COVID-19: A Phase 3 Multicenter Clinical Trial to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in Adults 18 Years of Age and Above With Co-morbidities
Phase: PHASE3
Conditions: Coronavirus, Covid19, SARS-CoV-2, Severe Acute Respiratory Syndrome
Sponsor: CureVac

Protocol Number: CV-NCOV-003 
 
Official Title: A Phase 3 multicenter clinical trial to evaluate the safety, reactogenicity 
and immunogenicity of the investigational SARS-CoV-2 mRNA vaccine 
CVnCoV in adults 18 years of age and above with co-morbidities 
 
NCT Number: NCT04860258 
 
Document Date: 27 July 2021 

 
Amendment 1 to CV-NCOV-003 Protocol Version 2.0 
 
 
CureVac AG 
27 July 2021 
CONFIDENTIAL 
Page 1 of 6 
 
 
AMENDMENT TO CLINICAL TRIAL PROTOCOL 
VERSION 2.0 
COVID-19: 
A Phase 3 multicenter clinical trial to evaluate the safety, reactogenicity and 
immunogenicity of the investigational SARS-CoV-2 mRNA vaccine CVnCoV in 
adults 18 years of age and above with co-morbidities 
Protocol Number: 
CV-NCOV-003 
EudraCT Number: 
2020-004070-22 
Investigational product: 
CV07050101 (referred to as CVnCoV) 
Phase: 
Phase 3 
Sponsor: 
CureVac AG 
Schumannstrasse 27 
60325 Frankfurt 
Germany 
Short Title: 
Safety, reactogenicity and immunogenicity of CVnCoV in 
adults 18 years of age and above with co-morbidities 
Version and Date: 
Amendment 1 dated 27 July 2021, to Protocol Version 2.0 
dated 29 March 2021 
 

 
Amendment 1 to CV-NCOV-003 Protocol Version 2.0 
 
 
CureVac AG 
27 July 2021 
CONFIDENTIAL 
Page 3 of 6 
 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
COVID-19: A Phase 3 multicenter clinical trial to evaluate the safety, 
reactogenicity and immunogenicity of the investigational SARS-CoV-2 
mRNA vaccine CVnCoV in adults 18 years of age and above with co-
morbidities 
Protocol Number:  
Protocol CV-NCOV-003, Version 2.0 Amendment 1 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol amendment, and I will conduct the trial as 
described in compliance with this protocol, GCP, and relevant ICH guidelines. 
Once the Independent Ethics Committee (IEC) has approved the protocol amendment, I will not 
modify this amendment without obtaining prior approval of CureVac and of the IEC. I will submit 
the protocol amendment 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. Assigned 
numbers on all electronic case report forms (eCRFs) and laboratory samples will identify all 
subjects. CureVac or its representatives or regulatory agencies may review clinical information. 
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 

 
Amendment 1 to CV-NCOV-003 Protocol Version 2.0 
 
 
CureVac AG 
27 July 2021 
CONFIDENTIAL 
Page 4 of 6 
 
Rationale of the Amendment to Protocol Version 2.0 
This amendment describes the changes to be implemented into protocol version 2.0 in the context 
of the pause of Trial CV-NCOV-003.  
In line with protocol section 5.2.2 “Pausing of the Trial,” the DSMB convened to review the 
available CVnCoV data across ongoing trials, and notably the available safety data of the pivotal 
phase 2b/3 trial CV-NCOV-004.  The DSMB confirmed a favourable safety profile for CVnCoV.  
The second Interim Analysis data on efficacy from CV-NCOV-004 suggested age dependent 
efficacy with inconclusive efficacy data in the group > 60 years of age.  In consultation with 
Investigators, a decision has been taken to stop further enrolment into CV-NCOV-003 and amend 
the current protocol version 2.0 to clarify that all subjects shall undergo safety and immunogenicity 
follow-up for 3 months following the last CVnCoV dose.  Due to the change in risk/benefit profile, 
there is sufficient scientific and medical rationale to support an enrolment halt of all ages with 
comorbidities and for enrolled subjects to complete study activities, allowing standard of care 
COVID vaccination procedures to be followed by the Investigators or the subject’s primary care 
physician. 
Description of changes to Trial CV-NCOV-003, Protocol Version 2.0 
Subjects who already received at least 1 CVnCoV dose are requested to remain in the study for 
3 months following their last CVnCoV dose for safety and immunogenicity follow-up. Subjects will 
follow the amended Schedule of Activities (Table 2) until they reach 3 months of follow-up post-
CVnCoV last dose. The follow-up period including Visit 9/Day 211 and Phone Contact/Day 302 is 
removed.  The previous End of Trial Visit/Day 393 is amended to 3 months post last injection of 
CVnCoV as described in Table 1. 
Any subjects currently in screening will be considered screen failures and will not receive CVnCoV 
vaccination in line with the enrolment halt. No additional screenings will be performed. 
Subjects will be provided with adequate information about the changes to the study, in accordance 
with applicable local regulations and in line with protocol section 12.4 “Informed Consent”. 
Table 1 
Summary of visits to be included in the 3-month follow-up 
The 
last 
injection 
of 
CVnCoV was on: 
The subject will perform the 
study visits as planned in 
the Schedule of Activities, 
up to: 
The subject will additionally 
have an end of trial visita at: 
Day 1 
Day 57 
Day 91 
Day 29 
Day 120b 
Day 120 b 
a) At this visit, the procedures described for the End of Trial in Table 2 should be performed. 
b) As Day 120 will be the end of trial visit, the procedures to be followed are those described for the 
End of Trial in Table 2.

 
Amendment 1 to CV-NCOV-003 Protocol Version 2.0 
 
 
CureVac AG 
27 July 2021 
CONFIDENTIAL 
Page 5 of 6 
 
Table 2 
Amended Schedule of Activities 
Visit  
 
Safety 
contacta 
Phone 
contact 
 
 
 
 
 
End of 
Trialc 
Trial Day 
2 
(D1 
+1d) 
9 
(D1 +8d) 
15 
(D1+ 14d) 
29 
(D1 +28d) 
30b 
(D29 +1d) 
43 
(D29 
+14d) 
57 
(D29 
+28d) 
120 
(D29 
+91d) 
Visit Window (days) 
-0/ +0 
-0/ +7 
-2/ +4 
-3/ +14 
 
-2/ +4 
-2/ +4 
-2/ +4 
Physical examinationd 
 
 
 
 
 
 
 
 
X 
Symptom-directed physical examination 
X 
 
 
X 
X 
X 
X 
 
 
Vital signsd 
X 
 
 
X 
X 
X 
X 
 
X 
Diary retraininge 
X 
 
 
 
X 
X 
 
 
 
Diary reviewe 
X 
X 
 
X 
X 
X 
X 
 
 
Solicited AEs collected by diarye 
X 
X 
 
X 
X 
 
 
 
 
Unsolicited AEs collected by diarye 
X 
X 
 
X 
X 
X 
X 
 
 
SAEsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intercurrent medical conditionsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AESIsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication/vaccination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety laboratory (~8 mL)g – Up to 50 subjects 
per co-morbidity 
X 
 
 
X 
X 
(X)h 
X 
(X)h 
 
Nasopharyngeal swab collection for rapid 
diagnosis on site and PCR testingi 
(X)  
Binding antibody to RBD of S (spike) protein of 
SARS-CoV-2 (~4mL blood)j 
 
 
 
X 
 
X 
 
X 
X 
Binding antibody to the N (nucleocapsid) protein 
of SARS-CoV-2 (~4 mL blood)j 
 
 
 
 
 
X 
 
X 
X 
Subset of up to 25 subjects per co-morbidity: 
SARS-CoV-2 neutralizing activity (6 mL blood)j,k 
 
 
 
X 
 
X 
 
X 
X 
Subset of up to 25 subjects per co-morbidity: 
Cell-mediated immunity (3 mL) j,k 
 
 
 
X 
 
X 
 
X 
 
Maximum total blood volume (mL) 
~8 
- 
- 
~21 
~8 
~17 
~8 
~17 
~14 
Trial end 
 
 
 
 
 
 
 
 
X 

 
Amendment 1 to CV-NCOV-003 Protocol Version 2.0 
 
 
CureVac AG 
27 July 2021 
CONFIDENTIAL 
Page 6 of 6 
 
AE: adverse event; AESI: adverse event of special interest; PCR: polymerase chain reaction; RBD: receptor-binding domain; SAE: serious adverse event. 
a) 
The safety contact is only applicable for the subjects who were allocated to this assessment at the time of enrolment to collect diary card data. The 
safety/reactogenicity data entered in the week after the first vaccination (i.e. all data recorded until Day 8 inclusively) has to be received by site and entered into 
electronic data capture as soon as possible. The site and the subject should agree on the best way to transfer this data. It can be done via different means such 
as a site visit, phone call or a transfer of the diary to site. 
b) 
Day 30 visit will be performed only for subjects who received their second CVnCoV injection. 
c) 
The day when performing the end of trial procedures is presented in Table 1.  This can be Day 91, Day 120, or at the time of Early Termination if the subject 
does not agree to continued follow-up as recommended but agrees to perform an Early Termination Visit. 
d) 
Physical examination and vital signs must be performed/measured by a qualified healthcare professional. See Section 9.1.4 of Protocol version 2.0 for an 
overview of the required assessments. 
e) 
Diary retraining, review, and recording of solicited and unsolicited AEs in diaries are applicable only to subjects who received their last dose of CVnCoV on 
either Day 1 or Day 29 (as applicable). 
f) 
SAEs, AESIs (including COVID-19) and intercurrent medical conditions that may affect the immune response to vaccination will be collected throughout the 
trial. 
g) 
Safety laboratory testing will be performed in the subjects who were allocated to this assessment at the time of enrolment. See Appendix 3 of Protocol version 
2.0 for an overview of the safety laboratory assessments. 
h) 
On Day 43 and Day 120, the safety laboratory only needs to be done if the previous result was abnormal. 
i) 
Swabs for COVID-19 testing will be collected in case the subject displays symptoms of acute respiratory infection (including, but not limited to COVID-19) (see 
Section 9.3 of Protocol version 2.0). 
j) 
No blood draws for immunogenicity will be performed after the subject receives their first dose of authorised vaccine. 
k) 
Sites shall continue to collect blood for this immunogenicity testing from the subjects who were allocated to this assessment at the time of enrolment. 

 
 
CLINICAL TRIAL PROTOCOL 
COVID-19: 
A Phase 3 multicenter clinical trial to evaluate the safety, reactogenicity 
and immunogenicity of the investigational SARS-CoV-2 mRNA vaccine 
CVnCoV in adults 18 years of age and above with co-morbidities 
Protocol Number: 
CV-NCOV-003 
EudraCT Number: 
2020-004070-22 
Investigational product: 
CV07050101 (referred to as CVnCoV) 
Phase: 
Phase 3 
Sponsor: 
CureVac AG 
Schumannstrasse 27 
60325 Frankfurt 
Germany 
Short Title: 
Safety, reactogenicity and immunogenicity of CVnCoV 
in adults 18 years of age and above with co-morbidities 
Protocol Version: 
2.0 
Protocol Date: 
29 March 2021 
 
PROTOCOL VERSION HISTORY: 
Version 1.0 dated 03 March 2021 
Version 2.0 dated 29 March 2021 
 
 
 
This protocol may not be reproduced or communicated to a third party without the written 
permission of CureVac AG. 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 3 of 87 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
COVID-19: A Phase 3 multicenter clinical trial to evaluate the 
safety, reactogenicity and immunogenicity of the investigational 
SARS-CoV-2 mRNA vaccine CVnCoV in adults 18 years of age 
and above with co-morbidities 
Protocol Number: CV-NCOV-003 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol, including appendices and I will conduct 
the trial as described in compliance with this protocol, GCP, and relevant ICH guidelines. 
Once the Independent Ethics Committee (IEC) has approved the protocol, 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. Assigned numbers on all electronic case report forms (eCRFs) and laboratory 
samples will identify all subjects. CureVac or its representatives or regulatory agencies 
may review clinical information. Agreement must be obtained from the subject before 
disclosure of subject information to a third party. 
CureVac to other clinical Investigators, regulatory agencies or other health authorities as 
required may disclose information developed in this clinical trial. 
Investigator Signatory 
 
 
Name 
 
Address 
 
Signature 
 
Date 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 4 of 87 
SAE hotline and medical monitor contacts 
SAE Hotline 
SAE reporting to PRA Health Sciences by fax or email within 24 hours after 
discovery: 
SAE Fax-no.: 
Email: 
Medical Monitor 
The Medical Monitor will provide 24/7 (24 hours per day and 7 days a week) on-call 
medical coverage to address trial-related questions from sites or Investigators, such as 
questions regarding eligibility requirements, the acceptability of concomitant medication 
or whether a subject should remain in the trial or needs to be discontinued. 
Name of primary 
Contact: 
 
Address: 
 
Phone: 
 
Fax: 
 
Email: 
 
 
 
