subjects with Grade 3 adverse reactions.  
  
Subjects will be enrolled in 2 age categories (18-40 years and 41-60 years) with an equal distribution across 
each category. The trial will include subjects with no history of COVID-19 disease as well as subjects with 
SARS-CoV-2 positive serology. The SARS-CoV-2 serology status at baseline will be evaluated 
retrospectively to allow separate analysis of subjects retrospectively SARS-CoV-2 seronegative at baseline 
and subjects retrospectively SARS-CoV-2 seropositive at baseline. To ensure the open-label sentinel 
subjects in each dose level are seronegative, the SARS-CoV-2 serological status will be determined prior 
to enrollment during eligibility assessment in these subjects. Additionally, assessment of SARS-CoV-2 
serological status may also be performed in the observer-blind placebo-controlled part of the trial, to identify 
subjects with SARS-CoV-2 positive serology. 
 
Due to the adaptive design of the trial, the actual number of subjects enrolled might be lower or higher than 
the target numbers. 
 
Throughout the trial, cases of COVID-19 disease will be identified and documented for later pooling of cases 
across trials in the clinical development program. 
 
Subjects will be enrolled in 4 trial sites, 3 in Germany and 1 in Belgium. The duration for each subject is 
approximately 13 months. 
A schematic overview of the design is provided in Figure 1 below.  
 
 
 
 
 
 
 
 
 


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Figure 1 
Overview of staggered enrollment during the dose escalation phase 
 
 
 
The 12, 16 and/or 20µg dose levels will only be given to subjects once initial data from the previous dose level have been reviewed by 
the iSRC and DSMB, not in parallel. 
 
8.1.1 Dose Escalation Steps 
The starting dose of CVnCoV is 2µg. Dose escalation steps will follow the scheme indicated in Table 1. In 
each dose escalation step, subjects will be equally distributed across the 2 age categories (with the 
exception of subjects with SARS-CoV-2 positive serology who receive dose levels >8µg). 
Additional potential dose levels that could be assessed are 1, 3 and 6µg, depending on the 
reactogenicity/safety findings after vaccination with respectively 2, 4 and 8µg dose levels; as well as 12, 16 
and/or 20µg. 
 
All subjects will be administered a second vaccine dose on Day 29 with the same dose level of CVnCoV or 
placebo as administered on Day 1. When safety data will be available at least 60 hours post dose 2 for all 
subjects within a dose level, the iSRC and DSMB will review all available safety (and, if available, 
immunogenicity) data to confirm the safety of the dose level after the second dose. 
 
 
 
 
 
 
 
 
 
 


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Protocol no: CV-NCOV-001 
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Table 1 Provisional dose levels during dose escalation 
Number of subjects vaccinated per CVnCoV dose level (µg)* 
2µg 
4µg 
8µg 
12/16/20µg**** 
18-40 
years 
41-60 
years 
18-40 
years 
41-60 
years 
18-40 
years 
41-60 
years 
18-40 
years 
41-60 
years 
1 
- 
- 
- 
- 
- 
 
 
Post-vaccination 
observation for 24 hours** 
- 
- 
- 
- 
 
 
1 
2 
- 
- 
- 
- 
 
 
Safety review of 24-hour 
post dose 1 data 
(iSRC+DSMB Chair) 
- 
- 
- 
- 
 
 
4 
4 
- 
- 
- 
- 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
18 + 4 
placebo*** 
18 + 4 
placebo*** 
2 
2 
- 
- 
 
 
- 
- 
Safety review of 24-hour 
post dose 1 data 
(iSRC+DSMB Chair) 
- 
- 
 
 
- 
- 
4 
4 
- 
- 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
18 + 4 
placebo*** 
18 + 4 
placebo*** 
2 
2 
 
 
- 
- 
- 
- 
Safety review of 24-hour 
post dose 1 data 
(iSRC+DSMB Chair) 
 
 
- 
- 
- 
- 
4 
4 
 
 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
- 
- 
18 + 4 
placebo*** 
18 + 4 
placebo*** 
2 
2 
- 
- 
- 
- 
- 
- 
Safety review of 24-hour 
post dose 1 data 
(iSRC+DSMB Chair) 
- 
- 
- 
- 
- 
- 
4 
4 
Safety review of 60-hour post dose 1 data (iSRC+DSMB) 
- 
- 
- 
- 
- 
- 
18 to 60 years 
- 
- 
- 
- 
- 
- 
4***** 
Light grey shaded cells indicate the open-label sentinel groups. 
Dark grey shaded cells indicate the observer-blind placebo-controlled groups. 
* Provisional dose levels of 2, 4 and 8µg will be evaluated. Additional potential dose levels that could be assessed are 
1, 3 and 6µg, depending on the reactogenicity/safety findings after vaccination with respectively 2, 4 and 8µg dose 
levels; as well as 12, 16 and/or 20µg. 
** If any Grade 3 ARs are reported within 24 hours following vaccination, the iSRC and DSMB Chair will be consulted 
before continuation of enrollment of the next open-label sentinel subjects. 
*** Including approximately 4 + 1 subjects with SARS-CoV-2 positive serology.  
**** The next dose level will only be given to subjects once initial data from the previous dose level have been reviewed 
by the iSRC and DSMB, e.g., if 12µg is investigated, it will only be administered after review of the 8µg data (post dose 
1 in 12 sentinel subjects), and if the dose level is then escalated to 16µg, it will only be administered after review of the 
12µg data (post dose 1 in 12 sentinel subjects). 
***** Subjects with SARS-CoV-2 positive serology. 
 


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On the first vaccination day, the first open-label sentinel subject aged 18-40 years confirmed to be SARS-
CoV-2 seronegative will be enrolled and vaccinated with CVnCoV at the lowest dose level (2µg). The 
subject will be observed for 24 hours after vaccination. If any Grade 3 adverse reactions, defined as solicited 
systemic, solicited local and unsolicited Grade 3 adverse events (AEs) considered as related to the trial 
vaccine according to the Investigator, are reported within 24 hours following vaccination, the iSRC and 
DSMB Chair will be consulted. In case no safety concerns are identified, the next open-label sentinel group 
of 3 subjects (1 aged 18-40 years and 2 aged 41-60 years) confirmed to be SARS-CoV-2 seronegative will 
be enrolled and vaccinated with CVnCoV at the lowest dose level (2µg). The 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 from these first 4 subjects will be collected and reviewed by the iSRC and DSMB 
Chair. In this review, the iSRC and DSMB Chair will review all available safety data, but focus specifically 
on Grade 3 adverse reactions, defined as solicited systemic, solicited local and unsolicited Grade 3 AEs 
considered as related to the trial vaccine according to the Investigator, and any SAE considered as related 
to the trial vaccine according to the Investigator. Based on this review, the iSRC and DSMB Chair will decide 
on the subsequent vaccination of an additional open-label sentinel group of 8 subjects (4 aged 18-40 years 
and 4 aged 41-60 years, confirmed to be SARS-CoV-2 seronegative) with the same dose level on the next 
vaccination day (at least 36 hours after the first vaccination day). 
 
Safety and reactogenicity data of subjects vaccinated on the first and second vaccination days will then be 
collected for at least 60 hours post-vaccination from each subject and reviewed by the iSRC and the DSMB. 
Based on this review, the iSRC and DSMB will recommend on continuation of enrollment at the same dose 
level (start of randomized expansion in observer-blind placebo-controlled groups) and initiation of 
enrollment in the next dose level: 
• In case of continuation of enrollment at the 2µg dose level, an additional 44 subjects will be enrolled, 
including 10 subjects with SARS-CoV-2 positive serology. Of these 44 subjects, 36 subjects (18 aged 
18-40 years and 18 aged 41-60 years) will receive CVnCoV at the 2µg dose level, including 
approximately 8 subjects with SARS-CoV-2 positive serology. The other 8 subjects (4 aged 18-40 years 
and 4 aged 41-60 years) will receive placebo in an observer-blind manner, including approximately 2 
subjects with SARS-CoV-2 positive serology. 
• In case of dose escalation, a newly enrolled open-label sentinel group of 4 subjects (2 aged 18-40 
years and 2 aged 41-60 years) confirmed to be SARS-CoV-2 seronegative will receive the next higher 
dose (4µg) or an intermediate dose depending on iSRC and DSMB recommendations guided by the 
BLRM. The subjects should be vaccinated at least 60 minutes apart. In case of favorable outcome of 
the review by the iSRC and DSMB Chair of at least 24-hour post-vaccination data and a maximum 
number of 2 subjects with Grade 3 adverse reactions, an additional open-label sentinel group of 8 
subjects (4 aged 18-40 years and 4 aged 41-60 years, confirmed to be SARS-CoV-2 seronegative) will 
receive the same dose level on the next vaccination day (at least 36 hours after the first vaccination 
day). 
For each subsequent step, continuation of enrollment within a dose level in a placebo-controlled observer-
blind manner and dose escalation will be assessed by the iSRC and DSMB based on 60-hour post-
vaccination safety data for each subject, including all available post-vaccination data from previously 
vaccinated subjects. The scheme for staggered enrollment and dose escalation in Figure 1 will be pursued 
if no safety concerns are found by the iSRC or DSMB. 
 
Once the open-label sentinel phase has been successfully concluded for a given dose level, enrollment will 
no longer be restricted to subjects with no history of COVID-19 disease or negative serology to SARS-CoV-
2, but will also include subjects with SARS-CoV-2 positive serology. These subjects will be enrolled at 
pre-defined site(s). For each dose level, the iSRC will review at least 24-hour post-vaccination safety data 
from the first 4 seropositive subjects. These first 4 seropositive subjects within each dose level should be 
vaccinated at least 60 minutes apart. Vaccination of additional subjects at that dose level and/or vaccination 


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of subjects with SARS-CoV-2 positive serology at a higher dose level will only proceed upon favorable 
outcome of this iSRC review. 
8.2 Adaptations of the Trial 
Depending on the safety and immunogenicity of the provisional dose levels, additional dose levels might 
be evaluated. In each case, the enrollment schedule will be performed as described as above.  
 
