Clinical trial NCT04674189
Conditions: Coronavirus Covid19 SARS-CoV-2 Severe Acute Respiratory Syndrome
Keywords: Vaccine SARS COVID Safety Immunogenicity
Sponsor: CureVac
Start date: 2020-12-23; Completion date: 2022-06-08
Enrollment: 2357 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to evaluate the safety (in all participants) and reactogenicity (in a subset of participants) of CVnCoV administered as a 2-dose schedule to adult participants 18 years of age or older. The study also aims to assess antibody responses to the receptor-binding domain (RBD) of spike (S) protein of SARS-CoV-2 after 1 and 2 doses of CVnCoV in adults 18 years of age or older included in a subset of participants.

Detailed description:

Arms: arm 1: Participants in Group 1 will be vaccinated with CVnCoV 12 µg mRNA on Day 1 and Day 29 in the deltoid area, preferably in the non-dominant arm. arm 2: Participants in Group 2 will be vaccinated with CVnCoV 12 µg mRNA on Day 1 and Day 29 in the deltoid area, preferably in the non-dominant arm. arm 3: Participants will receive a placebo on Day 1 and Day 29 in the deltoid area, preferably in the non-dominant arm.
Interventions: intervention 1: CVnCoV Vaccine intervention 2: Placebo
Intervention descriptions: intervention 1: Intramuscular injection intervention 2: Intramuscular injection

Protocol documents:
Prot_000.pdf: 
Protocol Number: CV-NCOV-005 
 
Official Title: COVID-19: A Phase 3, Randomized, Observer-Blinded, Placebo-Controlled Clinical 
Study Evaluating the Safety and Immunogenicity of Investigational SARS-CoV-2 mRNA Vaccine 
CVnCoV in Adult Health Care Workers in Mainz (Germany) 
NCT Number: NCT04674189 
 
Document Date: 22 December 2021 


Clinical Trial Protocol
CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
 CONFIDENTIAL
Page 1 of 132
CLINICAL TRIAL PROTOCOL
 
COVID-19:
A Phase 3, Randomized, Observer-Blinded, Placebo-Controlled Clinical Study
Evaluating the Safety and Immunogenicity of Investigational SARS-CoV-2 mRNA
Vaccine CVnCoV in Adult Health Care Workers in Mainz (Germany)
Protocol Number:
CV-NCOV-005
EudraCT Number:
2020-004066-19
Investigational Product:
CV07050101 (referred to as CVnCoV)
Phase:
Phase 3
Sponsor:
CureVac AG
Schumannstrasse 27
60325 Frankfurt
Germany
Short Title:
Immunogenicity and Safety of CVnCoV in Adults
Protocol Version:
5.0
Protocol Date:
22  December 2021
PROTOCOL VERSION HISTORY:
Version 1.0 dated 19 November 2020
Version 2.0 dated 19 March 2021
Version 3.0 dated 23 July 2021
Version 4.0 dated 11 August 2021
This protocol may not be reproduced or communicated to a third party without the written
permission of CureVac AG.


Clinical Trial Protocol
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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
 CONFIDENTIAL
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PROTOCOL APPROVAL SIGNATURES
Protocol Title:
COVID-19: 
A 
Phase 
3, 
Randomized, 
Observer-Blinded,
Placebo-Controlled 
Clinical 
Study 
Evaluating 
the 
Safety 
and
Immunogenicity of Investigational SARS-CoV-2 mRNA Vaccine
CVnCoV in Adult Health Care Workers in Mainz (Germany)
Protocol Number:
CV-NCOV-005
This trial will be conducted with the highest respect for the individual subjects in compliance
with the requirements of this clinical trial protocol (and amendments), and also in compliance
with the following:
 
The ethical principles that have their origin in the Declaration of Helsinki.
 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use (ICH) E6 (R2) Good Clinical Practice (GCP): Revised and consolidated
guidelines [1].
 
All applicable laws and regulations, including, without limitation, data privacy laws,
clinical trial disclosure laws, and regulations.
Sponsor Signatory
CureVac AG
Medical Responsible Person
CureVac AG
Clinical Operations
CureVac AG
Statistician
CureVac AG






Clinical Trial Protocol
CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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SAE Hotline and Medical Monitor Contacts
SAE Hotline
SAE reporting to PRA by fax or email within 24 hours after discovery:
Site Location
Email
(Primary Reporting Method)
Fax Number
(Secondary Reporting Method)
Europe
Safety Reporting after
End of Trial
Medical Monitor
The Medical Monitor will provide 24/7 (24 hours per day and 7 days a week) on-call medical coverage
to address trial-related questions from sites or Investigators, such as questions regarding eligibility
requirements, the acceptability of concomitant medication or whether a subject should remain in the
trial or needs to be discontinued.
Name of Primary Contact:
Address:
Phone:
Fax:
Email:


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................. 5
LIST OF TABLES ........................................................................................................... 7
LIST OF FIGURES ......................................................................................................... 7
LIST OF APPENDICES .................................................................................................. 7
LIST OF ABBREVIATIONS ............................................................................................ 9
1
SYNOPSIS ....................................................................................................................11
2
SCHEDULE OF ACTIVITIES ........................................................................................25
3
INTRODUCTION ...........................................................................................................32
3.1
Background ........................................................................................................32
3.1.1
Coronaviruses.........................................................................................32
3.1.2
COVID-19 Disease .................................................................................34
3.1.3
Development of CVnCoV ........................................................................34
3.1.4
Trial Rationale.........................................................................................35
3.2
Risk/Benefit Assessment ....................................................................................36
3.2.1
Known Potential Risks ............................................................................36
3.2.2
Known Potential Benefits ........................................................................39
3.2.3
Assessment of Potential Risks and Benefits ...........................................40
4
TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...............................................41
4.1
Objectives ..........................................................................................................41
4.1.1
Primary Objectives ..................................................................................41
4.1.2
Secondary Objectives .............................................................................41
4.1.3
Exploratory Objectives ............................................................................41
4.2
Endpoints ...........................................................................................................41
4.2.1
Primary Endpoints ..................................................................................41
4.2.2
Secondary Endpoints ..............................................................................42
4.2.3
Exploratory Endpoints .............................................................................43
4.3
Estimands ..........................................................................................................43
5
TRIAL DESIGN .............................................................................................................47
5.1
Overall Design....................................................................................................47
5.2
Scientific Rationale for Trial Design ....................................................................49
5.3
Justification for Dose ..........................................................................................50
5.4
End of Trial Definition .........................................................................................50
5.5
Stopping/Pausing Rules for Safety .....................................................................50
5.5.1
Individual Subject Stopping Rules ...........................................................50
5.5.2
Pausing of the Trial .................................................................................50
6
TRIAL POPULATION ....................................................................................................52
6.1
Inclusion Criteria for All Subjects ........................................................................52
6.2
Exclusion Criteria ...............................................................................................53
6.3
Vaccine Delay Recommendations ......................................................................54
6.4
Failure to Meet Eligibility Criteria ........................................................................54
7
TRIAL VACCINE ...........................................................................................................55
7.1
Trial Vaccine Administration ...............................................................................55
7.1.1
Description of the Trial Vaccines .............................................................55
7.1.2
Dosing and Administration ......................................................................55
7.2
Preparation/Handling/Storage/Accountability .....................................................55
7.2.1
CVnCoV Preparation ..............................................................................56
7.2.2
CVnCoV Product Storage and Stability ...................................................56
7.2.3
Placebo Control (Normal Saline) .............................................................56
7.2.4
Accountability .........................................................................................56
7.3
Randomization and Blinding ...............................................................................56
7.3.1
Randomization ........................................................................................57
7.3.2
Blinding ...................................................................................................57


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COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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7.3.3
Unblinding ...............................................................................................58
7.4
Vaccine Compliance ..........................................................................................58
7.5
Misuse and Overdose ........................................................................................58
7.6
Concomitant Therapy and Vaccines ...................................................................59
7.6.1
Permitted Medications/Vaccines During the Trial ....................................59
7.6.2
Prohibited Medications/Vaccines During the Trial ...................................60
7.7
Therapy Leading to Discontinuation ...................................................................60
7.8
Treatment After the End of Trial .........................................................................60
8
DISCONTINUATION/WITHDRAWAL CRITERIA...........................................................61
8.1
Discontinuation of Trial Vaccine Administration ..................................................61
8.2
Withdrawal from the Trial ...................................................................................62
8.3
Trial Termination ................................................................................................62
8.4
Lost to Follow-Up ...............................................................................................63
9
TRIAL ASSESSMENTS AND PROCEDURES ..............................................................64
9.1
Schedule of Trial Assessments and Procedures ................................................64
9.1.1
Immunogenicity/Reactogenicity Subset ..................................................64
9.1.2
All Other Subjects and subjects that, following unblinding, receive an
authorized vaccine after having received at least one dose of CVnCoV .............73
9.2
Efficacy Assessments ........................................................................................80
9.2.1
COVID-19 Cases ....................................................................................80
9.2.2
Asymptomatic Cases of SARS-CoV-2 Infection ......................................83
9.3
Safety Assessments ...........................................................................................83
9.3.1
Safety Assessments Specific for Subjects in the
Immunogenicity/Reactogenicity Subset ..............................................................84
9.3.2
Safety Assessments for All Subjects .......................................................84
9.3.3
Adverse Events .......................................................................................84
9.3.4
Pregnancies ............................................................................................87
9.3.5
Safety Laboratory Assessments .............................................................87
9.3.6
Vital Signs and Physical Examination .....................................................87
9.3.7
Medical and Surgical History ...................................................................88
9.3.8
Monitoring Committees ...........................................................................88
9.4
Immunogenicity Assessments ............................................................................89
9.4.1
Antibody Responses to CVnCoV Vaccination (RBD of S Protein and Viral
Neutralizing Antibodies) .....................................................................................89
9.4.2
Antibody Responses to SARS-CoV-2 (N Protein) ...................................89
9.4.3
Cell-mediated Immunity ..........................................................................90
9.5
Testing for SARS-CoV-2 Infection ......................................................................90
9.5.1
Virological Confirmation of COVID-19 Disease .......................................90
9.5.2
Confirmation of a Positive Test for SARS-CoV-2 Infection Performed
Outside of the Site ..............................................................................................91
10
STATISTICAL CONSIDERATIONS ...............................................................................92
10.1
Sample Size Determination ................................................................................92
10.1.1 Primary Safety Objective ........................................................................92
10.1.2 Primary Immunogenicity Objective ..........................................................92
10.2
Populations for Analyses ....................................................................................92
10.2.1 Safety Analysis Set .................................................................................92
10.2.2 Safety Analysis Subsets .........................................................................93
10.2.3 Per Protocol Immunogenicity Subset ......................................................93
10.2.4 Efficacy Analysis Set...............................................................................93
10.2.5 Summary of Analysis Sets ......................................................................94
10.3
Statistical Analyses ............................................................................................95
10.3.1 General Considerations ..........................................................................95
10.3.2 Demographic, Medical History, and Other Baseline aracteristics ............95
10.3.3 Trial Vaccine Administration ....................................................................95


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COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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10.3.4 Concomitant Medication and Vaccinations ..............................................95
10.3.5 Safety Analysis .......................................................................................95
10.3.6 Immunogenicity Analysis ........................................................................96
10.3.7 Efficacy Analyses ....................................................................................97
10.3.8 Interim Analysis ......................................................................................99
10.3.9 Missing Data ...........................................................................................99
11
QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 100
11.1
Electronic Case Report Forms ......................................................................... 100
11.2
Audit and Inspection ......................................................................................... 100
11.3
Monitoring ........................................................................................................ 100
11.4
Data Management and Coding ......................................................................... 101
12
ETHICS ....................................................................................................................... 102
12.1
Institutional Review Board/Independent Ethics Committee ............................... 102
12.2
Regulatory Authorities ...................................................................................... 102
12.3
Ethical Conduct of the Trial .............................................................................. 102
12.4
Informed Consent ............................................................................................. 102
13
DATA HANDLING AND RECORD KEEPING .............................................................. 104
13.1
Data Protection ................................................................................................ 104
13.2
Amendments to the Protocol ............................................................................ 105
13.3
Biological Samples and Record Retention ........................................................ 105
13.3.1 Biological Samples Retention and Destruction ...................................... 105
13.3.2 Retention of Trial Records .................................................................... 105
13.4
Clinical Trial Report .......................................................................................... 106
13.5
Publication Policy ............................................................................................. 106
14
REFERENCES ............................................................................................................ 107
15
APPENDICES ............................................................................................................. 110
LIST OF TABLES
Table 1
Schedule of Trial Assessments and Procedures for
Immunogenicity/Reactogenicity Subset ........................................................25
Table 2
Schedule of Trial Assessments and Procedures for All Other Subjects and for
Subjects who, Following Unblinding, Receive an Authorized Vaccine After
Having Received at least One Dose of CVnCoV ..........................................29
Table 3
Intensity Grading* for Solicited Local Adverse Events ..................................85
Table 4
Intensity Grading* for Solicited Systemic Adverse Events ............................86
Table 5
Probability of Observing at least one Adverse Event Given a True Incidence
Rate .............................................................................................................92
Table 6
Primary and Supportive Populations for the Analysis of Each Endpoint .......94
LIST OF FIGURES
Figure 1
Genome Organization of SARS-CoV-2 Compared with Other
Betacoronaviruses .......................................................................................33
LIST OF APPENDICES
Appendix 1
Responsibilities of the Investigator ............................................................. 110
Appendix 2
Emergency Procedures .............................................................................. 111
Appendix 3 
Definition of Severe COVID-19 Disease ..................................................... 112
Appendix 4 
Definition of Moderate and Mild COVID-19 Disease ................................... 113
Appendix 5 
Safety and SARS-CoV-2 Tests .................................................................. 114


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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Appendix 6 
Flow Diagram for COVID-19 Case Interview .............................................. 115
Appendix 7 
SARS-CoV-2 Testing Outcome .................................................................. 116
Appendix 8 
Potential Immune-Mediated Diseases ........................................................ 117
Appendix 9 
Adverse Events of Special Interest (AESIs) for SARS-CoV-2 Vaccines ..... 119
Appendix 10 
Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting ........................................................................... 120
Appendix 11
Protocol Amendment History ...................................................................... 127


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CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
 CONFIDENTIAL
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LIST OF ABBREVIATIONS
ADE
Antibody-dependent enhancement
AE
Adverse event
AESI
Adverse event of special interest
ARDS
Acute Respiratory Distress Syndrome
BoD
Burden of disease
CI
Confidence Interval
CMI
Cell-mediated immunity
CoV
Coronavirus
COVID-19
Coronavirus disease 2019
CPM
CovidPreventMainz
CRO
Contract research organization
CTL
Cytotoxic T lymphocyte
CVnCoV
Investigational SARS-CoV-2 mRNA vaccine
CyTOF
Cytometry by time-of-flight
DSMB
Data and Safety Monitoring Board
E
Envelope
EAS
Efficacy Analysis Set
eCRF
Electronic case report form
eDiary
Electronic Diary
ELISA
Enzyme-linked immunosorbent assay
ELISpot
Enzyme-linked immunospot
FDA
United States Food and Drug Administration
FIH
First-in-human
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GMC
Geometric Mean Concentration
GMFC
Geometric mean of fold change
GMT
Geometric mean titer
HCW
Health Care Worker
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use
ICS
Intracellular cytokine staining
IEC
Independent Ethics Committee
IFN
Interferon


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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IL
Interleukin
IM
Intramuscular(ly)
IMP
Investigational medicinal product
IRB
Institutional Review Board
IWRS
Interactive web response system
LL
Lower Limit
LLOQ
Lower limit of quantification
LNP
Lipid nanoparticles
M
Membrane
MedDRA
Medical Dictionary for Regulatory Activities
MERS
Middle East Respiratory Syndrome
mRNA
Messenger ribonucleic acid
N
Nucleocapsid
PBMC
Peripheral blood mononuclear cell
pIMD
Potential immune-mediated disease
PPI
Per Protocol Immunogenicity
PT
Preferred Term
RBD
Receptor-binding domain
RNA
Ribonucleic acid
RR
Relative Risk
RT-PCR
Reverse transcription polymerase chain reaction
S
Spike
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS
Severe Acute Respiratory Syndrome
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SAS
Safety Analysis Set
SASsol
Solicited adverse events Safety Analysis Set
SOC
System Organ Class
SUSAR
Suspected unexpected serious adverse reaction
TLR
Toll-like receptor
VDE
Vaccine-dependent Disease Enhancement
VE
Vaccine efficacy
VNT
Viral neutralizing titer
WHO
World Health Organization


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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1 SYNOPSIS
Name of
Investigational
Vaccine:
CVnCoV
Sponsor:
CureVac AG
Coordinating
Investigator:
Title of Trial:
COVID-19: A Phase 3, Randomized, Observer-Blinded, Placebo-Controlled
Clinical Study Evaluating the Safety and Immunogenicity of Investigational
SARS-CoV-2 mRNA Vaccine CVnCoV in Adult Health Care Workers in
Mainz (Germany)
Rationale:
Coronaviruses are a large family of zoonotic ribonucleic acid (RNA) viruses
causing respiratory disease, ranging from a common cold to severe diseases
such as Middle East Respiratory Syndrome (MERS) and Severe Acute
Respiratory Syndrome (SARS) in humans. In December 2019, an outbreak
of respiratory disease caused by a novel coronavirus strain was reported in
Wuhan City, Hubei Province, China. The novel coronavirus was named
-CoV-2), while the
disease associated with it was referred to as COVID-19 (coronavirus disease
2019). The virus spread to different parts of China and an increasing number
of countries worldwide and on 30 January 2020 the World Health
Organization (WHO) announced the outbreak under International Health
Regulations as a public health emergency of international concern
(the WHO's highest level of alarm). On 12 March 2020, the WHO announced
the outbreak as a pandemic.
There are currently no specific treatments for COVID-19. Development of an
effective COVID-19 vaccine represents the best hope to prevent further
epidemics and outbreaks of the disease. CureVac AG is developing a novel
SARS-CoV-2 vaccine referred to as CVnCoV. CVnCoV is a messenger RNA
(mRNA)-based COVID-19 vaccine in which the mRNA is protected and
delivered by encapsulation within lipid nanoparticles. The mRNA encodes
the stabilized full-length spike (S) protein from the SARS-CoV-2 virus.
Following intramuscular (IM) injection of CVnCoV, the S protein is translated
from the mRNA stimulating an antigen-specific humoral and cellular immune
response to the S protein. Importantly, functional viral neutralizing titers are
induced following vaccination with CVnCoV.
Phase 1 and 2a trial are being conducted to generate initial data on the
safety, reactogenicity, and immunogenicity of 2 doses of CVnCoV,
administered 28 days apart, to adults 18 years of age and older. In a subset
of subjects, a booster dose at 2 or 6 months after the first dose will be
investigated. The first-in-human (FIH) Phase 1 trial, CV-NCOV-001, is
evaluating different dose levels of CVnCoV in seronegative and seropositive
adults 18 to 60 years of age. Following review of the FIH data, a Phase 2a
trial, CV-NCOV-002, was initiated and is evaluating CVnCoV at selected
 61 years of age. Following the first part of
Trial CV-NCOV-002, expansion cohorts of 220 subjects aged 18 to 60 years
and 220
additional safety and immunogenicity data. Dose level selection for
subsequent trials will be informed by the safety and immunogenicity data
from these 2 trials.
The Trial CV-NCOV-004 is designed as a Phase 2b/3 pivotal efficacy and
safety trial in adults 18 years of age and older. The trial will have a
randomized, observer-blinded, placebo-controlled design. Subjects will be
enrolled at multiple sites globally and will be randomized in a 1:1 ratio to