 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 5 of 87 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................... 7 
LIST OF APPENDICES ............................................................................................ 7 
LIST OF ABBREVIATIONS ...................................................................................... 8 
1 
SYNOPSIS ............................................................................................................. 10 
2 
SCHEDULE OF ACTIVITIES ................................................................................. 22 
3 
INTRODUCTION .................................................................................................... 25 
3.1 
Background ................................................................................................. 25 
3.1.1 Coronaviruses ................................................................................. 25 
3.1.2 COVID-19 ........................................................................................ 25 
3.2 
Trial Rationale ............................................................................................. 26 
3.3 
Risk/Benefit Assessment............................................................................. 26 
3.3.1 Known Potential Risks ..................................................................... 26 
3.3.2 Known Potential Benefits ................................................................. 30 
3.3.3 Assessment of Potential Risks and Benefits .................................... 30 
4 
TRIAL OBJECTIVES AND ENDPOINTS ................................................................ 31 
4.1 
Objectives ................................................................................................... 31 
4.1.1 Primary ............................................................................................ 31 
4.1.2 Secondary ....................................................................................... 31 
4.1.3 Exploratory ...................................................................................... 31 
4.2 
Endpoints .................................................................................................... 31 
4.2.1 Primary ............................................................................................ 31 
4.2.2 Secondary ....................................................................................... 32 
4.2.3 Exploratory ...................................................................................... 32 
5 
TRIAL DESIGN ...................................................................................................... 34 
5.1 
Overall Design ............................................................................................ 34 
5.2 
Stopping/Pausing Rules for Safety .............................................................. 35 
5.2.1 Individual Subject Stopping Rules .................................................... 35 
5.2.2 Pausing of the Trial .......................................................................... 35 
5.3 
Scientific Rationale for Trial Design ............................................................. 36 
5.4 
Justification for Dose ................................................................................... 36 
5.5 
End of Trial Definition .................................................................................. 36 
6 
TRIAL POPULATION ............................................................................................. 37 
6.1 
Inclusion Criteria ......................................................................................... 37 
6.2 
Exclusion Criteria ........................................................................................ 38 
6.3 
Case Definitions Co-morbidities .................................................................. 39 
6.4 
Vaccine Delay Recommendations ............................................................... 41 
6.5 
Failure to Meet Eligibility Criteria ................................................................. 42 
7 
TRIAL VACCINE .................................................................................................... 43 
7.1 
Trial Vaccine Administration ........................................................................ 43 
7.1.1 Description of the Trial Vaccine ....................................................... 43 
7.1.2 Dosing and Administration ............................................................... 43 
7.2 
Preparation/Handling/Storage/Accountability .............................................. 43 
7.2.1 Preparation ...................................................................................... 43 
7.2.2 Product Storage and Stability .......................................................... 43 
7.2.3 Accountability .................................................................................. 43 
7.3 
Randomization and Blinding ........................................................................ 44 
7.4 
Vaccine Compliance ................................................................................... 44 
7.5 
Misuse and Overdose ................................................................................. 44 
7.6 
Concomitant Therapy and Vaccines ............................................................ 44 
7.7 
Therapy Leading to Discontinuation ............................................................ 44 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 6 of 87 
7.8 
Treatment After the End of Trial .................................................................. 45 
8 
DISCONTINUATION/WITHDRAWAL CRITERIA ................................................... 46 
8.1 
Discontinuation of Trial Vaccine Administration ........................................... 46 
8.2 
Withdrawal from the Trial ............................................................................ 47 
8.3 
Trial Termination ......................................................................................... 47 
8.4 
Lost to Follow-Up ........................................................................................ 48 
9 
TRIAL ASSESSMENTS AND PROCEDURES ....................................................... 49 
9.1 
Safety Assessments .................................................................................... 49 
9.1.1 Adverse Events ............................................................................... 49 
9.1.2 Pregnancies..................................................................................... 52 
9.1.3 Safety Laboratory Assessments ...................................................... 52 
9.1.4 Vital Signs, Physical Examination, and Electrocardiogram ............... 53 
9.1.5 Medical and Surgical History ........................................................... 53 
9.1.6 Safety Monitoring Committees ......................................................... 53 
9.2 
Immunogenicity Assessments ..................................................................... 54 
9.2.1 Antibody Responses to CVnCoV Vaccination (RBD of S Protein and 
Viral Neutralizing Antibodies) ...................................................................... 54 
9.2.2 Antibody Responses to SARS-CoV-2 (N Protein) ............................ 54 
9.2.3 Cell-Mediated Immunity ................................................................... 54 
9.3 
Laboratory Testing for COVID-19 ................................................................ 54 
10 STATISTICAL CONSIDERATIONS ........................................................................ 56 
10.1 
Sample Size Determination ......................................................................... 56 
10.2 
Populations for Analyses ............................................................................. 57 
10.3 
Statistical Analyses ..................................................................................... 58 
10.3.1 General Considerations ................................................................... 58 
10.3.2 Demographic, Medical History and Other Baseline Characteristics .. 58 
10.3.3 Trial Vaccine Administration ............................................................ 58 
10.3.4 Concomitant Medication and Vaccinations ...................................... 58 
10.3.5 Primary Analysis .............................................................................. 58 
10.3.6 Missing Data .................................................................................... 60 
10.3.7 Interim Analysis ............................................................................... 61 
11 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 62 
11.1. Electronic Case Report Forms .................................................................... 62 
11.2. Audit and Inspection .................................................................................... 62 
11.3. Monitoring ................................................................................................... 62 
11.4. Data Management and Coding ................................................................... 63 
12 ETHICS .................................................................................................................. 64 
12.1 
Independent Ethics Committee ................................................................... 64 
12.2 
Regulatory Authorities ................................................................................. 64 
12.3 
Ethical Conduct of the Trial ......................................................................... 64 
12.4 
Informed Consent ....................................................................................... 64 
13 DATA HANDLING AND RECORD KEEPING ......................................................... 66 
13.1 
Data Protection ........................................................................................... 66 
13.2 
Clinical Trial Report ..................................................................................... 67 
13.3 
Publication Policy ........................................................................................ 67 
14 REFERENCES....................................................................................................... 68 
15 APPENDICES ........................................................................................................ 70 
 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 7 of 87 
LIST OF TABLES 
Table 1 
Schedule of Trial Assessments and Procedures 
22 
Table 2 
Intensity Grading for Solicited Local Adverse Events 
50 
Table 3 
Intensity Grading for Solicited Systemic Adverse Events 
51 
Table 4 
Estimate of Number of Subjects Seroconverting for SARS-CoV-2 
S Protein Antibodies and 95% Credibility Interval 
56 
Table 5 
Probabilities (in %) for Assumed True Adverse Reaction Rates and for 
Assumed True Rates of Subjects with Seroconverting for SARS-CoV-2 S 
Protein Antibodies and Different Sample Sizes 
57 
Table 6 
Protocol-Required Safety Laboratory Assessments 
72 
LIST OF APPENDICES 
Appendix 1 
Responsibilities of the Investigator 
70 
Appendix 2 
Emergency Procedures 
71 
Appendix 3 
Safety Laboratory Assessments 
72 
Appendix 4 
Case Definition for COVID-19 
73 
Appendix 5 
Trial Governance Considerations 
74 
Appendix 6 
Protocol Changes 
75 
Appendix 7 
Potential Immune-Mediated Diseases 
76 
Appendix 8 
Adverse Events of Special Interest for SARS-CoV-2 Vaccines 
78 
Appendix 9 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
80 
Appendix 10 
Biological Samples and Record Retention 
87 
 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 8 of 87 
LIST OF ABBREVIATIONS 
ABPM 
Ambulatory blood pressure monitoring 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CA 
Competent authority 
CEPI 
Coalition for Epidemic Preparedness Innovations 
CI 
Credibility interval 
CMI 
Cell-mediated immunity 
CoV 
Coronavirus 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract research organization 
CVnCoV 
Investigational SARS-CoV-2 mRNA vaccine 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
estimated glomerular filtration rate 
FDA 
US Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMC 
Geometric mean concentration 
GMFC 
Geometric mean of the fold change 
GMT 
Geometric mean titer 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
hCG 
Human chorionic gonadotropin 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IL 
Interleukin 
IM 
Intramuscular(ly) 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 9 of 87 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
iSRC 
Internal safety review committee 
LLOQ 
Lower limit of quantification 
LNP 
Lipid nanoparticles 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
MET 
Metabolic equivalent threshold 
mRNA 
Messenger ribonucleic acid 
N 
Nucleocapsid 
NICE 
National Institute for Health and Care Excellence 
NYHA 
New York Heart Association 
PCR 
Polymerase chain reaction 
pIMD 
Potential immune-mediated disease 
PPI 
Per protocol immunogenicity subset 
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 
US 
United States 
VDE 
Vaccine-dependent disease enhancement 
WHO 
World Health Organization 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 10 of 87 
1 SYNOPSIS 
Name of 
Investigational 
Vaccine: 
CVnCoV 
Sponsor: 
CureVac AG 
Coordinating 
Investigator: 
 
Title of Trial: 
COVID-19: A Phase 3 multicenter clinical trial to evaluate the safety, 
reactogenicity 
and 
immunogenicity 
of 
the 
investigational 
SARS-CoV-2 mRNA vaccine CVnCoV in adults 18 years of age and 
above with co-morbidities 
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 Coronavirus Disease 2019 (COVID-19). The virus 
spread to different parts of China and an increasing number of 
countries worldwide and on 30 January 2020 the World Health 
Organization (WHO) announced the outbreak under International 
Health Regulations (IHR) as a public health emergency of 
international concern (PHEIC); the WHO's highest level of alarm. On 
12 March 2020, the WHO announced the outbreak as a pandemic.  
In view of the severity of respiratory disease caused by emerging 
coronaviruses, development of a vaccine has been undertaken by 
several pharmaceutical companies, and there are now emergency 
authorized vaccines available for prevention of COVID-19, in several 
countries worldwide. CureVac AG is developing a new SARS-CoV-2 
messenger ribonucleic acid (mRNA) vaccine formulated with lipid 
nanoparticles (referred to as CVnCoV) which is in advanced Phase 
2/3 
clinical 
development. 
The 
safety, 
reactogenicity 
and 
immunogenicity of this vaccine is being evaluated for the first time in 
humans in the dose-finding trial CV-NCOV-001 and in the dose-
confirmation trial CV-NCOV-002. The data from these trials 
confirmed the selection of the 12-µg dose level for further evaluation 
in Phase 2b and Phase 3 trials which started in December 2020. 
This current trial will be conducted to assess the safety, 
reactogenicity and immunogenicity of CVnCoV in adults 18 years of 
age and above with co-morbidities known to increase the risk for 
(severe) COVID-19, when administered as 2 doses according to a 0 
(Day 1) and 1-month (Day 29) vaccination schedule. 
Trial Duration for Each 
Subject: 
Approximately 13 months for each subject (at 
least 12 months following the last vaccination) 
Phase: 3 

Clinical Trial Protocol 
 
 
CV-NCOV-003 
CureVac AG 
V2.0 (29 March 2021) 
CONFIDENTIAL 
Page 11 of 87 
Objectives: 
All objectives will be analyzed in all subjects overall, as well as per 
underlying co-morbidity. 
Primary 
• 
To evaluate the safety and reactogenicity profile after 1 and 2 
dose administrations of CVnCoV. 
• 
To evaluate the humoral immune responses 14 days after 2 dose 
administrations of CVnCoV. 
Secondary 
• 
To evaluate the humoral immune responses after 1 and 2 dose 
administrations of CVnCoV at different time points during the 
trial. 
Exploratory 
• 
To evaluate the occurrence of laboratory-confirmed cases of 
COVID-19 after 1 and 2 doses of CVnCoV. 
• 
To evaluate the cell-mediated immune (CMI) response after 1 
and 2 dose administrations of CVnCoV in a subset of subjects. 
Overall Design: 
This is a Phase 3 open-label, single-arm trial to assess the safety, 
reactogenicity and immunogenicity of CVnCoV in an adult population 
with co-morbidities known to increase the risk for (severe) COVID-
19. The selected co-morbidities which will be investigated are 
obesity, chronic cardiovascular disease, chronic kidney disease, 
chronic 
obstructive 
pulmonary 
disease 
(COPD), 
human 
immunodeficiency virus (HIV) infection, type 2 diabetes mellitus and 
post-renal transplantation. 
Male and female subjects ≥18 years of age with 1 or more of the 
above co-morbidities will be eligible for the trial, with a life expectancy 
of at least 1 year as per the Investigator’s assessment. Eligible 
subjects at screening must have no overt clinical symptoms or signs 
of COVID-19. 
Subjects will be enrolled into 1 trial group:  
• 
CVnCoV (n = 1,200): CVnCoV 12 µg on Day 1 and Day 29.  
The CVnCoV dose level to be administered in this trial was selected 
based on data from trial CV-NCOV-001 and confirmed in trial 
CV-NCOV-002. The 12-µg dose level is currently being investigated 
in large-scale Phase 2b/3 trials in subjects 18 years of age and 
above, both in subjects in the CV-NCOV-004 “Herald” trial and also 
in health care workers in the CV-NCOV-005 trial. 
Stratification Based on Co-Morbidities 
Subjects will be stratified post-hoc into different pre-defined co-
morbidities or combinations thereof. To be eligible for the trial, 
subjects’ medical condition(s) must be controlled and stable as per 
the clinical Investigator’s judgment at the time of recruitment. For the 
purpose of enrollment in this trial, stratification of co-morbidities will 
be based on the subject’s main medical condition that increases their 
risk of severe illness from COVID-19. In some cases, subjects may 
have several high-risk co-morbidities. For these scenarios, the main 
co-morbidity as determined by the Investigator will be used for 
enrollment stratification. Data analyses, however, will take into 
consideration all pre-defined co-morbidities of interest in the trial 
population. 

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For chronic kidney disease, COPD, chronic cardiovascular disease 
and diabetes mellitus, the first 25 subjects enrolled in each co-
morbidity will be restricted to those with mild to moderate disease (as 
defined below in the section “Case definitions co-morbidities”).  
These first 25 subjects per co-morbidity will be followed up for safety 
and reactogenicity for at least 1 week after the first dose. An 
assessment of these data will be performed by CureVac’s internal 
Safety Review Committee (iSRC) and Data Safety Monitoring Board 
(DSMB) Chair overviewing the clinical development program of 
CVnCoV. After the favorable safety evaluation of CVnCoV on these 
25 subjects, subjects with more severe forms of the co-morbidity may 
be enrolled as per the Investigator’s decision. 
For obesity, HIV and renal transplant, no distinction will be made 
between the initial 25 subjects that can be enrolled and any further 
enrollments. 
As 
described 
above, 
for 
subjects 
with 
multiple 
high-risk 
co-morbidities, the subject’s main medical condition as determined 
by the Investigator will be used for enrollment stratification. A 
minimum of at least 50 subjects will be enrolled in each co-morbid 
condition with a maximum of ~200 subjects. 
Case Definitions 
Co-morbidities: 
Subjects with the following selected co-morbidities are at increased 
risk of severe illness from COVID-19 and will be included in the trial. 
Life expectancy of at least 1 year as per the Investigators’ 
assessment is required for inclusion of the subject into the trial. 
• 
Chronic kidney disease: Kidney function will be ascertained 
from a serum creatinine measurement done within the last 
6 months, converted into estimated glomerular filtration rate 
(eGFR) using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation, with impaired kidney function 
defined as eGFR <60 mL/min/1.73 m². 
o 
Mild chronic kidney disease is defined as an eGFR between 
60-89 mL/min/1.73 m2.  
o 
Moderate chronic kidney disease is defined as an eGFR 
between 31-59 mL/min/1.73 m2 with stable therapy and 
good maintenance over at least 6 months [23]. 
• 
COPD (including emphysema and chronic bronchitis). 
o 
Mild COPD with or without cough or sputum production is 
defined as forced expiratory volume in 1 second/forced vital 
capacity (FEV1/FVC) <0.7 and FEV1 ≥80% predicted.  
o 
Moderate COPD with or without cough or sputum production 
is defined as FEV1/FVC <0.7 and FEV1 ≥50%, but <80% 
predicted with stable treatment (GOLD Criteria for COPD 
severity). 
• 
Obesity with body mass index of >32 kg/m².  
• 
Chronic cardiovascular disease (heart failure, structural heart 
disorder, coronary artery disease, cardiomyopathies, arterial 
hypertension), including the following: 
o 
Heart failures (according to New York Heart Association 
[NYHA] classification [24]): 
- Class I: No limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 

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- Class II: Slight limitation of physical activity. Comfortable 
at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea (shortness of breath). 
o 
A structural heart disorder 
- without symptoms 
- with symptoms. 
o 
Coronary artery disease: 
- Mild with metabolic equivalent threshold (MET)1 <3, 
stable with medication. 
- Moderate with MET >3 – 5.9, stable with medication. 
o 
Cardiomyopathies of non-infective and metabolic origin:  
- Mild with MET <3, stable with medication. 
- Moderate with MET >3 – 5.9, stable with medication. 
o 
Hypertension (National Institute for Health and Care 
Excellence [NICE] categorization [26]): 
- Stage 1 hypertension: Clinic blood pressure ranging from 
140/90 mmHg to 159/99 mmHg and subsequent 
ambulatory blood pressure monitoring (ABPM) daytime 
average or home blood pressure monitoring (HBPM) 
average blood pressure ranging from 135/85 mmHg to 
149/94 mmHg. 
- Stage 2 hypertension: Clinic blood pressure of 
160/100 mmHg or higher but less than 180/120 mmHg 
and subsequent ABPM daytime average or HBPM 
average blood pressure of 150/95 mmHg or higher. 
• 
Chronic HIV infection with stable aviremia (<50 copies/mL) 
and CD4 count >350/mL as documented by blood samples 
taken within 12 months before enrollment. 
(Viral 
load 
<50 
copies/mL 
with 
transient 
changes 
of 
50-350 copies/mL is allowed.) 
• 
Type 2 
diabetes 
mellitus, 
controlled 
with 
medication 
[hemoglobin A1c (HbA1c) <58 mmol/mol (7.45%)]; [(HbA1c in % 
- 2.15) x 10.929 = HbA1c in mmol/mol];  
• 
Subjects with a renal transplant at least a year ago under 
stable conditions for at least 6 months with medications, 
categorized as low risk of rejection.  
Following inclusion of 25 cases of mild to moderate conditions under 
chronic kidney disease, COPD, chronic cardiovascular disease and 
diabetes mellitus, more severe conditions can be included into the 
trial upon iSRC and DSMB Chair approval and subjected to the 
clinical Investigator’s decision. 
                                                          
1  
MET is defined as the amount of oxygen consumed while sitting at rest and is equal to 3.5 mL 
O2 per kg body weight/min and is roughly equivalent to the expenditure of 1 kcal per kilogram 
of body weight per hour; 1 MET is the rate of energy expenditure while at rest. A 4 MET activity 
expends 4 times the energy used by the body at rest. Light MET is <3, moderate is 3 to 5.9 and 
vigorous is ≥6.0. MET 1 can take care of him/herself and may not maintain themselves and 
gets constraints on exertion. MET 4 can climb a flight of stairs or walk up a hill and can 
participate in other strenuous activities; >2-3 METs is fit normal person with well controlled with 
medication [25]. 