For dose levels >8µg, the enrollment schedule will be performed as described in Section 8.1.1 for the first 
12 sentinel subjects. After a review of the post dose 1 data from these subjects, 4 subjects (aged 18 to 60 
years) with SARS-CoV-2 positive serology will be enrolled to receive the same CVnCoV dose level. These 
4 open-label subjects will have the same assessments as subjects in the observer-blind placebo-controlled 
groups and are included when reference is made to the observer-blind placebo-controlled groups. 
In case the lowest dose of 2µg fails to meet the predefined safety criteria, a dose de-escalation to 1µg will 
be initiated. In case the 4µg dose level fails to meet the predefined safety criteria, a dose de-escalation to 
3µg can be initiated. Similarly, in case the 8µg dose level fails to meet the predefined safety criteria, a dose 
de-escalation to 6µg can be initiated.  
8.2.1 Stopping Rules for Second Dose 
Individual stopping AE rules will be applicable during the entire trial to ensure safe administration of the 
second dose 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 (Days 1-8): 
• 
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 as 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 as 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. The subject will be 
encouraged to continue participation until the end of the trial for safety and immunogenicity assessments.  
8.2.2 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 as 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 of awareness 
by 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. 
 
During the observer-blind placebo-controlled phase at each dose level, if >4 subjects experienced Grade 3 
adverse reaction(s) after administration of CVnCoV at a particular dose level, vaccination will be put on 
hold for all subjects in the applicable dose level and any higher dose level. 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 dose-de-escalation) with this and any higher dose level. 
 


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8.2.3 Justification for Dose 
Three provisional CVnCoV dose levels (2, 4 and 8 µg) will be evaluated, defined based on clinical data 
from the CV7202-104 trial with a Rabies vaccine using the same technology as well as non-clinical data. 
Refer to the Investigator’s Brochure for an overview of these data. 
Additional higher (12, 16 and/or 20µg), lower (1µg) and/or intermediate (3 and 6 µg) dose levels might be 
evaluated depending on the outcomes of the safety and reactogenicity evaluations and all available 
immunogenicity data. Identification of immunogenic dose levels with lower mRNA content might be of 
particular importance for efficient vaccination in a worldwide viral outbreak setting 
8.2.4 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 on Day 393. 
8.3 Sample Size Considerations 
This trial is designed to estimate the probability that the true rate of adverse reactions for each dose lies in 
an acceptable safety range (see Section 12.6) and to describe the safety profile of CVnCoV. Hence, its 
sample size was not determined based on formal statistical power calculations. 
During the trial, a minimum of 12 subjects evaluable for the dose determining set (DDS-2, as defined in 
Section 9.5.3) will be vaccinated per dose level until completion of the dose escalation. After completion of 
the open-label sentinel phase, subjects will be enrolled in placebo-controlled groups in an observer-blind 
manner within each dose level with a 4.5:1 ratio and stratified by the 2 age categories (18-40 and 41-60 
years). 
It is estimated that approximately 56 subjects per dose level will be enrolled, including 48 CVnCoV and 8 
placebo recipients, for ≤8µg and 16 subjects per dose level, all CVnCoV recipients, for >8µg. The actual 
number of subjects will depend on the number of dose levels/groups that are tested.  
The trial is designed to provide, by combining data from the open-label sentinel and the observer-blind 
placebo-controlled phases, a reasonable precision for the rate of subjects with Grade 3 adverse reaction(s). 
Table 2 provides the estimate and 95% credibility interval for given observed numbers of subjects for a 
sample size of 48 subjects per dose level (assuming a Beta (0.5, 0.5) prior distribution). 
 
 
 
 
 
 
 
 


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Table 2 Estimate rate of subjects with Grade 3 adverse reaction(s) and 95% credibility 
interval per dose level assuming a Beta(0.5. 0.5) prior distribution 
N subjects with Grade 3 
adverse reaction(s) 
Estimate (95% credibility interval) 
in % 
Probability adverse reaction 
rate <33% 
0 
1 (0 - 5.1) 
100 
2 
5.1 (0.9 - 12.7) 
100 
4 
9.2 (2.9 - 18.6) 
100 
6 
13.3 (5.4 - 24) 
99.9 
8 
17.3 (8.2 - 29) 
99.4 
10 
21.4 (11.2 - 33.8) 
96.7 
12 
25.5 (14.5 - 38.5) 
88.2 
14 
29.6 (17.8 - 43) 
71.,0 
16 
33.7 (21.3 - 47.3) 
47.3 
18 
37.8 (24.9 - 51.6) 
25.1 
20 
41.8 (28.5 - 55.8) 
10.2 
N = Number of subjects 
Table 3 provides probabilities (in %) that the following condition is met for assumed true rates of adverse 
reactions and a sample size of 48 subjects per dose level: There is a ≥80% probability that the true rate of 
Grade 3 adverse reaction(s) is <33%. 
For example, assuming a true adverse reactions rate of 20%, the condition is met with a probability of 
91.6%. 
Table 3 Probabilities that the rate of Grade 3 adverse reactions is <33% is ≥80% for given 
‘true’ adverse reactions rates during dose escalation for n=48 and assuming a Beta(0.5, 
0.5) prior distribution 
True rate of adverse reactions 
Probability (%) 
0.05 
100 
0.1 
100 
0.15 
99.1 
0.2 
91.6 
0.25 
69.8 
0.3 
39.7 
0.35 
16.1 
The number of placebo subjects is chosen to have a minimum number of subjects to descriptively evaluate 
the onset and the level of humoral immune response taking into account that there are 2 age groups, 2 
possible SARS-CoV-2 status at baseline, 3 different doses levels and a placebo group (Table 4). A total of 
24 placebo subjects, of whom 18 are expected to have a SARS-CoV-2 negative serology before the trial 
start, will provide a reasonable number in the placebo group to differentiate between each of the age groups 
receiving CVnCoV individually and all subjects on a dose level versus all placebo recipients. Despite the 
small sample size for the placebo group within a dose level, a pooled within‐trial analysis of all placebo 
recipients could provide a sufficient number to assess differences between CVnCoV and placebo recipients 
by providing anchoring information on ‘no dose’ for regression analyses. With the given number, an 
exploratory t-test might be conducted assuming a large vaccination effect, which cannot be quantified yet. 
As the effect is unknown since this is the FIH trial, no assumptions and power analyses were conducted. 
This trial will however allow to generate a hypothesis for the Phase 2/3 trials. 


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Table 4 Distribution of subjects as per the planned dose levels 
 
Subjects with no history of 
COVID-19 
Subjects with  SARS-CoV-2 
positive serology 
CVnCoV 
Placebo 
CVnCoV 
Placebo 
2/4/8μg: 18-40 years 
20 
9 
4 
3 
2/4/8μg: 41-60 years 
20 
9 
4 
3 
2/4/8μg: all age groups 
40 
18 
8 
6 
In addition, even in the absence of statistical power, the inclusion of blinding and placebo subjects can 
reduce biases in AE reporting occurring in open‐label trials. 
This trial is designed to estimate the probability that the true rate of adverse reactions for each dose lies in 
an acceptable safety range, and to describe the safety profile of CVnCoV. Hence, its sample size was not 
determined based on formal statistical power calculations.  
 
During the trial, a minimum of 12 subjects evaluable for the dose determining set (DDS-2, as defined in 
Section 9.5.3) will be vaccinated per dose level until completion of the dose escalation. It is estimated that 
approximately 168 subjects (56 per dose level) will be enrolled, including 144 CVnCoV recipients (48 per 
dose level). The actual number of subjects will depend on the number of dose levels/groups that are tested. 
The trial is designed to provide, by combining data from the open-label sentinel and the observer-blind 
placebo-controlled phases, a reasonable precision for the rate of subjects with Grade 3 adverse reaction(s). 
8.4 Randomization 
In the initial part of dose escalation for the provisional dose levels of 2, 4 and 8µg, subjects will be enrolled 
in sentinel groups in an open manner. In the second part, subjects will be enrolled in placebo-controlled 
groups in an observer-blind manner within each dose level with a 4.5:1 ratio and stratified by the 2 age 
categories (18-40 and 41-60 years). Double-blinding is not possible due to the difference in appearance of 
the investigational vaccine and placebo. 
 
Groups with a dose level >8µg will be open-label. 
8.5 Blinding/Unblinding 
The Sponsor and safety monitoring committees will be unblinded for data from the placebo-controlled 
groups, but will take appropriate measures to ensure subject blinding is kept at site-level until database 
lock. 
 Study Endpoints 
9.1 Primary Endpoints 
• 
The frequencies of Grade 3 adverse reactions and any SAE considered as related to the trial vaccine 
within at least 24 hours after the first vaccination by dose level, for decisions on subsequent 
vaccination of an additional open-label sentinel group with the same dose level. 
• 
The frequencies of Grade 3 adverse reactions and any SAE considered as related to the trial vaccine 
within at least 60 hours after the first vaccination by dose level, for decisions on dose escalation as 
well as continuation of enrollment at the same dose level in the observer-blind placebo-controlled 
part of the trial. 
• 
The frequencies, intensities and duration of solicited local AEs on each vaccination day and the 
following 7 days by dose and dose level, for the characterization of the safety and reactogenicity 
profile. 


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• 
The frequencies, intensities, duration and relationship to trial vaccination of solicited systemic AEs 
on each vaccination day and the following 7 days by dose and dose level, for the characterization of 
the safety and reactogenicity profile. 
• 
The occurrence, intensities and relationship to trial vaccination of unsolicited AEs on each 
vaccination day and the following 28 days by dose and dose level, for the characterization of the 
safety and reactogenicity profile. 
• 
The occurrence and relationship to trial vaccination of SAEs and AESIs at predefined time points 
throughout the trial, for the characterization of the safety and reactogenicity profile. 
9.2 Secondary Endpoints 
On Day 8, Day 15, Day 29, Day 36, Day 43, Day 57, Day 120, Day 211 and Day 393:  
• 
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, in subjects who did not get exposed to SARS-CoV-2 before the trial, or during the trial before 
the applicable sample was collected, as measured by ELISA to SARS-CoV-2 N-antigen. 
• 
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, in subjects 
who did not get exposed to SARS-CoV-2 before the trial, or during the trial before the applicable 
sample was collected, as measured by ELISA to SARS-CoV-2 N-antigen. 
9.3 Exploratory Endpoints 
Cell-mediated immune response 
On Day 29, Day 36 and Day 211** in peripheral blood mononuclear cells (PBMCs) from all subjects at the 
assigned site(s): 
• 
The frequency and functionality of SARS-CoV-2 spike-specific T-cell response after antigen 
stimulation. 
Intracellular cytokine staining (ICS) to investigate Th1 response and production of Th2 markers (e.g. 
secreted interleukin [IL-5]) 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. 
• 
The proportion of subjects with a detectable increase in SARS-CoV-2 spike-specific T-cell response. 
** Testing of samples collected on Day 211 will be done only in subjects categorized as T-cell responders 
on Day 29 and/or Day 36. 
Innate immune response 
On Day 2, Day 8, Day 29, Day 30 and Day 36 in all open-label sentinel 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). 
• 
Gene expression profiling. 