Clinical Trial Protocol
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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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receive a 2-dose schedule of either CVnCoV at a dose level of 12 µg mRNA
or placebo {normal saline (0.9% NaCl)} as the control.
The present trial CV-NCOV-005 is designed as a Phase 3 safety and
immunogenicity trial in health care workers (HCWs), 18 years of age and
older, in Mainz (Germany). The trial will be conducted as a randomized,
observer-blinded, placebo-controlled trial. HCWs participating in a
non-interventional cohort trial, COVID19-5-P-002 {or CovidPreventMainz
(CPM)prevac}, currently being performed at the Mainz University will be
asked to participate in trial CV-NCOV-005. Trial CV-NCOV-005 will also
include other HCWs, and potentially students in clinical training.
Subjects enrolled in CV-NCOV-005 will be randomized in a 1:1:1 ratio to
receive a 2-dose schedule, 28 days apart, of either 1 of 2 lots of CVnCoV at
a dose level of 12 µg mRNA or placebo {normal saline (0.9% NaCl) for
injection} as the control.
Primary objectives of CV-NCOV-005 trial are to generate additional safety
and immunogenicity data, in the intended trial population of adults at the
previously selected dose level. As a secondary objective, the efficacy of a
2-dose schedule of CVnCoV in the prevention of first episodes of
virologically-confirmed cases of COVID-19 of any severity in SARS-CoV-2
naïve subjects will be assessed. The severity of COVID-19 cases occurring
in the CVnCoV and placebo groups will also be described as a secondary
objective.
Lot-to-lot consistency of 2 lots of CVnCoV will also be assessed in this trial
as a secondary objective.
In an exploratory way, data regarding occurrence of COVID-19 cases and
antibody testing to nucleocapsid (N) protein of SARS-CoV-2 obtained from
subjects in the COVID19-5-P-002 trial not enrolling in CV-NCOV-005 will be
pooled with data obtained from subjects in the placebo group in
CV-NCOV-005 to provide additional controls in pooled efficacy analyses of
both trials. Pooling of data from the 2 trials is justified given the similarity of
the trial population for both trials at the Mainz site, the active surveillance and
similar process for confirmation of COVID-19 cases, and for assessment of
serostatus indicative of SARS-CoV-2 infection in both trials. Data from a
12-month follow-up period in trial COVID19-5-P-002, to be conducted in
parallel with trial CV-NCOV-005 will be considered for the pooling. The
results of the pooled analyses will be reported separately and a specific
statistical analysis plan (SAP) will be done.
This plan may be affected if another COVID-19 vaccine is approved and
made available to the subjects during this trial. If an important percentage of
subjects opt to receive that other vaccine, a re-randomization of additional
subjects from the CPMprevac non-interventional trial into this trial will be
considered.
The first vaccine to prevent COVID-19 caused by SARS-CoV-2 was
authorized by the European Medicines Agency on 21 December 2020. The
first vaccinations began in Germany on 27 December 2020 and initially took
place in a stepwise approach. Vaccines were initially available on a limited
basis and were made available primarily to defined risk groups of the
population. In Germany, extended availability of the authorized vaccines is
effective since 07 June 2021, allowing all adult population (aged 18 or older)
to access the vaccine.
The trial CV-NCOV-005 protocol has been amended to address the available
efficacy results of the study vaccine (CVnCoV).
The CV-NCOV-005 trial will run in parallel with CV-NCOV-004, and will follow
the design of that trial, including case collection and work-up, and antibody
testing to N protein of SARS-CoV-2.


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The final analysis data from the HERALD study (CV-NCOV-004),
conducted with the same study vaccine (CVnCoV) was made available on
the 30th June 2021. The HERALD study results were statistically significant
for the primary study objective. The final efficacy analysis showed an
overall efficacy of 48.2% (LL (lower limit) 31,0%) for CVnCoV in the
prevention of COVID-19 cases of any severity, reaching the predefined
success criterion. Similar confirmatory results were observed in the
prevention of moderate to severe COVID-19 cases, a key secondary
efficacy objective, with an overall vaccine efficacy of 70.7% (LL 42.5%).
Whereas, in the HERALD study, CVnCoV efficacy in the prevention of
COVID-19 cases of any severity was confirmed in the 18 to 60 age group
(VE 52.5%, LL 36.2%), data in study participants older than 60 years was
not conclusive including due to the low number of cases (only 9% of all
cases) and low number of participants under follow up in that age group.
There was also no clear trend of efficacy in this age group. Similarly,
vaccine efficacy in the prevention of moderate to severe disease was
77.2% (LL 51.8%) in participants 18 to 60 years old and no conclusive
results were observed in participants older than 60 years.
Since the efficacy results from the HERALD study for CVnCoV are available
and all subjects in the CV-NCOV-005 study are currently eligible to receive
an authorized vaccine, all subjects in this CV-NCOV-005 study will be
unblinded.
Each subject will be informed by the study physician of the available study
results and whether he/she received the study vaccine (CVnCoV) or placebo
in the study. The purpose of this measure is to provide the
participants/subjects with sufficient information so that they can decide
whether to take an authorized vaccine or not in a fully informed way.
All subjects that received placebo in this study should follow the official
recommendations regarding vaccination against SARS-CoV-2 outside of the
study; no further follow up will be required and the subjects will leave the
study.
The subjects that received at least one dose of CVnCoV and already decided
to take an authorized vaccine, will be asked to remain in the study to allow
safety follow-up:
Since for subjects older than 60 years, a favorable benefit-risk for CVnCoV
could not be established based on the HERALD study results, subjects who
received CVnCoV should follow the official recommendations regarding
vaccination against SARS-CoV-2 outside of the study.
Subjects 60 and younger willing to take the authorized vaccine should
inform the site and are encouraged to speak with the study doctor/
investigator for further information on the CVnCoV final efficacy analysis
results and how to access the authorized vaccine, out of the clinical study
setting.
All subjects receiving the authorized vaccine following at least one dose of
CVnCoV should continue the safety follow-up in the study until the end of
the trial (Schedule of Activities- Table 2).
To date, no clinical trial has proactively investigated or been designed to
evaluate the administration of authorized vaccines after vaccination with
CVnCoV.
A post-hoc analysis in June 2021 showed that 438 participants across
CVnCoV studies were administered authorised COVID-19 vaccine through
national vaccination programmes after having received one or two 12µg-
doses of CVnCoV during clinical studies. The most frequent authorised


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vaccine administered after receiving CVnCoV was Comirnaty® (Pfizer-
BioNTech); the second most frequently administered vaccine was Spikevax®
(Moderna) followed by Vaxzevria® (AstraZeneca). Fewer participants
received the Janssen COVID-19 Vaccine and finally the Sinopharm COVID-
19 Vaccine. Although this set of data has important limitations, the
assessment of the safety database for the 438 subjects who received an
authorized vaccine after CVnCoV resulted in the following observations:
No cluster of adverse events (AEs) or events of concern have been
observed after the administration of an authorized COVID-19
vaccine within a follow-up period between 1 and 18 weeks.
The most frequently reported AEs after administration of the
authorized vaccine are related to local and systemic symptoms
which are commonly reported after vaccination. Fatigue, headache,
fever and body ache were the most frequently reported symptoms.
Two serious adverse events were reported in one subject, in the
CV-NCOV-005 study. This subject has a history of recurrent
asthma exacerbation and has reported two serious AEs (both
exacerbation of asthma) after receiving an authorized vaccine
(Vaxzevria, AstraZeneca). This subject had also reported the same
serious AE after receiving the first dose of CVnCoV.
Trial Duration for
Each Subject:
Each subject will participate in the trial for
approximately 13 months.
Phase: 3
Primary Objectives: 
Primary Safety Objective
 
To evaluate the safety (in all subjects) and reactogenicity (in a subset of
subjects) of CVnCoV administered as a 2-dose schedule to adults
18 years of age or older.
Primary Immunogenicity Objective
 
To assess antibody responses to the Receptor-binding domain (RBD) of
S protein of SARS-CoV-2 after 1 and 2 doses of CVnCoV in adults
18 years of age or older included in a subset of subjects.
Secondary
Objectives:
Secondary Efficacy Objectives
 
To assess the efficacy of a 2-dose schedule of CVnCoV in the prevention
of first episodes of virologically-confirmed symptomatic cases of
COVID-19 of any severity in SARS-CoV-2 naïve subjects.
 
To describe the severity of first episodes of virologically-confirmed
symptomatic cases of COVID-19 in SARS-CoV-2 naïve subjects,
receiving a 2-dose schedule of CVnCoV compared to those administered
placebo.
 
To assess the efficacy of a 2-dose schedule of CVnCoV in reducing the
burden of disease (BoD) from COVID-19.
Secondary Immunogenicity Objectives
 
To assess SARS-CoV-2 virus neutralizing antibody responses after 1
and 2 doses of CVnCoV in adults 18 years of age or older included in a
subset of subjects.
 
To assess lot-to-lot consistency of 2 CVnCoV lots, as measured by
antibody responses to the RBD of S protein of SARS-CoV-2, after
2 doses of CVnCoV, in adults 18 years of age or older included in a
subset of subjects.


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CureVac AG
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Version 5.0 (22 December 2021)
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Overall Design:
The trial will be conducted as a randomized, observer-blinded,
placebo-controlled trial. Subjects will receive a 2-dose schedule, 28 days
apart, of either 1 of 2 lots of CVnCoV, at a dose level of 12 µg mRNA, or
placebo {normal saline (0.9% NaCl}) in a 1:1:1 ratio. Approximately
2,520 subjects (840 by randomization group), 18 years of age or older,
previously enrolled in the non-interventional trial performed at the Mainz
University, Germany (COVID19-5-P-002), other HCWs and potentially
students in clinical training will be enrolled.
The safety, reactogenicity, immunogenicity and efficacy of a 2-dose schedule
of CVnCoV in HCW will be assessed descriptively.
The primary safety objective is to expand the safety database that will
demonstrate the safety profile of CVnCoV. The safety and reactogenicity of
a 2-dose schedule of CVnCoV will be assessed in detail by measuring the
frequency and severity of the following adverse events (AEs): solicited local
and systemic AEs on the day of vaccination and for the following 7 days after
each vaccination in a subset of subjects (Immunogenicity/Reactogenicity
Subset); unsolicited AEs on the day of vaccination and for the following
28 days 
after 
each 
vaccination 
in 
a 
subset 
of 
subjects
(Immunogenicity/Reactogenicity Subset); medically-attended AEs through
6 months after the second trial vaccination in all subjects; and AEs of special
interest (AESIs) and serious adverse events (SAEs) through 1 year after the
second trial vaccination in all subjects (see Appendix 9 and Appendix 10).
A Data and Safety Monitoring Board (DSMB) will perform a review at regular
meetings of the available safety data from CV-NCOV-004, CV-NCOV-005
and other trials with CVnCoV.
The immunogenicity of CVnCoV after 1 and 2 doses will be evaluated in a
subset of subjects (Immunogenicity/Reactogenicity Subset) by measuring
binding antibodies to the SARS-CoV-2 RBD of S protein for the co-primary
immunogenicity objective, and by measuring viral neutralizing antibodies for
the secondary immunogenicity objective.
It 
will 
be 
evaluated 
descriptively 
in 
a 
subset 
of 
subjects
(Immunogenicity/Reactogenicity Subset) if antibody responses to the RBD of
S protein of SARS-CoV-2 induced by 2 different lots of CVnCoV are
equivalent when measured on Day 29 and 43.
As a secondary efficacy objective, the efficacy of a 2-dose schedule of
CVnCoV in the prevention of first episodes of virologically-confirmed cases
of COVID-19 of any severity in SARS-CoV-2 naïve subjects will be assessed.
The severity of COVID-19 cases occurring in the CVnCoV and placebo
groups will also be described as a secondary objective.
Subjects will undergo active surveillance for COVID-19 (see Appendix 6).
During all site visits and phone calls, subjects will be reminded to contact the
site if they have an acute illness with any symptoms clinically consistent with
COVID-19 or if they tested positive for SARS-CoV-2 outside of the trial
context. In addition, subjects will be messaged up to twice a week and will
provide a yes or no response to having COVID-19 symptoms. Those who
-up interview and
assessment, if the investigator considers the symptoms could potentially
indicate a COVID-19 case. If a subject is suspected of having COVID-19
illness, he/she will undergo testing for SARS-CoV-2 infection with samples
collected at the site or at a home visit. If the subject is confirmed to have
COVID-19, the subject will be followed until resolution of their disease. If the
by the Investigator and a discharge summary obtained at the end of the
hospitalization. Information on clinical symptoms and signs, their duration
and severity, and treatment and outcome of the COVID-19 episode will be
documented by trial staff and recorded in the electronic case report form
(eCRF). Upon resolution, subjects will continue to be followed through the


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trial end in the same manner as those who have not presented with
COVID-19. A second or subsequent episode of COVID-19 in a subject with
prior disease will be counted for the exploratory objective assessing the
reoccurrence of COVID-19 in vaccinated subjects.
For the analysis of efficacy, the case must meet the following criteria
(moderate and severe COVID-19 disease is defined in Appendix 4 and
Appendix 3, respectively):
 
Must be a virologically-confirmed case of COVID-19 defined as a positive
SARS-CoV-2 specific reverse transcription polymerase chain reaction
(RT-PCR) test in a person with clinically symptomatic COVID-19 (see
Section 9.2).
 
Symptom
following the second trial
vaccination.
 
The subject must not have a history of virologically-confirmed COVID-19
at enrollment (based on exclusion criterion 1) or have developed a case
of virologically-confirmed COVID-19 before 15 days after the second trial
vaccination {see Section 10.2.4, Efficacy Analysis Set (EAS) population
for more details}.
These efficacy cases might be confirmed by the Adjudication Committee.
The DSMB will periodically monitor COVID-19 cases across CV-NCOV-004,
CV-NCOV-005 
and 
other 
trials 
with 
CVnCoV 
for 
signals 
of
vaccine-dependent disease enhancement (VDE) with pre-specified criteria
for halting based on these signals.
An interim analysis is planned. The cut-off date for the interim analysis in
CV-NCOV-005 will be based on the regulatory requirements to obtain early
conditional approval in Europe. Trial CV-NCOV-005 will continue and remain
fully blinded, except for the unblinded Submission Team, until CA and EC
approval of study protocol version 3. Accrual of COVID-19 cases will
continue.
Trial
Visits/Contacts:
For subjects in the Immunogenicity/Reactogenicity Subset (see
Table 1):
 
7 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 57,
Day 120, Day 211, and Day 393.
 
3 protocol-scheduled phone contacts (safety calls) on Day 2,
Day 30 and Day 302.
For all the other subjects and for subjects that, following
unblinding, receive an authorized vaccine after having received at
least one dose of CVnCoV (see Table 2):
 
5 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 211
and Day 393.
 
3 protocol-scheduled phone contacts (safety calls) on Day 57,
Day 120 and Day 302.
For subjects who received placebo:
 
All subjects will be invited for an unscheduled End of Study-Visit in
order to conduct a final safety assessment.
Collection of Blood
Samples:
The maximum total volume of blood taken over the trial period from each
subject is described below:
For subjects in the Immunogenicity/Reactogenicity Subset
 
Up to 318 mL taken over 56 weeks (Table 1).


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Version 5.0 (22 December 2021)
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For all Other Subjects and for subjects that, following unblinding,
receive an authorized vaccine after having received at least one
dose of CVnCoV
18 mL taken over 56 weeks (Table 2).
Safety
Assessments:
The safety, reactogenicity, and tolerability of a 2-dose schedule of CVnCoV
will be assessed by measuring the frequency and severity of the following
AEs as described below.
Safety 
assessments 
specific 
for 
subjects 
in
the
Immunogenicity/Reactogenicity Subset:
 
Reactogenicity will be assessed daily on each vaccination day and the
following 7 days by collection of solicited local AEs (injection site pain,
redness, swelling, and itching) and solicited systemic AEs (fever,
headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and
diarrhea) using electronic diaries (eDiaries). In addition, other indicators
of safety will be collected (e.g., body temperature).
 
eDiaries will be used for collection of unsolicited AEs on each vaccination
day and the following 28 days.
Safety assessments for all subjects:
 
Medically-attended AEs will be collected through 6 months after the
second trial vaccination.
 
AESIs will be collected through 1 year after the second trial vaccination.
AESIs to be monitored include potential immune-mediated diseases
(pIMDs), AESIs for SARS-CoV-2 vaccines, and non-serious intercurrent
medical conditions that may affect the immune response to vaccination.
 
SAEs will be collected through 1 year after the second trial vaccination.
 
AEs leading to vaccine withdrawal or trial discontinuation will be collected
through 1 year after the second trial vaccination.
Testing for
COVID-19:
During the trial, subjects clinically suspected of having COVID-19 disease or
with a positive result in a test for SARS-CoV-2 performed outside of the trial
context will undergo testing for the SARS-CoV-2 virus as described below.
Sample collection for the tests may be performed at the site or at a home visit
by trial staff. Ideally, samples should be collected within 5 days of symptom
onset or positive result.
 