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• 
Under cardiovascular disease the following cases can be 
included:  
o 
Heart failures (according to NYHA classification [24]) Class 
III: Marked limitation of physical activity. Comfortable at rest. 
Less than ordinary activity causes fatigue, palpitation, or 
dyspnea (shortness of breath). 
o 
Coronary artery disease: Severe with MET >6, stable with 
medication. 
o 
Cardiomyopathies of non-infective and metabolic origin: 
Severe with MET >6, stable with medication. 
o 
Hypertension (NICE categorization [26]): Stage 3 or severe 
hypertension: Clinic systolic blood pressure of 180 mmHg or 
higher or clinic diastolic blood pressure of 120 mmHg or 
higher. 
• 
Under diabetes mellitus, cases of uncontrolled diabetes mellitus 
with recent HbA1c of >59 mmol/mol (7.45%) with medication can 
be included. For uncontrolled diabetes mellitus, HbA1c should be 
within <10% variation and the subject should not have any history 
of diabetic ketoacidosis or episode of severe symptomatic 
hypoglycemia within the past 3 months. 
Trial Visits/ Contacts: 
• 
10 protocol-scheduled visits on Day -7, Day 1, Day 2, Day 29, 
Day 30, Day 43, Day 57, Day 120, Day 211 and Day 393. 
• 
1 protocol-scheduled safety contact to collect diary card data on 
Day 9 for the first 25 subjects enrolled in the co-morbidities 
chronic kidney disease, COPD, chronic cardiovascular disease 
and diabetes mellitus. 
• 
2 protocol-scheduled phone contacts on Day 15 and Day 302. 
In addition, subjects will be contacted once per week to be reminded 
to report symptoms of COVID-19. 
Collection of Blood 
Samples: 
Blood samples will be taken for safety and/or immunogenicity testing 
according to the Schedule of Activities (Table 1). The total volume of 
blood taken over the trial period from each subject will be 
approximately 136 mL in the subset of subjects participating in the 
immunological assessments and the safety laboratory testing.  
For the subset of subjects in whom the CMI will be assessed, the 
maximum volume of blood for these analyses will be 12 mL. 
Safety Assessments: 
Reactogenicity will be assessed daily on each vaccination day and 
the following 7 days via collection of solicited local adverse events 
(AEs) (injection site pain, redness, swelling, and itching) and 
systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, 
nausea/vomiting, and diarrhea) using paper diary cards. In addition, 
other indicators of safety will be collected (e.g., body temperature). 
Diaries will also be used for collection of unsolicited AEs on each 
vaccination day and the following 28 days. In addition, subjects will 
be contacted by phone to verify whether they had any health 
concerns since the last visit.  
Since no control group is included in the trial, the subjects will serve 
as their own control for reactogenicity and safety assessments. For 
this purpose, the subjects will complete the pre-vaccination diary card 
on a daily basis as of Day -7 (i.e., during 1 week before the first 
vaccination) to give an indication of their normal life with 
co-morbidities. Solicited systemic AEs as well as unsolicited AEs will 

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need to be collected similar to what is done during the 7 days after 
vaccination.  
Subjects with any Grade 3 solicited or unsolicited AEs are asked to 
report this to the Investigator. Unscheduled visits will be performed 
when deemed necessary for safety assessments by the clinical 
Investigator and to ensure data integrity. 
Serious AEs (SAEs), AEs of special interest (AESIs), and AEs 
leading to vaccine withdrawal or trial discontinuation will be collected 
throughout the trial. AESIs to be monitored include potential 
immune-mediated diseases (pIMDs), AESIs for SARS-CoV-2 
vaccines, and non-serious intercurrent medical conditions that may 
affect the immune response to vaccination. 
In case of confirmed COVID-19, a disease-specific diary will be 
completed by the subject and/or the treating health care provider in 
case of hospitalization. 
Laboratory Testing for 
COVID-19: 
Subjects will be screened for any symptoms or signs of COVID-19. 
Subjects who suffered from COVID-19 within the last six months prior 
to screening will not be enrolled in the trial.  
Subjects will be contacted once per week to enquire if they have 
developed any of the following symptoms*:  
 
Fever or chills 
 
Shortness of breath or difficulty breathing 
 
New loss of taste or smell 
 
Cough 
 
Fatigue 
 
Muscle or body aches 
 
Headache 
 
Sore throat 
 
Congestion or runny nose 
 
Nausea or vomiting 
 
Abdominal pain 
 
Diarrhea  
*FDA Guidance for Industry, Development and Licensure of Vaccines to Prevent 
COVID-19, June 2020. 
During every clinic visit and phone call, subjects will be instructed and 
reminded to call the trial site should they develop any of these 
symptoms.  
If any of these symptoms are observed, the Investigator will collect 
appropriate nasopharyngeal samples as soon as feasible to do a 
rapid diagnostic antigen test on site. In case of a positive result of the 
rapid test, another specimen will be sent to the central lab for 
confirmatory reverse transcription polymerase chain reaction (RT-
PCR) to evaluate for infection with SARS-CoV-2. If the rapid test is 
negative, a specimen may be sent to the central lab at the clinical 
Investigator’s discretion. 
For positive RT-PCR tests, viral RNA of SARS-CoV-2 will be 
sequenced to identify spike (S) protein variants. 
Any subject with clinical suspicion of SARS-CoV-2 infection following 
vaccination will undergo appropriate testing and referral within the 
local healthcare system as appropriate. Subjects with confirmed 
SARS-CoV-2 infection after the first vaccine dose administration 
should only receive the second dose of CVnCoV 2 weeks after 
complete recovery and if it falls under the time window as per Table 1. 

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Planned Number of 
Subjects: 
Approximately 1,200 subjects will be enrolled. 
Criteria for Inclusion 
and Exclusion: 
Inclusion criteria: 
Subjects will be enrolled in this trial only if they meet all of the 
following criteria: 
1. Male and female subjects ≥18 years of age with 1 or more co-
morbidities as defined by the case definitions specified in the 
section “Case definitions co-morbidities”. 
2. For the co-morbidities chronic kidney disease, COPD, chronic 
cardiovascular disease and diabetes mellitus, the first 25 
subjects per co-morbidity should include only mild to moderate 
cases as described in the section “Case definitions co-
morbidities”. Thereafter, more severe conditions may be 
recruited (see the section “Overall design”) following iSRC and 
DSMB Chair approval.  
3. Subject has no overt clinical signs or symptoms of COVID-19. 
4. Subject has to sign the informed consent form (ICF) before any 
trial procedures.  
5. Subjects with a life expectancy of at least 1 year as per the 
Investigator’s assessment. 
6. Expected to be compliant with protocol procedures and available 
for clinical follow-up through the last planned visit. 
7. Physical examination without acute clinically significant findings 
according to the Investigator’s assessment.  
8. Female subjects: 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). 
Note: Women that are postmenopausal (defined as amenorrhea 
for ≥ 12 consecutive months prior to screening without an 
alternative medical cause) or permanently sterilized will be 
considered as not having reproductive potential. 
9. Female subjects of childbearing potential must use highly 
effective methods of birth control from 2 weeks before the first 
administration of the trial vaccine until 3 months following the last 
administration.  
The following methods of birth control are considered highly 
effective when used consistently and correctly:  
 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, 
intravaginal or transdermal); 
 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable); 
 
Intrauterine devices; 
 
Intrauterine hormone-releasing systems; 
 
Bilateral tubal occlusion; 
 
Vasectomized partner; 
 
Same sex relationships. 

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Sexual abstinence [periodic abstinence (e.g., calendar, ovulation 
symptothermal and post-ovulation methods)] and withdrawal are 
not acceptable methods. 
Refer to the Clinical Trial Facilitation Group recommendations on 
contraception and pregnancy testing for further details [22]. 
Exclusion criteria: 
Subjects will not be enrolled in this trial if they meet any of the 
exclusion criteria. 
1. A previous clinical and laboratory-confirmed diagnosis of COVD-
19 within the last six months prior to screening. 
2. 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. 
3. Receipt of any other vaccines within 28 days prior to enrollment 
in this trial or planned receipt of any vaccine within 28 days of trial 
vaccine administration. Planned vaccination with an inactivated 
influenza vaccine is permitted. 
4. Receipt of any investigational, authorized or licensed SARS-CoV-
2, other coronavirus vaccine or any other lipid nanoparticle (LNP) 
containing mRNA vaccine prior to the administration of the trial 
vaccine. For authorized or licensed SARS-CoV-2: planned 
administration during the trial up to 6 weeks after the foreseen 
date of second dose administration of CVnCoV. 
5. Any treatment with immunosuppressants or other immune-
modifying drugs (including, but not limited to, corticosteroids, 
biologicals, and methotrexate) for >14 days in total within 
6 months prior to the administration of the trial vaccine or planned 
use during the trial. For corticosteroid use, this means prednisone 
or equivalent, 0.5 mg/kg/day for 14 days or more. The use of 
inhaled, topical, or localized injections of corticosteroids (e.g., for 
joint pain/inflammation) is permitted. 
Note: This exclusion does not apply to the renal transplant cases 
and is at the Investigator’s discretion for subjects with other co-
morbidities (e.g., COPD). 
6. Any medically diagnosed or suspected immunosuppressive or 
immunodeficient condition based on medical history and physical 
examination, excluding the co-morbidities specified in the section 
“Case definitions co-morbidities”. 
(Subjects with chronic HIV infection with controlled Hep B 
infection with therapy or aviremic Hep C may be eligible for the 
trial, based on the Investigator’s judgment). 
7. History of immune-mediated or autoimmune disease. 
8. History of anaphylaxis or allergy to any component of CVnCoV or 
aminoglycoside antibiotics. 
9. History of or current alcohol and/or drug abuse. 
10. History of confirmed SARS or MERS disease. 
11. Administration of immunoglobulins and/or any blood products 
within the 3 months preceding the administration of any dose of 
the trial vaccine. 
12. Presence of evidence of significant uncontrolled acute or chronic 
medical or psychiatric illness, excluding the co-morbidities 
specified in the section “Case definitions co-morbidities”. 

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Significant medical or  psychiatric illnesses include but are not 
limited to: 
 
Uncontrolled respiratory disease 
 
Uncontrolled 
neurological 
disorders 
or 
Guillain-Barré 
syndrome or history of seizure, except for febrile seizures 
during childhood. 
 
Current or past malignancy, unless completely resolved 
without sequelae for >5 years. 
13. Foreseeable non-compliance with protocol, as judged by the 
Investigator. 
14. For female subjects: pregnancy or lactation. 
15. Subjects with impaired coagulation or any bleeding disorder in 
whom an intramuscular injection or a blood draw is 
contraindicated. This includes subjects on treatment with 
anticoagulants 
(e.g., 
vitamin 
K 
antagonists, 
novel 
oral 
anticoagulants, and heparin). Use of platelet aggregation 
inhibitors is not exclusionary. However, use of anticoagulants is 
accepted in certain co-morbidities according to the clinical 
Investigator’s judgment and if the INR remains ≤3. 
16. Subjects employed by the Sponsor, Investigator, or trial site, or 
relatives of research staff working on this trial. 
Endpoints: 
Primary 
Safety 
 
The frequency, intensity, and duration of solicited local AEs on 
each vaccination day and the following 7 days. 
 
The frequency, intensity, duration, and relationship to trial 
vaccination of solicited systemic AEs on each vaccination day 
and the following 7 days. 
 
The occurrence, intensity 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. 
Immunogenicity 
On Day 43: 
 
The proportion of subjects seroconverting for SARS-CoV-2 
S protein receptor-binding domain (RBD) antibodies, as 
measured by an immunoassay. 
 
Individual SARS-CoV-2 S protein RBD-specific antibody levels in 
serum, as measured an immunoassay. 
 
Geometric mean titers (GMTs) of serum SARS-CoV-2 S protein 
RBD antibodies, as measured by an immunoassay. 
 
In a subset of subjects*: the proportion of subjects seroconverting 
for SARS-CoV-2 neutralizing antibodies, as measured by an 
activity assay. 
 
In a subset of subjects*: individual SARS-CoV-2 neutralizing 
antibody levels in serum, as measured by an activity assay. 
 
In a subset of subjects*: GMTs of serum SARS-CoV-2 
neutralizing antibodies, as measured by an activity assay. 
Secondary 
On Day 29, Day 120, Day 211 and Day 393: 
 
The proportion of subjects seroconverting for SARS-CoV-2 
S protein RBD antibodies, as measured by an immunoassay. 

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 
Individual SARS-CoV-2 S protein RBD-specific antibody levels in 
serum, as measured by an immunoassay. 
 
GMTs of serum SARS-CoV-2 S protein RBD antibodies, as 
measured by an immunoassay. 
In a subset of subjects*, on Day 29 and Day 120: 
 
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, as 
measured by an activity assay. 
 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as 
measured by an activity assay. 
Exploratory 
Occurrence of confirmed COVID-19 cases 
 
Number of subjects with RT-PCR-confirmed SARS-CoV-2 
infection as measured by RT-PCR at clinically determined time 
points throughout the trial. 
 
Number of subjects with asymptomatic SARS-CoV-2 infection as 
measured by serological titers of nucleocapsid antibodies on Day 
1, Day 43, Day 120 and Day 393. 
CMI response 
On Day 1, Day 29, Day 43 and Day 120 in peripheral blood stimulated 
with antigen, in a subset of subjects*: 
 
The SARS-CoV-2 S-specific T cell response, as measured by 
cytokine and chemokine expression after antigen stimulation 
using a standardized whole blood collection and culture system. 
* The subset of subjects to participate in neutralizing activity and CMI 
response testing shall consist of approximately 25 subjects for each 
co-morbidity (up to a maximum of 175 subjects):  
 
Twelve subjects from each co-morbidity will be enrolled as part 
of the first 25 cases.  
 
The other 13 subjects will be enrolled as part of the next 
25 enrolled subjects for each co-morbidity. 
Sample Size 
Justification: 
The trial is designed to provide a reasonable precision for an estimate 
of the number of subjects seroconverting for SARS-CoV-2 S protein 
RBD-specific antibodies and an acceptable rate of Grade 3 adverse 
reactions (defined as solicited local Grade 3 AEs, and solicited 
systemic or unsolicited Grade 3 AEs considered as related to the trial 
vaccine). 
Analysis Sets: 
Immunogenicity set  
The immunogenicity set will include all subjects who received at least 
1 dose of CVnCoV and for whom the baseline blood sample and at 
least 1 additional blood sample are available for analysis.  
Safety Set 
The safety set will consist of all subjects who received at least 1 dose 
of CVnCoV and for whom any post-vaccination safety data are 
available. 
Per Protocol Immunogenicity Subset 
The Per Protocol Immunogenicity subset (PPI) will include all 
subjects who:  
 
Received both doses within the windows defined in the protocol. 
 
Have no major protocol deviations expected to impact the 
immunogenicity outcomes as specified in the statistical analysis 
plan (SAP). 

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 
Have not received medical treatments (such as blood products, 
immunoglobulin therapy) that may interfere with any of the 
proposed immunogenicity measurements. 
 
Have at least 1 blood sample collected starting at 14 days (Day 
43) post-second vaccination available for analysis. 
The PPI will be the primary analysis population for SARS-CoV-2 RBD 
of S protein antibody responses and SARS-CoV-2 viral neutralizing 
antibody responses in the subset studied. 
Statistical Analyses: 
Analysis of Demographics and Other Baseline Characteristics 
Data will be summarized with respect to demographic characteristics 
(age, gender), medical history and all safety measurements using 
descriptive statistics (quantitative data) and contingency tables 
(qualitative data). Medical history will only be listed. Subjects will be 
stratified (post-hoc) by pre-defined co-morbidities. Subjects with 
multiple co-morbidities will contribute to the different corresponding 
strata. 
Primary Safety Analyses 
Solicited AEs: 
The number and percentage of subjects with at least 1 solicited AE 
of any kind, by severity grade, for local AEs, systemic AEs, and 
overall, will be summarized, after the first vaccination and after the 
second vaccination. 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. 
Primary Immunogenicity Analysis 
The following analyses will be done for SARS-CoV-2 RBD of the 
S protein antibody concentrations and for neutralizing antibodies 
titers: 
 
Geometric mean concentrations (GMC) / GMT by group will be 
summarized with their 95% credibility interval at each blood 
sampling time point for all evaluable subjects and then separately 
in subjects seronegative at baseline and in subjects seropositive 
at baseline.  
 