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* Samples may be used for assay validation and additional studies of the mechanism of action of the 
vaccine. 
Evaluation of infection 
• 
Number of subjects with virologically-confirmed SARS-CoV-2 infection as measured by reverse 
transcription polymerase chain reaction (RT-PCR) at clinically determined time points throughout the 
trial. 
• 
Number of subjects with asymptomatic SARS-CoV-2 infection as measured by retrospective 
serology at predefined time points. 
9.4 Endpoint Attributes 
Objectives 
Endpoints 
Population 
Primary 
 
 
• 
To evaluate the safety 
and reactogenicity profile 
after 1 and 2 dose 
administrations 
of 
CVnCoV at different dose 
levels. 
• 
The frequencies of Grade 3 adverse reactions and 
any SAE considered as related to the trial vaccine 
within at least 24 hours after the first vaccination.  
• 
The frequencies of Grade 3 adverse reactions and 
any SAE considered as related to the trial vaccine 
within at least 60 hours after the first vaccination.  
• 
The frequencies, intensities and duration of 
solicited local AEs on each vaccination day and the 
following 7 days. 
• 
The 
frequencies, 
intensities, 
duration 
and 
relationship to trial vaccination of solicited systemic 
AEs on each vaccination day and the following 7 
days. 
• 
The occurrence, intensities and relationship to trial 
vaccination of unsolicited AEs on each vaccination 
day and the following 28 days.  
• 
The occurrence and relationship to trial vaccination 
of SAEs and AESIs throughout the trial. 
DDS-1* 
 
DDS-2* 
 
 
Safety Set 
Secondary 
 
 
• 
To evaluate the humoral 
immune response after 1 
and 
2 
dose 
administrations 
of 
CVnCoV at different dose 
levels. 
 
• 
Seroconversion 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-2spike 
protein 
antibodies, as measured by ELISA, in subjects who 
did not get exposed to SARS-CoV-2 before the trial, 
or during the trial before the applicable sample was 
collected, as measured by ELISA to SARS-CoV-2 
N-antigen. 
• 
Seroconversion 
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, in 
Immunogenicity 
Set 


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Objectives 
Endpoints 
Population 
subjects who did not get exposed to SARS-CoV-2 
before the trial, or during the trial before the 
applicable sample was collected, as measured by 
ELISA to SARS-CoV-2 N-antigen. 
Exploratory 
 
 
Cell-mediated 
immune 
response 
• 
To 
evaluate 
the 
cell-
mediated 
immune 
response after 1 and 2 
dose 
administrations 
of 
CVnCoV at different dose 
levels in all subjects from 
the assigned site(s). 
 
• 
The frequency and functionality of nCoV spike-
specific T-cell response after stimulation, as 
measured by intracellular cytokine staining (ICS) or 
ELISPOT 
• 
Detectable increase in nCoV spike-specific T-cell 
response. 
Immunogenicity 
Set 
Innate immune response 
• 
To evaluate the innate 
immune response after 1 
and 
2 
dose 
administrations 
of 
CVnCoV at different dose 
levels in all open-label 
sentinel subjects  
• 
Serum cytokine concentrations, including but not 
limited to IFN-α, IFN-γ, IL-6, CCL2, IP-10 for open 
sentinel subjects 
• 
Gene expression profiling. 
Immunogenicity 
Set 
Evaluation of infection 
• 
To identify and assess 
cases 
of 
COVID-19 
disease. 
• 
To describe the rate of 
asymptomatic infections 
with SARS-CoV-2. 
 
• 
Virologically-confirmed SARS-CoV-2 infection as 
measured 
by 
RT-PCR 
at 
clinically 
defined 
timepoints throughout the trial. 
• 
Asymptomatic SARS-CoV-2 infection as measured 
by retrospective serology at predefined time points. 
 
Safety Set 
 
Immunogenicity 
Set 
* DDS-1 and DDS-2 sets are primarily for the dose escalation phase of the study.  
 
9.5 Population Sets 
9.5.1 Safety Set 
The safety set will consist of all subjects who received at least one dose of trial vaccine and for whom any 
post-vaccination safety data are available.  
9.5.2 Dose-determining Set 1 (DDS-1) 
The DDS-1 will consist subjects, 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. Of particular interest are the 4 first 
subjects at each dose level. The DDS-1 will be used for the first dose expansion decision at a particular 
dose level. The minimum vaccination and safety evaluation requirements will have been met if the subject 


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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 dose-determining set. Since DDS-1 is only 
used during dose escalation, DDS-1 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. 
9.5.3 Dose-determining Set 2 (DDS-2) 
The DDS-2 will consist of all subjects in 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 60 hours, or completed the 60-hour observation period without experiencing Grade 3 adverse 
reactions or SAEs considered as related to the trial vaccine according to the Investigator. The DDS-2 set 
will be used for dose escalation decisions and for decisions to continue enrollment after the 60-hour safety 
reviews. 
 
The DDS-1 and DDS-2 population are used in the dose escalation phase and not for analysis associated 
with the statistical analysis plan.  
9.5.4 Immunogenicity Set 
The immunogenicity set will include all subjects who received at least one dose of trial vaccine and for 
whom the baseline blood sample and at least 1 post-baseline blood sample are available for analysis. 
 Conventions and Derivations 
All data obtained in this trial and documented in the CRF will be listed and summarized with sample statistics 
or frequency tables as appropriate. In all tables, listings and figures (TFLs), the dose groups will be reported 
from the lowest to the highest dose. The safety and immunogenicity analyses will be done overall and by 
baseline serology status for SARS-CoV-2. 
The statistical analyses will be reported using tables, listings, and figures (TLFs). The International Council 
for Harmonisation (ICH) numbering convention will be used for all TLFs. 
10.1 Baseline and Change from Baseline 
Unless otherwise noted, baseline is defined as the last valid measurement at Visit 1: Day 1 prior 
administration of the trial vaccine.  
Change from Baseline is defined as:  
Observed result at nominal time point – observed result at baseline. 
10.2 Missing Data 
Analysis of vaccination data 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 
and Virus Neutralization, concentration values marked as below the cut point (CP) will be set to 0.5*CP.  
 
For the cytokine concentrations the following rules will be used: 
• 
If Value < LLOQ set to 0.5*LLOQ 
• 
If Value "BLQ" set to 0.5*LLOQ 
• 
If Value “0” set to 0.5*LLOQ 
• 
If Value "ALQ" set to ULOQ 
 


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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.  
 
For unsolicited AEs, solicited AEs occurring after Day 8 and concomitant medications, some missing or 
partially missing variables will be imputed as follows:  
 
For AE or concomitant medication start date:  
 
• 
If start date year value is missing, the date uncertainty is too high to impute a rational date. 
Therefore, if year value is missing, the imputed AE start date is set to missing.  
• 
If start date year value is before the vaccination start date year value, started before the vaccination. 
Therefore:  
o 
If month is missing, the imputed start date is set to the mid-year point (i.e., 01JULYYYY).  
o 
If month is not missing, the imputed start date is set to the mid-month point (i.e., 
15MONYYYY).  
• 
If start date year value is equal to the vaccination start date year value, the start date month needs 
to be compared against the vaccination start date month, to determine the imputation rule to apply. 
Therefore:  
o 
If month is missing, the imputed month and imputed day is the same as start of vaccination 
o 
If month is lower than vaccination start date month and start date day is missing, the 
imputed start date is set to the mid-month point (i.e. 15MONYYYY). 
o 
If month is equal to the vaccination start date and start date day is missing, the start day 
will be set to the start day of vaccination. 
o 
If month is greater than the vaccination start date month and start date day is missing, the 
imputed start date is set to the beginning of the month (i.e., 01MONYYYY). 
• 
If start date year value is greater than the vaccination start date year value, started after vaccination. 
Therefore,  
o 
If month is missing, the imputed start date is set to the year start point (i.e., 01JANYYYY).  
o 
If start date month is not missing and start date day is missing, the imputed start date is 
set to the beginning of the month (i.e., 01MONYYYY).  
• 
If after imputation of start and resolution date (see below) a start date is after the resolution date 
(for example if a missing day of a start date is set to 15 and the resolution date is before the 15th of 
the same month and year) then the start date will be set to the resolution date 
 
For resolution date:  
 
• 
If date of resolution is completely missing, it is assumed that it resolved at the date of the end of 
the trial.  
• 
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 trial 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 trial 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. 


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10.3 Prior and Concomitant Medications 
Prior medications are medications with a start date prior first date of vaccination. Concomitant medications 
are those ongoing at or starting on or after the start of vaccination.  
10.4 Adverse Events (AEs) 
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 
vaccination. 
10.4.1 Solicited AEs 
Solicited local AEs (injection site pain, redness, swelling and itching) and solicited systemic AEs (chills, 
fever, nausea/vomiting, diarrhea, headache, fatigue, myalgia and arthralgia) will be collected on the day of 
vaccination and the following 7 days for dose 1 and 2 on a specific diary and after that together with all AEs 
occurring throughout the trial  
 
Solicited AEs will be assessed on an intensity scale of absent, mild, moderate and severe (Table 5 and 
Table 6).  
 
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 5 
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 normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
*FDA toxicity grading scale [1]. 