The nasopharyngeal swab sample collected will be used to perform a
SARS-CoV-2 specific RT-PCR test. The RT-PCR test result will be
considered definitive.
For positive RT-PCR tests, viral RNA of the SARS-CoV-2 might be
sequenced to identify S protein variants.
If the RT-PCR test is negative, but COVID-19 is still suspected based on
nasopharyngeal swab sample should be taken as soon as feasible for
RT-PCR testing. The RT-PCR retest result will be considered definitive.
COVID-19 Case
Detection and Case
Definition for
Efficacy Analysis:
Case Detection:
 
During all site visits and phone calls, subjects will be reminded to contact
the site if they tested positive for SARS-CoV-2 outside of the trial context
or have at least 1 of the following symptoms*:


Clinical Trial Protocol
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CureVac AG
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Version 5.0 (22 December 2021)
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 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
Diarrhea
*FDA Guidance for Industry, Development and Licensure of Vaccines to Prevent
COVID-19, June 2020.
 
In addition, subjects will be messaged up to twice a week to provide a
yes or no response to having COVID-19 symptoms. Those who respond
-up information, if the
investigator considers the symptoms could potentially indicate a COVID-
19 case.
 
Based on a phone interview, if the subject is suspected of having COVID-
19 illness or tested positive for SARS-CoV-2 outside of the trial context,
he/she will undergo RT-PCR testing for SARS-CoV-2 infection as
described above. If the subject is confirmed to have COVID-19, he/she
will be followed until resolution of their disease, even if the initial
presentation 
is 
considered 
as 
mild. 
Information 
on 
clinical
signs/symptoms and duration, treatments and outcome of the disease
will be documented by trial staff and recorded in the eCRF.
Definition of Virologically-Confirmed COVID-19 Case:
A virologically-confirmed case of COVID-19 is defined as a positive SARS-
CoV-2 specific RT-PCR test in a person with clinically symptomatic disease
consisting of 1 or more of the following symptoms (based on the same
screening symptoms as above):
 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
Diarrhea
This definition is intended to capture all severities of virologically-confirmed
clinically symptomatic cases of COVID-19. As such, different disease
severities defined for COVID-19 (e.g., mild or severe disease) will be a subset
of these cases.
Definition of Virologically-Confirmed COVID-19 Case for the Efficacy
Analysis:
For the analysis of efficacy, the case must meet the following criteria:
 
Must be a virologically-confirmed case of COVID-19 defined as a positive
SARS-CoV-2 specific RT-PCR test in a person with clinically
symptomatic COVID-19 as described above.
following the second trial
vaccination.
 
The subject must not have a history of virologically-confirmed COVID-19
illness at enrollment or have developed a case of virologically-confirmed
COVID-19 before 15 days following the second trial vaccination.
 
The subject must have been SARS-CoV-2 naïve at baseline and Day 43
(defined as seronegative to N protein in the blood samples collected at
baseline and Day 43).
These efficacy cases might be confirmed by the Adjudication Committee.


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Planned Number of
Subjects:
HCWs participating in the observational COVID19-5-P-002 trial, other HCWs,
and potentially students in clinical training will be enrolled. The total
enrollment for the trial will be approximately 2,520 subjects (840 by
randomization group).
Criteria for
Inclusion and
Exclusion:
Inclusion criteria for all subjects:
Subjects will be enrolled in this trial only if they meet all of the following
criteria:
1. 
Male or female subjects 18 years of age or older.
2. 
HCWs, employees or students in clinical training.
3. 
Provide written informed consent prior to initiation of any trial
procedures.
4. 
Expected compliance with protocol procedures and availability for
clinical follow-up through the last planned visit.
5. 
Females of non-childbearing potential defined as follows: surgically
sterile 
(history 
of 
bilateral 
tubal 
ligation/occlusion, 
bilateral
oophorectomy or hysterectomy) or postmenopausal {defined as
 12 consecutive months prior to screening (Day 1)
without an alternative medical cause}. A follicle-stimulating hormone
level may be measured at the discretion of the Investigator to confirm
postmenopausal status.
6. 
Females of childbearing potential: negative urine pregnancy test (human
chorionic gonadotropin) within 24 hours prior to each trial vaccination on
Day 1 and Day 29.
7. 
Females of childbearing potential must use highly effective methods of
birth control from 2 weeks before the first administration of the trial
vaccine until 3 months following the last administration. The following
methods of birth control are considered highly effective when used
consistently and correctly:
 Combined (estrogen and progestogen containing) hormonal
contraception 
associated 
with 
inhibition 
of 
ovulation 
(oral,
intravaginal or transdermal);
 Progestogen-only hormonal contraception associated with inhibition
of ovulation (oral, injectable or implantable);
 Intrauterine devices;
 Intrauterine hormone-releasing systems;
 Bilateral tubal ligation;
 Vasectomized partner or infertile partner;
 Sexual abstinence {periodic abstinence (e.g., calendar, ovulation,
symptothermal and post-ovulation methods) and withdrawal are not
acceptable}.
Exclusion criteria for all subjects:
Subjects will not be enrolled in this trial if they meet any of the following
criteria:
1. 
History of virologically-confirmed SARS-CoV-2 infection or SARS-CoV-
2 positive serology.
2. 
For females: pregnancy or lactation.
3. 
Use of any investigational or non-registered product (vaccine or drug)
within 28 days preceding the administration of the first trial vaccine or
planned use during the trial.
4. 
Receipt of licensed vaccines within 28 days (for live vaccines) or 14 days
(for inactivated vaccines) prior to the administration of the first trial
vaccine.


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Version 5.0 (22 December 2021)
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5. 
Prior administration of any investigational SARS-CoV-2 vaccine or
another coronavirus (SARS-CoV, MERS-CoV) vaccine or planned use
during the trial.
6. 
Any treatment with immunosuppressants or other immune-modifying
drugs (including but not limited to corticosteroids, biologicals and
methotrexate) for > 14 days total within 6 months preceding the
administration of trial vaccine or planned use during the trial. For
corticosteroid use, this means prednisone or equivalent, 0.5 mg/kg/day
for 14 days or more. The use of inhaled, topical, or localized injections
of corticosteroids (e.g., for joint pain/inflammation) is permitted.
7. 
Any medically diagnosed or suspected immunosuppressive or
immunodeficient condition based on medical history and physical
examination including known infection with human immunodeficiency
virus; current diagnosis of or treatment for cancer including leukemia,
lymphoma, Hodgkin disease, multiple myeloma or generalized
malignancy; chronic renal failure or nephrotic syndrome; and receipt of
an organ or bone marrow transplant.
8. 
Active or chronic disease of, or currently on treatment for, hepatitis B
virus or hepatitis C virus.
9. 
History of angioedema (hereditary or idiopathic) or history of any
anaphylactic reaction.
10. History of pIMD.
11. History of allergy to any component of CVnCoV vaccine.
12. Administration of immunoglobulins or any blood products within
3 months prior to the administration of trial vaccine or planned receipt
during the trial.
13. Subjects with a significant acute or chronic medical or psychiatric illness
that, in the opinion of the Investigator, precludes trial participation (e.g.,
may increase the risk of trial participation, render the subject unable to
meet the requirements of the trial, or may interfe
evaluations). These include severe and/or uncontrolled cardiovascular
disease, gastrointestinal disease, liver disease, renal disease,
respiratory disease, endocrine disorder, and neurological and
psychiatric illnesses. However, those with controlled and stable cases
can be included in the trial.
14. Subjects with impaired coagulation or any bleeding disorder in whom an
IM injection or a blood draw is contraindicated.
15. Foreseeable non-compliance with the trial procedures as judged by the
Investigator.
Primary Endpoints: 
Primary Safety Endpoints
 
Occurrence, intensity and relationship of medically-attended AEs
collected through 6 months after the second trial vaccination in all
subjects.
 
Occurrence, intensity and relationship of SAEs and AESIs collected
through 1 year after the second trial vaccination in all subjects.
 
Occurrence of fatal SAEs through 1 year after the second trial vaccination
in all subjects.
 
Occurrence of AEs leading to vaccine withdrawal or trial discontinuation
through 1 year after the second trial vaccination in all subjects.
 
Occurrence, intensity and duration of each solicited local AE within
7 days after each trial vaccination in a subset of subjects.
 
Occurrence, intensity, duration of each solicited systemic AE within
7 days after each trial vaccination in a subset of subjects.
 
Occurrence, intensity and relationship of unsolicited AEs occurring within
28 days after each trial vaccination in a subset of subjects.


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
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Primary Immunogenicity Endpoint
SARS-CoV-2 RBD of S protein antibody responses in a subset of subjects
On Days 1, 29 and 43:
 
Serum antibodies to SARS-CoV-2 RBD of S protein.
 
Occurrence of seroconversion to SARS-CoV-2 RBD of S protein.
 
Seroconversion is defined as detectable SARS-CoV-2 RBD of
S protein antibodies in the serum of subjects who tested
seronegative at baseline.
Secondary
Endpoints:
Secondary Efficacy Endpoints
 
Occurrence of first episodes of virologically-confirmed (RT-PCR) cases
of COVID-19 of any severity meeting the case definition for the efficacy
analysis.
 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive)
cases of COVID-19 meeting the case definition for the efficacy analysis
by severity (mild, moderate, severe and moderate to severe COVID-19)
as defined in Appendix 3 and Appendix 4.
 
BoD scores calculated based on first episodes of virologically-confirmed
(RT-PCR positive) cases of COVID-19 of any severity meeting the case
definition for the efficacy analysis.
 
BoD #1
 no disease (not infected or asymptomatic infection) = 0;
mild or moderate disease = 1; severe disease = 2.
 
BoD #2
 no disease (not infected or asymptomatic infection) = 0;
disease without hospitalization = 1; disease with hospitalization = 2;
death = 3
Secondary Immunogenicity Endpoints
SARS-CoV-2 virus neutralizing antibody responses in a subset of subjects
On Days 1, 29 and 43:
 
Serum neutralizing antibodies to SARS-CoV-2 virus, as measured by a
virus neutralizing assay.
 
Occurrence of seroconversion to SARS-CoV-2 virus, as measured by a
virus neutralizing assay.
 
Seroconversion is defined as detectable SARS-CoV-2 virus
neutralizing antibodies in the serum of subjects who tested
seronegative at baseline.
Lot-to-lot consistency of 2 CVnCoV lots, as measured by SARS-CoV-2 RBD
of S protein antibody responses in a subset of subjects
On Day 43:
 
Serum antibodies to SARS-CoV-2 RBD of S protein.
Data and Safety
Monitoring Board:
An independent DSMB will be convened to oversee the safety and efficacy
of subjects participating in the trials CV-NCOV-004 and CV-NCOV-005, to
assess the progress and conduct of the trials, to review the cumulative safety
data from the trials, and to make recommendations to CureVac whether to
continue, modify, or stop the trials. The DSMB will have regularly scheduled
meetings to perform these responsibilities. During these meetings, the DSMB
will be informed of the safety data being generated in other ongoing clinical
trials of CVnCoV. In addition to safety data, the DSMB will be asked to review
efficacy data at the interim analysis and at other time points during the trial
for a continued assessment of the risk-benefit of the trial. As part of the risk-


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benefit analysis, the DSMB will periodically monitor COVID-19 cases for
signals of VDE.
The DSMB Charter will describe in detail the composition and objectives of
the DSMB; the responsibilities of the DSMB, CureVac and the contract
research organization; the schedule and conduct of the DSMB meetings; and
the datasets to be reviewed.
Sample Size
Justification:
HCWs participating to the observational COVID19-5-P-002 trial, other HCWs
or students in clinical training will be enrolled. The anticipated sample size is
2,520 subjects. This number of subjects will give the trial more than 80%
statistical power to detect AEs that may occur at about 1:1000 incidence.
Analysis Sets:
The main analysis populations are:
Safety Analysis Set
The Safety Analysis Set (SAS) will include all subjects randomized in the
trial who received at least 1 dose of any lot of CVnCoV or placebo vaccine.
The SAS will be the primary population for the safety endpoints collected on
all subjects.
Solicited and unsolicited AE endpoints will be analyzed on the SAS subjects
who belong to the Immunogenicity/Reactogenicity subset.
Per Protocol Immunogenicity Subset
The Per Protocol Immunogenicity subset (PPI) will include all subjects who
belong to the Immunogenicity/Reactogenicity Subset and who:
 
Received both doses as randomized and within the windows defined in
the protocol.
 
Have no major protocol deviations expecting to impact the
immunogenicity outcomes as specified in the SAP.
 
Have not received medical treatments (such as blood products,
immunoglobulin therapy) that may interfere with 1 or both of the proposed
immunogenicity measurements.
 
Have at least 1 blood sample collected starting at 14 days (Day 43) post-
second vaccination available for analysis.
The PPI will be the primary analysis population for SARS-CoV-2 RBD of S
protein antibody responses and SARS-CoV-2 viral neutralizing antibody.
Lot-to-lot consistency analysis will be performed on PPI subjects who:
 
Received 2 doses of CVnCoV coming from the same lot.
Have a negative SARS-CoV-2 RBD of S protein antibody titer at baseline.
Efficacy Analysis Set
The Efficacy Analysis Set (EAS) will include all subjects of the SAS who:
 
Received both trial doses (2 doses of CVnCoV or 2 doses of placebo)
according to their randomization.
 
Had not developed a virologically-confirmed case of COVID-19 before
trial entry (based on exclusion criteria 1) or before 15 days following the
second vaccination.
 
Had not stopped the trial before 15 days following the second
vaccination.
 
Were SARS-CoV-2 naïve at trial entry and at Day 43 visit (based on
seronegativity to N protein).
The EAS will be the primary analysis population for all efficacy endpoints.


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Statistical
Methodology:
Missing data/discontinuation:
Concentration values of SARS-CoV-2 antibodies marked as below the lower
limit of quantification (LLOQ) will be set to 0.5*LLOQ for the purpose of
geometric mean concentration (GMC) computation.
No imputation of missing values will be performed for any analysis (except
the imputation for missing partial dates of AEs and concomitant medication).
Currently no replacement of drop-out subjects is foreseen. This plan may be
affected if another COVID-19 vaccine is approved and made available to the
subjects during this trial. If an important percentage of subjects opt to receive
that other vaccine, a re-randomization of additional subjects from the
CPMprevac non-interventional trial into this trial will be considered.
Statistical
Analyses:
Analysis of Demographics and Other Baseline Characteristics:
Data will be summarized with respect to demographic and baseline
characteristics, medical history, immune response measurements, and all
safety measurements using descriptive statistics (quantitative data) and
contingency tables (qualitative data) for each CVnCoV lot separately, for
pooled CVnCoV lots, for placebo and overall.
Safety Analyses:
Safety endpoints will be described for each CVnCoV lot separately, for pooled
lots, for placebo and overall.
Solicited AEs:
The frequencies and percentages of subjects experiencing each solicited
local and systemic AE within 7 days after each vaccination will be presented
by intensity and overall.
Unsolicited AEs:
Unsolicited AEs including SAEs and AESIs will be coded using the Medical
Dictionary for Regulatory Activities (MedDRA) by System Organ Class (SOC)
and Preferred Term (PT). The frequency and percentage of subjects
reporting at least 1 AE and each unsolicited AE within 28 days after each
vaccination and overall will be tabulated at the SOC and PT levels. Additional
similar tabulations will be performed to evaluate severity and relationship to
trial vaccine.
Immunogenicity Analysis:
Descriptive statistics for the immunogenicity endpoints will be provided for
each CVnCoV lot separately (samples of 200 subjects analyzed), for pooled
lots and for 50 subjects of the placebo group on Days 1, 29 and 43..
GMCs/Geometric mean titers (GMTs) with 95% confidence interval (CI) will
be computed for SARS-CoV-2 RBD of S protein antibody levels and for
neutralizing antibodies, overall and separately in subjects seronegative at
baseline and in subjects seropositive at baseline. Geometric mean of fold
change from baseline will be added for subjects seropositive at baseline.
For each readout, seroconversion rates will also be summarized at each
blood sampling time point in subjects who are SARS-CoV-2 seronegative at
baseline.
To assess lot-to-lot consistency descriptively, two-sided 95% CI of the ratio
of GMCs of SARS-CoV-2 RBD of S protein antibodies between subjects
receiving 2 different lots of CVnCoV will be computed for Day 43.
Efficacy Analyses:
The attack rates of first episodes of virologically-confirmed COVID-19 of any
severity (according to case definition) in CVnCoV (pooled lots) and placebo
groups will be computed as well as VE, defined as the percent reduction in
the frequency of COVID-19 cases in vaccinated subjects compared with
subjects who received placebo with its exact 95% CI as follows:


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CureVac AG
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Version 5.0 (22 December 2021)
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VE = 1- RR = 1 - (ARV/ARP) = 1 - (p / r (1-p))
where
ARV = attack rate in vaccinated groups (pooled lots) = nv/Nv = number of
subjects reporting at least 1 COVID-19 episode in the CVnCoV groups / total
follow-up time of evaluable subjects in the CVnCoV groups (number of
person-month)
ARP = attack rate in placebo group = np/Np = number of subjects reporting
at least 1 COVID-19 episode in the placebo group / total follow-up time of
evaluable subjects in the placebo group (number of person-month)
RR = relative risk = ARV/ARP
p = proportion of COVID-19 cases coming from the CVnCoV groups (pooled
lots) among all cases = nv/(nv+np)
r = ratio of total follow-up time of evaluable subjects in the CVnCoV groups
(pooled lots) over total follow-up time of evaluable subjects in the placebo
group = Nv/Np
Similar analyses will be performed to describe the efficacy in the prevention
of asymptomatic infections. The number and percentage of subjects reporting
at least 1 mild, moderate, severe, and moderate to severe COVID-19 episode
will be presented in each group.
In order to consider incidence and severity of COVID-19 disease, a VE
measure based on the BoD scores (VEBoD) will be derived. VEBoD is defined
as the relative reduction in the BoD score in the CVnCoV groups compared
to the placebo group and is calculated as 1 minus the relative risk.
All efficacy endpoints will be analyzed without success criteria testing.