The fold change from baseline will be computed for seropositive 
subjects at baseline and geometric mean of the fold change 
(GMFC) by group will be displayed with their 95% CI at each 
blood sampling time point after baseline. 

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 
The number and percentage of subjects SARS CoV-2 
seronegative at baseline for whom a seroconversion is observed 
will be summarized and presented at each blood sampling time 
point after baseline with exact 95% CI. Seroconversion is defined 
as detectable antibodies in the serum [≥ lower limit of 
quantification (LLOQ)]. 
Data will be presented after each vaccine dose.  
Missing Data/Discontinuation 
Concentration values of RBD and neutralizing antibodies marked as 
below the lower limit of quantification (LLOQ) will be set to 0.5*LLOQ.  
No imputation of missing values will be performed for any analysis 
(except the imputation for missing partial dates of AEs and 
concomitant medication).  
Currently no replacement of discontinued or withdrawn subjects is 
foreseen. This plan may be affected if an important percentage of 
subjects opt to receive any of the authorized/licensed COVID-19 
vaccines, in which case enrollment of additional subjects into this trial 
will be considered. 
 

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2 SCHEDULE OF ACTIVITIES  
Table 1 
Schedule of Trial Assessments and Procedures 
 
Screening 
Vaccination Period 
Follow-up 
End of 
Trial 
Visit Number 
1 
2 
3 
Safety 
contacta 
Phone 
contact 
4 
5 
6 
7 
8 
9 
Phone 
contact 
10 
Visit Window (days) 
-7/+0 
n/a 
-0/+0q 
-0/+7 
-2/+4 
-3/+14 
-0/+0q 
-2/+4 
-2/+4 
-2/+4 
-7/+7 
-7/+7 
-0/+30 
Trial Day 
-7 
1 
2 
9 
15 
29 
30 
43 
57 
120 
211 
302 
393 
Signed informed consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriab 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review of criteria for delay or cancellation of 
vaccinationc 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Investigational vaccine administration 
(including 1 hour observation) 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Physical examinationd 
X 
Xe 
 
 
 
X 
 
 
 
 
 
 
X 
Symptom-directed physical examination 
 
(X)e 
X 
 
 
 
X 
X 
X 
 
 
 
 
Vital signsd 
X 
Xf 
X 
 
 
Xf 
X 
X 
X 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Diary dispensation / (re)trainingg 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Diary reviewg 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Solicited AEs collected by diaryg 
Xh 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
Unsolicited AEs collected by diaryg 
Xh 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
SAEsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intercurrent medical conditionsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs leading to vaccine withdrawal or trial 
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 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Screening 
Vaccination Period 
Follow-up 
End of 
Trial 
Visit Number 
1 
2 
3 
Safety 
contacta 
Phone 
contact 
4 
5 
6 
7 
8 
9 
Phone 
contact 
10 
Visit Window (days) 
-7/+0 
n/a 
-0/+0q 
-0/+7 
-2/+4 
-3/+14 
-0/+0q 
-2/+4 
-2/+4 
-2/+4 
-7/+7 
-7/+7 
-0/+30 
Trial Day 
-7 
1 
2 
9 
15 
29 
30 
43 
57 
120 
211 
302 
393 
Safety laboratory (~8 mL)k - 50 subjects per co-
morbidity 
X 
Xo 
X 
 
 
Xo 
X 
(X)l 
X 
(X)l 
 
 
 
Serum pregnancy test (~3 mL)m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testm 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Nasopharyngeal swab collection for rapid 
diagnosis on site and PCR testingn 
(X)n 
Binding antibody to RBD of S (spike) protein of 
SARS-CoV-2 (~4mL blood) 
 
Xo 
 
 
 
Xo 
 
X 
 
X 
X 
 
X 
Binding antibody to the N (nucleocapsid) 
protein of SARS-CoV-2 (~4 mL blood) 
 
Xo 
 
 
 
 
 
X 
 
X 
 
 
X 
Subset of 25 subjects per co-morbidity: 
SARS-CoV-2 neutralizing activity (6 mL blood)p 
 
Xo 
 
 
 
Xo 
 
X 
 
X 
X 
 
X 
Subset of 25 subjects per co-morbidity: 
Cell-mediated immunity (3 mL)p 
 
Xo 
 
 
 
Xo 
 
X 
 
X 
 
 
 
Maximum total blood volume (mL) 
~8 
~25 
~8 
- 
- 
~21 
~8 
~17 
~8 
~17 
~10 
- 
~14 
Trial end 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE: adverse event; AESI: adverse event of special interest; ECG: electrocardiogram; PCR: polymerase chain reaction; RBD: receptor-binding domain; SAE: serious adverse event. 
a. The safety contact is only applicable for the first 25 subjects enrolled in the co-morbidities chronic kidney disease, COPD, chronic cardiovascular disease and diabetes mellitus to collect 
diary card data. The safety/reactogenicity data entered in the week after the first vaccination (i.e. all data recorded until Day 8 inclusively) has to be received by site and entered into EDC 
as soon as possible. The site and the subject should agree on the best way to transfer this data. It can be done via different means such as a site visit, phone call or a transfer of the diary 
to site. 
b. Procedures to establish subject eligibility will be performed within 7 days prior to trial vaccine administration along with consent collection and physical examinations and paper diary 
training. Eligibility criteria need to be reviewed on the day of vaccination prior to trial vaccine administration.  
c. See Section 6.4 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 eCRF. 
d. Physical examination and vital signs must be performed/measured by a qualified healthcare professional. See Section 9.1.4 for an overview of the required assessments. 
e. If results of a complete physical examination performed within 7 days prior to trial vaccine administration are available and sufficient in view of the protocol requirements, 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 1 hour 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. Solicited and unsolicited AEs will be recorded in diaries. Diaries will be dispensed at Visit 1, Visit 2 and Visit 4. 
h. Subjects should complete the diary card for solicited systemic AEs as well as unsolicited AEs on a daily basis as of Day -7 (i.e., during 1 week before the first vaccination) to give an 
indication of their normal life with co-morbidities. 

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i. 
SAEs, AESIs (including COVID-19), intercurrent medical conditions that may affect the immune response to vaccination, and AEs leading to vaccine withdrawal or trial discontinuation 
will be collected throughout the trial. 
j. 
Immunosuppressants or other immune-modifying drugs, with the exception of topically-applied, inhaled, or intranasal steroids, taken within 6 months prior to enrollment and any other 
medication/vaccination taken within 1 month prior to enrollment should be recorded to establish eligibility and any exception if relevant. 
k. Safety laboratory testing will be performed in the first 50 subjects enrolled and vaccinated from each co-morbidity. See Appendix 3 for an overview of the safety laboratory assessments. 
l. 
At Visit 6 and Visit 8 the safety laboratory only needs to be done if the previous result was abnormal. 
m. A blood sample for serum pregnancy testing will be taken from women of childbearing potential at screening 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. 
n. Swabs for COVID-19 testing will be collected in case the subject displays symptoms of acute respiratory infection (including, but not limited to COVID-19)  (see Section 9.3). 
o. Blood samples on Day 1 and Day 29 must be collected prior to vaccination. 
p. This will include 12 subjects for each co-morbidity condition enrolled as part of the first 25 cases and 13 subjects enrolled as part of the next 25 subjects for each co-morbidity. 
q. In case a subject cannot come to site on the day after the vaccination due to vaccination reactions/side effects it is acceptable to conduct this visit within a window of +2 days. 
 
Total blood volume taken is approximately 136 mL in the subset of subjects participating in the immunological assessments and the safety laboratory testing, separated over 10 times. 
 

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3 INTRODUCTION 
3.1 Background 
3.1.1 Coronaviruses 
Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded ribonucleic acid 
(RNA) viruses that belong to the subfamily Coronavirinae, family Coronavirdiae, order 
Nidovirales. The virion has a nucleocapsid composed of genomic RNA and 
phosphorylated nucleocapsid (N) protein, which is buried inside phospholipid bilayers and 
covered by spike (S) proteins [2]. The membrane (M) protein (a type III transmembrane 
glycoprotein) and the envelope (E) protein are located among the S proteins in the virus 
envelope. CoVs were given their name based on a characteristic crown-like appearance. 
There are 4 genera of CoVs, namely, Alphacoronavirus (αCoV), Betacoronavirus (βCoV), 
Deltacoronavirus (δCoV), and Gammacoronavirus (γCoV) [3]. Evolutionary analyses have 
shown that bats and rodents are the gene sources of most αCoVs and βCoVs, while avian 
species are the gene sources of most δCoVs and γCoVs. CoVs have repeatedly crossed 
species barriers and some have emerged as important human pathogens, causing 
generally-mild acute respiratory illnesses known as the common cold [4].  
Prior to December 2019, when clusters of pneumonia cases with unknown etiology were 
detected in Wuhan City, Hubei Province, China, only 2 additional strains of CoVs had 
caused outbreaks of severe acute respiratory disease in humans: the severe acute 
respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome 
coronavirus (MERS-CoV) in 2003 and 2012 respectively with the host jump of 
coronaviruses from bat to humans. 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 then globally. On 30 January 2020, the World Health 
Organization (WHO) announced the outbreak its highest alert under International Health 
Regulations (IHR) as a Public Health Emergency of International Concern (PHEIC), 
raising alarm for all the member states and on 12 March 2020, declared it as a pandemic.  
3.1.2 COVID-19 
SARS-CoV-2 is transmitted mainly through close contact and respiratory droplets. The 
mean incubation period is 4 to 6 days with about 95% of patients developing symptoms 
within 14 days after infection [5,6]. The most common symptoms of COVID-19 include 
fever, cough, dyspnea, and occasionally watery diarrhea. 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 [7-10]. Chemosensory dysfunction, such as anosmia and dysgeusia, 
have increasingly been reported.  
The global mortality rate is currently around 2% [11]. 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 [11]. As of 1 March 2021, according to WHO, >113.6 million cases 
have been confirmed globally, including over >2.5 million deaths [11]. 

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3.2 Trial Rationale 
In view of the severity of respiratory disease caused by emerging coronaviruses, 
development of a vaccine has been undertaken by several pharmaceutical companies, 
and there are now emergency authorized vaccines available for prevention of COVID-19, 
in several countries worldwide. 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 when administered as a 2-dose vaccination 
schedule. CVnCoV was developed with CureVac’s proprietary RNActive® technology 
platform, which uses chemically unmodified mRNA molecules as a basis for vaccination. 
The safety, reactogenicity and immunogenicity of this vaccine is being evaluated in the 
first-in-human dose-finding trial CV-NCOV-001 and in the dose-confirmation trial CV-
NCOV-002. At this time, different dose levels (2, 4, 6, 8, 12, 16 and 20 µg) have been 
tested in 250 healthy adults 18 to 60 years of age in the CV-NCOV-001 trial and the dose 
levels of 6 and 12 µg have been tested in >600 individuals 18-60 and >60 years of age in 
the CV-NCOV-002 trial. The data from the CV-NCOV-001 trial confirmed the selection of 
the 12-µg dose level for further evaluation in Phase 2b and Phase 3 trials which started in 
December 2020. A total of >6,000 subjects have received the active dose of the vaccine 
till end of February 2021. 
This trial will be conducted to assess the safety, reactogenicity and immunogenicity of 
CVnCoV in adults ≥18 years of age with co-morbidities known to increase the risk for 
(severe) COVID-19, when administered as 2 doses according to a 0 (Day 1) and 1-month 
(Day 29) vaccination schedule. The dose level to be administered in this trial was selected 
based on data from the trials CV-NCOV-001 and CV-NCOV-002. 
Please refer to the Investigator’s Brochure for details on the RNActive® technology, 
information regarding the (non-)clinical studies of the investigational CVnCoV vaccine, 
and additional information. 
3.3 Risk/Benefit Assessment 
3.3.1 Known Potential Risks 
Non-clinical studies show that CVnCoV is well tolerated in relevant animal species with no 
identified safety risks. 
 
 
 
 
 
 
 
 
 
 

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Furthermore, CureVac consulted with external regulatory and scientific experts, including 
the Coalition for Epidemic Preparedness Innovations (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 are being evaluated, as recommended by Wang and 
colleagues [20]. These approaches are in line with those agreed upon for COVID-19 
vaccine development by the International Coalition of Medicines Regulatory Authorities 
[21].  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, 
or other AE specific to SARS-CoV-2 vaccines) occurs 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 RBD of S-protein. Similarly, drugs that enhance the immune response like 
certain cytokines (IFN-α, IL-2) may increase the response to the vaccines which could 
theoretically result in increased efficacy but also in an increased risk of toxicity. 

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Risks from phlebotomy are well known and minimal. Venipuncture is a routine procedure 
the medical community commonly uses to obtain blood samples. Immediate complications 
may include slight pain during puncture of the skin and, rarely, dizziness and syncope. 
Additionally, a hematoma may result from the venipuncture, but this has minimal risk. 
Infection of the skin/soft tissue at the puncture site, vein, or blood stream can occur, but 
are very rare with venous blood draws. Subject monitoring and aseptic techniques, such 
as using sterile disposable blood collection apparatuses and adhering to standard medical 
precautions, reduce any risk to a minimum. The amount of blood to be taken for sampling 
will not be harmful to the subject’s health. 
CVnCoV has not been investigated in an adult population with co-morbidities known to 
increase the risk for (severe) COVID-19. The safety and reactogenicity as well as 
immunogenicity of CVnCoV in this population will be investigated in the current trial. 
The current trial is designed to observe if these comorbid subjects have additional risks to 
vaccination to assess risk-benefit ratio. 
3.3.2 Known Potential Benefits 
Subjects receiving the investigational CVnCoV vaccine may not directly benefit from this 
vaccination since the immune response is still being further evaluated in humans and it is 
thus not known if the vaccine is effective in protecting against COVID-19. Furthermore, no 
correlate of protection or threshold of protection has been established for COVID-19. 
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). 
3.3.3 Assessment of Potential Risks and Benefits 
To minimize the risk for subjects participating in this trial, a DSMB will oversee the safety 
of the subjects throughout the trial.  
Potential important medical risks associated with CVnCoV, as specified in Section 3.3.1, 
can be managed at the clinical trial sites, should they occur. 

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4 TRIAL OBJECTIVES AND ENDPOINTS 
4.1 Objectives 
All objectives will be analyzed in all subjects overall, as well as per underlying 
co-morbidity. 
4.1.1 Primary 
 
To evaluate the safety and reactogenicity profile after 1 and 2 dose administrations 
of CVnCoV. 
 
To evaluate the humoral immune responses 14 days after 2 dose administrations of 
CVnCoV. 
4.1.2 Secondary 
 
To evaluate the humoral immune responses after 1 and 2 dose administrations of 
CVnCoV at different time points during the trial. 
4.1.3 Exploratory 
 
To evaluate the occurrence of laboratory-confirmed cases of COVID-19 after 1 and 
2 doses of CVnCoV. 
 
To evaluate the cell-mediated immune (CMI) response after 1 and 2 dose 
administrations of CVnCoV in a subset of subjects.  
4.2 Endpoints 
Any immunogenicity samples may also be used for assay validation and additional 
studies of the mechanism of action of the vaccine. 
4.2.1 Primary 
Safety 
 
The frequency, intensity, and duration of solicited local AEs on each vaccination day 
and the following 7 days. 
 
The frequency, intensity, duration, and relationship to trial vaccination of solicited 
systemic AEs on each vaccination day and the following 7 days. 
 
The occurrence, intensity 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. 

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Immunogenicity 
On Day 43: 
 
The proportion of subjects seroconverting for SARS-CoV-2 S protein RBD 
antibodies, as measured by an immunoassay. 
 
Individual SARS-CoV-2 S protein RBD-specific antibody levels in serum, as 
measured by an immunoassay. 
 
Geometric mean titers (GMTs) of serum SARS-CoV-2 S protein RBD antibodies, as 
measured by an immunoassay. 
 
In a subset of subjects*: the proportion of subjects seroconverting for SARS-CoV-2 
neutralizing antibodies, as measured by an activity assay. 
 
In a subset of subjects*: individual SARS-CoV-2 neutralizing antibody levels in 
serum, as measured by an activity assay. 
 