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Table 6 
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 normal activity 
2 
Moderate, some interference with normal 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 normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
Chills  
0 
Absent 
1 
Mild, no interference with normal activity 
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
Myalgia 
0 
Absent 
1 
Mild, no interference with normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal activity 
Arthralgia 
0 
Absent 
1 
Mild, no interference with normal activity  
2 
Moderate, some interference with normal activity 
3 
Significant, prevents normal 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 IV 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 IV 
hydration 
*FDA toxicity grading scale [1]; IV = Intravenous. 
10.4.2 Unsolicited Adverse Events 
Unsolicited AEs occurring on the day of vaccination and the following 28 days will be collected. For 
unsolicited AEs occurring on the day of dose 2 the following rule will be used:  
 
If the AE is occurring on the day of dose 2 but before vaccination the AE will be presented with AEs for 
dose 1, if the AE is occurring on day of dose 2 but on or after vaccination it will be presented with AEs for 
dose 2. If this rule cannot be applied but the AE occurred on the day of vaccination for dose it will be 
presented with the AEs for dose 2.   


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10.4.3 Serious Adverse Events 
SAEs are defined as any untoward medical occurrence that results in death, is life-threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, 
is a congenital anomaly/birth defect in the offspring of the subject, or is an important medical event. 
 
SAEs and AEs leading to vaccine withdrawal or trial discontinuation will be collected throughout the trial. 
Non-serious inter-current medical conditions that may affect the immune response to vaccination will also 
be collected throughout the trial. 
10.4.4 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 1), 
• 
COVID-19 disease, 
• 
other AEs relevant to SARS-CoV-2 vaccine development or the target disease (see Appendix 2).  
AESIs will be collected on CRF throughout the trial 
10.4.5 Medically Attended Adverse Events 
Medically attended AEs will be collected on the CRF throughout the trial. 
10.4.6 Duration Solicited Adverse Events  
Duration of solicited local and systemic adverse events are defined as the consecutive days with 
local/systemic adverse events (days 1 to 8) for the same grade. For example, fatigue with grade 1 occurring 
on day 2 and 3 and day 7 will be counted as two separate events with the duration 2 days and 1 day. For 
the duration of solicited local and systemic ongoing beyond Day 8, end of duration is defined as end date 
on the CRF. 
10.4.7 Adverse Reactions 
Adverse Reactions are defined as solicited systemic, solicited local and unsolicited adverse events (AEs) 
considered as related to the trial vaccine according to the investigator. 
 
10.4.8 Adverse Events Related to Standardised and Customized MedDRA Queries 
Subjects’ AEs are filtered for the following Standardised MedDRA Queries (SMQs): 
 
• 
Anaphylactic reaction (SMQ) 
• 
Convulsions (SMQ) 
• 
Embolic and thrombotic events (SMQ) 
• 
Hypersensitivity (SMQ) 
• 
Immune-mediated/autoimmune disorders (SMQ)  
• 
Liver related investigations, signs and symptoms (Sub-SMQ) 
 
In addition, two customized MedDRA queries are defined for taste and smelling disorder and events related 
to paraesthesia, hypoaesthesia, and hyperaesthesia. The related terms are listed in the Appendix 7. The 
MedDRA SMQs for the specifc terms are not included in the appendix. See official MedDRA documentation.  
 
 


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10.4.9 Credibility Interval and related Estimate  
The estimate, using Beta(0.5, 0.5), is calculated as follows:  
• 
(number of reactions + prior a) / (total number of subjects + prior a + prior b). 
The lower and upper intervals are calculated as follows for a given number of reactions: 
• 
Using SAS: betainv(0.025, number of reactions + prior a, total number of subjects – number of 
reactions + prior a) and betainv(0.975, number of reactions + prior a, total number of subjects – 
number of reactions + prior a). The SAS function betainv returns a quantile from the beta distribution. 
10.5 Immunogenicity Assessments 
10.5.1 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.  
10.5.2 Retrospective SARS-CoV-2 Baseline Serology Status 
The retrospective SARS-CoV-2 status is defined as follows for pre-vaccination samples. 
Pre-vaccination collected results (RT-PCR, pre-study SARS-CoV-2 serology or antibody results) and N 
ELISA and Spike ELISA data will be considered. In general, the below algorithm and cut-off values will be 
used to determine a subject’s status at baseline:   
• 
N ELISA IgG GMT of equal or below 250 is defined as retrospectively SARS-CoV-2 seronegative 
at baseline 
• 
N ELISA IgG GMT of equal or above 2000 is defined as retrospectively SARS-CoV-2 seropositive 
at baseline 
• 
If N ELISA IgG GMT is >250 and <2000 and Spike ELISA IgG GMT is equal or below 1300 at 
baseline this is defined as retrospectively SARS-CoV-2 seronegative at baseline, otherwise as 
retrospectively SARS-CoV-2 seropositive at baseline  
If any of the tests (RT-PCR, pre-study SARS-CoV-2 serology or antibody results) is positive at baseline 
the subject is regarded as seropositive at baseline independently if the algorithm and cut-off values 
indicate that subject is seronegative.  
 
The baseline is defined as the samples taken at the screening/clinic visit 1 – day 1.  
 
For subjects in which the retrospectively baseline serology status cannot be determined these will not be 
included in the counts of seroconverted subjects.   
 
This definition is used throughout the endpoints for the sub-analysis. 
10.5.3 Subjects not exposed to SARS-CoV-2 during the trial 
In addition to being seronegative at baseline according to the definition in section 10.5.2 a subject will be 
regarded as seropositive at any given time point post-baseline if  
 
• 
a RT-PCR is positive, 
• 
or N ELISA IgG GMT is equal or above 2000 
If a subject is defined as seropositive at any given visit, the subject will remain seropositive.   


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10.5.4 Evaluation of Infection 
Virologically-confirmed SARS-CoV-2 infections are measured by RT-PCR at clinically determined time 
points throughout the trial. 
 
Subjects with asymptomatic SARS-CoV-2 infections will be measured by retrospective serology at 
predefined time points (see section 10.5.2 and 10.5.3). The selection of asymptomatic subjects will be 
based on the exclusion of subjects with adverse of events of special interest indicating COVID-19 
disease.   
10.5.5 Geometric Mean  
The ELISA and virus naturalizing antibodies are expressed as GMT (geometric mean of reciprocal duplicate 
dilutions). It is assumed that the data is skewed hence the geometric mean (GM) and geometric standard 
deviation (GSD) will be presented. The GM is calculated as the anti-logarithm of the mean of the log-
transformed data. The GSD will be calculated as the anti-logarithm transformation of the standard deviation 
of the log-transformed data.  
10.5.6 Seroconversion SARS-CoV-2 Spike and SARS-CoV-2 Neutralizing Antibodies 
In subjects who did not get exposed to SARS-CoV-2 before the trial or during the trial before the applicable 
sample was collected, as measured by ELISA to SARS-CoV-2 N-antigen, seroconversion is defined as an 
increase in titer in antibodies against SARS-CoV-2 spike or SARS-CoV-2 versus baseline, as per the 
definition in section 10.5.2 
In subjects seropositive for SARS-CoV-2 at baseline the definition for seroconversion is a 2-fold increase 
in titer in antibodies against SARS-CoV-2 spike protein versus baseline. 
10.6 Censoring Rules for Subjects Unblinded and/or Treated with Alternate 
Licensed/Authorized Vaccine 
 
If during the conduct of study CV-NCOV-001 an alternate licensed/authorized vaccine becomes available 
to some subjects, based on ethical reasons and requests from health authorities these subjects can request 
to be unblinded from the study treatment to decide whether they would like to receive the alternate 
licensed/authorized vaccine. The following censoring rules will be applied to these subjects to avoid any 
study bias.  
• 
Subjects who are unblinded will be censored for the safety endpoints at the first day after 
unblinding. Any related follow-up data that is collected from censoring time point forward will 
be included in the listings output. 
• 
Subjects who are unblinded but decide not to receive the alternate licensed/authorized vaccine 
and to stay in the study will be analyzed for immunogenicity as planned. 
• 
Subjects who are unblinded, but decide to receive the alternate licensed/authorized vaccine, 
will have their immunogenicity data censored at the first day after receiving the alternate 
licensed/authorized vaccine. However, any related follow-up data that is collected from this 
time point forward will be included in the listings output. 
• 
Subjects who received an alternate licensed/authorized vaccine without or before being 
unblinded or being part of the open-label group will be censored for safety and immunogenicity 
at the first day after receiving the alternate licensed/authorized vaccine. As described above, 
data collected from the censoring timepoint forward will be included in the listings output. 
 


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This is summarized in Table 7. 
Table 7 
Censoring Rules for Unblinded Subjects 
Analysis 
Treatment Received 
in CV-NCOV-001 
Alternate 
Licensed/Authorized 
Vaccine Received? 
Censoring Rule 
Safety 
CVnCoV 
No 
Censored at the first day 
after unblinding or at the 
first day after receiving 
the alternate 
licensed/authorized 
vaccine, whichever is 
earlier 
 
Yes 
Placebo 
No 
Yes 
Immunogenicity 
CVnCoV 
No 
Analyzed as planned 
Yes 
Censored at the first day 
after receiving the 
alternate 
licensed/authorized 
vaccine. 
Placebo 
No 
Analyzed as planned 
Yes 
Censored at the first day 
after receiving the 
alternate 
licensed/authorized  
vaccine 
 
The following details are to be followed regarding censoring the day after unblinding: 
• 
Unblinding day ( = Pacific Time Zone) must be adjusted to the subject's time zone. 
• 
Unblinding time does not matter for anything apart from the above time zone normalization. (As 
case start time is not collected.) 
• 
If the case start day and the unblinding day occur on the same day the case will count for the 
analysis. (Censoring starts at the day after the unblinding.) 
The following details are to be followed regarding censoring the day after receiving the alternate 
licensed/authorized vaccine: 
• 
Times are not relevant as neither alternate licensed/authorized vaccine time nor case start time are 
collected. 
• 
If alternate licensed/authorized vaccine date is complete then censoring starts at first day after the 
alternate licensed/authorized vaccine day. 
• 
If alternate licensed/authorized vaccine date is incomplete (only day missing) then censoring starts 
after this month.  
• 
If alternate licensed/authorized vaccine date is incomplete (month missing, year available) then 
censoring starts after this year. 
• 
If alternate licensed/authorized vaccine date is completely missing then no censoring can be made. 