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h. The eDiary will serve as a memory aid for the subject to report the following AEs during the safety follow-up. Subjects should be trained on the use of the eDiary.
Medically-attended AEs will be collected through 6 months after the second trial vaccination. Medically-attended AEs are defined as AEs with medically-attended
visits that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit
to or from medical personnel (medical doctor) for any reason. SAEs, AESIs, and AEs leading to vaccine withdrawal or trial discontinuation will be collected through 1
year after the second trial vaccination. During all site visits and phone calls, trial staff will remind subjects to call the site immediately to report the following: if he/she
experiences any concerning medical event; any medically-attended visits that are not routine visits for physical examination or vaccination, such as visits for
hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason; or experience a serious
medical event, have a change in overall health or be diagnosed with a new medical condition by a doctor. These should be reported regardless of the perceived
relationship between the event and the trial vaccine.
i. 
During all site visits (except the End of Trial visit) and phone calls, trial staff will remind subjects to contact the site if they have any of the symptoms suggestive of
COVID-19. In addition, subjects will be messaged up to twice a week basis to provide a yes or no response to having COVID-
will be contacted by trial staff for follow-up information, if the investigator considers the symptoms could potentially indicate a COVID-19 case, and the process outlined
in Section 9.2.1 should be followed. At the End of Trial visit, symptoms suggestive of COVID-19 or any confirmed COVID-19 case will be recorded.
j. 
Blood samples should be collected prior to trial vaccination on Day 1 and Day 29.
k. Binding antibodies to the RBD (receptor-binding domain) of the S (spike) protein and to the N (nucleocapsid) protein of SARS-CoV-2 will be measured by
immunoassay. Viral neutralizing antibodies directed against SARS-CoV-2 will be measured by a functional activity assay. The N protein is not a component of the
CVnCoV vaccine, but is being measured to determine serostatus of subjects to the SARS-CoV-2 virus (naïve or non-naïve to SARS-CoV-2); distinguish immune
responses elicited by infection with SARS-CoV-2 from those induced by CVnCoV vaccination; and determine the occurrence of SARS-CoV-2 infection during the trial.
l. 
Blood will be collected for measurement of antibody responses on Days 1, 29, 43, 57, 120 and 211, and cell-mediated immunity on Days 1, 29, 43, 57, 120, and 211
for a total volume of up to 318 mL.






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f. Vital signs will be measured pre- and post-vaccination prior to discharge. Subjects will be observed for at least 30 minutes following each vaccination. Vital signs must
be within normal or clinically non-relevant abnormal ranges or have returned to pre-vaccination values for the subject to be discharged.
g. The eDiary will serve as a memory aid for the subject to report the following AEs during the safety follow-up. Subjects should be trained on the use of the eDiary.
Medically-attended AEs will be collected through 6 months after the second trial vaccination. Medically-attended AEs are defined as adverse events with medically-
attended visits that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise
unscheduled visit to or from medical personnel (medical doctor) for any reason. SAEs, AESIs, and AEs leading to vaccine withdrawal or trial discontinuation will be
collected through 1 year after the second trial vaccination. During all site visits and phone calls, trial staff will remind subjects to call the site immediately to report the
following: if he/she experiences any concerning medical event; any medically-attended visits that are not routine visits for physical examination or vaccination, such
as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason; or experience
a serious medical event, have a change in overall health or be diagnosed with a new medical condition by a doctor. These should be reported regardless of the
perceived relationship between the event and the trial vaccine.
h. During all site visits (except the End of Trial visit) and phone calls, trial staff will remind subjects to contact the site if they have any of the symptoms suggestive of
COVID-19. In addition, subjects will be messaged up to twice a week basis to provide a yes or no response to having COVID-
will be contacted by trial staff for follow-up information, if the investigator considers the symptoms could potentially indicate a COVID-19 case, and the process outlined
in Section 9.2.1 should be followed. At the End of Trial visit, symptoms suggestive of COVID-19 or any confirmed COVID-19 case will be recorded.
i. Binding antibodies to the N (nucleocapsid) protein of SARS-CoV-2 will be measured by immunoassay. The N protein is not a component of the CVnCoV vaccine, but
is being measured to determine serostatus of subjects to the SARS-CoV-2 virus (naïve or non-naïve to SARS-CoV-2) and the occurrence of SARS-CoV-2 infection
during the trial. The baseline blood sample should be collected prior to trial vaccination on Day 1.
j. After implementation of protocols version 3 and 4 no longer to be performed in placebo subjects.


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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 (N) composed of genomic RNA and
phosphorylated 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, Alph
3]. Evolutionary analyses have
shown that bats and r
species barriers and some have emerged as important human pathogens, causing
generally-mild acute respiratory illnesses known as the common cold [4].
Prior to December 2019, when clusters of pneumonia cases with unknown etiology were
detected in Wuhan City, Hubei Province, China, only 2 additional strains of CoVs had
caused outbreaks of severe acute respiratory disease in humans: the Severe Acute
Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome
coronavirus (MERS-CoV). On 9 January 2020, a novel CoV, named severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), was officially identified as the cause
of an outbreak of viral pneumonia in Wuhan. In the following weeks, the virus spread
rapidly within China and an increasing number of countries worldwide. On
30 January 2020 the World Health Organization (WHO) announced the outbreak under
International Health Regulations as a public health emergency of international concern
(the WHO's highest level of alarm) and on 12 March 2020, the WHO announced the
outbreak as a pandemic.
SARS-CoV-
and other wild animals (SARS-CoV, bat SARS-like CoV, and others). Similar to other
-CoV-2 genome contains 2 flanking untranslated regions and a single
long open reading frame encoding a polyprotein [3]. The SARS-CoV-2 genome is
-replicase (orf1/ab)-structural proteins [S-E-M-
the hemagglutinin-
illustrated in Figure 1.
High sequence similarity (> 99%) has been reported following analysis of virus isolates
from patients with SARS-CoV-2 infection [5-8].


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Figure 1 
Genome 
Organization 
of 
SARS-CoV-2 
Compared 
with 
Other
Betacoronaviruses
Source: Chan et al., 2020 [3]
The S gene of SARS-CoV-2 appears to be highly divergent to other CoVs, with less than
75% nucleotide sequence identity to all previously described SARS-CoVs, except a 93.1%
nucleotide identity to RaTG13 [6]. The S genes of SARS-CoV-2 and RaTG13 S gene are
longer than other SARS-CoVs. The major differences in SARS-CoV-2 are 3 short
insertions in the N-terminal domain, and 4/5 key residues changes in the receptor-binding
motif, in comparison with SARS-CoV. At the amino acid sequence level, the S glycoprotein
of SARS-CoV-2 was found to have 76.3% identity and 87.3% similarity with the
S glycoprotein of SARS-CoV [9].
The S2 subunit of SARS-CoV-2 was found to be highly conserved, sharing 99% sequence
identity with those of the 2 bat SARS-like CoVs (SL-CoV ZXC21 and ZC45) and human
SARS-CoV [3]. The S1 subunit of SARS-CoV-2 shares around 70% identity to that of the
2 bat SARS-like CoVs and human SARS-CoV. The domain of the receptor-binding domain
(RBD) (excluding the external subdomain) is highly conserved, but the external subdomain
of the SARS-CoV-2 RBD (which is responsible for the direct interaction with the host
receptor) shares only 40% amino acid identity with other SARS-related CoVs.


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To date, there is no information available on the immune responses to SARS-CoV-2. An
immunoinformatics approach predicted 5 cytotoxic T lymphocyte (CTL) epitopes,
3 sequential B cell epitopes and 5 discontinuous B cell epitopes in the S glycoprotein [9].
Simulations suggested that the CTL epitopes bind the major histocompatibility complex
class I peptide-binding grooves via multiple contacts, with continuous hydrogen bonds and
salt bridge anchors, supporting their potential in generating immune responses. Of note,
the simulations found only 1 overlapping CTL epitope between MERS-CoV and
SARS-CoV-2 and no comparable epitopes with SARS-CoV.
3.1.2 
COVID-19 Disease
SARS-CoV-2 is transmitted mainly through close contact and respiratory droplets. The
mean incubation period is 4-6 days with about 95% of patients developing symptoms
within 14 days after infection [10,11]. The most common symptoms of coronavirus disease
2019 (COVID-19) include fever, cough, dyspnea, and occasionally watery diarrhea. In an
analysis of >1000 hospitalized patients from China, 44% initially presented with fever
(although 89% developed fever at some point during hospitalization) and 68% with cough.
Other symptoms included fatigue (23%), myalgia (15%) and gastrointestinal symptoms
(8%) [11]. As with other systemic viral infections, a large spectrum of possible clinical
manifestations are being reported in COVID-19 patients, including neurological symptoms
and signs, cardiac disease, and cutaneous lesions [12-15]. Chemosensory dysfunction,
such as anosmia and dysgeusia, are increasingly reported.
Data from more than 72,000 patients from China classified cases as mild (including mild
pneumonia, 81%), severe (14%) or critical (5%) [16]. Severe and critical cases presented
with severe pneumonia, septic shock and Acute Respiratory Distress Syndrome (ARDS).
The critically ill patients requiring intensive care management present a large spectrum of
complications in addition to ARDS, such as acute cardiac injury, acute renal injury,
acro-ischemia, 
disseminated 
intravascular 
complications, 
bacterial 
or 
fungal
superinfections [17,18].
In early stages of the outbreak, the reported case-fatality rate in China was 17% [19]. In
admitted patients in Wuhan, mortality reached 25% in the middle of the epidemic. Similarly
high death rates are recorded in those requiring intensive care: in a large retrospective
cases series on COVID-19 confirmed patients admitted to intensive care units (Lombardy,
Italy), mortality reached 26% [20]. The global mortality rate is estimated to be around 3%
[21].
According to the 2020 World Health Statistics, the COVID-19 pandemic is causing
significant loss of life, disrupting livelihoods, and threatening the recent advances in health
and progress towards global sustainable development goals [22]. On 11 November 2020,
according to WHO, 51 251 715 cases have been confirmed globally, including 1 270 930
deaths.
3.1.3 
Development of CVnCoV
In spite of the severity of respiratory disease caused by emerging CoVs, there is currently
no licensed vaccine available for prevention of CoV-associated disease. CureVac AG is
developing a new SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine formulated
with lipid nanoparticles (LNP), referred to as CVnCoV, for the prevention of COVID-19
disease when administered as a 2-dose primary vaccination schedule.


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CVnCoV is an mRNA-based COVID-19 vaccine in which the mRNA is protected and
delivered by encapsula
proprietary RNActive® technology platform, which uses chemically unmodified mRNA
molecules as the basis for vaccination. The mRNA encodes the stabilized full-length
S protein from the SARS-CoV-2 virus. Following intramuscular (IM) injection of CVnCoV,
the S protein is translated from the mRNA stimulating an antigen-specific humoral and
cellular immune response to the S protein. Importantly, functional viral neutralizing titers
(VNTs) and T-cell mediated immunity are induced following vaccination with CVnCoV.
Phase 1 and 2a trials are generating initial data on the safety, reactogenicity and
immunogenicity of CVnCoV administered to adults 18 years of age and older. Available
rochure.
The HERALD Trial CV-NCOV-004 is designed as a Phase 2b/3 pivotal efficacy and safety
trial in adults 18 years of age and older. The trial is conducted as a randomized, observer-
blinded, placebo-controlled trial. Subjects were enrolled at multiple sites globally and were
randomized in a 1:1 ratio to receive a 2-dose schedule of either CVnCoV at a dose level
of 12 µg or placebo {normal saline (0.9% NaCl) for injection} as the control.
The objective of the Phase 2b part of the trial is to further characterize the safety,
reactogenicity and immunogenicity of CVnCoV in the intended trial population of adults,
18 years of age and older, at the dose level selected for Phase 3 investigation. The design
of Phase 2b is consistent with the Phase 3 efficacy part of the trial, allowing cases of
COVID-19 that occur in Phase 2b to be pooled with those in Phase 3 for the primary
analysis of vaccine efficacy (VE), thereby increasing the efficiency of the overall
Phase 2b/3 trial. Combining COVID-19 cases in Phase 2b and 3 to expedite an efficacy
outcome was considered to be justified in a pandemic setting. The detailed reactogenicity
and immunogenicity data generated in Phase 2b will be the main dataset to be submitted
in support of early conditional approval of CVnCoV.
The co-primary objectives of the combined Phase 2b/3 trial are to demonstrate the efficacy
of a 2-dose schedule of CVnCoV in the prevention of COVID-19 cases of any severity or
COVID-19 cases of moderate or higher severity. Due to the uncertain incidence rate of
COVID-19 cases in a pandemic setting, the trial is conducted as a case-driven trial based
on the any severity COVID-19 endpoint due to the higher number of cases required, which
will include 2 interim analyses and a final analysis both triggered by achieving a predefined
number of cases for each analysis. The safety objective of the trial is to generate a large-
scale safety database that will demonstrate the safety of CVnCoV across the adult age
3.1.4 
Trial Rationale
The present trial CV-NCOV-005 is designed as a Phase 3 safety and immunogenicity trial
in health care workers (HCW), 18 years of age and older, in Mainz (Germany). The trial
will be conducted as a randomized, observer-blinded, placebo-controlled trial. HCW
participating in a non-interventional cohort trial, COVID19-5-P-002 {or CovidPreventMainz
(CPM)prevac}, currently being performed at the Mainz University will be asked to
participate in Trial CV-NCOV-005. Trial CV-NCOV-005 will also include other HCWs, and
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In addition, a list of AEs of special interest (AESIs) to be monitored following administration
of investigational SARS-CoV-2 vaccines has been identified by the Brighton Collaboration
Safety Platform for Emergency vACcines (SPEAC) Project. If any suspected AESI (pIMD
or other AE specific to SARS-CoV-2 vaccines) should occur in a subject who received
CVnCoV, a diagnostic workup should be performed by a specialist depending on the type
of suspected reaction (e.g., endocrinologist for suspected autoimmune thyroiditis) and this
condition will be monitored and documented throughout the trial.
CVnCoV has not been investigated in combination with other drugs or vaccines. Given the
mechanism of action which relies on building up an adequate immune response, it is
expected that immunosuppressive drugs like steroids may inhibit the desired
pharmacological effect of the induction of a specific immune response against the
SARS-CoV-2 RBD of S protein. Similarly, drugs that enhance the immune response like
certain cytokines (IFN-
-2) may increase the response to the vaccines which could
theoretically result in increased efficacy, but also in an increased risk of toxicity.
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 h
3.2.2 
Known Potential Benefits
Subjects receiving the investigational CVnCoV vaccine may not directly benefit from this
vaccination as it is not known if CVnCoV is effective in protecting against COVID-19
disease. Subjects receiving saline placebo will not directly benefit from trial vaccination.
Trial subjects will receive the following benefits:
 
Subjects participating in this trial may benefit from having regular health checks as
part of the trial procedures (e.g., physical examination, vital signs assessment). Where
illnesses are newly diagnosed, a referral will be made for the subject to an appropriate
health provider.
 
If CVnCoV is found to be efficacious and meets regulatory approval, subjects in the
placebo group may be offered CVnCoV as soon as feasible.
 
If CVnCoV is found to be efficacious, then subjects will have made a significant public
health contribution.


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3.2.3 
Assessment of Potential Risks and Benefits
To minimize the risk for subjects participating in this trial, an independent DSMB will
oversee the safety of the participating subjects throughout the trial (see Section 9.3.8.1).
Potential important medical risks associated with CVnCoV, as specified in Section 3.2.1,
can be managed should they occur.
Since the efficacy results from the HERALD study for CVnCoV are available and all
subjects in the CV-NCOV-005 study are currently eligible to receive an authorized vaccine,
all subjects in this CV-NCOV-005 study will be unblinded.
Each subject will be informed by the study physician of the available study results and
whether he/she received the study vaccine (CVnCoV) or placebo in the study. The
purpose of this measure is to provide the participants/subjects with sufficient information
so that they can decide whether to take an authorized vaccine or not in a fully informed
way.


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4 TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS
4.1 Objectives
4.1.1 
Primary Objectives
Primary Safety Objective
 
To evaluate the safety (in all subjects) and reactogenicity (in a subset of subjects) of
CVnCoV administered as a 2-dose schedule to adults 18 years of age or older.
Primary Immunogenicity Objective
 
To assess antibody responses to the RBD of S protein of SARS-CoV-2 after 1 and
2 doses of CVnCoV in adults 18 years of age or older included in a subset of subjects.
4.1.2 
Secondary Objectives
Secondary Efficacy Objectives
 
To assess the efficacy of a 2-dose schedule of CVnCoV in the prevention of first
episodes of virologically-confirmed symptomatic cases of COVID-19 of any severity in
SARS-CoV-2 naïve subjects.
 
To describe the severity of first episodes of virologically-confirmed symptomatic cases
of COVID-19 in SARS-CoV-2 naïve subjects, receiving a 2-dose schedule of CVnCoV
compared to those administered placebo.
 
To assess the efficacy of a 2-dose schedule of CVnCoV in reducing the burden of
disease (BoD) from COVID-19.
Secondary Immunogenicity Objectives
 
To assess SARS-CoV-2 virus neutralizing antibody responses after 1 and 2 doses of
CVnCoV in adults 18 years of age or older included in a subset of subjects.
 
To assess lot-to-lot consistency of 2 CVnCoV lots, as measured by antibody
responses to the RBD of S protein of SARS-CoV-2, after 2 doses of CVnCoV, in adults
18 years of age or older included in a subset of subjects.
4.1.3 
Exploratory Objectives
Exploratory Efficacy Objective
 
To investigate in subjects with first episodes of virologically-confirmed COVID-19
during the trial:
 
The occurrence of second episodes of virologically-confirmed symptomatic
cases of COVID-19 of any severity, in SARS-CoV-2 naïve adults receiving a
2-dose schedule of CVnCoV compared to those administered placebo.
4.2 Endpoints
4.2.1 
Primary Endpoints
Primary Safety Endpoints


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Occurrence, intensity and relationship of medically-attended AEs collected through
6 months after the second trial vaccination in all subjects.
 
Occurrence, intensity and relationship of SAEs and AESIs collected through 1 year
after the second trial vaccination in all subjects.
 
Occurrence of fatal SAEs through 1 year after the second trial vaccination in all
subjects.
 
Occurrence of AEs leading to vaccine withdrawal or trial discontinuation through
1 year after the second trial vaccination in all subjects.
 
Occurrence, intensity and duration of each solicited local AE within 7 days after each
trial vaccination in a subset of subjects.
 
Occurrence, intensity, duration of each solicited systemic AE within 7 days after each
trial vaccination in a subset of subjects.
 
Occurrence, intensity and relationship of unsolicited AEs occurring within 28 days after
each trial vaccination in a subset of subjects.
Primary Immunogenicity Endpoints
SARS-CoV-2 RBD of S protein antibody responses in a subset of subjects
On Days 1, 29 and 43 in 250 subjects (200 subjects having received CVnCoV; 50 subjects
having received placebo):
 
Serum antibodies to SARS-CoV-2 RBD of S protein.
 