In a subset of subjects*: GMTs of serum SARS-CoV-2 neutralizing antibodies, as 
measured by an activity assay. 
4.2.2 Secondary 
On Day 29, Day 120, Day 211 and Day 393: 
 
The proportion of subjects seroconverting for SARS-CoV-2 S protein RBD 
antibodies, as measured by an immunoassay. 
 
Individual SARS-CoV-2 S protein RBD-specific antibody levels in serum, as 
measured by an immunoassay. 
 
GMTs of serum SARS-CoV-2 S protein RBD antibodies, as measured by an 
immunoassay. 
In a subset of subjects*, on Day 29 and Day 120: 
 
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, as measured by an 
activity assay. 
 
GMTs of serum SARS-CoV-2 neutralizing antibodies, as measured by an activity 
assay. 
4.2.3 Exploratory 
Occurrence of confirmed COVID-19 cases 
 
Number of subjects with reverse transcription polymerase chain reaction (RT-PCR)-
confirmed SARS-CoV-2 infection as measured by RT-PCR at clinically determined 
time points throughout the trial. 
 
Number of subjects with asymptomatic SARS-CoV-2 infection as measured by 
serological titers of nucleocapsid antibodies on Day 1, Day 43, Day 120 and 
Day 393. 

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CMI response 
On Day 1, Day 29, Day 43 and Day 120 in peripheral blood stimulated with antigen in a 
subset of subjects*: 
 
The SARS-CoV-2 S-specific T cell response, as measured by cytokine and 
chemokine expression after antigen stimulation using a standardized whole blood 
collection and culture system. 
* The subset of subjects to participate in neutralizing activity and CMI response testing 
shall consist of approximately 25 subjects for each co-morbidity (up to a maximum of 
175 subjects):  
 
Twelve subjects for each co-morbidity will be enrolled as part of the first 25 cases.  
 
The other 13 subjects will be enrolled as part of the next 25 enrolled subjects for 
each co-morbidity.  

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5 TRIAL DESIGN 
5.1 Overall Design 
This is a Phase 3 open-label, single-arm trial to assess the safety, reactogenicity and 
immunogenicity of CVnCoV in an adult population with co-morbidities known to increase 
the risk for (severe) COVID-19. The selected co-morbidities which will be investigated are 
obesity, chronic cardiovascular disease, chronic kidney disease, chronic obstructive 
pulmonary disease (COPD), human immunodeficiency virus (HIV) infection, type 2 
diabetes and post-renal transplantation. 
Male and female subjects ≥18 years of age with 1 or more of the above co-morbidities will 
be eligible for the trial, with a life expectancy of at least 1 year as per the Investigator’s 
assessment. Eligible subjects at screening must have no overt clinical symptoms or signs 
of COVID-19. 
Subjects will be enrolled into 1 trial group: 
 
CVnCoV (n = 1,200): CVnCoV 12 µg on Day 1 and Day 29. 
The CVnCoV dose level to be administered in this trial was selected based on data from 
trial CV-NCOV-001 and confirmed in trial CV-NCOV-002. The 12-µg dose level is currently 
being investigated in large-scale Phase 2b/3 trials in subjects >18 years of age, both in 
subjects in the CV-NCOV-004 Herald trial and also in health care workers in the 
CV-NCOV-005 trial. 
The trial contains 10 protocol-scheduled visits and 2 protocol-scheduled phone contacts 
as detailed in Table 1. In addition, there will be a protocol-scheduled safety contact to 
collect diary card data on Day 9 for the first 25 subjects enrolled in the co-morbidities 
chronic kidney disease, COPD, chronic cardiovascular disease and diabetes mellitus (see 
below for details on the stratification). 
Stratification Based on Co-Morbidities 
Subjects will be stratified post-hoc into different pre-defined co-morbidities or 
combinations thereof. To be eligible for the trial, subjects’ medical condition(s) must be 
controlled and stable as per the Investigator’s judgment at the time of recruitment. For the 
purpose of enrollment in this trial, stratification of co-morbidities will be based on the 
subject’s main medical condition that increases their risk of severe illness from COVID-19. 
In some cases, subjects may have several high-risk co-morbidities. For these scenarios, 
the main co-morbidity as determined by the Investigator will be used for enrollment 
stratification. Data analyses, however, will take into consideration all pre-defined 
co-morbidities of interest in the trial population. 
For chronic kidney disease, COPD, chronic cardiovascular disease and diabetes mellitus, 
the first 25 subjects enrolled in each co-morbidities will be restricted to those with mild to 
moderate disease (as defined in Section 6.3).  
These first 25 subjects per co-morbidity will be followed up for safety and reactogenicity 
for at least 1 week after the first dose. An assessment of these data will be performed by 
CureVac’s internal Safety Review Committee (iSRC) and DSMB Chair overviewing the 
clinical development program of CVnCoV. Once the safety of CVnCoV has been assessed 

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in these 25 subjects and following iSRC and DSMB Chair approval, subjects with more 
severe forms of the co-morbidity may be enrolled as per the Investigator’s decision. 
For obesity, HIV and renal transplant, no distinction will be made between the initial 
25 subjects that can be enrolled and any further enrollments. As described above, for 
subjects with multiple high-risk co morbidities, the subject’s main medical condition as 
determined by the Investigator will be used for enrollment stratification. A minimum of at 
least 50 subjects will be enrolled in each co-morbidity with a maximum of ~200 subjects. 
5.2 Stopping/Pausing Rules for Safety 
5.2.1 Individual Subject 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. 
Individual subject stopping rules are met in case any of the following events occur on the 
day of vaccination or the 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: 
o 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 24 hours to Grade ≤2 
o Transient Grade 3 local AE that resolved within 24 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. 
5.2.2 Pausing of the Trial 
The decision to pause the trial (i.e., temporary stopping of enrollment and vaccinations) 
due to a safety signal will be based on a recommendation from the DSMB in consultation 
with the Sponsor (see Section 9.1.6). The DSMB may recommend pausing the trial for a 
safety concern following a review of accumulating safety data presented at the regularly 
scheduled DSMB meetings or from an ongoing review of AEs, which include but are not 
limited to, suspected unexpected serious adverse reactions (SUSARs); all SAEs judged 
as related to trial vaccine; concerning SAEs (e.g., AESIs); and all life-threatening SAEs 
and deaths. These events will be monitored by the DSMB (which is for entire COVID-19 
vaccine clinical development trials encompassing CV-NCOV-001, -002, -004, -005 
and -003) on a regular basis during the trial. The selected AEs and procedures for the 
safety review are described in detail in the DSMB Charter.  
To ensure subject safety on an ongoing basis, a listing of the AEs as described above will 
be routinely monitored by the Chair of the DSMB (or designee) at regular intervals. For 
each review, the Chair [or designee(s)] will determine whether any single event or group 
of events constitute a new safety signal. If not, the Chair will inform the Trial Team that 
there are no safety concerns. Conversely, if there is a safety concern, the Chair may 
convene an ad-hoc DSMB meeting for further assessment of the event(s). 

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An iSRC will review the AEs across the clinical trials on a weekly basis and the meeting 
minutes will be shared with the DSMB Chair. 
Based on the assessment of the benefit-risk ratio and biologic plausibility of a causal 
relationship of the AE(s) to the trial vaccine, the DSMB will make a recommendation to 
the Sponsor to either continue the trial as planned, modify its conduct, or pause the trial 
to allow further evaluation of the AE(s). If the latter, the Sponsor will make the decision to 
pause the trial in consultation with the DSMB. 
Please refer to the DSMB Charter for additional discussion of the DSMB’s role and 
responsibilities. 
5.3 Scientific Rationale for Trial Design 
This trial will evaluate the safety, reactogenicity and immunogenicity of CVnCoV in adults 
≥18 years of age with co-morbidities known to increase the risk for (severe) COVID-19. 
As this population is at higher risk of SARS-CoV-2 infection, it is critical to investigate 
CVnCoV in this population and determine if the vaccine is safe and well tolerated. While 
subjects with co-morbidities are also included in other Phase 3 trials in the program, the 
current trial will ensure investigation of CVnCoV in a trial population with very well 
characterized co-morbidities. 
The duration of the trial, allowing a 365 days of safety follow-up after the last dose for all 
subjects, to collect and evaluate safety data as needed, is considered appropriate for 
mRNA vaccines.  
5.4 Justification for Dose 
CVnCoV will be evaluated at the dose level of 12 µg, defined based on clinical data from 
the ongoing trials CV-NCOV-001 and CV-NCOV-002. Refer to the Investigator’s Brochure 
for an overview of the CVnCoV clinical and non-clinical data. 
5.5 End of Trial Definition 
A subject is considered to have completed the trial when he/she has completed all visits. 
End of Trial is defined as the point at which the last subject has completed the last visit. 

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6 TRIAL POPULATION 
The criteria for enrollment are to be followed explicitly. If it is noted that a subject who does 
not meet 1 or more of the inclusion criteria and/or meets 1 or more of the exclusion criteria 
is inadvertently enrolled and dosed, the Sponsor must be contacted immediately. 
6.1 Inclusion Criteria 
Subjects will be enrolled in this trial only if they meet all of the following criteria: 
1. Male and female subjects ≥18 years of age with 1 or more co-morbidities as defined 
by the case definitions in Section 6.3. 
2. For the co-morbidities chronic kidney disease, COPD, chronic cardiovascular disease 
and diabetes mellitus, the first 25 subjects per co-morbidity should include only mild 
to moderate cases as described in Section 6.3. Thereafter, more severe conditions 
may be recruited (see Section 5.1) following iSRC and DSMB Chair approval. 
3. Subject has no overt clinical signs or symptoms of COVID-19. 
4. Subject has to sign the informed consent form (ICF) before any trial procedures. 
5. Subjects with a life expectancy of at least 1 year as per the Investigator’s assessment. 
6. Expected to be compliant with protocol procedures and available for clinical follow-up 
through the last planned visit. 
7. Physical examination without acute clinically significant findings according to the 
Investigator’s assessment.  
8. Female subjects: 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). 
Note: Women that are postmenopausal (defined as amenorrhea for ≥ 12 consecutive 
months prior to screening without an alternative medical cause) or permanently 
sterilized will be considered as not having reproductive potential. 
9. Female subjects of childbearing potential must use highly effective methods of birth 
control from 2 weeks before the first administration of the trial vaccine until 3 months 
following the last administration. The following methods of birth control are considered 
highly effective when used consistently and correctly: 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal or transdermal); 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable or implantable); 
 
Intrauterine devices; 
 
Intrauterine hormone-releasing systems; 

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 
Bilateral tubal occlusion; 
 
Vasectomized partner; 
 
Same sex relationships. 
Sexual abstinence [periodic abstinence (e.g., calendar, ovulation, symptothermal and 
post-ovulation methods)] and withdrawal are not acceptable methods. 
Refer to the Clinical Trial Facilitation Group recommendations on contraception and 
pregnancy testing for further details [22]. 
6.2 Exclusion Criteria 
Subjects will not be enrolled in this trial if they meet any of the exclusion criteria. 
1. A previous clinical and laboratory-confirmed diagnosis of COVID-19 within the last six 
months prior to screening. 
2. 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. 
3. Receipt of any other vaccines within 28 days prior to enrollment in this trial or planned 
receipt of any vaccine within 28 days of trial vaccine administration. Planned 
vaccination with an inactivated influenza vaccine is permitted. 
4. Receipt of any investigational, authorized or licensed SARS-CoV-2, other coronavirus 
vaccine or any other LNP-containing mRNA vaccine prior to the administration of the 
trial vaccine. For authorized or licensed SARS-CoV-2: planned administration during 
the trial up to 6 weeks after the foreseen date of second dose administration of 
CVnCoV. 
5. Any treatment with immunosuppressants or other immune-modifying drugs (including, 
but not limited to, corticosteroids, biologicals, and methotrexate) for >14 days in total 
within 6 months prior to the administration of the trial vaccine or planned use during 
the trial. For corticosteroid use, this means prednisone or equivalent, 0.5 mg/kg/day 
for 14 days or more. The use of inhaled, topical, or localized injections of 
corticosteroids (e.g., for joint pain/inflammation) is permitted. 
Note: This exclusion does not apply to the renal transplant cases and is at the 
Investigator’s discretion for subjects with other co-morbidities (e.g., COPD). 
6. Any medically diagnosed or suspected immunosuppressive or immunodeficient 
condition based on medical history and physical examination, excluding the 
co-morbidities specified in Section 6.3. 
(Subjects with chronic HIV infection with controlled Hep B infection with therapy or 
aviremic Hep C may be eligible for the trial, based on the Investigator’s judgment). 
7. History of immune-mediated or autoimmune disease. 
8. History of anaphylaxis or allergy to any component of CVnCoV or aminoglycoside 
antibiotics. 

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9. History of or current alcohol and/or drug abuse. 
10. History of confirmed SARS or MERS disease  
11. Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the administration of any dose of the trial vaccine. 
12. Presence or evidence of significant uncontrolled acute or chronic medical or 
psychiatric illness, excluding the co-morbidities specified in Section 6.3. Significant 
medical or psychiatric illnesses include but are not limited to: 
 
Uncontrolled respiratory disease. 
 
Uncontrolled neurological disorders or Guillain-Barré syndrome or history of 
seizure, except for febrile seizures during childhood.  
 
Current or past malignancy, unless completely resolved without sequelae for 
>5 years. 
13. Foreseeable non-compliance with protocol, as judged by the Investigator. 
14. For female subjects: pregnancy or lactation. 
15. Subjects with impaired coagulation or any bleeding disorder in whom an intramuscular 
(IM) injection or a blood draw is contraindicated. This includes subjects on treatment 
with anticoagulants (e.g., vitamin K antagonists, novel oral anticoagulants, and 
heparin). Use of platelet aggregation inhibitors is not exclusionary. However, use of 
anticoagulants is accepted in certain co-morbidities according to the clinical 
Investigator’s judgment and if the INR remains ≤3. 
16. Subjects employed by the Sponsor, Investigator, or trial site, or relatives of research 
staff working on this trial. 
6.3 Case Definitions Co-morbidities 
Subjects with the following selected co-morbidities are at increased risk of severe illness 
from COVID-19 and will be included in the trial. Life expectancy of at least 1 year as per 
the Investigators’ assessment is required for inclusion of the subject into the trial. 
 
Chronic kidney disease: Kidney function will be ascertained from the serum 
creatinine measurement within the last 6 months, converted into estimated glomerular 
filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) 
equation, 
with 
impaired 
kidney 
function 
defined 
as 
eGFR 
<60 mL/min/1.73m². 
o Mild 
chronic 
kidney 
disease 
is 
defined 
as 
an 
eGFR 
between 
60-89 mL/min/1.73 m2. 
o Moderate chronic kidney disease is defined as an eGFR between 
31-59 mL/min/1.73 m2 with stable therapy and good maintenance over at least 
6 months [23]. 

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 
Chronic obstructive pulmonary disease (COPD) (including emphysema and 
chronic bronchitis).  
o Mild COPD with or without cough or sputum production is defined as forced 
expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <0.7 and FEV1 
≥80% predicted. 
o Moderate COPD with or without cough or sputum production is defined as 
FEV1/FVC <0.7 and FEV1≥50%, but <80% predicted with stable treatment (GOLD 
Criteria for COPD severity). 
 
Obesity with body mass index >32 kg/m². 
 
Chronic cardiovascular disease (heart failure, structural heart disorder, coronary 
artery disease, cardiomyopathies, arterial hypertension), including the following: 
o Heart failures (according to New York Heart Association [NYHA] classification 
[24]): 
- Class I: No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea (shortness of breath). 
- Class II: Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of breath). 
o A structural heart disorder 
- without symptoms 
- with symptoms. 
o Coronary artery disease: 
- Mild with metabolic equivalent threshold (MET)2 <3, stable with medication. 
- Moderate with MET >3 – 5.9, stable with medication. 
o Cardiomyopathies of non-infective and metabolic origin:  
- Mild with MET <3, stable with medication. 
- Moderate with MET >3 – 5.9, stable with medication. 
o Hypertension (National Institute for Health and Care Excellence [NICE] 
categorization [26]): 
- Stage 1 hypertension: Clinic blood pressure ranging from 140/90 mmHg to 
159/99 mmHg and subsequent ambulatory blood pressure monitoring (ABPM) 
daytime average or home blood pressure monitoring (HBPM) average blood 
pressure ranging from 135/85 mmHg to 149/94 mmHg. 
                                                          
2  
MET is defined as the amount of oxygen consumed while sitting at rest and is equal to 3.5 mL 
O2 per kg body weight/min and is roughly equivalent to the expenditure of 1 kcal per kilogram 
of body weight per hour; 1 MET is the rate of energy expenditure while at rest. A 4 MET activity 
expends 4 times the energy used by the body at rest. Light MET is <3, moderate is 3 to 5.9 and 
vigorous is ≥6.0. MET 1 can take care of him/herself and may not maintain themselves and 
gets constraints on exertion. MET 4 can climb a flight of stairs or walk up a hill and can 
participate in other strenuous activities; >2-3 METs is fit normal person with well controlled with 
medication [25]. 