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As these imputations of incomplete licensed/authorized vaccine dates are not an ideal solution this is only 
to be considered as a fallback solution in case complete licensed/authorized vaccine dates cannot be 
retrieved and an interim workaround for unclean data during study conduct. 
All incomplete or missing licensed/authorized vaccine dates need to be queried. 
 Interim Analyses, DSMB and iSRC 
11.1 Interim Analyses 
At least one interim analyses may be performed for this trial. The analyses will be based on a data snapshot. 
The first interim analyses will include 135 known pre-trial seronegative subjects (excluding subjects from 
DE003 site in which known pre-trial seropositive subjects are enrolled) who were taking part in the trial until 
at least day 43. The dose levels 2, 4, 6 and 8 μg will be included. The scope for the first interim analysis 
will not include the entire sub-analysis of subjects retrospectively SARS-CoV-2 seronegative at baseline, 
and for subjects retrospectively SARS-CoV-2 seropositive at baseline. 
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 of the current pandemic and the public heath 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. Each dose escalation step is considered as an interim analysis (refer 
to Section 8.1.1 for the dose escalation steps). 
11.2 Safety Monitoring Committees  
Specified safety data will be reviewed by an iSRC and an external and independent DSMB. The iSRC will 
consist of the Principal Investigator at each trial site, the Medical Monitor and medical representatives of 
the Sponsor. Details on the composition, objectives, and role and responsibilities of the iSRC and DSMB 
will be described in separate charters, agreed with the respective committee members and Sponsor. The 
charters will also define and document the content of the safety and/or immunogenicity summaries, and 
general procedures (including communications). The iSRC and DSMB review will be based on unblinded 
data.  
The iSRC and DSMB Chair will review all available safety data obtained during at least 24 hours post-
vaccination for each open-label sentinel subject vaccinated on the first vaccination day per dose level, and 
assess for Grade 3 adverse reaction(s) and any SAE considered as related to the trial vaccine according 
to the Investigator. Based on this review, the iSRC and DSMB Chair will decide on the enrollment of the 
subjects planned on the next vaccination day within each dose level. For each dose level, the iSRC will 
review at least 24-hour post-vaccination safety data from the first 4 seropositive subjects. Vaccination of 
additional seropositive subjects at that dose level and/or vaccination of subjects with SARS-CoV-2 positive 
serology at a higher dose level will only proceed upon favorable outcome of this iSRC review. The iSRC 
will also perform ongoing safety assessments for subjects beyond the first 24 hours on all available data. 
In addition, the iSRC together with the DSMB will review all available safety data obtained during at least 
60 hours post-vaccination for each subject to recommend on continuation of enrollment at the same dose 
level and dose escalation. If no stopping rule is met, the DSMB Chair can decide to allow trial progression 
without obtaining a DSMB quorum. 
During the observer-blind placebo-controlled phase at each dose level, if >4 subjects experienced Grade 3 
adverse reaction(s) after administration of CVnCoV at a particular dose level, vaccination will be put on 
hold for all subjects in the applicable dose level and any higher dose level. The DSMB will perform a 


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comprehensive review of all relevant safety and reactogenicity data before making a decision to stop, 
continue or modify vaccination (including dose-de-escalation) with this and any higher dose level. 
 
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 dose-de-escalation). 
 
If a stopping rule or trial suspension rule is limited to subjects with SARS-CoV-2 positive serology, 
vaccination will only be put on hold for subjects with SARS-CoV-2 positive serology. 
The DSMB may recommend additional measures including modification or halt of the trial. After completion 
of vaccination for all subjects, the DSMB will continue to review safety data every 3 months, or more 
frequently if needed based on the safety data. 
 Statistical Methods 
Due to the exploratory nature of this trial, only descriptive statistics will be used. No confirmatory statistical 
inference will be performed.  
All data collected during this study will be displayed in data listings, unless otherwise specified. Data listings 
will be sorted by dose level and subject identifier. Screening failures will be excluded from all listings and 
tables if not otherwise stated. Listings will include all relevant assigned/derived variables. 
Unless otherwise noted, categorical variables will be summarized using counts and percentages. 
Descriptive statistics (mean, median, standard deviation (SD), Q1, and Q3, minimum and maximum values) 
for continuous variable will be presented. Mean, median, Q1 and Q3 will be presented to 1 decimal more 
than original data. SD will be presented with 2 decimals more than original data. Minimum and maximum 
will match the decimal points in the original data.  
Descriptive summaries and tabulations will be presented overall and by age groups (age 18-40, age 41-60) 
unless otherwise specified.  
All data summaries and tabulations will be prepared using SAS Version 9.4 or higher. 
12.1 Subject Disposition 
The number and percentage of subjects screened, randomized and treated with the vaccine in the study 
will be presented with the number and percentage of subjects who withdrew from the study prematurely 
and a breakdown of the corresponding reasons for early termination and discontinuation.  
The number and percentage of subjects included in each analysis set will be provided. Reasons for 
exclusion from each analysis set will not be tabulated, but will be listed. Subjects not fulfilling any 
inclusion/exclusion criteria will be listed only.  
Subject visits will be listed only. 
12.2 Important Protocol Deviations 
Per PRA processes, protocol deviations data will be entered into PRA system of record (PSO). The trial 
team and the Sponsor will conduct on-going reviews of the deviation data from PSO and the resulting set 
of evaluable subjects throughout the trial, adjusting the deviation criteria as seems appropriate.  
Protocol deviation data will be reviewed prior to each formal analysis (i.e. interim analyses of final analyses) 
and if applicable important deviations leading to elimination of subjects from analysis sets will be identified. 
If applicable detailed definitions and further guidance on additional programmatic approaches for 
identification of protocol deviations and/or other criteria will be provided in an appendix to the final SAP. 


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The detailed definitions of important protocol deviations leading to elimination of subjects from analysis sets 
will be provided in the final version of the SAP and/or in the final signed minutes of the data review meetings 
prior to each formal analysis and prior to database lock. 
Protocol deviation data will be listed only. 
12.3 Demographic and Baseline Characteristics 
Demographic characteristics to be summarized will include gender, ethnicity, race, age at screening (years), 
age group (18 – 40 years, 41-60 years), baseline immune status measured retrospectively, height (cm), 
weight (kg), BMI (kg/m2) and childbearing potential.  
12.4 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) using version 
24.1. Medical history will be listed only.  
12.5 Trial Vaccine 
12.5.1 Trial Vaccine Exposure 
The administrations of CVnCoV or placebo will be listed and the number of vaccinations will be summarized.  
12.5.2 Prior and Concomitant Medications and Vaccinations 
Prior and concomitant medication will be summarized with number and percentage and listed according to 
WHODRUG (Version September  2021 Global B3 or newer), by Anatomical Therapeutic Chemical (ATC). 
Prior vaccinations will be listed according to WHODRUG (Version September  2021 Global B3), by 
Anatomical Therapeutic Chemical (ATC).  
12.6 Primary Analysis 
The primary safety analysis for the dose escalation phase will be conducted by the sponsor. The primary 
descriptive safety analysis for the dose escalation will be conducted by PRA.  Of primary interest for the 
dose escalation phase are the following endpoints:  
• 
Frequencies of Grade 3 adverse reactions and any serious adverse event (SAE) considered as 
related to the trial vaccine within at least 24 hours after the first vaccination by dose level. 
• 
Frequencies of Grade 3 adverse reactions and any SAE considered as related to the trial vaccine 
within at least 60 hours after the first vaccination by dose level. 
12.6.1 Primary Safety Analysis for Dose Escalation Phase  
The assumption is that the rate of subjects with Grade 3 adverse reactions will be similar in subjects 
independent of baseline serology status (seronegative or seropositive) and therefore similar in subjects 
with no history of COVID-19 disease and subjects with SARS-CoV-2 positive serology. Both groups will be 
analyzed together for the primary analysis of Grade 3 adverse reactions. Additional subgroup analyses will 
be performed for subjects retrospectively SARS-CoV-2 seronegative at baseline and subjects 
retrospectively SARS-CoV-2 seropositive at baseline. 
 
An adaptive BLRM guided by the EWOC principle will be used for the dose escalation while decisions of 
dose level expansion in the sentinel groups of 4 subjects is based on a maximum number of 2 subjects with 
Grade 3 adverse reactions. Of note, dose escalation can also not proceed if any SAE considered as related 
to the trial vaccine according to the Investigator occurs. The use of Bayesian response adaptive models for 
Phase 1 studies has been advocated by the EMA adopted guideline on small populations (EMA, 2006) and 
by Rogatko et al., 2007 [2] and is one of the key elements of the FDA’s Critical Path Initiative. 


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A modified 2-parameter BLRM will be used for dose escalation [3]. All information currently available about 
the dose-adverse reaction relationship of CVnCoV is summarized in a prior distribution. This prior 
distribution is then updated after each group of subjects with all of the adverse reactions data available in 
the safety set from the current trial. Once updated, the distribution summarizes the probability that the true 
rate of adverse reactions for each dose lies in the following categories: 
• 0% to <33%: targeted tolerance; and 
• ≥33% to 100%: intolerance. 
The EWOC principle mandates that any dose of CVnCoV that has more than a 50% chance of being in the 
intolerance category is not considered for the next dose administrations [3,4]. A clinical synthesis of the 
available safety and reactogenicity information (including adverse reactions that are not Grade 3 adverse 
reactions), laboratory values and, if available, immune response information as well as the 
recommendations from the Bayesian model and the iSRC/DSMB will be used to determine the dose level(s) 
for the next group at a dose-escalation teleconference. In any case where there is a change in dose level 
to be administered to the next enrolled subjects, a new model will be defined using a Meta-Analytic-
Predictive prior, based on the observed data. 
 