Occurrence of seroconversion to SARS-CoV-2 RBD of S protein.
 
Seroconversion is defined as detectable SARS-CoV-2 RBD of S protein antibodies
in the serum of subjects who tested seronegative at baseline.
4.2.2 
Secondary Endpoints
Secondary Efficacy Endpoints
 
Occurrence of first episodes of virologically-confirmed {reverse transcription
polymerase chain reaction (RT-PCR) positive} cases of COVID-19 of any severity
meeting the case definition for the efficacy analysis.
 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) cases of
COVID-19 meeting the case definition for the efficacy analysis by severity (mild,
moderate, severe and moderate to severe COVID-19) as defined in Appendix 3 and
Appendix 4.
 
BoD scores calculated based on first episodes of virologically-confirmed (RT-PCR
positive) cases of COVID-19 of any severity meeting the case definition for the efficacy
analysis.
 
BoD #1  no disease (not infected or asymptomatic infection) = 0; mild or moderate
disease = 1; severe disease = 2.


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BoD #2  no disease (not infected or asymptomatic infection) = 0; disease without
hospitalization = 1; disease with hospitalization = 2; death = 3.
Secondary Immunogenicity Endpoints
SARS-CoV-2 virus neutralizing antibody responses in a subset of subjects
On Days 1, 29 and 43:
 
Serum neutralizing antibodies to SARS-CoV-2 virus, as measured by a virus
neutralizing assay.
 
Occurrence of seroconversion to SARS-CoV-2 virus, as measured by a virus
neutralizing assay.
 
Seroconversion is defined as detectable SARS-CoV-2 virus neutralizing antibodies
in the serum of subjects who tested seronegative at baseline.
Lot-to-lot consistency of 2 CVnCoV lots, as measured by SARS-CoV-2 RBD of S protein
antibody responses in a subset of subjects
On Day 43:
 
Serum antibodies to SARS-CoV-2 RBD of S protein.
4.2.3 
Exploratory Endpoints
Exploratory Efficacy Endpoint
The following endpoint will be analyzed in subjects who had a first episode of a
virologically-confirmed (RT-PCR positive) case of COVID-19 of any severity meeting the
case definition for the efficacy analysis:
 
Occurrence of second episodes of virologically-confirmed (RT-PCR positive)
symptomatic cases of COVID-19 of any severity.
4.3 Estimands
ENDPOINTS (subject level)
ESTIMANDS (population level)
Primary Safety
 
Occurrence, intensity and relationship
of medically-attended AEs collected
through 6 months after the second trial
vaccination in all subjects.
 
Occurrence, intensity and relationship
of SAEs and AESIs collected through 1
year after the second trial vaccination in
all subjects.
 
Occurrence of fatal SAEs through 1
year after the second trial vaccination in
all subjects.
 
Occurrence of AEs leading to vaccine
withdrawal 
or 
trial 
discontinuation
In subjects who received at least 1 dose of
CVnCoV or placebo vaccine, the number and
percentage of subjects by group reporting at
least 1 and of each type {by System Organ Class
(SOC)/preferred term (PT)} of:
 
Medically-attended AE collected through
6 months after the second trial vaccination


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through 1 year after the second trial
vaccination in all subjects.
 
Occurrence, intensity and duration of
each solicited local AE within 7 days
after each trial vaccination in a subset
of subjects.
 
Occurrence, intensity, duration and
relationship of each solicited systemic
AE within 7 days after each trial
vaccination in a subset of subjects.
 
Occurrence, intensity and relationship
of unsolicited AEs occurring within 28
days after each trial vaccination in a
subset of subjects.
overall, by intensity and by causal relationship
to trial vaccine.
 
SAE collected through 1 year after the second
trial vaccination overall and by causal
relationship to trial vaccine.
 
AESI collected through 1 year after the
second trial vaccination overall, by intensity
and by causal relationship to trial vaccine.
 
Fatal SAE collected through 1 year after the
second trial vaccination.
 
At least 1 AE leading to vaccine withdrawal
or trial discontinuation through 1 year after
the second trial vaccination.
In subjects who received at least 1 dose of
CVnCoV or placebo vaccine, and belong to the
Immunogenicity/Reactogenicity subset,
the number and percentage of subjects by group
reporting:
 
Each solicited local AE within 7 days after
each trial vaccination by intensity and overall.
 
Each solicited systemic AE within 7 days after
each trial vaccination by intensity, by
relationship to trial vaccine and overall.
 
At least 1 unsolicited AE, at least 1 grade 3
unsolicited AE and each unsolicited AE by
SOC/PT occurring within 28 days after each
trial vaccination and overall by causal
relationship to trial vaccine and overall.
The mean duration in days by group with
standard deviation of solicited AEs will be
described.
Primary Immunogenicity
SARS-CoV-2 RBD of S protein antibody
responses
On Days 1, 29 and 43:
 
Serum antibodies to SARS-CoV-2 RBD
of S protein.
 
Occurrence 
of 
seroconversion 
to
SARS-CoV-2 RBD of S protein
 
Seroconversion 
is 
defined 
as
detectable SARS-CoV-2 RBD of S
protein antibodies in the serum of
subjects who tested seronegative
at baseline.
In subjects belonging to the
Immunogenicity/Reactogenicity subset and
evaluable {complying with the definition of Per
Protocol Immunogenicity Subset (PPI)}:
On Days 1, 29 and43:
 
Geometric mean concentrations (GMCs) with
95% CI of SARS-CoV-2 RBD of S protein
antibody responses by group and by baseline
sero-status.
On Days 29 and43 for subjects seropositive at
baseline:
 
Geometric mean of Fold Change from
baseline (GMFC) with 95% CI of SARS-CoV-2
RBD of S protein antibody responses by
group.
On Days 29 and 43 for subjects seronegative at
baseline:
 
Number and percentage with exact 95%CI of
subjects by group for whom a seroconversion


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is observed (detectable SARS-CoV-2 RBD of
S protein antibodies in the serum).
Secondary Efficacy
 
Occurrence of first episodes of
virologically-confirmed (RT-PCR
positive) cases of COVID-19 of any
severity meeting the case definition for
the efficacy analysis.
In naïve evaluable subjects {complying with the
definition of efficacy analysis set (EAS)} at least
15 days following second vaccination:
 
VE = 1- RR with exact 95% CI
Where RR (relative risk) is the ratio of attack
rates of COVID-19 cases per 100 person-month
in the CVnCoV vaccine groups (pooled lots) over
the placebo group
 
Occurrence of first episodes of
virologically-confirmed (RT-PCR
positive) cases of COVID-19 meeting
the case definition for the efficacy
analysis by severity (mild, moderate,
severe and moderate to severe
COVID-19) as defined in Appendix 3
and Appendix 4.
In naïve evaluable subjects (complying with the
definition of EAS) at least 15 days following
second vaccination:
 
The number and percentage of subjects who
developed 
a 
first 
episode 
of
virologically-confirmed 
(RT-PCR 
positive)
cases of COVID-19 meeting the case
definition for the efficacy analysis, by severity
(mild, moderate, severe and moderate to
severe, as defined in Appendix 3 and
Appendix 4).
 
BoD scores calculated based on first
episodes 
of 
virologically-confirmed
(RT-PCR positive) cases of COVID-19
of any severity meeting the case
definition for the efficacy analysis.
 
BoD #1
 no disease (not infected
or asymptomatic infection) = 0; mild
or moderate disease = 1; severe
disease = 2.
 
BoD #2
 no disease (not infected
or asymptomatic infection) = 0;
disease without hospitalization = 1;
disease with hospitalization = 2;
death = 3.
In naïve evaluable subjects (complying with the
definition of EAS) at least 15 days following
second trial vaccination:
 
VEBoD= 1-RR with 95% CI
Where RR is the ratio of the BoD score in the
CVnCoV vaccine groups (pooled lots) divided
by the BoD score in the placebo group


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Secondary Immunogenicity
SARS-CoV-2 virus neutralizing antibody
responses in a subset of subjects
On Days 1, 29 and43:
 
Serum 
neutralizing 
antibodies 
to
SARS-CoV-2 virus, as measured by a
virus neutralizing assay.
 
Occurrence 
of 
seroconversion 
to
SARS-CoV-2 virus, as measured by a
virus neutralizing assay.
 
Seroconversion 
is 
defined 
as
detectable 
SARS-CoV-2 
virus
neutralizing antibodies in the serum
of 
subjects 
who 
tested
seronegative at baseline.
In subjects belonging to the
Immunogenicity/Reactogenicity subset and
evaluable (complying with the definition of the
PPI):
On Days 1, 29 and 43:
 
GMT with 95% CI of neutralizing antibodies to
SARS-CoV-2 virus by group and by baseline
sero-status
On Days 29 and 43 for subjects seropositive at
baseline:
 
GMFC with 95% CI of neutralizing antibodies
to SARS-CoV-2 virus by group.
On Days 29 and 43 for subjects seronegative at
baseline:
 
Number and percentage with exact 95%CI of
subjects by group for whom a seroconversion
is 
observed 
(detectable 
neutralizing
antibodies to SARS-CoV-2 virus in the
serum).
Lot-to-lot consistency of 2 CVnCoV lots, as
measured by SARS-CoV-2 RBD of S
protein antibody responses in a subset of
subjects
On Day 43:
Serum antibodies to SARS-CoV-2 RBD
of S protein.
In evaluable subjects of the
Immunogenicity/Reactogenicity Subset, who
belong to 1 of the CVnCoV vaccine groups, have
a negative SARS-CoV-2 RBD of S protein
antibody concentration at baseline:
 
Ratio of GMCs of SARS-CoV-2 RBD of
S protein 
antibodies 
between 
subjects
receiving 2 different lots of CVnCoV on
Day 43
Exploratory Efficacy
The following endpoint will be analyzed in
subjects who had a first episode of a
virologically-confirmed (RT-PCR positive)
case of COVID-19 of any severity meeting
the case definition for the efficacy analysis.
 
Occurrence of second episodes of
virologically-confirmed 
(RT-PCR
positive) cases of COVID-19 of any
severity.
In naïve evaluable subjects (complying with the
definition of EAS) who had a first episode of a
virologically-confirmed (RT-PCR positive) case of
COVID-19 of any severity meeting the case
definition for the efficacy analysis, at least 15 days
following second trial vaccination:
 
The number and percentage of subjects who
developed a second episode of COVID-19.


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5 TRIAL DESIGN
5.1 Overall Design
The trial will be conducted as a randomized, observer-blinded, placebo-controlled trial.
Subjects will receive a 2-dose schedule, 28 days apart, of either 1 of 2 lots CVnCoV, at a
dose level of 12 µg mRNA, or placebo {normal saline (0.9% NaCl}) in a 1:1:1 ratio.
Approximately 2,520 subjects (840 by randomization group), 18 years of age or older,
previously enrolled in the non-interventional trial performed at the Mainz University,
Germany (COVID19-5-P-002), other HCWs and potentially students in clinical training will
be enrolled.
The safety, reactogenicity and immunogenicity of a 2-dose schedule of CVnCoV in HCWs
will be assessed descriptively.
The primary safety objective is to expand the safety database that will demonstrate the
safety profile of CVnCoV. The safety and reactogenicity of a 2-dose schedule of CVnCoV
will be assessed in detail by measuring the frequency and severity of the following AEs:
solicited local and systemic AEs on the day of vaccination and for the following 7 days
after each vaccination in a subset of subjects (Immunogenicity/Reactogenicity Subset);
unsolicited AEs on the day of vaccination and for the following 28 days after each
vaccination 
in 
a subset 
of subjects 
(Immunogenicity/Reactogenicity 
Subset);
medically-attended AEs through 6 months after the second trial vaccination in all subjects;
and AESIs and SAEs through 1 year after the second trial vaccination in all subjects (see
Appendix 9 and Appendix 10).
A DSMB will perform a review at regular meetings of the available safety data of both
Trials CV-NCOV-004 and CV-NCOV-005.
The immunogenicity of CVnCoV after 1 and 2 doses will be evaluated in a subset of
subjects (Immunogenicity/Reactogenicity Subset) by measuring binding antibodies to the
SARS-CoV-2 RBD of S protein for the primary immunogenicity objective, and by
measuring viral neutralizing antibodies for the secondary immunogenicity objective.
Antibody persistence will be evaluated.
It will be evaluated descriptively in a subset of subjects (Immunogenicity/Reactogenicity
Subset) if antibody responses to the RBD of S protein of SARS-CoV-2 induced by
2 different lots of CVnCoV are equivalent when measured on Day 43.
As a secondary efficacy objective of the CV-NCOV-005 trial, the efficacy of a 2-dose
schedule of CVnCoV in the prevention of first episodes of virologically-confirmed cases of
COVID-19 of any severity in SARS-CoV-2 naïve subjects will be assessed. The severity
of COVID-19 cases occurring in the CVnCoV and placebo groups will also be described
as a secondary objective.
Subjects will undergo active surveillance for COVID-19 (see Appendix 6). During all site
visits and phone calls, subjects will be reminded to contact the site if they have an acute
illness with any symptoms clinically consistent with COVID-19 or if they tested positive for
SARS-CoV-2 outside of the trial context. In addition, subjects will be messaged up to twice
a week and will provide a yes or no response to having COVID-19 symptoms. Those who
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the investigator considers the symptoms could potentially indicate a COVID-19 case. If a
subject is suspected of having COVID-19 illness or if they tested positive for SARS-CoV-2
outside of the trial context, he/she will undergo testing for SARS-CoV-2 infection with
samples collected at the site or at a home visit. All subjects with confirmed COVID-19 will
be followed until resolution of their disease. If the virogically-confirmed COVID-19 case
occurred after the first trial vaccination but prior to the second, this second vaccination can
be administered once the subject is 2 weeks symptom-free, and provided the dose can be
administered within the predefined visit window.
progress must continue to be followed by the Investigator and a discharge summary
obtained at the end of the hospitalization. Information on clinical symptoms and signs,
their duration and severity, and treatment and outcome of the COVID-19 episode will be
documented by trial staff and recorded in the electronic case report form (eCRF). Upon
resolution, subjects will continue to be followed through the trial end in the same manner
as those who have not presented with COVID-19. A second or subsequent episode of
COVID-19 in a subject with prior disease will be counted for the exploratory objective
assessing the reoccurrence of COVID-19 in vaccinated subjects.
For the analysis of efficacy against COVID-19 disease, the case must meet the following
criteria (mild, moderate and severe COVID-19 disease is defined in Appendix 3 and
Appendix 4):
 
Must be a virologically-confirmed case of COVID-19 defined as a positive
SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19
(see Section 9.2).
following the second trial vaccination.
 
The subject must not have a history of virologically-confirmed COVID-19 at enrollment
(based on exclusion criterion 1) or have developed a case of virologically-confirmed
COVID-19 before 15 days following the second trial vaccination (see Section 10.2.4,
EAS population for more details).
 
The subject must have been demonstrated to be SARS-CoV-2 naïve at baseline and
at Day 43 (seronegative to N protein).
These efficacy cases might be confirmed by the Adjudication Committee.
The DSMB will periodically monitor COVID-19 cases across CV-NCOV-004 and
CV-NCOV-005 for signals of VDE with pre-specified criteria for halting based on these
signals.
An interim analysis is planned. The cut-off date for the interim analysis in CV-NCOV-005
will be based on the regulatory requirements to obtain early conditional approval in
Europe. All subjects will be unblinded after the final analysis results of trial CV-NCOV-004.
Subjects of the study CV-NCOV-005 who were assigned to CVnCoV will continue, until
the end of the trial {when the last subject has completed the last visit on Day 393 (see
Section 5.4)}. During this period, accrual of COVID-19 cases will continue. Subjects who
were assigned to placebo will not continue after unblinding and will be invited to an End
of Trial visit for a final safety examination.