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- Stage 2 hypertension: Clinic blood pressure of 160/100 mmHg or higher but 
less than 180/120 mmHg and subsequent ABPM daytime average or HBPM 
average blood pressure of 150/95 mmHg or higher. 
 
Chronic HIV infection with stable aviremia (<50 copies/mL) and CD4 count 
>350/mL as documented by blood samples taken within 12 months before enrollment. 
Viral load <50 copies/mL over 12 months with transient changes of 50-350 copies/mL 
is allowed. 
 
Type 2 diabetes mellitus, controlled with medication [HbA1c <58 mmol/mol (7.45%)]; 
[(HbA1c in % - 2.15) x 10.929 = HbA1c in mmol/mol. 
 
Subjects with a renal transplant at least a year ago under stable conditions for at 
least 6 months with medications, categorized as low risk of rejection. 
Following inclusion of 25 cases of mild to moderate conditions under chronic kidney 
disease, COPD, chronic cardiovascular disease and diabetes mellitus, more severe 
conditions can be included into the trial upon iSCR and DSMB Chair approval and 
subjected to the clinical Investigator’s decision (refer to Section 5.1 for details on the 
stratification based on co-morbidities). 
 
Under cardiovascular disease, the following cases can be included:  
o Heart failures (according to NYHA classification [24]) Class III: Marked limitation 
of physical activity. Comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea (shortness of breath). 
o Coronary artery disease: Severe with MET >6, stable with medication. 
o Cardiomyopathies of non-infective and metabolic origin: Severe with MET >6, 
stable with medication. 
o Hypertension (NICE categorization [26]): Stage 3 or severe hypertension: Clinic 
systolic blood pressure of 180 mmHg or higher or clinic diastolic blood pressure 
of 120 mmHg or higher. 
 
Under diabetes mellitus, cases of uncontrolled diabetes mellitus with recent HbA1c of 
>59 mmol/mol (7.45%) with medication can be included. For uncontrolled diabetes 
mellitus, HbA1c should be within <10% variation and the subject should not have any 
history of diabetic ketoacidosis or episode of severe symptomatic hypoglycemia within 
the past 3 months. 
6.4 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 and SARS-CoV-2 infection is either not clinically 
suspected or testing is negative) or body 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 body 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. Body 
temperature should be measured orally and by using the thermometer provided to the 
subject at Visit 1. 

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 
For subjects who develop laboratory-confirmed COVID-19 after the first dose but prior 
to receiving the second dose of CVnCoV, once the subject has recovered from 
COVID-19, the subject can be vaccinated with the second dose of CVnCoV, following 
two weeks of complete recovery if within the per protocol defined allowed time 
windows as specified in Table 1. 
 
Subjects who took antipyretic medication within 8 hours before intended trial 
vaccination (this is not applicable to the intake of low dose acetylsalicylic acid taken 
for prevention of cardiac disease). 
In case of delay, the vaccination should take place within the allowed time windows 
specified in Table 1. 
In case of any complications, the subsequent vaccination may be stopped or delayed. 
6.5 Failure to Meet Eligibility Criteria 
The Investigator must account for all subjects who sign an ICF. If the subject is found to 
be not eligible (i.e., did not meet all inclusion criteria or met one or more exclusion criteria), 
the Investigator should document this in the subject’s source data and electronic case 
report form (eCRF). 
Re-doing the full assessments for eligibility assessment as per Table 1 or re-testing (i.e., 
re-doing a single assessment) is allowed if the reason for ineligibility is a transient event.  
An example of a condition under which re-assessment may be considered includes: 
 
Subjects who required treatment for an acute illness that resolved (e.g., a urinary 
tract infection) may be re-assessed once the illness resolved or the medical problem 
stabilized. 
An example of a condition under which re-testing may be considered includes: 
 
Subjects who have clinical laboratory test value(s) that are not in line with the 
medical history and clinical evaluation of the subjects may be re-tested to confirm 
the value of the tests, if still allowed within the enrollment period (Day -7 to Day 1). 
If not feasible, the subject should be re-assessed for eligibility. 

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7 TRIAL VACCINE 
7.1 Trial Vaccine Administration 
7.1.1 Description of the Trial Vaccine 
CVnCoV is an investigational LNP-formulated RNActive® SARS-CoV-2 vaccine containing 
12 µg mRNA. The IMP is composed of the active pharmaceutical ingredient, an mRNA 
that encodes the stabilized full-length S protein, and 4 lipid components: cholesterol, 
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), PEG-ylated lipid, and a cationic lipid. 
7.1.2 Dosing and Administration 
All subjects will be administered a first vaccine dose of CVnCoV on Day 1 and a second 
vaccine dose on Day 29.  
Injections must be performed IM by needle in the deltoid area (preferably in the 
non-dominant arm). 
CVnCoV is intended strictly for IM injection and must not be injected subcutaneously, 
intradermally, or intravenously. The instruction for injection described in the trial-specific 
pharmacy manual must be followed. An intravascular injection is highly unlikely at this site 
due the lack of larger blood vessels. 
Subjects should be observed for 1 hour following each vaccination. Since there is a 
theoretical risk of anaphylactic reactions, the vaccine must only be administered if 
emergency equipment for the treatment of anaphylactic reactions (intravenous fluids, 
corticosteroids, H1 and H2 blocking agents, epinephrine, equipment for cardiopulmonary 
resuscitation) is readily available, as presented in  
1. Review and provide a signature as approval of the content of the clinical trial report (to 
be reported by the coordinating Investigator). 
Appendix 2. If anaphylaxis or severe hypersensitivity reactions occur following IMP 
administration, no further doses should be given. 
7.2 Preparation/Handling/Storage/Accountability 
7.2.1 Preparation 
Mixing of CVnCoV and 0.9% NaCl to produce dosing solutions for IM injection will occur 
according to the handling manual provided by CureVac AG.  
7.2.2 Product Storage and Stability 
CVnCoV is presented as an aqueous solution and stored below -60°C. 
7.2.3 Accountability 
It is the responsibility of the Investigator to ensure that the current and accurate records 
of trial supplies received, stored, and dispensed at the site are maintained using 
appropriate forms according to applicable regulations and guidelines. The trial supplies 
must be stored under the recommended storage conditions and locked with restricted 
access (refer to the pharmacy manual). Authorized personnel must dispense the vaccine 

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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 CVnCoV 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 
Not applicable, since this is an open-label, single-arm trial.  
7.4 Vaccine Compliance 
The Investigator will record all CVnCoV injections 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 of CVnCoV should be pursued.  

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

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8 DISCONTINUATION/WITHDRAWAL CRITERIA 
Participation in the trial is strictly voluntary. A subject has the right to withdraw from the 
trial at any time and for any reason. The Investigator has the right to withdraw a subject 
from further trial vaccine administration and/or the trial if this is considered in the subject’s 
best interest or as a result of a protocol deviation.  
For discontinuations due to an AE, every effort should be made to document the outcome 
of the event.  
Subjects who received at least 1 dose of trial vaccine will be encouraged to continue 
participation until the end of the trial for safety assessments. Assessments of solicited AEs 
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 discontinue from 
trial product administration. Blood samples for immunogenicity assessments may be taken 
at the Investigator’s discretion.  
8.1 Discontinuation of Trial Vaccine Administration 
The primary reason for discontinuation of further administrations of trial vaccine doses will 
be recorded in the subject’s eCRF according to the following categories: 
 
Consent withdrawal by the subject. 
The reason for withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(i.e., withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category). 
 
AE (including known side effects of the trial vaccine). 
If discontinuation is due to an AE possibly related to the trial vaccine or trial 
procedures, the subject must be followed up by additional examinations according to 
the medical judgment of the Investigator until the condition is resolved or the 
Investigator deems further observations or examinations to be no longer medically 
indicated. 
 
Change in the subject’s overall medical status prohibiting further participation. 
 
Pregnancy (see Section 9.1.2). 
Any subject who, despite the requirement for adequate contraception, becomes 
pregnant during the trial will not receive further trial vaccine doses. The site should 
maintain contact with the pregnant subject and complete a “Clinical Trial Pregnancy 
Form” as soon as possible. In addition, the subject should be followed up until the birth 
of the child, or spontaneous or voluntary termination. When pregnancy outcome 
information becomes available, the information should be captured using the same 
form. The subject should be reported as an IMP discontinuation and the reason (i.e., 
pregnancy) should be given. 
 
SARS-CoV-2 infection, virologically confirmed by positive RT-PCR test (as specified 
in Table 1). 
Note: Subjects who develop laboratory-confirmed COVID-19 after the first vaccine 
dose administration should only receive the second vaccine dose 2 weeks after getting 
fully recovered and if it falls under the time windows (see Section 6.4). 

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 
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. 
 
Wants to receive authorized/licensed vaccine. 
 
Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
8.2 Withdrawal from the Trial 
Subjects should be withdrawn from the trial in case any of the following situations occur: 
 
Continued participation jeopardizes the subject’s health, safety, or rights. 
 
The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is 
unwilling to continue because of the AE. The reasons for not performing further safety 
or immunogenicity assessments should be documented. 
 
The subject did not return to the trial site and multiple attempts (at least 3) to contact 
the subject were unsuccessful (lost to follow-up). 
 
The subject wishes to withdraw from the trial. The reason for withdrawal, if provided, 
should be recorded. 
All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (i.e., withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category). 
Any subject who prematurely terminates participation and who has received at least 1 trial 
vaccine dose will undergo the same procedures as for the end of trial visit, unless such 
procedures are considered to pose unacceptable risk to the subject. 
Discontinued or withdrawn subjects will not be replaced. 
8.3 Trial Termination 
The Sponsor reserves the right to terminate the trial at any time. Possible reasons for trial 
termination include the following: 
 
Safety reasons: the incidence of AEs in this or any other trial using the same or a 
related vaccine indicates a potential health risk for the subjects. 
 
New scientific knowledge becomes available 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. 

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

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9 TRIAL ASSESSMENTS AND PROCEDURES 
The Schedule of Activities is detailed in Table 1. For each procedure, subjects are to be 
assessed by the same Investigator or site personnel whenever possible. 
After each vaccination, subjects should be monitored for 1 hour at the site before 
discharge from the hospital for measurement of vital signs (see Section 9.1.4) and 
inspection of injection site. 
In case subjects are not able to come to the site for protocol-specified visits (e.g., due to 
the public health emergency related to COVID-19), safety assessments may be performed 
using alternative methods (e.g., phone contact, virtual visit, alternative location for 
assessment).  
Procedures to establish subject eligibility, recording of demographic information and 
medical history can be performed within 7 days prior to trial vaccine administration, 
i.e., spread out over more than 1 day. Eligibility criteria need to be reviewed on the day of 
vaccination prior to trial vaccine administration. However, completion of the diary card for 
baseline, before vaccination, should start only on Day -7.  
The total volume of blood taken over the trial period from each subject will be 
approximately 136 mL in the subset of subjects participating in the immunological 
assessments and the safety laboratory testing. For the subset of subjects in whom the 
CMI will be assessed, the maximum volume of blood for these analyses will be 12 mL. 
The blood volumes to be collected for each parameter are specified in Table 1. 
9.1 Safety Assessments 
9.1.1 Adverse Events 
Definitions of AEs/SAEs, procedures for recording, evaluating, follow-up, and reporting of 
AEs/SAEs/pregnancy/overdose, as well as assessments of intensity and causality of AEs, 
are provided in Appendix 9. 
Subjects with any Grade 3 solicited or unsolicited AEs are asked to immediately report 
these to the Investigator. Unscheduled visits will be performed when deemed necessary 
for safety assessments by the clinical Investigator and to ensure data integrity. 
Since no control group is included in the trial, the subjects will serve as their own control 
for reactogenicity and safety assessments. For this purpose, the subjects will complete 
the pre-vaccination diary card on a daily basis as of Day -7 (i.e., during 1 week before the 
first vaccination) to give an indication of their normal life with co-morbidities. Solicited 
systemic AEs as well as unsolicited AEs will need to be collected similar to what is done 
during the 7 days after vaccination. 
9.1.1.1 Solicited Adverse Events 
Solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, 
nausea/vomiting, and diarrhea) will be recorded from Day -7 until Day -1 using a paper 
diary. These records shall provide a baseline for reactogenicity and safety for each 
enrolled subject. 

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Solicited local AEs (injection site pain, redness, swelling, and itching) and solicited 
systemic AEs will be recorded on the days of vaccination (Day 1 and Day 29) and the 
following 7 days using a paper diary. 
Body temperature should be measured orally and by using the thermometer provided to 
the subject at Visit 1. 
Solicited AEs will be assessed on an intensity scale of absent, mild, moderate, and severe 
(Table 2 and Table 3). In case of related Grade 3 solicited or unsolicited AEs reported for 
more than 1 day in the diary, the subject will be questioned to establish the total duration 
of the AE as exactly as possible and this information will be recorded in the eCRF.  
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 solicited local AEs occurring from the time of first vaccination 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 2 
Intensity Grading for Solicited Local Adverse Events  
Adverse Event 
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 
Based on the United States Food and Drug Administration toxicity grading scale [27]. 

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Table 3 
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 activity  
2 
Moderate, some interference with activity 
3 
Significant, prevents activity 
Nausea/ 
Vomiting 
0 
Absent  
1 
Mild, no interference with activity and/or 1 – 2 episodes/ 
24 hours 
2 
Moderate, 
some 
interference 
with 
activity 
and/or 
>2 episodes/ 24 hours 
3 
Significant, prevents daily activity, requires outpatient 
intravenous hydration 
Diarrhea 
0 
Absent 
1 
2 – 3 loose stools  
2 
4 – 5 stools  
3 
6 or more watery stools/over 24 hours or requires outpatient 
intravenous hydration 
Based on the United States Food and Drug Administration toxicity grading scale [27]. 
9.1.1.2 Unsolicited Adverse Events and Serious Adverse Events 
Diaries will also be used for collection of unsolicited AEs in the week before the first 
vaccination as well as on each vaccination day and the following 28 days. In addition, 
subjects will be contacted by phone to verify whether they had any health concerns since 
the last visit. 

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The occurrence of AEs (serious and non-serious) will be assessed by non-directive 
questioning of the subject at each visit. AEs volunteered by the subject during or between 
visits in the diary or detected through observation, physical examination, laboratory tests, 
or other assessments during the entire trial, will be recorded in the eCRF, if they fall within 
the reporting period. Subjects should be instructed to report immediately any AEs with 
serious symptoms, subjective complaints or objective changes in their well-being to the 
Investigator or the site personnel, regardless of the perceived relationship between the 
event and the trial vaccine. 
The Investigator will assess the relationship between trial vaccine and each occurrence of 
AE/SAE. 
SAEs and AEs leading to vaccine withdrawal or trial discontinuation will be collected 
throughout the trial.  
9.1.1.3 Adverse Events of Special Interest 
The following events will be considered as AESIs during this trial: 
 
AEs with a suspected immune-mediated etiology (pIMDs, see Appendix 7). 
 
Other AEs relevant to SARS-CoV-2 vaccine development or the target disease (see 
Appendix 8 for the current list of AESIs and see Section 9.3 for details on laboratory 
testing for COVID-19). 
 