The frequency of Grade 3 adverse reactions and SAEs considered as related to the trial vaccine according 
to the Investigator will be tabulated by dose after 24 hours and 60 hours post-vaccination and information 
about the Grade 3 adverse reactions and SAEs considered as related to the trial vaccine according to the 
Investigator will be listed by dose and dose level. 
12.6.1.1 Bayesian Logistic Regression Model 
The objective of the design is to determine the highest dose with less than 50% risk of a true Grade 3 
adverse reaction rate being equal to or above 33%. The dose escalation will be guided by a modified 
Bayesian 2-parameter logistic regression model with overdose control.  
The model is formulated as follows: 
 
logit(p(d)) = log(α) + β*log(d/d*), 
 
where logit(p) = log(p/(1-p)). p(d) represents the probability of having a Grade 3 adverse reaction in the first 
24 hours at dose d, d* = 8µg is the reference dose, allowing for the interpretation of α as the odds of an 
adverse reaction at dose d*, and θ = (log(α), log(β)) with α, β >0 is the parameter vector of the model. 
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter vector θ needs 
to be specified. This prior distribution will be specified as a multivariate normal distribution, i.e., 
π(θ) = MVN(μ, Σ) 
the multivariate normal distribution with mean vector μ and covariance matrix Σ, with 
 






=
Σ
2
22
,
22
,
11
,
22
,
11
,
2
11
,
i
i
i
i
i
i
i
i
i
σ
ρ
σ
σ
ρ
σ
σ
σ


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Prior derivation 
Since no prior information is available, the uncertainty about the dose-tolerance relationship is expressed 
by a mixture distribution composed of a main component (a priori assuming 10% and 20% adverse reaction 
probabilities at 2µg and 8µg, respectively), a low tox (a priori assuming 5% and 15% adverse reaction 
probabilities at 2µg and 8µg, respectively) and a high tox component (a priori assuming 25% and 50% 
adverse reaction probabilities at 2µg and 8µg, respectively). All mixture components are attached with high 
uncertainty expressed by unit variances of the coefficients. A summary of the prior probabilities of Grade 3 
adverse reactions at different doses, as well as the corresponding probability of targeted and overdosing, 
are shown in Table 9. Graphically, the prior medians with accompanying 95% credible intervals are shown 
in Figure 2. The uncertainty around the medians is large, showing the low amount of in-men information 
this prior provides. 
Table 8  
Summary of prior distribution 
Prior Component 
Mixture Weight 
Mean Vector 
STD Vector 
Correlation 
Main 
0.8 
-1.386 
1 
0 
-0.536 
1 
Low tox 
0.1 
-1.735 
1 
0 
-0.136 
1 
High tox 
0.1 
0.000 
1 
0 
-0.233 
1 
-0.761 
1 
Table 9  
Prior probabilities of Grade 3 adverse reaction at selected doses 
Dose 
(µg) 
Probability 
of 
true
adverse reaction rate in Mean 
STD 
Quantiles 
[0-0.33) 
[0.33-1] 
2.5% 
50% 
97.5% 
2 
0.898 
0.102 
0.133 
0.145 
0 
0.083 
0.545 
4 
0.841 
0.159 
0.179 
0.161 
0.007 
0.128 
0.615 
8 
0.708 
0.292 
0.26 
0.185 
0.034 
0.213 
0.721 
 
Doses in bold type meet the overdose criterion, P(overdose) < 0.20. 
* STD = standard deviation. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2 
Prior medians and 95% credibility intervals 
 
The highest acceptable dose may be considered reached if both of the following criteria are fulfilled: 
1. 
The posterior probability of the true Grade 3 adverse reaction rate in the target interval [0%-33%) is 
at least 50% and the probability of being above the target is below 50%. 
2. 
At least 12 subjects have been vaccinated with this dose level. 
Statistical model assessment 
The model was assessed using 2 different metrics: 
1. 
Hypothetical data scenarios: For various potential data constellations as they could occur in the 
actual trial, the maximal next doses as allowed by the model and by the 200% escalation limit are 
investigated. Data scenarios thus provide a way to assess the “on-trial” behavior of the model. 
2. 
Simulated operating characteristics: These illustrate for different assumed true dose-tolerance 
relationships, how often a correct dose would be declared as highest acceptable dose by the model. 
They are a way to assess the “long-run” behavior of the model. 
In summary, the model showed very good behavior as assessed by these metrics. More details can be 
found in Appendix 3.  
12.6.2 Primary Descriptive Safety Analysis  
The descriptive safety analyses will be performed for all subjects, for subjects SARS-CoV-2 seronegative 
at baseline, and for subjects retrospectively SARS-CoV-2 seropositive at baseline, if not otherwise stated.  
12.6.2.1 Adverse Events 
• 
Overall summary of AEs (unsolicited AEs, related unsolicited AEs, SAEs, related SAEs, any 
intercurrent medical conditions affecting immune response, medically attended AEs, AESIs AEs 
leading to withdrawal from study), including percentage and frequencies. 


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• 
Summary of solicited AEs and maximum grade occurring on the day of vaccination and the following 
7 days for dose 1 and dose 2. 
• 
Frequencies and percentages of subjects for individual solicited local AEs terms and maximum grade 
occurring on the day of vaccination and the following 7 days for dose 1 and dose 2.  
• 
Frequencies and percentages of subjects for individual solicited systemic AEs terms and maximum 
grade occurring on the day of vaccination and the following 7 days for dose 1 and dose 2. 
• 
Frequencies and percentages of subjects for related individual solicited systemic AEs terms and 
maximum grade occurring on the day of vaccination and the following 7 days for dose 1 and dose 2. 
• 
Day of first onset, daily summary and duration of solicited local AEs, systemic AEs occurring on the 
day of vaccination and the following 7 days for dose 1 and dose 2.  
• 
The number and percentage of subjects with solicited 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.  
• 
Occurrence and maximum grading of unsolicited AEs, and related unsolicited AEs occurring on the 
day of vaccination and the following 28 days for dose 1 and dose 2. 
• 
Occurrence and maximum grading of SAEs, and related SAEs occurring on the day of vaccination 
and the following 28 days for dose 1 and dose 2. 
• 
Occurrence of unsolicited AEs, SAEs, related SAEs, intercurrent medical conditions affecting 
immune response, AESIs, medically attended AEs, AEs leading to study withdrawal throughout the 
trial. 
• 
Occurrence of AEs related to SMQs as defined in Section 10.4.8 (includes solicited AEs). This 
analysis will be performed for all subjects only. 
• 
Occurrence of AEs related to customized MedDRA queries as defined in Section 10.4.8 (includes 
solicited AEs). This analysis will be performed for all subjects only. 
Individual local and systemic solicited adverse events will be displayed in by subject figures. The duration 
of grade 3 solicited AEs will be presented in a figure. Solicited and unsolicited summary tables by gender 
will be presented.  
 
Unsolicited AEs and SAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
24.1) by System Organ Class (SOC) and Preferred Term (PTT).  
12.6.3 Secondary and Exploratory Endpoints 
Descriptive statistics for the secondary and exploratory immunogenicity endpoints will be provided by age 
category. Data will be presented after each vaccine dose.  
12.6.3.1 Secondary Endpoints 
The humoral immune response will be evaluated on Day 1, Day 8, Day 15, Day 29, Day 36, Day 43, Day 
57, Day 120, Day 211 and Day 393. The outputs related to the secondary endpoints will be based on the 
immunogenicity set (population). In addition, a separate analysis will be conducted based on the following 
subset: 
 
• 
Subjects seronegative at baseline and throughout the trial as defined in section 10.5. 
• 
Subjects who received the dose at day 1 and day 29 with one sample 15 days post dose 2. 
• 
And subjects without any protocol deviations impacting immunogenicity measurements. 
 


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Individual values and GMT of SARS-CoV-2 spike protein antibody and receptor-binding domain (RBD) 
levels and of SARS-CoV-2 neutralizing antibodies, percentages of immune cell populations and cellular 
responders will be summarized for each dose level in all subjects, in those subjects retrospectively 
SARS-CoV-2 seronegative at baseline, and in those subjects retrospectively SARS-CoV-2 seropositive at 
baseline. The GMTs are assumed to be skewed hence for applicable outputs the geometric mean and 
geometric standard deviation with confidence intervals will be presented.  
 
 
• 
The proportion and 95%-confidence intervals (exact Clopper-Pearson) of subjects seroconverting 
with a 2-fold, a 4-fold, and any increase for SARS-CoV-2 spike protein antibodies , as measured by 
ELISA.  
• 
Geometric mean (GM), geometric SDs  (GDS) and 95%-confidence intervals of serum SARS-CoV-
2 spike protein antibodies  as well as fold change from baseline. 
• 
The proportion and 95%-confidence intervals (exact Clopper-Pearson) of subjects seroconverting 
with a 2-fold, a 4-fold, and any increase for SARS-CoV-2 neutralizing antibodies, as measured by an 
activity assay.  
• 
GM, GSDs and 95%-confidence intervals of serum SARS-CoV-2 neutralizing antibodies, as 
measured by an activity assay as well as fold change from baseline. 
 
GMTs of serum SARS-CoV-2 spike protein antibodies  and SARS-CoV-2 neutralizing antibody levels in 
serum over time will be presented in the following figures overall and by age group: 
• 
Individual line plots of fold change from baseline by dose level. 
• 
Line plot of geometric mean fold change from baseline by dose level. 
• 
Individual line plots of GMTs by dose level. 
• 
Line plot of GMTs with geometric mean and confidence intervals by dose level. 
• 
Boxplots with median, Q1 and Q3, and whiskers representing minimum and maximum. 
12.6.3.2 Exploratory Endpoints 
 
Cell-mediated immune response 
Cell-mediated assessments will be performed on Day 1, Day 29, Day 36 and Day 211. Testing on Day 211 
will only be performed on subjects who are determined as T-cell responders on Day 29 and/or Day 36.  
This data will be listed only.  
 
Innate immune response 
The innate immune response will only be evaluated in subjects in the open-label sentinel groups. 
Measurement of serum cytokines, including but not limited to IFN-α, IFN-γ, IL-6, CCL2 and IP-10, will be 
performed on Day 1, Day 2, Day 8, Day 29, Day 30 and Day 36. In addition, gene expression changes will 
be determined using the PAXgene® blood RNA system by transcriptome profiling on Day 1, Day 2, Day 8, 
Day 29, Day 30 and Day 36. 
 
• 
Serum cytokine concentrations, including but not limited to interferon (IFN)-α, IFN-γ, interleukin (IL)-
6, chemokine ligand (CCL) 2 and IFN-γ-induced protein 10 (IP-10) will be presented with descriptive 


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statistics including 95%-confidence intervals with change from baseline. Two baseline 
measurements will be used, Day 1 and Day 29.  
• 
Gene expression profiling as changes in gene transcripts is not part of the statistical analysis plan. 
 