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5.2 Scientific Rationale for Trial Design
See also Sections 3.2 and 5.1.
The difference in appearance and presentation of the investigational CVnCoV vaccine and
placebo requires the trial to be conducted in an observer-blinded manner, which is a
commonly used and well-accepted method for trial blinding. The randomized,
observer-blinded, and placebo-controlled design will reduce the risk of bias in the safety,
immunogenicity and efficacy outcomes of the trial (see also Section 7.3).
A total of 3,500-4,000 subjects is aimed to participate in the observational trial COVID19-5-
P-002 at the University of Mainz. HCWs participating to the observational trial COVID19-
5-P-002 will be invited to participate in the CV-NCOV-005 trial. Pending the number of
subjects continuing from the observational trial in the CV-NCOV-005 trial, additional
HCWs, and potentially students in clinical training will be recruited for the present trial.
Participants of COVID19-5-P-002 who do not join CV-NCOV-005 will continue
participation in COVID19-5-P-002.
The primary safety objective is to generate a large-scale safety database that will
demonstrate the safety of CVnCoV among HCWs. The safety and reactogenicity of a
2-dose schedule of CVnCoV will be assessed in detail by measuring the frequency and
severity of the following AEs: solicited local and systemic reactions for 7 days after each
vaccination; unsolicited AEs for 28 days after each vaccination; medically-attended AEs
through 6 months after the second trial vaccination; and AESIs and SAEs through 1 year
after the second trial vaccination. As such, each subject will participate in the trial for
approximately 13 months for the safety follow-up.
The detailed reactogenicity and immunogenicity data generated in Phase 2b of Trial
CV-NCOV-004 will be the main dataset to be submitted in support of early conditional
approval of CVnCoV. The present trial will provide additional safety and immunogenicity
data, in the intended trial population of adults at the selected dose level, to be available
for the file to be submitted to obtain early conditional approval in the European Union.
As a secondary efficacy objective, the efficacy of a 2-dose schedule of CVnCoV in the
prevention of first episodes of virologically-confirmed cases of COVID-19 of any severity
in SARS-CoV-2 naïve subjects will be assessed.
For the analysis of efficacy against COVID-19 disease, COVID-19 case ascertainment
following the second vaccination of CVnCoV. This time point allows
the immune response to mature and reach its full height following the second dose. As
such, case ascertainment starting at this time point represents the evaluation of full VE of
CVnCoV against COVID-19.
The trial will run in parallel with CV-NCOV-004, and will follow the design of the Phase 3
part of that trial, including case collection and work-up, so that an integrated analysis of
VE taking potential trial heterogeneity into account can be conducted (see Section 3.1.4).
Individuals with history of virologically-confirmed COVID-19 illness will be excluded from
participating in this trial, as well as subjects with history of asymptomatic
virologically-confirmed SARS-CoV-2 infection
or SARS-CoV-2 positive serology.
SARS-CoV-2 serology will be known for all subjects enrolled in Trial CV-NCOV-005 from
the trial COVID19-5-P-002, but not necessarily for other HCWs and medical students


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enrolling in trial CV-NCOV-005. The CV-NCOV-005 trial will not screen these subjects for
virologically-confirmed SARS-CoV-2 infection or SARS-CoV-2 positive serology. In
addition, routine RT-PCR testing will not be performed at screening to exclude individuals
with SARS-CoV-2 infection at the time of enrollment.
5.3 Justification for Dose
Selection of the 12 µg mRNA dose level of CVnCoV for Trial CV-NCOV-005 was based
on the safety, tolerability and immunogenicity results from Trials CV-NCOV-001 and
CV-NCOV-002.
5.4 End of Trial Definition
A subject is considered to have completed the trial when he/she has completed all visits,
and procedures and tests applicable for the group to which he/she was randomized to.
End of trial CV-NCOV-005 is defined as when the last subject who received CVnCoV has
completed the last visit on Day 393 or prematurely discontinued the trial. Placebo subjects
will discontinue the trial once study protocol version 3.0 and 4.0 are approved.
5.5 Stopping/Pausing Rules for Safety
5.5.1 
Individual Subject Stopping Rules
The individual subject stopping rules are met in case any of the following events occur
after the first trial vaccination:
An allergic/anaphylactic reaction considered as related to the trial vaccine
Any SAE considered as related to the trial vaccine
If any of these rules are met, the subject must not receive the second vaccine dose. The
subject will be encouraged to continue participation until the end of the trial for safety.
5.5.2 
Pausing of the Trial
The decision to pause the trial (i.e. temporary stopping of enrollment and vaccinations)
due to a safety signal will be based on a recommendation from the DSMB in consultation
with the Sponsor (see Section 9.3.8.1). The DSMB may recommend pausing the trial for
a safety concern following a review of accumulating safety data presented at the regularly
scheduled DSMB meetings or from an ongoing review of AEs, which include but are not
limited to, suspected unexpected serious adverse reactions (SUSARs); all SAEs judged
as related to trial vaccine; concerning SAEs (e.g., AESIs); and all life-threatening SAEs
and deaths. These events will be monitored by the DSMB on a regular basis during the
trial. The selected AEs and procedures for the safety review are described in detail in the
DSMB Charter.
To ensure subject safety on an ongoing basis, a blinded 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


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Trial Team that there are no safety concerns. Conversely, if there is a safety concern, the
Chair may unblind the AE or AEs and, if necessary, convene an ad-hoc DSMB meeting
for further assessment of the event(s).
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.
responsibilities.


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6 TRIAL POPULATION
The criteria for enrollment are to be followed explicitly. If it is noted that a subject who does
not meet 1 or more of the inclusion criteria and/or meets 1 or more of the exclusion criteria
is inadvertently enrolled and dosed, the Sponsor must be contacted immediately.
In this trial, individuals with history of virologically-confirmed COVID-19 illness will be
excluded from participating in this trial, as well as subjects with history of asymptomatic
virologically-confirmed SARS-CoV-2 infection or SARS-CoV-2 positive serology.
SARS-CoV-2 serology will be known for all subjects enrolled in trial CV-NCOV-005 from
the trial COVID19-5-P-002, but not necessarily for other HCWs and medical students
enrolling in trial CV-NCOV-005. The CV-NCOV-005 trial will not screen these subjects for
virologically-confirmed SARS-CoV-2 infection or SARS-CoV-2 positive serology. In
addition, routine RT-PCR testing will not be performed at screening to exclude individuals
with SARS-CoV-2 infection at the time of enrollment.
Any country specific regulation(s) will be adhered to in addition.
6.1 Inclusion Criteria for All Subjects
Subjects will be enrolled in this trial only if they meet all of the following criteria:
1. 
Male or female subjects 18 years of age or older.
2. 
HCWs, employees or students in clinical training.
3. 
Provide written informed consent prior to initiation of any trial procedures.
4. 
Expected compliance with protocol procedures and availability for clinical follow-up
through the last planned visit.
5. 
Females of non-childbearing potential defined as follows: surgically sterile (history
of bilateral tubal ligation/occlusion, bilateral oophorectomy or hysterectomy) or
postmenopausal {
 12 consecutive months prior to
screening (Day 1) without an alternative medical cause}. A follicle-stimulating
hormone level may be measured at the discretion of the Investigator to confirm
postmenopausal status.
6. 
Females of childbearing potential: negative urine pregnancy test (human chorionic
gonadotropin) within 24 hours prior to each trial vaccination on Day 1 and Day 29.
7. 
Females of childbearing potential must use highly effective methods of birth control
from 2 weeks before the first administration of the trial vaccine until 3 months
following the last administration. The following methods of birth control are
considered highly effective when used consistently and correctly:
 
Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal or transdermal);
 
Progestogen-only hormonal contraception associated with inhibition of ovulation
(oral, injectable or implantable);
 
Intrauterine devices;
 
Intrauterine hormone-releasing systems;


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


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trial participation, render the subject unable to meet the requirements of the trial, or
uncontrolled cardiovascular disease, gastrointestinal disease, liver disease, renal
disease, respiratory disease, endocrine disorder, and neurological and psychiatric
illnesses. However, those with controlled and stable cases can be included in the trial.
14. Subjects with impaired coagulation or any bleeding disorder in whom an IM injection
or a blood draw is contraindicated.
15. Foreseeable non-compliance with the trial procedures as judged by the Investigator.
6.3 Vaccine Delay Recommendations
After enrollment, subjects may encounter clinical circumstances that could warrant a delay
of trial vaccine administration as described below.
of intended trial vaccination on Day 1 or Day 29. This includes symptoms that could
represent COVID-19 illness.
- 
Trial vaccination should be delayed until the active infection or other acute disease
< 38.0°C (< 100.4°F). Following resolution of the illness, the subject may be
rescheduled for trial vaccination based on the judgment of the Investigator.
- 
Afebrile subjects with a minor illness may be vaccinated at the discretion of the
Investigator.
 
For subjects who develop virologically-confirmed COVID-19 after the first trial
vaccination but prior to the second; this second vaccination can be administered once
the subject is 2 weeks symptom-free, and provided the dose can be administered
within the predefined visit window.
 
Receipt of a licensed vaccine within 28 days (for live vaccines) or 14 days
(for inactivated vaccines) prior to or after scheduled administration of trial vaccine. As
these are recommended windows, rescheduling trial vaccination to be compliant with
these windows should only be done if practical.
6.4 Failure to Meet Eligibility Criteria
The Investigator must account for all subjects who sign an informed consent. If the subject
is found to be not eligible (i.e., did not meet all inclusion criteria or met 1 or more exclusion
c
Re-screening, i.e., re-doing the full assessments for eligibility criteria as per Table 1 and
Table 2 or re-doing 1 assessment, are allowed by the Investigator.


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7 TRIAL VACCINE
7.1 Trial Vaccine Administration
7.1.1 
Description of the Trial Vaccines
CVnCoV is an investigational LNP-formulated RNActive® SARS-CoV-2 vaccine. The IMP
is composed of the active pharmaceutical ingredient, an mRNA that encodes the stabilized
full-length S protein, and 4 lipid components: cholesterol, 1,2-distearoyl-sn-glycero-3-
phosphocholine, PEG-ylated lipid and a cationic lipid. It is supplied as a concentrate at
1 mg/mL of mRNA drug substance. Two different lots of the CVnCoV vaccine will be used.
The placebo vaccine will be sterile normal saline (0.9% NaCl) for injection.
7.1.2 
Dosing and Administration
7.1.2.1 CVnCoV
Subjects randomized to CVnCoV will receive 2 injections of CVnCoV at a dose level of
12 µg mRNA, administered 28 days apart.
Administration of CVnCoV must be performed by IM injection in the deltoid area,
preferably in the non-dominant arm. CVnCoV is intended strictly for IM injection and must
not be injected subcutaneously, intradermally, or intravenously. The instructions for
injection as described in the Pharmacy Manual must be followed.
7.1.2.2 Placebo Control (Normal Saline)
Subjects randomized to the control group of the trial will receive 2 doses of saline placebo
{normal saline (0.9% NaCl) for injection}, administered 28 days apart.
Administration of saline placebo must be performed by IM injection in the deltoid area,
preferably in the non-dominant arm. The instructions for injection described in the
Pharmacy Manual must be followed.
7.1.2.3 Hypersensitivity Reactions to Vaccination
CVnCoV should not be administered to subjects with a known hypersensitivity to any of
the components of the vaccine.
Since there is a theoretical risk of anaphylactic reactions, trial vaccine must only be
administered if emergency equipment for the treatment of anaphylactic reactions
(intravenous fluids, corticosteroids, H1 and H2 blocking agents, epinephrine, equipment
for cardiopulmonary resuscitation) is readily available. All subjects must remain under
direct supervision of personnel trained in the treatment of these reactions for at
least 30 minutes following administration of trial vaccine.
If anaphylaxis or severe hypersensitivity reactions occur following trial vaccine
administration, no further doses should be given (see Sections 5.5.1 and 8.1).
7.2 Preparation/Handling/Storage/Accountability
Refer to the Pharmacy Manual for detailed information on the preparation, handling,
storage and blinding of CVnCoV and saline placebo.


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7.2.1 
CVnCoV Preparation
The concentrated CVnCoV must be diluted in the provided sterile normal saline (0.9%
NaCl) diluent containing preservative to produce the dose solution for IM injection. This
will be prepared by an unblinded qualified pharmacist/site personnel according to the
Handling Manual for the IMP provided by CureVac AG. The unblinded pharmacist/site
personnel will have no other trial function following vaccination and will maintain the
treatment assignments in strict confidence.
7.2.2 
CVnCoV Product Storage and Stability
Concentrated CVnCoV will be shipped to the site frozen at below -60°C.
Once at the site, concentrated CVnCoV should be stored frozen at below -60°C.
7.2.3 
Placebo Control (Normal Saline)
The normal saline placebo control vaccine should be stored according to the Summary of
Product Characteristics. Placebo will be prepared for injection by an unblinded
pharmacist/site personnel.
7.2.4 
Accountability
It is the responsibility of the Investigator to ensure that the current and accurate records
of trial supplies received, stored, and dispensed at the site are maintained using
appropriate forms according to applicable regulations and guidelines. The trial supplies
must be stored under the recommended storage conditions, locked with restricted access
(refer to the Pharmacy Manual). Authorized personnel must dispense the vaccine at the
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 site with the following
information:
 
Dates and quantities of CVnCoV received from CureVac.
 
Unique subject identifier.
 
Date and quantity of trial vaccine dispensed to each subject.
 
Initials of the person preparing the dose.
Initials of the person administering the vaccine.
These logs must be readily available for inspections and are open to regulatory inspection
at any time.
7.3 Randomization and Blinding
The trial will be randomized, observer-blinded, and placebo-controlled. The difference in
appearance of the investigational CVnCoV vaccine and placebo required the trial to be
conducted in an observer-blinded manner, which is a well-accepted method for blinding.


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7.3.1 
Randomization
Approximately 2,520 subjects 18 years of age or older will be enrolled at the site at Mainz
University, Germany and will be randomized in a 1:1:1 ratio (840 by randomization group)
to receive either 1 of 2 different lots of CVnCoV (CVn CoV Lot 1 group and CVnCoV Lot
2 group) or placebo (placebo group). The randomization will be performed centrally and
be generated and maintained by the Statistical and Data Management group at the
contract research organization (CRO), PRA. Subjects will be enrolled into the trial online
and randomized using an interactive web response system (IWRS). After demographic
and eligibility criteria are entered into the system, subjects enrolled into the trial will be
assigned their treatment assignment.
The 
first 
1,260 
subjects 
enrolled 
are 
planned 
to 
be 
included 
in 
the
Immunogenicity/Reactogenicity Subset.
7.3.2 
Blinding
Subjects will be randomized and vaccinated with CVnCoV or placebo in an
observer-blinded manner (due to the difference in appearance and presentation of the
investigational CVnCoV vaccine and placebo). The pharmacist/ personnel preparing the
trial vaccine at the site will not be blinded to the identity of the trial vaccine being
administered to the subject. However, the vaccinator, Investigator and all site personnel
involved in the conduct of the trial (including follow-up of safety and COVID-19 case
ascertainment) will be blinded to trial vaccine and subject treatment assignments. To
maintain the blinding of the vaccinator, the unblinded pharmacist/site personnel will
provide the dose of trial vaccine to the vaccinator prefilled in a syringe with a label covering
the liquid contents so that it is not visible. All personnel at the CRO and Sponsor directly
involved in the conduct of the trial will also be blinded. There will be certain individuals at
the CRO and Sponsor whose function requires them to be unblinded during the trial {e.g.,
unblinded monitoring for trial vaccine accountability in the pharmacy; unblinded
independent statistician assisting the DSMB; review of immunogenicity data (see next
paragraph)}. These unblinded individuals will be identified and their responsibilities
documented.
the independent laboratory performing the assays will keep the results in strict confidence.
An unblinded person, named at the start of the trial and independent of the conduct of the
trial, will have the responsibility of reviewing the quality of the immunogenicity data as it is
being generated. This person will maintain the results in strict confidence. To maintain the
blind, the immunogenicity data will only be merged with the clinical database following
unblinding of the trial.
It will be at the discretion of the DSMB members whether or not safety data reviewed at
the DSMB meetings will be unblinded. If there are any safety concerns, the DSMB may
request unblinding of an individual subject or a specific dataset at any time. In addition,
the DSMB will periodically monitor COVID-19 cases by vaccine group for signals of VDE.
For the submission of documents for regulatory approval during the ongoing conduct of
Trial CV-NCOV-004 and CV-NCOV-005 (e.g., if efficacy is demonstrated at 1 of the interim
analyses), an unblinded Submission Team will be formed which will be completely


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independent of the team conducting the trial. The Submission Team will comprise
individuals from the Sponsor and CRO, and their roles and responsibilities on the
unblinded team will be clearly defined.
7.3.3 
Unblinding
7.3.3.1 Emergency Unblinding
Individual unblinding should only occur in emergency situations for reasons of subject
safety when knowledge of the trial vaccine is essential for the clinical management or
welfare of the subject. Unblinding in this situation will be based on the judgment of the
Investigator, ideally in discussion with the Sponsor.
In general, the identity of the trial vaccine should not affect the clinical management of any
SAE/AE. Whenever possible, the Investigator should attempt to contact the Sponsor
before breaking the blind to discuss the need for emergency unblinding. Once agreed,
code-breaking will be carried out via the IWRS.
When the blind is broken, the date, exact timing, and reason must be fully documented in
the source documents. The Investigator should not inform other blinded trial staff of the
identity of the IMP.
If the code has been broken and there are no medical reasons for discontinuation, the
subject may continue in the trial. If the subject has received at least 1 dose of trial vaccine,
it will be the judgment of the Investigator, in consultation with the Sponsor, whether the
subject will be vaccinated with the second dose. If the subject is discontinued from the
trial, every effort should be made to continue safety follow-up of the subject until the end
of the trial.
7.3.3.2 Authorized/Licensed Vaccine
Unblinding is allowed in case a subject becomes eligible to receive an authorized/licensed
vaccine.
Following the availability of the efficacy results from the HERALD study for CVnCoV and
given that all subjects in this present study are currently eligible to receive an authorized
vaccine, all subjects in this CV-NCOV-005 trial will be unblinded.
7.4 Vaccine Compliance
page.
7.5 Misuse and Overdose
Definition of misuse: Situations where the trial vaccine is intentionally and
inappropriately used not in accordance with the protocol dosing instructions or authorized
product information.
Definition of overdose: Administration of a quantity of the trial vaccine given per
administration or cumulatively which is above the maximum recommended dose
according to the protocol dosing instructions or authorized product information.


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No toxic effects are expected from current clinical and non-clinical experience. Possible
local reactions (pain) or systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia,
nausea/vomiting and diarrhea) may be treated symptomatically with physical measures,
paracetamol, or non-steroidal anti-inflammatory drugs.
7.6 Concomitant Therapy and Vaccines
Concomitant medication for underlying diseases and the underlying disease for which it is
For all subjects, concomitant therapies associated with an SAE or an AESI will be collected
and recorded in the eCRF from the moment of informed consent was obtained through
the end of the trial. Concomitant therapies associated with medically-attended AEs
occurring from the moment of vaccination until 6 months after vaccination will also be
collected and recorded in the eCRF.
For all subjects, concomitant therapies associated with COVID-19 will be captured in the
eCRF for the duration of the trial.
For subjects in the immunogenicity / reactogenicity subset of the trial, concomitant
therapies associated with unsolicited AEs occurring from the time of vaccination through
28 days after vaccination will be collected and recorded in the eCRF. Concomitant
therapies associated with solicited AEs occurring from the time of vaccination through 7
days after vaccination will also be collected and recorded in the eCRF.
Throughout the entire trial, any medications/vaccines prohibited according to
Section 7.6.2, including immunosuppressants or other immune-modifying drugs need to
be documented, if taken by a subject.
7.6.1 
Permitted Medications/Vaccines During the Trial
Subjects are permitted to use antipyretics and other pain medications to treat any ongoing
condition(s) the subject may have. Antipyretics (e.g., paracetamol) or other pain
medication may be used to treat any local and/or systemic reactions associated with trial
vaccination. Paracetamol taken prophylactically for potential vaccine-associated reactions
is also permitted in this trial. For example, if a subject experiences adverse reactions
following the first trial vaccination, paracetamol may be taken prophylactically for these
reactions for the second trial vaccination. In this case, paracetamol (up to 1 gram dose)
may be taken after trial vaccination and at bedtime, and then in the morning and at bedtime
during the next day. Alternatively, a 500 mg dose of paracetamol may be taken every
6 hours after trial vaccination for up to 36 hours. The dose and dosing schedule of
paracetamol should be discussed with the Investigator.
Paracetamol administered as a treatment for vaccine-associated reactions or for
prophylaxis, along with timing of administration with respect to trial vaccination must be
documented in the eCRF.
Other than the prohibited medications and vaccines described in Section 6.2 and listed
below in Section 7.6.2
pre-existing medical conditions are permitted.


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7.6.2 
Prohibited Medications/Vaccines During the Trial
 
Use of any investigational or non-registered product (vaccine or drug) is prohibited
during the trial.
 