Non-serious intercurrent medical conditions that may affect the immune response to 
vaccination will also be collected throughout the trial. 
AESIs will be collected throughout the trial.  
9.1.2 Pregnancies 
Pregnancy is an exclusion criterion for enrollment in this trial, but subjects could potentially 
become pregnant during their active participation in this trial. Refer to Appendix 9 for 
details on the reporting and follow-up of pregnancies. 
9.1.3 Safety Laboratory Assessments 
Blood samples for determination of hematology (complete blood count, including 
differential and platelets), clinical biochemistry, and coagulation will be analyzed as 
indicated in Table 1 in the first 50 subjects enrolled and vaccinated from each co-morbidity 
condition. Blood samples on Day 1 and Day 29 must be collected prior to vaccination. 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 to establish eligibility at screening. Urine pregnancy tests will be 
performed before each vaccination, unless the serum pregnancy test was performed less 
than 3 days before and yielded a negative result. 
Laboratory data will be graded according with the United States Food and Drug 
Administration (US FDA) toxicity grading scale [27]. Any institutional normal reference 
ranges should be provided to demonstrate that they are appropriate.  
A laboratory abnormality is however only considered an AE if considered clinically 
significant in the medical and scientific judgment of the Investigator.  

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9.1.4 Vital Signs, Physical Examination, and Electrocardiogram 
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 the vaccination visits on Day 1 and Day 29, vital signs will be measured pre- 
and post-vaccination prior to discharge. Subjects will be observed for 1 hour 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.  
A complete physical examination should be performed at the time points specified in 
Table 1, except if results of a complete physical examination performed within 7 days prior 
to Day 1 are available and sufficient in view of the protocol requirements, in which case a 
symptom-directed physical examination can be performed on Day 1 prior to the vaccine 
administration. The complete physical examination will include: general appearance, 
eyes/ears/nose/throat, head/neck/thyroid, lymph node areas, cardiovascular system, 
lung/chest, abdomen, extremities and neurological examination, skin examination, and 
measurement of weight and height. At the other trial visits, a symptom-directed physical 
examination will be performed at the discretion of the Investigator. 
An electrocardiogram (ECG) with conventional 12-lead traces will be recorded at the 
screening for all subjects. Additionally, ECGs should be performed as clinically indicated. 
9.1.5 Medical and Surgical History 
All significant findings and pre-existing conditions present in a subject prior to enrollment 
must be reported on the relevant medical history/current medical conditions screen of the 
eCRF. 
Any changes in severity of the underlying condition will be monitored. Increases in severity 
meeting the definition of an SAE and considered to be related to the trial vaccine will be 
reported as a SUSAR (see Appendix 9). 
Information should be provided on medical and surgical history and concomitant medical 
conditions specifying those ongoing on Day -7. 
9.1.6 Safety Monitoring Committees 
An independent DSMB will be convened to oversee the safety of subjects participating in 
this trial. The DSMB will perform a comprehensive review of all relevant safety and 
reactogenicity data before making a decision to pause the trial (i.e., temporary stopping of 
enrollment and vaccinations) due to a safety signal in consultation with the Sponsor. 
CureVac’s Safety Review Team (SRT) also reviews the AEs reported across the 
CV-NCOV clinical trials on a weekly basis and the meeting minutes are shared with the 
DSMB Chair. 
As described in Section 5.1, for the co-morbidities chronic kidney disease, COPD, chronic 
cardiovascular disease and diabetes mellitus, the first 25 subjects per co-morbidity should 
include only mild to moderate cases. The iSRC and DSMB Chair will perform an 
assessment of the safety and reactogenicity data up to at least 1 week after the first dose, 
prior to proceding with enrollment of subjects with more severe forms of the co-morbidity 
as per the Investigator’s decision. 

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In addition, as part of the risk-benefit analysis, the DSMB will periodically monitor 
COVID-19 cases for signals of VDE (see Section 3.3.1). 
Details on the composition, objectives, and responsibilities of the DSMB, and the schedule 
and conduct of the DSMB meetings will be described in the DSMB Charter. 
9.2 Immunogenicity Assessments 
An overview of the timing of blood sample collection for immunogenicity assessment is 
provided in Table 1. Blood samples on Day 1 and Day 29 must be collected prior to 
vaccination. 
9.2.1 Antibody Responses to CVnCoV Vaccination (RBD of S Protein and 
Viral Neutralizing Antibodies) 
The immune response induced by vaccination with CVnCoV will be evaluated by 2 assays 
at the time points specified in Table 1: 
 
Binding antibodies to the SARS-CoV-2 RBD of the S protein measured in serum by 
an immunoassay for all subjects. 
 
Viral neutralizing antibodies directed against SARS-CoV-2 measured in serum by a 
functional activity assay for a subset of approximately 25 subjects per co-morbidity. 
This will include 12 subjects for each co-morbidity enrolled as part of the first 25 cases 
and 13 subjects enrolled as part of the next 25 subjects for each co-morbidity. 
9.2.2 Antibody Responses to SARS-CoV-2 (N Protein)  
Antibody responses to SARS-CoV-2 will be evaluated for all subjects by measuring the 
binding antibodies to the SARS-CoV-2 N protein (virus antigen not contained in the 
vaccine construct) at the time points specified in Table 1, and will be performed by an 
immunoassay.  
9.2.3 Cell-Mediated Immunity 
CMI will only be evaluated in approximately 25 subjects per co-morbidity at the time points 
specified in Table 1. This will include 12 subjects for each co-morbidity enrolled as part of 
the first 25 cases and 13 subjects enrolled as part of the next 25 subjects for each 
co-morbidity. 
The induction, by the vaccine, of SARS-CoV-2 S protein-specific T-cell responses after 
antigen stimulation will be measured by secretion of T cell specific cytokines and 
chemokines (including but not limited to IFN-gamma, TNF-alpha, IL-2, IFN-γ-induced 
protein 10 [IP-10], IL-4, IL-5, IL-17, IL-21) after antigen stimulation using a standardized 
whole blood collection and culture system.  
9.3 Laboratory Testing for COVID-19 
Subjects will be screened for any symptoms or signs of COVID-19. Subjects who suffered 
from COVID-19 within the last six months prior to screening will be not be enrolled into the 
trial. 

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Subjects will be contacted once per week to enquire if they developed any of the following 
symptoms*: 
 
Fever or chills 
 
Shortness of breath or difficulty breathing 
 
New loss of taste or smell 
 
Cough 
 
Fatigue 
 
Muscle or body aches 
 
Headache 
 
Sore throat 
 
Congestion or runny nose 
 
Nausea or vomiting 
 
Abdominal pain 
 
Diarrhea 
*FDA Guidance for Industry, Development and Licensure of Vaccines to Prevent COVID-19, June 
2020 [28]. 
During every clinic visit and phone call, subjects will be instructed and reminded to call the 
trial site if they develop any of these symptoms. 
If any of these symptoms are observed, the Investigator will collect appropriate 
nasopharyngeal samples as soon as feasible to do a rapid diagnostic  antigen test on site. 
In case of a positive result of the rapid test, another specimen will be sent to the central 
lab for confirmatory RT-PCR to evaluate for infection with SARS-CoV-2. If the rapid test 
is negative, a specimen may be sent to the central lab at the clinical Investigator’s 
discretion. 
For positive RT-PCR tests, viral RNA of SARS-CoV-2 will be sequenced to identify 
S protein variants. 
Any subject with clinical suspicion of SARS-CoV-2 infection following vaccination will 
undergo appropriate testing and referral within the local healthcare system as appropriate. 
Subjects with confirmed SARS-CoV-2 infection after the first vaccine dose administration 
should only receive the second dose of CVnCoV 2 weeks after complete recovery and if 
it falls within the per protocol-defined allowed time window as specified in Table 1. 
The currently available case definition for COVID-19 is provided in Appendix 4. 

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10 STATISTICAL CONSIDERATIONS 
10.1 Sample Size Determination 
The sample size of the trial ensures that sufficient safety and immunogenicity data will be 
available in a population with co-morbidities. We aim to enroll 1,200 subjects. 
The trial is designed to provide a reasonable precision for an estimate of the number of 
subjects seroconverting for SARS-CoV-2 S protein RBD-specific antibodies and an 
acceptable rate of Grade 3 adverse reactions (defined as solicited local Grade 3 AEs, and 
solicited systemic or unsolicited Grade 3 AEs considered as related to the trial vaccine). 
Table 4 provides the estimate and 95% credibility interval (CI) for the observed numbers 
of subjects seroconverting for SARS-CoV-2 S protein antibodies for sample sizes of 150 
(providing characteristics for a pre-defined co-morbidity) and 1,200 assuming a Beta (1.9, 
0.1) priors for seroconversion for SARS-CoV-2 S protein antibodies and Beta (0.5, 1.5) 
priors for Grade 3 adverse reactions are assumed. 
Table 4 
Estimate of Number of Subjects Seroconverting for SARS-CoV-2 
S Protein Antibodies and 95% Credibility Interval 
Rate (%) 
Sample Size 
150 
1200 
N 
95% CI 
N 
95% CI 
80 
120 
80.2 (73.5 - 86.1) 
960 
80 (77.7 - 82.2) 
85 
128 
85.5 (79.5 - 90.6) 
1020 
85 (82.9 - 87) 
90 
135 
90.1 (84.9 - 94.3) 
1080 
90 (88.3 - 91.6) 
95 
142 
94.7 (90.6 - 97.6) 
1140 
95 (93.7 - 96.2) 
100 
150 
99.9 (99.4 - 100) 
1200 
100 (99.9 - 100) 
CI: credibility interval; N: subjects seroconverting for SARS-CoV-2 S protein antibodies 
Table 5 provides probabilities (in %) that the following 2 conditions are simultaneously met 
for assumed true adverse reaction rates and for assumed true rates of subjects 
seroconverting for SARS-CoV-2 S protein antibodies and for different sample sizes: 
 
There is a ≥80% probability that the true rate of Grade 3 adverse reactions is ≤33%, 
and 
 
There is a ≥90% probability that the true rate of subjects seroconverting for 
SARS-CoV-2 S protein antibodies is >95%. 
For example, assuming a true adverse reaction rate of 20% and a true rate of subjects 
seroconverting for SARS-CoV-2 S protein antibodies of 97.5%, the 2 conditions are met 
with a probability of 68% and 100% sample sizes of 150 and 1,200 respectively. 

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Table 5 
Probabilities (in %) for Assumed True Adverse Reaction Rates and for 
Assumed 
True 
Rates 
of 
Subjects 
with 
Seroconverting 
for 
SARS-CoV-2 S Protein Antibodies and Different Sample Sizes 
True 
adverse 
reaction 
rate (%) 
Sample Size 
150 
1200 
True rate of subjects with 
seroconverting for SARS-CoV-2 
S protein antibodies (%) 
True rate of subjects with 
seroconverting for SARS-CoV-2 
S protein antibodies (%) 
95 
97.5 
100 
95 
97.5 
100 
5 
13 
68 
100 
10 
100 
100 
10 
13 
68 
100 
10 
100 
100 
15 
13 
68 
100 
11 
100 
100 
20 
13 
68 
100 
10 
100 
100 
25 
11 
61 
91 
10 
100 
100 
30 
6 
32 
47 
10 
92 
92 
35 
1 
6 
8 
0 
1 
1 
10.2 Populations for Analyses 
Immunogenicity set 
The immunogenicity set will include all subjects who received at least 1 dose of CVnCoV 
and for whom the baseline blood sample and at least 1 additional blood sample are 
available for analysis.  
Safety Set 
The safety set will consist of all subjects who received at least 1 dose of CVnCoV and for 
whom any post-vaccination safety data are available. 
Per Protocol Immunogenicity Subset 
The Per Protocol Immunogenicity subset (PPI) will include all subjects who: 
 
Received both doses within the windows defined in the protocol. 
 
Have no major protocol deviations expected to impact the immunogenicity outcomes 
as specified in the statistical analysis plan (SAP). 
 
Have not received medical treatments (such as blood products, immunoglobulin 
therapy) that may interfere with any of the proposed immunogenicity measurements. 
 
Have at least 1 blood sample collected starting at 14 days (Day 43) post-second 
vaccination available for analysis. 
The PPI will be the primary analysis population for SARS-CoV-2 RBD of S protein antibody 
responses and SARS-CoV-2 viral neutralizing antibody responses in the subset studied. 

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10.3 Statistical Analyses 
10.3.1 General Considerations 
All data obtained in this trial and documented in the eCRF will be listed and summarized 
with sample statistics or frequency tables as appropriate. The safety and immunogenicity 
analyses will be done overall. 
An 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. 
Subjects will be stratified post-hoc by pre-defined co-morbidities. Subjects with multiple 
co-morbidities will contribute to the different corresponding strata. 
Data from this trial may be pooled with data from potential follow-up trials. 
10.3.2 Demographic, Medical History and Other Baseline Characteristics 
Data will be summarized with respect to demographic characteristics (age, gender), 
medical history, and all safety measurements using descriptive statistics (quantitative 
data) and contingency tables (qualitative data). Medical history will only be listed. 
10.3.3 Trial Vaccine Administration 
The administrations of CVnCoV will be listed and the number of vaccinations will be 
summarized in contingency tables. 
10.3.4 Concomitant Medication and Vaccinations 
Concomitant medication/vaccination after the start of the trial vaccine will be listed and 
summarized by Anatomical Therapeutic Chemical term in contingency tables.  
10.3.5 Primary Analysis 
10.3.5.1 
Primary Safety Analysis 
The safety measurements will include: 
2. AEs (type, intensity, frequency and relationship to trial vaccination), i.e., incidence and 
severity of AEs for both solicited local (injection site pain, redness, swelling, and 
itching) and solicited systemic events (fever, headache, fatigue, chills, myalgia, 
arthralgia, nausea/vomiting, and diarrhea) occurring on the day of vaccination and the 
following 7 days, and unsolicited events (occurring on the day of vaccination and the 
following 28 days). 
3. SAEs and AESIs throughout the trial. 
Solicited AEs: For reactogenicity assessment, 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 and after the second vaccination. 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 

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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% 
CI based on the Beta (0.5, 0.5) prior distribution 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. Additional similar tabulations will be performed 
to evaluate severity and relationship to the trial vaccine. AEs that are reported as related 
to the trial vaccine will be considered trial vaccine-related; missing classifications 
concerning trial vaccine relationship will also be considered trial vaccine-related. 
Safety laboratory values will be classified into low/normal/high based on laboratory normal 
ranges. Each parameter will be presented by descriptive statistics at each visit including 
change from baseline. Shift tables with 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 and a listing will be provided. 
10.3.5.2 
Primary Immunogenicity Analysis 
No formal hypothesis on immunogenicity will be tested. Descriptive statistics for the 
immunogenicity endpoints will be provided. 
The following analyses will be done for SARS-CoV-2 RBD of the S protein antibody 
concentrations and for neutralizing antibodies titers: 
 
Geometric mean concentrations (GMC) / GMT by group will be summarized with their 
95% CI at each blood sampling time point for all evaluable subjects and then 
separately in subjects seronegative at baseline and in subjects seropositive at 
baseline.  
 
The fold change from baseline will be computed for seropositive subjects at baseline 
and geometric mean of the fold change (GMFC) by group will be displayed with their 
95% CI at each blood sampling time point after baseline. 
 
The number and percentage of subjects SARS-CoV-2 seronegative at baseline for 
whom a seroconversion is observed will be summarized and presented at each blood 
sampling time point after baseline with exact 95% CI. Seroconversion is defined as 
detectable antibodies in the serum [≥ lower limit of quantification (LLOQ)]. 
Concentrations/titers marked as below the LLOQ will be arbitrary replaced by half of the 
LLOQ for GMC/GMT and GMFC computations purpose. 
The analyses of CMI in terms of induction by the vaccine of SARS-CoV-2 S protein-
specific T-cell responses will be detailed in the SAP.  
Additional immunogenicity analyses including graphs will be described in the SAP as 
applicable. 

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10.3.6 Missing Data 
Analysis of vaccination variables will be done on a valid case basis, i.e., for missing 
observations, no imputation for missing data, such as last observation carried forward, will 
be applied. For the RBD and neutralizing 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 discontinued or withdrawn subjects is foreseen. This plan 
may be affected if an important percentage of subjects opt to receive any of the 
authorized/licensed COVID-19 vaccines, in which case an enrollment of additional 
subjects into this trial will be considered. 
For safety data, some missing or partially missing variables will be imputed as follows:  
For start date: 
 If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is 
set to missing. 
 If the AE start date year value is less than the vaccination start date year value, the AE 
started before the vaccination. Therefore: 
o 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). 
o 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. 