Evaluation of infection 
• 
Number of subjects and percentages with virologically-confirmed SARS-CoV-2 infection as 
measured by reverse transcription polymerase chain reaction (RT-PCR) at clinically determined time 
points throughout the trial. 
• 
Number of subjects and percentages with asymptomatic SARS-CoV-2 infection as measured by 
retrospective serology at predefined time points. 
12.6.4 Laboratory Data 
Blood samples for determination of hematology, clinical biochemistry and coagulation will be analyzed on 
Day 1, and one and 7 days after each vaccine dose administration (Days, 2, 8, 30 and 36). At all other 
visits, safety laboratory assessment will only be done in case an abnormal value was observed at the 
previous visit if not otherwise stated in the safety laboratory summary outputs. 
All laboratory data will be summarized in International System (SI) units. The conversion factors from 
conventional to SI units will be documented in the Local Lab Conventions document for this study.  
Safety laboratory values will be classified into low/normal/high based on laboratory normal ranges. Each 
parameter will be presented by descriptive statistics (n, mean, SD, median, Q1, Q3, minimum and 
maximum) at each visit including change from baseline. Shift tables based on normal ranges will be 
presented for selected visits. All laboratory values will be listed. A separate listing for abnormal lab values 
will be presented. 
The mean value with standard deviation for the safety laboratory parameters will be displayed in a line plot 
by visit.  
12.6.4.1 Hematology 
Hematology parameters include Erythrocytes, Hematocrit, Hemoglobin, Platelets, Leukocytes, Basophils 
(Absolute), Basophils/Leukocytes (%), Eosinophils (Absolute), Eosinophils/Leukocytes (%), Lymphocytes 
(Absolute), Lymphocytes/Leukocytes (%), Monocytes (Absolute), Monocytes/Leukocytes (%), Neutrophils 
(Absolute), Neutrophils/Leukocytes (%), Reticulocytes (Absolute), Reticulocytes/Erythrocytes (%), Ery. 
Mean Corpuscular Hemoglobin (MCH), Ery. Mean Corpuscular HBG Concentration (MCHC) and Ery. Mean 
Corpuscular Volume (MCV).  
12.6.4.2 Chemistry 
Clinical Chemistry/Biochemistry parameters include Alanine Aminotransferase, Albumin, Alkaline, 
Phosphatase, Aspartate Aminotransferase, Bilirubin (Total), Direct Bilirubin, Indirect Bilirubin, C-Reactive 
Protein, Calcium, Creatinine, Gamma Glutamyl Transferase, Lactate Dehydrogenase, Magnesium, 
Potassium, Total Protein, Sodium, Urea Nitrogen and Urea. 
12.6.4.3 Coagulation 
Coagulation parameters include Activated Partial Thromboplastin Time, Prothrombin Intl. Normalized Ratio 
and Prothrombin Time. 
12.6.4.4 Serum/Urine Pregnancy Test. 
For subjects of childbearing potential, a serum pregnancy test will be performed on the day of enrollment. 
On Day 1 (pre-vaccination) a urine pregnancy test (hCG) will be performed (only required if the serum 
pregnancy test was performed more than 3 days before). Pregnancy test results will be listed only.   


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12.6.5 Vital Signs 
Vital signs will be summarized descriptively at each study timepoint they are collected, including screening. 
Change from baseline values will be summarized for the post-vaccination timepoint. Vital signs parameters 
to be summarized include systolic blood pressure (mmHg), diastolic blood pressure (mmHg), pulse rate 
(bpm) and body temperature (°C).  
12.6.6 Physical Examinations, ECGs, and Other Observations Related to Safety 
12.6.6.1 Physical Examinations 
At specific trial visits a complete physical examination will be performed and the results collected if there 
are clinically significant results. Physical examination results will be listed only.  
12.6.6.2 Electrocardiogram 
ECG interpretation and clinically significance will be collected on Day 1 for all subjects. Additionally, ECGs 
should be performed as clinically indicated. ECG results will be listed only. 
 
 References 
1. US Department of Health and Human Services. Food and Drug Administration (FDA). Guidance for 
Industry. Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine 
Clinical 
Trials. 
2007. 
[Available 
from: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Vaccines/ucm091977.pdf; 'Accessed at: March 2019]. 
2. Rogatko A, Schoeneck D, Jonas W, et al. Translation of innovative designs into phase I trials. J Clin 
Oncol. 2007 Nov 1;25(31):4982-6. 
3. Neuenschwander B, Branson M, Gsponer T.Critical aspects of the Bayesian approach to phase I 
cancer trials. Stat Med. 2008 Jun 15;27(13):2420-39.  
4. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose 
control. Stat Med. 1998 May 30;17(10):1103-20. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Glossary of Abbreviations 
LIST OF ABBREVIATIONS 
ALQ 
Above limit of quantification 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANA 
Antinuclear antibody 
ARI 
Acute respiratory infection 
BLRM 
Bayesian logistic regression model 
BLQ 
Below limit quantification 
BMI 
Body mass index 
CCL 
Chemokine ligand 
CEPI 
Coalition for Epidemic Preparedness Innovations 
CMI 
Cell-mediated immunity 
CoV 
Coronavirus 
CRO 
Contract research organization 
CTL 
Cytotoxic T lymphocyte 
CVnCoV 
Investigational SARS-CoV-2 mRNA vaccine 
DDS 
Dose-determining set 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
DSMB 
Data and safety monitoring board 
E 
Envelope 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EWOC 
Escalation with overdose control 
FDA 
US Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GMT 
Geometric mean titer 
hCG 
Human chorionic gonadotropin 


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IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International 
Council 
on 
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 
IRB 
Institutional Review Board 
iSRC 
Internal safety review committee 
IUD 
Intrauterine device 
IUS 
Intrauterine systems 
IV 
Intravenous 
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 
PCR 
Polymerase chain reaction 
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 


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SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
TSH 
Thyroid stimulating hormone 
VDE 
Vaccine dependent disease enhancement 
WHO 
World Health Organization 
 
 
 


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 Appendices 
Appendix 1 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  


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o Narcolepsy  
o Optic neuritis  
o Transverse Myelitis  
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 2 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 AR following immunization 
 


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Appendix 3 Statistical Appendix Including Model Performance and Data 
Scenarios 
The model was assessed by 2 different metrics: hypothetical on-trial data scenarios and long-run operating 
characteristics. 
Hypothetical Data Scenarios 
Exemplary hypothetical data scenarios are shown in Table 10 to Table 12. These scenarios reflect potential 
on-trial data constellations and related escalation as allowed by the model and the 200% escalation limit. 
For each scenario, the probability of overdosing for the current dose, as well as the next potential dose and 
related probabilities of target-dosing are shown.  
These settings illustrate the adaptive behavior of the model which takes into account all observed data from 
previous dose levels and show a reasonable behavior of the model. 
Table 10 
Escalation from 2µg to 4µg: Escalate to 4µg if not more than 4 in 12 subjects experience 
a Grade 3 adverse reaction. 
Scenario 
Dose 
#AR 
#Pat 
CD - 
P(OD) 
Next 
Dose 
ND - 
P(TD) 
ND - 
P(OD) 
1 
2 
0 
12 
0.000 
4 
0.994 
0.006 
2 
2 
4 
12 
0.269 
4 
0.524 
0.476 
3 
2 
5 
12 
0.496 
2 
0.504 
0.496 
CD=Current dose  
P(OD)= Probability of overdose 
ND= Next dose 
P(TD)= Probability of target dose 
P(OD)= Probability of overdose 
Table 11 
Escalation from 4µg to 8µg: Only borderline scenarios are provided with maximum number 
of Grade 3 adverse reactions at 4µg which just allow to escalate. 3 to 4 adverse reactions at 
4µg support escalation to 8µg depending on the outcome on previous dose levels. 
Scenario 
Dose 
#AR 
#Pat 
CD - 
P(OD) 
Next 
Dose 
ND - 
P(TD) 
ND - 
P(OD) 
3 
2 
0 
12 
 
 
 
 
4 
4 
12 
0.052 
8 
0.599 
0.401 
4 
2 
1 
12 
 
 
 
 
4 
4 
12 
0.106 
8 
0.568 
0.432 
5 
2 
2 
12 
 
 
 
 
4 
3 
12 
0.094 
8 
0.658 
0.342 
6 
2 
3 
12 
 
 
 
 
4 
3 
12 
0.193 
8 
0.558 
0.442 
7 
2 
4 
12 
 
 
 
 
4 
2 
12 
0.18 
8 
0.61 
0.39 


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Table 12 
Confirmation of 8µg: Scenarios represent the situations with the maximum number of 
Grade 3 adverse reactions at 8µg which still allow to confirm the highest dose level. 3 to 5 
adverse reactions at 8µg support confirmation of safety of 8 µg depending on the outcome 
in previous dose levels. 
Scenario 
Dose 
#AR 
#Pat 
CD - 
P(OD) 
Next 
Dose 
ND - 
P(TD) 
ND - 
P(OD) 
8 
2 
0 
12 
 
 
 
 
4 
0 
12 
 
 
 
 
8 
5 
12 
0.391 
8 
0.609 
0.391 
9 
2 
0 
12 
 
 
 
 
4 
2 
12 
 
 
 
 
8 
5 
12 
0.452 
8 
0.548 
0.452 
10 
2 
0 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
4 
12 
0.328 
8 
0.672 
0.328 
11 
2 
0 
12 
 
 
 
 
4 
4 
12 
 
 
 
 
8 
4 
12 
0.402 
8 
0.598 
0.402 
12 
2 
1 
12 
 
 
 
 
4 
1 
12 
 
 
 
 
8 
5 
12 
0.321 
8 
0.679 
0.321 
13 
2 
1 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
5 
12 
0.497 
8 
0.503 
0.497 
14 
2 
1 
12 
 
 
 
 
4 
4 
12 
 
 
 
 
8 
4 
12 
0.433 
8 
0.567 
0.433 
15 
2 
2 
12 
 
 
 
 
4 
2 
12 
 
 
 
 
8 
5 
12 
0.431 
8 
0.569 
0.431 
16 
2 
2 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
4 
12 
0.375 
8 
0.625 
0.375 
17 
2 
2 
12 
 