Authorized SARS-CoV-2 vaccines are allowed. An interval of at least 21 days should
be observed between the last dose of CVnCoV and the authorized vaccine.
 
Other licensed vaccines should not be administered within 28 days (for live vaccines)
or 14 days (for inactivated vaccines) of trial vaccine administration during the trial.
 
Receipt of any other investigational SARS-CoV-2 vaccine or vaccines against other
virus from the coronavirus family is prohibited during the trial.
 
Any treatment with immunosuppressants or other immune-modifying drugs (including
but not limited to corticosteroids, biologicals and methotrexate) is prohibited during the
trial. For corticosteroid use, this means prednisone or equivalent, 0.5 mg/kg/day for
14 days or more. The use of inhaled, topical, or localized injections of corticosteroids
(e.g., for joint pain/inflammation) is permitted.
 
Administration of immunoglobulins or any blood products is prohibited during the trial.
7.7 Therapy Leading to Discontinuation
If a subject requires therapy listed as an exclusion criterion in Section 6.2 and which
cannot be delayed, discontinuation would be considered to ensure integrity of the trial
data, following individual case review. Every effort should be made to continue safety
follow-up of the subject until the end of the trial.
7.8 Treatment After the End of Trial
No post-trial care will be provided.


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8 DISCONTINUATION/WITHDRAWAL CRITERIA
Participation in the trial is strictly voluntary. A subject has the right to withdraw from the
trial at any time and for any reason. The Investigator has the right to withdraw a subject
from
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 CVnCoV will be encouraged to continue
participation until the end of the trial for safety assessments.
8.1 Discontinuation of Trial Vaccine Administration
The primary reason for discontinuation of further administration of trial vaccine will be
 
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
category).
 
The subject becomes eligible to receive an authorized/licensed SARS-CoV-2 vaccine,
requests to be unblinded, and refrains from getting the second dose of trial vaccine.
 
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.
 
Pregnancy (see Section 9.3.4).
Any subject who, despite the requirement for adequate contraception, becomes
pregnant during the trial will not receive further trial vaccine doses. The site should
y
-up until the birth
of the child, or spontaneous or voluntary termination. When pregnancy outcome
information becomes available, the information should be captured using the same
form. The subject should be reported as an IMP discontinuation and the reason
(i.e. pregnancy) should be given.
 
Trial terminated by the Sponsor (in which case the minimum safety follow-up
conducted at the end of trial visit on Day 393 would be performed in subjects who
received CVnCoV).


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Major protocol deviation.
 
Other.
8.2 Withdrawal from the Trial
Subjects should be withdrawn from the trial in case any of the following situations occur:
 
The subject has experienced an AE that requires early termination because
subject is unwilling to continue because of the AE. The reasons for not performing
further safety or immunogenicity assessments should be documented.
 
The subject did not return to the site and multiple attempts (a minimum of
3 attempts) to contact the subject were unsuccessful (lost to follow-up).
 
The subject wishes to withdraw from the trial. The reason for withdrawal, if
provided, should be recorded; this could include the availability of an approved
COVID-19 vaccine.
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
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.
After trial unblinding, i.e. after approval of study protocol version 3.0 and 4.0, all placebo
subjects should be withdrawn at the earliest possible timepoint, if their originally planned
End of Trial visit is later than February 2022 and will undergo the same procedures as for
the End of Trial visit at their withdrawal visit. If a withdrawal visit cannot be scheduled for
placebo subjects due to the pandemic setting, the end of trial assessment, i.e. collection
of final safety data, can also be done by phone. In the e-CRF, the withdrawal reason for
Discontinued or withdrawn subjects will not be replaced.
8.3 Trial Termination
The Sponsor reserves the right to terminate the trial at any time. Possible reasons for trial
termination include the following:
 
Outcome of the interim analysis may show high VE or futility.
 
Safety reasons: the incidence of AEs in this or any other trial using a related vaccine
indicates a potential health risk for the subjects.


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New scientific knowledge becomes known that makes the objectives of the trial no
longer feasible/valid.
 
The site is unlikely to be able to recruit sufficient subjects within the agreed time frame.
 
The site does not respond to trial management requests.
 
Repeated protocol deviations.
 
Unsafe or unethical practices.
 
Administrative decision.
Following a trial termination decision, the Investigator must contact all subjects within a
time period set by the Sponsor. All trial materials must be collected and relevant
documentation completed to the greatest extent possible.
The trial can also be terminated by the Regulatory Authority for any reason or if
recommended by the DSMB, or at a site level by the Institutional Review Board or
Independent Ethics Committee (IRB/IEC). The Sponsor may close the site prematurely
for reasons such as poor protocol compliance or unsatisfactory recruitment of subjects.
8.4 Lost to Follow-Up
All efforts should be made to contact subjects who have not returned for the scheduled
trial visit or who are unable to be contacted for a scheduled phone call. A minimum of
3 attempts should be made and documented. If a subject is lost to follow-up before
resolution of related SAEs or AEs, the Sponsor may consider further attempts to contact
the subject in order to collect follow-up safety information.


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9 TRIAL ASSESSMENTS AND PROCEDURES
The trial assessments and procedures for trial CV-NCOV-005 are presented in Table 1,
and Table 2. The trial assessments and procedures are discussed in this section.
For subjects who are unable to come to the site for protocol-specified site visits (e.g., due
to the public health emergency related to COVID-19), safety assessments may be
performed using alternative methods (e.g., phone contact, virtual visit, alternative location
for assessment).
For further flexibility in trial conduct in the pandemic setting, home visits will be allowed to
perform safety assessments and procedures including the collection of blood and
nasopharyngeal swabs. If site visits, phone contacts or sample collection cannot be
performed within the protocol-defined windows, in such unique circumstances as a public
health emergency, it will be acceptable to perform these tasks outside of these windows.
In the pandemic setting, the protocol-defined windows for site visits and phone contacts
are provided for guidance and will not be considered deviations, if not strictly adhered to.
An electronic diary (eDiary) will be used during the trial for efficient collection of
safety-related information. However, paper diaries may be substituted for some subjects
during the trial.
9.1 Schedule of Trial Assessments and Procedures
By signing the informed consent form, subjects will be consenting to participate in trial CV-
NCOV-005 for a total of approximately 13 months.
Refer to Table 1 (Immunogenicity/Reactogenicity Subset) and Table 2 (All Other Subjects
and subjects that, following unblinding, receive an authorized vaccine after having
received at least one dose of CVnCoV) for the Schedule of Trial Assessments and
Procedures.
The trial assessments and procedures apply to all subjects, independent of their serology
status at baseline.
During the conduct of the trial and interactions with subjects, any person with early warning
signs of COVID-19 should be referred to emergency medical care immediately. These
signs include, but are not limited to, the following: difficulty breathing, persistent pain or
pressure in the chest, new confusion, inability to awake or stay awake, or bluish lips or
face.
9.1.1 
Immunogenicity/Reactogenicity Subset
The Immunogenicity/Reactogenicity Subset will include the first 1,260 subjects enrolled.
Subjects participating in the Immunogenicity/Reactogenicity Subset will be given a
thermometer to measure body temperature orally and a measuring tape to determine the
size of local injection site reactions. Subjects will be instructed on how to enter the solicited
AEs daily for 7 days in the eDiary.


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9.1.1.1 Clinic Visit 1: Day 1 - First Trial Vaccination
Note that procedures to establish subject eligibility, recording of demographic information
and medical history may be performed within 21 days prior to trial vaccine administration,
i.e., spread out over more than 1 day. However, if all information is available and
assessments and procedures can be performed, eligibility can be established on the same
day of trial vaccine administration. All eligibility criteria must be reviewed prior to trial
vaccine administration on Day 1.
Pre-vaccination Procedures
 
Obtain the signed informed consent form.
 
Signed informed consent must be obtained prior to the subject entering into the
trial, 
and 
before 
any 
protocol-directed 
procedures 
are 
performed
(see Section 12.4).
 
By signing the informed consent form, the subject voluntarily agrees to participate
in the trial CV-NCOV-005.
 
Review inclusion/exclusion criteria (see Section 6.1 and 6.2) and review prohibited
medications listed as an exclusion criterion (see Section 6.2).
 
Record demographic information.
 
Record medical history.
 
Record concomitant medications and vaccinations, including recurring medications for
intermittent conditions, if taken within 6 months prior to enrollment in this trial.
 
Perform 
a 
complete 
physical 
examination, 
including 
height 
and 
weight
(see Section 9.3.6). If a complete physical examination was performed out of the
scope of this trial within 21 days prior to trial vaccine administration, a
symptom-directed physical examination should be performed on the day of vaccination
prior to trial vaccine administration.
 
Measure vital signs (body temperature, pulse, blood pressure; see Section 9.3.6).
 
Perform urine pregnancy test in females of childbearing potential (Appendix 5).
 
Collect pre-vaccination blood samples (see Table 1) for binding antibody testing to
RBD of S protein of SARS-CoV-2 (~6 mL blood); SARS-CoV-2 viral neutralizing
activity (~6 mL blood); and binding antibody testing to N protein of SARS-CoV-2
(~6 mL blood).
 
Collect pre-vaccination blood samples for CMI (~38 mL blood) from subjects of the
CMI Subset.
 
Randomize the subject (see Section 7.3.1).
Vaccination Procedure
 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for
an overview of the criteria leading to delay or cancellation of vaccine administration.


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In case of delay, the vaccination should take place within the allowed time windows.
The reasons fo
 
Administer the trial
Post-vaccination Procedures
 
Observe the subject on site for at least 30 minutes following vaccination for safety
monitoring. At the end of the observation period:
 
Measure vital signs (body temperature, pulse, blood pressure; see Section 9.3.6).
 
The subject may not be discharged until vital signs are within normal range or have
returned to pre-vaccination levels.
 
Record the occurrence of any AEs following trial vaccination.
 
Instructions for the subject:
 
Instruct the subject how to measure solicited AEs and how to complete the eDiary.
The subject should record solicited local and systemic AEs occurring on the day
of vaccination and the following 7 days, and unsolicited AEs (i.e., the occurrence
of all other AEs) occurring on the day of vaccination and the following 28 days.
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning local or systemic reactions or other
medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
Note: Subjects without symptoms may have been tested for several reasons, for
example, close exposure to a known person with SARS-CoV-2 infection or as part
of their routine screening as a healthcare provider.


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9.1.1.2 Phone Call: Day 2 (-0/+0 day)
-being and
to assess safety 1 day after the first trial vaccination.
 
During the phone call:
 
Review and record any newly reported safety data including solicited and
unsolicited AEs, or other AEs (medically-attended AEs, SAEs).
 
Record concomitant medications and vaccinations, vaccinations according to
instructions in Section 7.6.
 
If the subject reports any concerning local or systemic reactions, or other AEs (e.g.,
medically-attended AEs, SAEs), these should be followed-up either by a phone
call(s) or by an unscheduled site visit based on the judgment of the Investigator.
 
Instructions for the subject:
 
Remind the subject to continue recording solicited and unsolicited AEs (i.e., the
occurrence of all other AEs) in the eDiary.
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning local or systemic reactions or other
medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
 be contacted by trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.1.3 Clinic Visit 2: Day 29 - Second Trial Vaccination (-3/+7 days)
Pre-vaccination Procedures
 
Review and record any newly reported safety data including solicited and unsolicited
AEs, or other AEs (medically-attended AEs, SAEs).


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Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
Perform a symptom-directed physical examination (see Section 9.3.6).
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
 
Perform urine pregnancy test in females of childbearing potential (Appendix 5).
 
Collect pre-vaccination blood samples (see Table 1) for binding antibody testing to
RBD of S protein of SARS-CoV-2 (~6 mL blood) and SARS-CoV-2 viral neutralizing
activity (~6 mL blood). No testing of antibody to N protein of SARS-CoV-2 will be
performed at this time point.
 Collect pre-vaccination blood samples for CMI (~38 mL blood) from subjects of the CMI
Subset.
Vaccination Procedure
 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for
an overview of the criteria leading to delay or cancellation of vaccine administration.
In case of delay, the vaccination should take place within the allowed time windows.
 
Administer the trial vacc
Post-vaccination Procedures
 
Observe the subject on site for at least 30 minutes following vaccination for safety
monitoring. At the end of the observation period:
 
Measure vital signs (body temperature, pulse, blood pressure; see Section 9.3.6).
 
The subject may not be discharged until vital signs are within normal range or have
returned to pre-vaccination levels.
 
Record the occurrence of any AEs following trial vaccination.
 
Instructions for the subject:
 
Re-instruct the subject how to measure solicited AEs and how to complete the
eDiary. The subject should record solicited local and systemic AEs occurring on
the day of vaccination and the following 7 days, and unsolicited AEs (i.e., the
occurrence of all other AEs) occurring on the day of vaccination and the following
28 days.
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning local or systemic reactions or other
medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.


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 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.1.4 Phone Call: Day 30 (-0/+0 day)
-being and
to assess safety 1 day after the second trial vaccination.
The assessments and procedures are identical to those performed during the phone call
on Day 2.
9.1.1.5 Clinic Visit 3: Day 43 (-3/+3 days)
 
Review and record any newly reported safety data including solicited and unsolicited
AEs, or other AEs (medically-attended AEs, SAEs).
 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
Perform a symptom-directed physical examination (see Section 9.3.6).
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
 
Collect blood samples (see Table 1) for binding antibody testing to RBD of S protein
of SARS-CoV-2 (~6 mL blood); SARS-CoV-2 viral neutralizing activity (~6 mL blood);
and binding antibody testing to N protein of SARS-CoV-2 (~6 mL blood).
 
Collect blood samples for CMI (~38 mL blood) from subjects of the CMI Subset.
 
Instructions for the subject:
 
Inform the subject that recording of solicited local and systemic reactions in the
eDiary is complete. Remind the subject to continue recording unsolicited AEs (all
AEs).
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency


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room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported,
regardless of the perceived relationship between the event and the trial
vaccine.
 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
 be contacted by trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.1.6 Clinic Visit 4: Day 57 (-3/+7 days)
 
Review and record any newly reported safety data including unsolicited AEs or other
AEs (medically-attended AEs, SAEs).
 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
Perform a symptom-directed physical examination (see Section 9.3.6).
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
 
Collect a blood sample for immunogenicity assessment (see Table 1) for binding
antibody testing to RBD of S protein of SARS-CoV-2 (~6 mL blood) and SARS-CoV-2
viral neutralizing activity (~6 mL blood). No testing of binding antibody to N protein of
SARS-CoV-2 will be performed at this time point.
 Collect blood samples for CMI (~38 mL blood) from subjects of the CMI Subset.
 
Instructions for the subject:
 
Inform the subject that reporting of unsolicited AEs is complete.
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.


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Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.1.7 Clinic Visit 5: Day 120 (-7/+7 days)
 
Review and record any newly reported AEs since the site visit on Day 57
(medically-attended AEs, SAEs).
 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
Perform a symptom-directed physical examination (see Section 9.3.6).
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
 
Collect blood samples (see Table 1) for binding antibody testing to RBD of S protein
of SARS-CoV-2 (~6 mL blood) and SARS-CoV-2 viral neutralizing activity (~6 mL
blood). No testing of binding antibody to N protein of SARS-CoV-2 will be performed
at this time point.
 
Collect blood samples for CMI (~38 mL blood) from subjects of the CMI Subset.
 
Instructions for the subject:
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
contacted by trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).


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The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.1.8 Clinic Visit 6: Day 211 (-7/+7 days)
The assessments and procedures are identical to those performed during Clinic Visit 5 on
Day 120, except for the below.
 
Collect blood samples (see Table 1) for binding antibody testing to RBD of S protein
of SARS-CoV-2 (~6 mL blood); SARS-CoV-2 viral neutralizing activity (~6 mL blood);
and binding antibody testing to N protein of SARS-CoV-2 (~6 mL blood).
 
Collect blood samples for CMI (~38 mL blood) from subjects of the CMI Subset.
9.1.1.9 Phone Call: Day 302 (-7/+7 days)
-being and
to assess safety since the site visit on Day 211.
 
During the phone call:
 
Review and record any newly reported AEs since the site visit on Day 211 (SAEs).
 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
If the subject reports by phone any concerning AEs, these should be followed-up
either by a phone call(s) or by an unscheduled site visit based on the judgment of
the investigator.
 
Instructions for the subject:
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).


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The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.1.10
End of Trial Visit: Day 393 (-0/+21 days) in CVnCoV subjects;
for placebo subjects the visit (or phone call) might take place earlier
as they will be withdrawn after trial unblinding
For subjects who received CVnCoV, the end of trial visit will be performed on Day 393,
1 year after the last trial vaccine administration. For subjects who received placebo, the
end of trial visit will be conducted after unblinding. If possible, this visit should also include
subjects who prematurely discontinued vaccination during the trial. The following
assessments should be performed:
 
Review and record any newly reported AEs since the phone contact on Day 302
(SAEs).
 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
Record symptoms suggestive of COVID-19 or any confirmed COVID-19 case.
 
Perform 
a 
complete 
physical 
examination, 
including 
height 
and 
weight
(see Section 9.3.6).
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
9.1.2 
All Other Subjects and subjects that, following unblinding, receive
an authorized vaccine after having received at least one dose of
CVnCoV
Following enrollment of subjects into the Immunogenicity/Reactogenicity Subset
(n=1,260), the remaining 1,260 subjects, 18 years of age and older, will be enrolled to this
group.
Also, all subjects initially enrolled to the Immunogenicity/Reactogenicity Subset that
receive an authorized vaccine following at least one dose of CVnCoV will be included in
this group from the day when the authorized vaccine is administered (Schedule of
Activities- Table 2).
9.1.2.1 Clinic Visit 1: Day 1
 First Trial Vaccination
Note that procedures to establish subject eligibility, recording of demographic information
and medical history may be performed within 21 days prior to trial vaccine administration,
i.e., spread out over more than 1 day. However, if all information is available and
assessments and procedures can be performed, eligibility can be established on the same
day of trial vaccine administration. All eligibility criteria must be reviewed prior to trial
vaccine administration on Day 1.
Pre-vaccination Procedures
 
Obtain the signed informed consent form.


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Signed informed consent must be obtained prior to the subject entering into the
trial, 
and 
before 
any 
protocol-directed 
procedures 
are 
performed
(see Section 12.4).
 
By signing the informed consent form, the subject voluntarily agrees to participate
in the trial CV-NCOV-005.
 