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10.3.7 Interim Analysis 
One or more interim analyses may be performed for this trial. The analyses will be based 
on a data snapshot. As this trial is of exploratory nature and no inferential statistics are 
planned, no adjustment for multiple testing will be done. Depending on the evolving state 
of the current pandemic and the public health need, an early analysis may be performed, 
and a study report based on interim data may be written to engage with collaborators 
and/or regulators. 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. Electronic Case Report Forms 
In this trial, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications/vaccines, medical history, and physical assessments) will be entered onto 
eCRFs in a timely fashion by the Investigator and/or the Investigator’s dedicated site staff. 
All data entered into the eCRF must be verifiable against source documents at the trial 
site. Any changes to the data entered into the electronic data capture system will be 
recorded in the audit trail. 
The Investigator will maintain adequate and accurate records for each subject entered into 
the trial. Source documents such as hospital, clinic or office charts, laboratory reports, trial 
worksheets, and signed informed consent documents are to be included in the 
Investigator’s files along with subject trial records. 
The Sponsor or the contract research organization (CRO), as presented in Appendix 5, 
will check eCRF entries against source documents according to the guidelines of Good 
Clinical Practice (GCP). The ICF will include a statement by which subjects allow the 
Sponsor or designee, as well as authorized regulatory agencies, to have direct access to 
source data that support data of the eCRF (e.g., subject medical files, appointment books, 
original laboratory records, etc.). The Sponsor or designee, bound by secrecy, will not 
disclose subject identities or personal medical information. 
11.2. Audit and Inspection 
The trial site also may be subject to quality assurance audits by the Sponsor or designees. 
In this circumstance, the Sponsor-designated auditor will contact the site in advance to 
arrange an auditing visit. The auditor may ask to visit the facilities where laboratory 
samples are collected, where the vaccine is stored and prepared, and any other facility 
used during the trial. In addition, there is the possibility that this trial may be inspected by 
regulatory agencies, including those of local (European Union member state local or 
competent authorities) or foreign governments (e.g., US FDA and others). If the trial site 
is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The Investigator and institution guarantee direct access for quality assurance 
auditors and inspectors to all trial documents and source data. 
11.3. Monitoring 
Data for each subject will be recorded in the subject’s eCRF. Data collection must be 
completed for each subject who signs an ICF. For subjects who failed to meet the eligibility 
criteria, only demographic data and reason for failure will be documented. 
In accordance with GCP, and regulatory requirements, the trial monitor will perform source 
document verification at regular intervals to ensure that the data collected in the eCRF are 
accurate and reliable. The frequency of monitoring visits will be determined by the rate of 
subject recruitment following the local guidelines. 
The compliance with the protocol will be examined with regard to inclusion and exclusion 
criteria, therapies leading to elimination and timing and availability of planned 
assessments. Protocol deviations will be monitored on an ongoing basis during the trial 

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

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12 ETHICS 
12.1 Independent Ethics Committee 
Before initiation of the trial at the trial site, the protocol, the ICF, other written material 
given to the subjects, and any other relevant trial documentation will be submitted to the 
appropriate IEC. Written approval of the trial and all relevant trial information must be 
obtained before the trial vaccine is released to the Investigators. Any necessary 
extensions or renewals of IEC approval must be obtained for changes to the trial such as 
modification of the protocol, the ICF, or other trial documentation. The written approval of 
the IEC together with the approved ICF must be filed in the trial files. 
The Investigators will report promptly to the IEC any new information that may adversely 
affect the safety of the subjects or the conduct of the trial. The Investigators will submit 
written summaries of the trial status to the IEC as required. On completion of the trial, the 
IEC will be notified that the trial has ended. 
12.2 Regulatory Authorities 
The protocol, name and trial site of the Investigators, the votes of the IEC(s), as well as 
other relevant trial documentation will be submitted to the regulatory authority(ies) of the 
participating country/ies, according to local/national requirements, for review and approval 
before the beginning of the trial. 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. Any changes to the approved version of this protocol 
will require formal approvals by the IEC(s), as specified in Appendix 6. 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.  
The responsibilities of the Investigators are further described in Appendix 1. 
12.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 

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The Investigators are responsible for ensuring that no subject undergoes any trial-related 
examination or activity before that subject has given written informed consent to 
participate in the trial.  
The Investigator or designated personnel will inform the subject of the objectives, 
methods, anticipated benefits, and potential risks and inconveniences of the trial. The 
subject should be given every opportunity to ask for clarification of any points he/she does 
not understand and if necessary, ask for more information. At the end of the interview, the 
subject will be given ample time to consider the trial. Subjects will be required to sign and 
date the ICF. After signatures are obtained, the ICF will be kept and archived by the 
Investigator in the Investigator’s trial file. A signed and dated copy of the subject ICF will 
be provided to the subject or his/her authorized representative. 
It should be emphasized to the subject that the participation in the trial is voluntary and 
the subject may refuse to participate or discontinued from the trial at any time, without 
consequences for his/her further care or penalty or loss of benefits to which the subject is 
otherwise entitled. Subjects who refuse to give or who withdraw written informed consent 
should not be included or continue in the trial. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial, a new ICF will be approved by the IECs (and regulatory 
authorities if required). The trial subjects will be informed about this new information and 
re-consent will be obtained. 

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13 DATA HANDLING AND RECORD KEEPING 
Essential documents are those documents that individually and collectively permit 
evaluation of the trial and quality of the data produced. After completion of the trial, all 
documents and data relating to the trial will be kept in an orderly manner by the 
Investigator in a secure trial file. This file will be available for audits by the Sponsor/CRO 
or inspections by the regulatory agencies. Essential documents should be retained for 
15 years after end of the trial. It is the responsibility of the Sponsor to inform the trial site 
of when these documents no longer need to be retained. The Investigator must contact 
the Sponsor before destroying any trial-related documentation. In addition, all subject 
medical records and other source documentation will be kept for the maximum time 
required by the hospital, institution, or medical practice and in accordance with the national 
requirements. If an Investigator moves, withdraws from the trial, or retires, the 
responsibility for maintaining the records may be transferred to another person who will 
accept responsibility. Notice of transfer must be made to and agreed by the Sponsor. 
Biological samples and record retention are described in Appendix 10. 
In this trial, processing of personal data will be carried out on behalf of the Sponsor by a 
CRO (i.e., acting as a data processor), governed by a contract and strictly according to 
and subject to the General Data Protection Regulation (GDPR) and any applicable data 
protection rules and regulations. The Sponsor and the CRO (data processor) will 
implement appropriate technical and organizational measures to ensure a level of security 
appropriate to the risk, taking into account the state of the art, the costs of implementation, 
and the nature, scope, context, and purposes of processing as well as the risk of varying 
likelihood and severity for the rights and freedoms of the subjects. Quality control will occur 
at each stage of data handling to ensure that all data are reliable and have been processed 
correctly. The Sponsor will ensure oversight of any trial-related duties and functions 
carried out on its behalf, including trial-related duties and functions that are subcontracted 
to another party by the CRO. 
This trial will be registered on ClinicalTrials.gov in accordance with applicable laws or 
publication policy and may also be registered on other publicly accessible websites as 
necessary. 
13.1 Data Protection 
All information generated in this trial is considered highly confidential and must not be 
disclosed to any person or entity not directly involved in the trial unless prior written 
consent is gained from the Sponsor. However, authorized regulatory officials, IEC 
personnel, the Sponsor and its authorized representatives are allowed full access to the 
records. All personal details will be treated as confidential by the Investigator and staff at 
the CRO. Prior to the processing, the Sponsor performs an assessment of the impact of 
the envisaged processing operations on the protection of personal data (according to 
Article 35 of GDPR). 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. All 
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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). 
The subject must be informed that his/her personal trial-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject who will be required to give consent for their data to be used as 
described in the ICF. The subject must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.  
Subjects may request their medical information be given to their personal physician or 
other appropriate medical personnel responsible for their welfare. 
13.2 Clinical Trial Report 
The Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with the clinical trial report according to the applicable regulatory requirements. 
The Sponsor will ensure that this report meets the standards of the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). 
13.3 Publication Policy 
Any publication or scientific communication related to this trial can only take place once 
the manuscript has been reviewed by the Sponsor and once a written agreement between 
the Sponsor and the Investigators has been reached. The Sponsor will comply with the 
requirements for publication of trial results. In accordance with standard editorial and 
ethical practice, the Sponsor will generally support publication of multicenter trials only in 
their entirety and not as individual site data. In this case, a Coordinating Investigator will 
be designated by mutual agreement. Authorship will be determined by mutual agreement 
and in line with International Committee of Medical Journal Editors authorship 
requirements. 

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14 REFERENCES 
1. ICH Guidelines. Available at: https://www.ich.org/page/efficacy-guidelines. Accessed 
10 July 2020. 
2. Li G, Fan Y, Lai Y, et al. Coronavirus Infections and Immune Responses. J Med Virol. 
2020 Jan 25. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25685 
3. Chan JF, Kok KH, Zhu Z, et al. Genomic characterization of the 2019 novel human-
pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting 
Wuhan. Emerg Microbes Infect. 2020 Dec;9(1):221-236. 
4. Wu P, Hao X, Lau EHY, et al. Real-time tentative assessment of the epidemiological 
characteristics of novel coronavirus infections in Wuhan, China, as at 22 January 
2020. 
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Surveill. 
2020 
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content/10.2807/1560-7917.ES.2020.25.3.2000044#r11 
5. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 
(COVID-19) from publicly reported confirmed cases: Estimation and application. Ann 
Intern Med. 2020 Mar 10. 
6. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection 
in China. New England Journal of Medicine. 2020 Feb 28. 
7. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with 
Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Apr 10. 
8. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-
19 and other coronaviruses. Brain Behav Immun. 2020 Mar 30. 
9. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. Journal of the 
European Academy of Dermatology and Venereology. [cited 2020 Apr 16]; 
https://onlinelibrary.wiley.com/doi/abs/10.1111/jdv.16387 
10. Atri D, Siddiqi HK, Lang J, et al. COVID-19 for the cardiologist: A current review of the 
virology, clinical epidemiology, cardiac and other clinical manifestations and potential 
therapeutic strategies. JACC Basic Transl Sci. 2020 Apr 10. 
11. WHO Coronavirus disease (COVID-19) WHO Health Emergency Dashboard – 
1 March 2021. https://covid19.who.int 
12. 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. 
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9789240005105-eng.pdf 
13. 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. 
14. 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. 
15. Hong HS, Koch SD, Scheel B, et al. Distinct transcriptional changes in non-small cell 
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multi-antigenic 
RNActive® 
CV9201 
immunotherapy. 
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2016;5(12):e1249560. 
doi:10.1080/2162402X.2016.1249560. 

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16. Rausch S, Schwentner C, Stenzl A, et al. mRNA vaccine CV9103 and CV9104 for the 
treatment of prostate cancer. Hum Vaccin Immunother. 2014;10(11):3146-52. 
17. 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. 
18. 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. 
19. 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 
20. 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. 
21. 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. 
22. 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 
23. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney 
disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002; 39(2 
Suppl 1):S1-266. 
24. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed Little, Brown & Co; 
Boston, Mass: 1994. pp. 253–256. 
25. Weinstein AS, Sigurdsson MI, Bader AM. Comparison of Preoperative Assessment of 
Patient's Metabolic Equivalents (METs) Estimated from History versus Measured by 
Exercise Cardiac Stress Testing. Anesthesiol Res Pract. 2018:5912726. doi: 
10.1155/2018/5912726. eCollection 2018. 
26. National Institute for Health and Care Excellence (2019) Hypertension in adults: 
diagnosis 
and 
management 
NG136. 
Available 
at: 
https://www.nice.org.uk/guidance/ng136 Accessed 2 March 2021. 
27. US Department of Health and Human Services. Food and Drug Administration (FDA). 
Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 2007. [Available from: 
https://www.fda.gov/media/73679/download; Accessed 14 July 2020]. 
28. US Department of Health and Human Services. Food and Drug Administration (FDA). 
Guidance for Industry. Development and Licensure of Vaccines to Prevent COVID-19. 
2020. 
[Available 
from: 
https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/development-and-licensure-vaccines-prevent-covid-19; 
Accessed March 2021]. 

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15 APPENDICES 
Appendix 1 
Responsibilities of the Investigator 
Clinical research trials 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 (to 
be reported by the coordinating Investigator). 

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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 6 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 6 
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 
Case Definition for COVID-19 
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 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 5 
Trial Governance Considerations 
CureVac AG is the Sponsor of this trial. PRA Health Sciences is the CRO appointed to 
coordinate the conduct of this trial. 

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Appendix 6 
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 7 
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 Morphea  
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 immunoglobulin A 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 8 
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 
o Subacute thyroiditis 
Respiratory disorders: 
o Acute respiratory distress syndrome 
o COVID-19 
Cardiac disorders: 
Acute cardiac injury including: 
o Microangiopathy 
o Heart failure and cardiogenic shock 
o Stress cardiomyopathy 
o Coronary artery disease 
o Arrhythmia 
o Myocarditis, pericarditis 
Hematological disorders:  
o Thrombocytopenia 
Coagulation disorder: 
o Deep vein thrombosis 
o Pulmonary embolus 
o Cerebrovascular stroke 
o Limb ischemia 
o Hemorrhagic disease 
Renal disorders: 
o Acute kidney injury 
Gastrointestinal disorders 
o Liver injury 
o Pancreatitis 
Neurological disorders:  
o Generalized convulsion 
o Guillain-Barré Syndrome 
o Acute disseminated encephalomyelitis 
o Anosmia, ageusia 
o Meningoencephalitis 
Dermatologic disorder: 
o Chilblain-like lesions 
o Single organ cutaneous vasculitis 
o Erythema multiforme 

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Other: 
o Serious local/systemic adverse reaction following immunization 
o Rhabdomyolysis 
** These are generally the conditions one encounters in normal subjects as AESI, but in this trial we use comorbid subjects 
and some of them may have coronary disease, arrhythmias or myocarditis to start with. 

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Appendix 9 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of an Adverse Event (AE) 
Definition of an AE: 
 
An AE is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. 
 
An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
 
All AEs fall into 1 of 2 categories: “non-serious” or “serious”. 
Examples of an AE include: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., not related 
to a known concomitant disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after administration of the trial vaccine even 
though it may have been present before the start of the trial. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either trial 
vaccine or a concomitant medication/vaccination. 
 
An adverse effect of the trial vaccine or concomitant medication/vaccination. 
 
An accident or injury. 
Events NOT Meeting the AE Definition: 
 
Medical or surgical procedures or other therapeutic interventions themselves are 
not AEs, but the condition for which the surgery/intervention is required is an AE 
and should be documented accordingly. 
 
Planned surgical measures and the condition(s) leading to these measures are not 
AEs, if the condition(s) was (were) known before the period of observation (see 
below) and did not worsen during trial. 
 
In the latter case the condition should be reported as medical history. 
 
Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the trial that do not worsen. 
Death is not considered an AE but an outcome. 

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

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Assessment of Intensity and Causality 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the trial and assign it to one of the following categories [27]. 
Absent (Grade 0): No AE. 
Mild (Grade 1): An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate (Grade 2): An event that causes sufficient discomfort to interfere with normal 
everyday activities. 
Severe (Grade 3): An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe. 
 
Assessment of Causality 
 
The Investigator is obligated to assess the relationship between the trial vaccine 
and each occurrence of each AE/SAE. Causality will be determined as: 
 
Related: There is a reasonable causal relationship between the trial vaccine 
and the AE. 
 
Unrelated: There is no reasonable causal relationship between the trial vaccine 
and the AE. 
 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
 
The Investigator will use clinical judgment to determine the relationship. Alternative 
causes, such as underlying disease(s), concomitant therapy or vaccination, and 
other risk factors, as well as the temporal relationship of the event to the trial 
vaccine administration will be considered and investigated. 
 
The Investigator will also consult the Investigator’s Brochure for CVnCoV in his/her 
assessment. 
 
For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the CRO. However, it is very 
important that the Investigator always makes an assessment of causality for 
every event before the initial transmission of the SAE data to the CRO. 
 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
All local solicited symptoms are considered related to vaccination. 

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

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

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

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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 10 
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.