 
 
 
4 
4 
12 
 
 
 
 
8 
4 
12 
0.484 
8 
0.516 
0.484 
18 
2 
3 
12 
 
 
 
 
4 
3 
12 
 
 
 
 
8 
4 
12 
0.44 
8 
0.56 
0.44 
Operating Characteristics 
Operating characteristics are a way to assess the long-run behavior of a model. Under an assumed true 
dose-tolerance curve, metrics such as the probability of recommending a dose with true Grade 3 adverse 
reaction rate in the target interval can be approximated via simulation. Table 13 describes 3 assumed true 
scenarios which were used to assess the operating characteristics of the model. These scenarios reflect a 
wide range of possible cases as follows: 
• 
Scenario 1 (P): aligned with prior means 
• 
Scenario 2 (H): high-intolerance scenario 


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• 
Scenario 3 (LH): low-intolerance followed by high-intolerance 
Table 13 
Assumed True Dose-Tolerance Scenarios 
Scenario 
 
 
 
 
 
Dose 
2 
4 
8 
1(P) 
P(Grade 3 adverse 
reactions) 
0.13 
0.18 
0.26 
2(H) 
0.30 
0.50 
0.60 
3(LH) 
0.15 
0.30 
0.45 
Bold numbers indicate true adverse reaction rates in the target interval [0-0.33). 
For each of these scenarios, 500 trials were simulated. It was then assessed how often a dose was declared 
safe with true Grade 3 adverse reaction rate in the targeted or over-dose range. Furthermore, the average, 
minimum and maximum number of subjects per trial and the average number of Grade 3 adverse reactions 
per trial are reported. Results are shown in Table 14. 
Table 14 
Hypothetical Data Scenarios 
Scenario 
% of trials recommending a 
dose with true Grade 3 
adverse reaction rate in 
Stopped 
# Subjects 
# Grade 3 adverse 
reactions 
 
Target dose 
Overdose 
% of trials 
Mean (Min - Max) 
Mean (Min - Max) 
1 (P) 
98.2 
0 
1.8 
33.58 (4 - 36) 
6.21 (0 - 11) 
2 (H) 
56.4 
21 
22.6 
18.79 (4 - 36) 
7.18 (3 - 15) 
3 (LH) 
74.2 
24 
1.8 
28.75 (4 - 36) 
7.66 (3 - 13) 
In Scenario 1, which reflects the case that the true dose-tolerance relationship is aligned with prior means, 
98.2% of the simulated trials declared a dose as safe with true Grade 3 adverse reaction rate in the targeted 
dose range, while 1.8% of the simulated trials were stopped without declaring a dose to be safe. 
In Scenario 2 (high-intolerance scenario), the starting dose has already 30% probability of observing at 
least 1 Grade 3 adverse reaction at the first dose level. This contributes to the increased percentage of 
22.6% of all simulated trials for which the trial is stopped since none of the doses is considered tolerable 
anymore. This is an expected situation for a high-intolerance scenario. Despite the high intolerance 
probabilities assumed, only 21% of the simulated trials declared a dose safe with true Grade 3 adverse 
reaction rate in the overdose range. 
 
Scenario 3, 74.2% of the simulated trials declared a dose safe with true Grade 3 adverse reaction rate in 
the targeted dose range and in only 1.8% the trial was stopped, while in 24% of the trials, a safe dose in 
the overdose range was declared. 
The mean subject numbers ranged from 18.79 subjects (high scenario) to 33.58 subjects (prior means 
scenario) and the maximum number of subjects was 36. Mean numbers of grade 3 ARs ranged from 6.21 
to 7.66. 
 
In summary, the operating characteristics demonstrate a good precision of the highest acceptable dose 
determination. 
 
 
 
 
 


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Appendix 4 Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
Subjects will be enrolled in this trial only if they meet all of the following criteria: 
 
1. 
Healthy male and female subjects aged 18 to 60 years inclusive. 
Healthy subject is defined as an individual who is in good general health, not having any mental or 
physical disorder requiring regular or frequent medication. 
2. 
Expected to be compliant with protocol procedures and available for clinical follow-up through the 
last planned visit. 
3. 
Physical examination and laboratory results without clinically significant findings according to the 
Investigator’s assessment. 
4. 
Body mass index (BMI) ≥18.0 and ≤30.0kg/m2 (≥18.0 and ≤32.0kg/m2 for subjects with SARS-CoV-
2 positive serology). 
5. 
Females: At the time of enrollment, negative human chorionic gonadotropin (hCG) pregnancy test 
(serum) for women presumed to be of childbearing potential on the day of enrollment. On Day 1 (pre-
vaccination): negative urine pregnancy test (hCG), (only required if the serum pregnancy test was 
performed more than 3 days before). 
6. 
Females of childbearing potential must use highly effective of birth control from 1 month 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 (IUDs); 
o 
Intrauterine hormone-releasing systems (IUSs); 
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). 
Exclusion CriteraSubjects will not be enrolled in this trial if they meet any of the exclusion criteria. 
The following criterion applies to all open-label sentinel subjects: 
 
7. 
Subjects with confirmed SARS-CoV-2 positive serology as confirmed by testing at enrollment. 
The following criteria apply to all subjects, except those with SARS-CoV-2 positive serology: 
8. 
Subjects considered at the Investigator’s discretion to be at increased risk to acquire COVID-19 
disease (including, but not limited to, health care workers with direct involvement in patient care or 
care of long-term care recipients). 


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9. 
History of confirmed COVID-19 disease or known exposure to an individual with confirmed COVID-
19 disease or SARS-CoV-2 infection within the past 2 weeks. 
The following criteria apply to all subjects: 
10. 
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. 
11. 
Receipt of any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) 
prior to enrollment in this trial or planned receipt of any vaccine within 28 days of trial vaccine 
administration. 
12. 
Receipt of any investigational SARS-CoV-2 or other CoV vaccine prior to the administration of the 
trial vaccine. 
13. 
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 steroids. 
Corticosteroids used in the context of COVID-19 disease of subjects with SARS-CoV-2 positive 
serology are not exclusionary. 
14. 
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. 
15. 
History of a pIMD. 
16. 
History of angioedema. 
17. 
Any known allergy, including allergy to any component of CVnCoV or aminoglycoside antibiotics. A 
history of hay fever or seasonal allergies (pollinosis) that does not require current treatment (e.g., 
anti-histamines) during the vaccination period (1 month before first vaccination until 1 month after 
last vaccination) is not exclusionary. 
18. 
History of or current alcohol and/or drug abuse. 
19. 
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.  
20. 
Acute or currently active SARS-CoV-2 infection as confirmed by reactive PCR within 3 days of first 
trial vaccine administration. 
21. 
History of confirmed SARS or MERS. 
22. 
Administration of immunoglobulins (Igs) and/or any blood products within the 3 months preceding 
the administration of any dose of the trial vaccine. 
23. 
Presence or evidence of significant acute or chronic medical or psychiatric illness. Significant medical 
or psychiatric illnesses include but are not limited to: 
- 
Respiratory disease (e.g., chronic obstructive pulmonary disease, asthma) requiring daily 
medications currently or any treatment of respiratory disease exacerbations (e.g., asthma 
exacerbation) in the last 5 years. 
- 
Respiratory disease with clinically significant dyspnea in the last 5 years (except COVID-19 
disease in subjects with SARS-CoV-2 positive serology). 


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- 
Asthma medications: inhaled, oral, or intravenous (IV) corticosteroids, leukotriene modifiers, long- 
and short-acting beta agonists, theophylline, ipratropium, biologics.  
- 
Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, ischemic heart 
disease, history of stroke, peripheral artery disease, pulmonary embolism) or history of 
myocarditis or pericarditis as an adult.  
- 
Elevated blood pressure or hypertension, even if well-controlled. 
- 
Diabetes mellitus type 1 or 2. 
- 
History of any neurological disorders or seizures including Guillain-Barré syndrome, with the 
exception of febrile seizures during childhood. 
- 
Current or past malignancy, unless completely resolved without sequelae for >5 years. 
24. 
Foreseeable non-compliance with protocol as judged by the Investigator. 
25. 
For females: pregnancy or lactation. 
26. 
History of any anaphylactic reactions. 
27. 
Subjects with impaired coagulation or any bleeding disorder in whom an IM injection or a blood draw 
is contraindicated. 
28. 
Subjects employed by the Sponsor, Investigator or trial site, or relatives of research staff working on 
this trial. 
 
 
Appendix 5 List of TFLs 
A complete list of all TFLs is provided in a separate document CV-NCOV-001 Statistical Analysis Plan. The 
document will be managed outside of this SAP.  
Appendix 6 Identification of Protocol Deviations Leading to Exclusion from 
Analysis Sets 
Details on the identification of protocol deviations leading to exclusion of subjects from analysis sets are 
described in a separate document CV-NCOV-001 Statistical Analysis Plan. The document will be 
maintained outside of this SAP. 
Appendix 7 MedDRA Terms for CMQs 
Based on MeddRA Version 24.1 
 
A. Customized MedDRA Queries related to taste and smelling disorder 
Preferred Term 
Ageusia 
Anosmia 
Dysgeusia 
Hypergeusia 


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Hypogeusia 
Hyposmia 
Parosmia 
Taste disorder 
 
B. Customized MedDRA Querie related to paraesthesia, hypoaesthesia, and hyperaesthesia 
Preferred Term 
Anal hypoaesthesia 
Anal paraesthesia 
Dental paraesthesia 
Eye paraesthesia 
Genital hyperaesthesia 
Genital hypoaesthesia 
Genital paraesthesia 
Hemihyperaesthesia 
Hemiparaesthesia 
Hyperaesthesia 
Hyperaesthesia eye 
Hyperaesthesia teeth 
Hypoaesthesia 
Hypoaesthesia eye 
Hypoaesthesia oral 
Hypoaesthesia teeth 
Intranasal hypoaesthesia 
Intranasal paraesthesia 
Oral hyperaesthesia 
Paraesthesia 
Paraesthesia ear 
Paraesthesia mucosal 
Paraesthesia oral 
Pharyngeal hypoaesthesia 
Pharyngeal paraesthesia 
Thermohyperaesthesia 
Thermohypoaesthesia