Review inclusion/exclusion criteria (see Section 6.1 and 6.2) and review prohibited
medications listed as an exclusion criterion (see Section 6.2).
 
Record demographic information.
 
Record medical history.
 
Record concomitant medications and vaccinations, including recurring medications for
intermittent conditions, if taken within 6 months prior to enrollment in this trial.
 
Perform 
a 
complete 
physical 
examination, 
including 
height 
and 
weight
(see Section 9.3.6). If a complete physical examination was performed out of the
scope of this trial within 21 days prior to trial vaccine administration, a symptom-
directed physical examination should be performed on the day of vaccination prior to
trial vaccine administration.
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
 
Perform urine pregnancy test in females of childbearing potential (Appendix 5).
 
Collect a pre-vaccination blood sample (see Table 2) for binding antibody testing to
N protein of SARS-CoV-2 (~6 mL blood).
 
Randomize the subject (see Section 7.3.1).
Vaccination Procedure
 
Review criteria for delay or cancellation of vaccination. See Sections 6.3 and 8.1 for
an overview of the criteria leading to delay or cancellation of vaccine administration.
In case of delay, the vaccination should take place within the allowed time windows.
The reasons for delay or cancellation should be documented in the subject chart.
 
Administer the trial
ment.
Post-vaccination Procedures
 
Observe the subject on site for at least 30 minutes following vaccination for safety
monitoring. At the end of the observation period:
- 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
- 
The subject may not be discharged until vital signs are within normal range or have
returned to pre-vaccination levels.
- 
Record the occurrence of any new AEs following trial vaccination.
 
Instructions for the subject:
- 
Remind the subject to call the site immediately to report the following:


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


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Observe the subject on site for at least 30 minutes following vaccination for safety
monitoring. At the end of the observation period:
- 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
- 
The subject may not be discharged until vital signs are within normal range or have
returned to pre-vaccination levels.
- 
Record the occurrence of any new AEs following trial vaccination.
 
Instructions for the subject:
- 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning local or systemic reactions or other
medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
- 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
- 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.2.3 Clinic Visit 3: Day 43 (-3/+3 days)
 
Review and record any newly collected safety data including medically-attended AEs
and SAEs.
 
Record concomitant medications and vaccinations, vaccinations according to
instructions in Section 7.6.
 
Perform a symptom-directed physical examination (see Section 9.3.6).
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).
 
Collect a blood sample (see Table 2) for binding antibody testing to N protein of
SARS-CoV-2 (~6 mL blood).
 
Instructions for the subject:


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- 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning local or systemic reactions or other
medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
- 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
- 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.2.4 Phone Call: Day 57 (-3/+7 days) and Day 120 (-7/+7 days)
-being and
to assess safety since the last phone contact or site visit.
 
During the phone call:
- 
Review and record any newly reported AEs since the site visit or phone call
(medically-attended AEs, SAEs).
- 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
- 
If the subject reports by phone any concerning AEs, these should be followed-up
either by a phone call(s) or by an unscheduled site visit based on the judgment of
the investigator.
 
Instructions for the subject:
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.


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 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.
 
Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.2.5 Clinic Visit 4: Day 211 (-7/+7 days)
The assessments and procedures are identical to those performed during Clinic Visit 3 on
Day 43.
9.1.2.6 Phone Call: Day 302 (-7/+7 days)
 after approval of protocols
version 3 and 4 no longer to be performed in placebo subjects
-being and to
assess safety since the last site visit on Day 211.
 
During the phone call:
 
Review and record any newly reported AEs since the site visit on Day 211 (SAEs).
 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
If the subject reports by phone any concerning AEs, these should be followed-up
either by a phone call(s) or by an unscheduled site visit based on the judgment of
the investigator.
 
Instructions for the subject:
 
Remind the subject to call the site immediately to report the following:
 If he/she experiences any concerning medical event.
 Any medically-attended visits that are not routine visits for physical
examination or vaccination, such as visits for hospitalization, an emergency
room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
 Experience a serious medical event, have a change in overall health or be
diagnosed with a new medical condition by a doctor. These should be reported
regardless of the perceived relationship between the event and the trial
vaccine.


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Remind the subject to contact the site immediately if he/she has any of the
symptoms suggestive of COVID-19. In addition, subjects will be messaged up to
twice a week to provide a yes or no response to having COVID-19 symptoms.
trial staff for follow-up information,
if the investigator considers the symptoms could potentially indicate a COVID-19
case (see Section 9.2.1 and Section 9.5).
 
The subject should also be reminded to contact the site immediately if he/she had
a positive SARS-CoV-2 test performed outside of the site, irrespective of whether
they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.
9.1.2.7 End of Trial Clinic Visit: Day 393 (-0/+21 days) in CVnCoV subjects;
for placebo subjects the visit (or phone call) might take place earlier
as they will be withdrawn after trial unblinding
The end of trial visit will be performed on Day 393, 1 year after the last trial vaccine
administration. If possible, this visit should include subjects who prematurely discontinued
vaccination during the trial. The following assessments should be performed:
 
Review and record any newly reported AEs since the phone contact on Day 302
(SAEs).
 
Record concomitant medications and vaccinations, according to instructions in
Section 7.6.
 
Record symptoms suggestive of COVID-19 or any confirmed COVID-19 case.
 
Perform 
a 
complete 
physical 
examination, 
including 
height 
and 
weight
(see Section 9.3.6).
 
Measure vital signs (body temperature, pulse, blood pressure, see Section 9.3.6).


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9.2 Efficacy Assessments
9.2.1 
COVID-19 Cases
Case detection will begin with the identification of subjects reporting at least 1 symptom
from a standardized list of symptoms consistent with COVID-19 disease. Based on a
phone interview with trial staff (see Appendix 6), subjects suspected of having COVID-19
disease will undergo testing for SARS-CoV-2 infection, consisting of a molecular-based
RT-PCR test performed at the site. The testing strategy is described in Section 9.5 and
Appendix 7. If the subject is confirmed to have COVID-19, subjects will be followed until
resolution of their disease, even if the initial presentation is considered as mild. If the
Investigator and a medical/discharge summary must be obtained at the end of the
hospitalization.
9.2.1.1 Case Detection
9.2.1.1.1 Routine Surveillance for COVID-19
During all site visits and phone calls, subjects will be reminded to contact the site if they
tested positive for SARS-CoV-2 outside of the trial context or if they have 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
Diarrhea
* FDA Development and Licensure of Vaccines to Prevent COVID-19 guidance [33].
Subjects will also be messaged up to twice a week to provide a yes or no response to
having COVID-19 symptoms. For both of the trial vaccinations, messaging will not begin
until 4 days after vaccination to avoid confusing vaccine-associated reactions occurring
during this time period (e.g., fever, chills, headache, fatigue, myalgia) with potential
COVID-19 symptoms.
Those who report symptoms either at the site visit or by phone call, or respo
having symptoms by messaging will be contacted by trial staff for a follow-up phone
interview. The trial staff will use a scripted interview (in which he/she has been trained on)
ch will be used to
determine the probability of the subject having COVID-19. The interview script is provided
in Appendix 6. If the subject is suspected of having COVID-19 illness, he/she will undergo
testing for SARS-CoV-2 infection (see next section). If suspicion is low, then a subsequent
progressed and if the suspicion of COVID-19 has reached a sufficient level to test the
subject. Based on clinical judgment, phone contact may be made as frequently as daily.
All symptomatic subjects will be provided a thermometer and oxygen saturation monitor
for home use. Trial staff will instruct subjects to take their oral body temperature and
oxygen saturation levels at least 3 to 4 times per day, or whenever they feel symptomatic.


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The testing strategy for SARS-CoV-2 infection is presented in Section 9.5 and Appendix 7.
Testing will consist of a molecular-based RT-PCR test performed at the site. Depending
on the Investigator and his/her facility and trial staff, nasopharyngeal swab samples for
testing will be collected either at the site or at a home visit. The visit to the site or home
visit by trial
documented as such in the eCRF.
If the subject is virologically-confirmed to have COVID-19 by a positive RT-PCR test,
subjects will be followed until resolution of their disease, even if the initial presentation is
be followed by the Investigator and a discharge summary must be obtained at the end of
the hospitalization. Information on clinical symptoms and signs, their duration and severity,
and treatment and outcome of the COVID-19 episode will be documented by trial staff and
recorded in the eCRF.
For positive RT-PCR tests, viral RNA of the SARS-CoV-2 might be sequenced to identify
S protein variants.
Upon resolution, subjects will continue to be followed in the same manner as those who
have not presented with COVID-19 (i.e. they will return to routine case surveillance). A
second episode of COVID-19 in a subject with prior disease will be included in the
exploratory objective assessing the occurrence of second episodes of COVID-19 in
vaccinated subjects.
If the subject is not virologically-confirmed by RT-PCR testing, he/she will return to routine
surveillance for COVID-19 disease as a subject who is naïve to SARS-CoV-2 infection
(unless determined otherwise by a seropositive test to the N protein).
9.2.1.1.2 Non-Routine Surveillance for COVID-19 (Positive Test Outside of the
Site)
Subjects will be reminded to contact the site immediately if he/she has a positive
SARS-CoV-2 test performed outside of the site, whether they were symptomatic
(COVID-19 illness) or asymptomatic at the time of the test.
If the subject was symptomatic, trial staff will use the scripted interview to collect
-19 symptoms and medical condition (interview
script in Appendix 6). The subject should be retested as soon as feasible to confirm the
result. A nasopharyngeal swab sample should be taken for RT-PCR testing; the RT-PCR
test result will be considered definitive as a virologically-confirmed case of COVID-19. If
the subject is confirmed to have COVID-19, subjects will be followed until resolution of
their disease, as described above for subjects who were detected by routine surveillance.
If the subject is not virologically-confirmed by RT-PCR testing, he/she will return to routine
surveillance for COVID-19 disease as a subject who is naïve to SARS-CoV-2 infection
(unless determined otherwise by a seropositive test to the N protein).


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9.2.1.2 Definition of Virologically-Confirmed COVID-19 Case
A virologically-confirmed case of COVID-19 is defined as a positive SARS-CoV-2 specific
RT-PCR test in a person with clinically symptomatic disease consisting of 1 or more of the
following symptoms (based on the same screening symptoms as above):
 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
Diarrhea
This definition is intended to capture all severities of virologically-confirmed clinically
symptomatic cases of COVID-19. As such, COVID-19 cases classified by severity (e.g.,
mild, moderate, or severe) will be a subset of these cases. See Appendix 3 and
Appendix 4 for clinical definitions of severe and mild/moderate COVID-19, respectively.
9.2.1.3 COVID-19 Case Definition for the Efficacy Analysis
For the analysis of efficacy, the case must meet the following criteria:
 
Must be a virologically-confirmed case of COVID-19 defined as a positive
SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19,
as defined above in Section 9.2.1.2.
following the second trial vaccination.
 
The subject must not have a history of virologically-confirmed COVID-19 illness at
enrollment or have developed a case of virologically-confirmed COVID-19 before
15 days following the second trial vaccination {see Section 10.2.4, (EAS) for more
details}.
 
The subject must have been SARS-CoV-2 naïve at baseline and Day 43 (defined as
seronegative to N protein in the blood samples collected at baseline and Day 43).
These efficacy cases might be confirmed by the Adjudication Committee.
Day 43 is 14 days post-second dose which allows the immune response to CVnCoV to
mature and reach its height following the second dose. As such, COVID-19 case
ascertainment
CVnCoV against COVID-19 disease.
9.2.1.4 Adjudication of COVID-19 Cases
An independent Committee of clinicians will be formed which might adjudicate COVID-19
cases. The Committee will be blinded to the treatment assignment of the subject. The
cases might be adjudicated by the members with respect to the following questions
consistent with the endpoints of the trial.
 
Is the case a virologically-confirmed case of COVID-19 defined as a positive
SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19
with 1 or more of the symptoms listed above in Section 9.2.1.2.


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Was the RT-PCR test performed at the CureVac designated laboratory at the site?
following the second vaccination? Or
did it occur before 15 days following the second trial vaccination?
 
Was the subject naïve or non-naïve to SARS-CoV-2 at baseline and Day 43? (defined
as being seronegative or seropositive to the SARS-CoV-2 N protein).
 
Was the subject asymptomatic? If asymptomatic, was the RT-PCR test positive
 15 days following the second vaccination or before?
 
Was it a mild, moderate, or severe case of COVID-19 based on the provided clinical
definitions?
 
Did the subject require supplemental oxygenation? What type of oxygen support did
the subject receive?
 
Was the subject hospitalized? Was the subject admitted to the intensive care unit?
 
Did the subject die? Due to COVID-19 or other cause?
9.2.2 
Asymptomatic Cases of SARS-CoV-2 Infection
There will be no active surveillance in this trial for asymptomatic SARS-CoV-2 infections.
Subjects will be reminded to contact the site immediately if he/she had a positive
SARS-CoV-2 test performed outside of the site, irrespective of whether they were
symptomatic (COVID-19 illness) or asymptomatic at the time of the test. Subjects without
symptoms may have been tested for several reasons, for example, close exposure to a
known person with SARS-CoV-2 infection or as part of their routine screening as a
healthcare provider.
If the subject was asymptomatic, trial staff will contact the subject immediately to collect
information about the positive SARS-CoV-2 test the subject reported for information to be
collected). The subject should be retested as soon as feasible to confirm the result. A
nasopharyngeal swab sample should be taken for RT-PCR testing; a positive RT-PCR
test result will be considered definitive as a virologically-confirmed case of SARS-CoV-2
infection.
If the subject is confirmed to have SARS-CoV-2 infection, the subject will be followed by
trial staff for at least 2 weeks for the development of any COVID-19 symptoms, to ensure
that this is an asymptomatic infection. If the subject develops COVID-19, he/she will be
followed-up as a COVID-19 case. If the subject is confirmed to be asymptomatic,
information will be collected by the trial staff and documented on the appropriate eCRF
page.
If the subject is not virologically-confirmed by RT-PCR testing, he/she will return to routine
surveillance for COVID-19 disease as a subject who is naïve to SARS-CoV-2 infection
(unless determined otherwise by a seropositive test to the N protein).
9.3 Safety Assessments
The safety, reactogenicity, and tolerability of a 2-dose schedule of CVnCoV will be
assessed as described below.


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9.3.1 
Safety Assessments Specific for Subjects in the
Immunogenicity/Reactogenicity Subset
 
Reactogenicity will be assessed daily on each vaccination day and the following 7 days
by collection of solicited local AEs (injection site pain, redness, swelling, and itching)
and 
systemic 
AEs 
(fever, 
headache, 
fatigue, 
chills, 
myalgia, 
arthralgia,
nausea/vomiting, and diarrhea) using eDiaries. In addition, other indicators of safety
will be collected (e.g., body temperature).
 
The eDiary will also be used as a memory aid for the subject for the collection of
unsolicited AEs on each vaccination day and the following 28 days.
9.3.2 
Safety Assessments for All Subjects
 
Medically-attended AEs will be collected through 6 months after the second trial
vaccination.
 
AESIs will be collected through 1 year after the second trial vaccination. AESIs to be
monitored include pIMDs, AESIs for SARS-CoV-2 vaccines, and non-serious
intercurrent medical conditions that may affect the immune response to vaccination
(Appendix 9).
 
SAEs will be collected through 1 year after the second trial vaccination.
 
AEs leading to vaccine withdrawal or trial discontinuation will be collected through
1 year after the second trial vaccination.
{If the subject does not receive their second trial vaccination, the AE follow-up time
(6 months or 1 year) will be determined based on the date scheduled for their second
vaccination on Day 29}.
 
The eDiary will be used as a memory aid for the subject for the collection of
medically-attended AEs, AESIs, and SAEs.
9.3.3 
Adverse Events
Definitions of AEs/SAEs, procedures for recording, evaluating, follow-up and reporting of
AEs/SAEs/pregnancy/overdose, as well as assessments of intensity and causality of AEs,
are provided in Appendix 10.
It is important to note that COVID-19 illness and its complications/sequelae are consistent
with the efficacy endpoints of the trial and, as such, should not be recorded as AEs. These
data will be captured on the relevant eCRF pages for cases of COVID-19 illness that occur
in the trial, which are expected outcomes of the trial. Therefore, COVID-19 illness and its
complications/sequelae will not be reported according to the standard expedited process
for SAEs, even though the event may meet the criteria for an SAE. COVID-19 is to be
reported as an AESI, according to Appendix 9.
9.3.3.1 Solicited Adverse Events
An eDiary will be distributed to all subjects in the Immunogenicity/Reactogenicity Subset
for collection of solicited local AEs (injection-site pain, redness, swelling and itching) and
solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia,






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Medically-attended AEs are defined as AEs with medically-attended visits that are not
routine visits for physical examination or vaccination, such as visits for hospitalization, an
emergency room visit, or an otherwise unscheduled visit to or from medical personnel
(medical doctor) for any reason.
The occurrence of AEs (serious and non-serious) will be assessed by non-directive
questioning of the subject at each visit. AEs volunteered by the subject during or between
visits as eDiary entries or detected through observation, physical examination, laboratory
test, or other assessments during the entire trial, will be recorded in the eCRF if they fulfil
the definitions as specified in section 9.3.2. Subjects should be instructed to report
immediately any AEs with serious symptoms, subjective complaints or objective changes
in their well-being to the Investigator or the site personnel, regardless of the perceived
relationship between the event and the trial vaccine.
The Investigator will assess the relationship between trial vaccine and occurrence of each
AE/SAE.
Non-serious intercurrent medical conditions that may affect the immune response to
vaccination will also be collected throughout the trial.
9.3.3.3 Adverse Events of Special Interest
AESIs will be collected through 1 year after the second trial vaccination. The following
events will be considered as AESI during this trial:
 
AEs with a suspected immune-mediated etiology (pIMDs, see Appendix 8).
 
Other AEs relevant to SARS-CoV-2 vaccine development or the target disease (see
Appendix 9).
 
Non-serious intercurrent medical conditions that may affect the immune response to
vaccination will also be collected throughout the trial.
9.3.4 
Pregnancies
Pregnancy is an exclusion criterion for enrollment in this trial, but subjects could potentially
become pregnant during their active participation in this trial. Refer to Appendix 10 for
details on the reporting and follow-up of pregnancies.
9.3.5 
Safety Laboratory Assessments
(See Appendix 5)
A urine sample for pregnancy testing will be taken from women of childbearing potential
on Day 1 prior to trial vaccination to establish eligibility. A urine pregnancy test will also be
performed before the second trial vaccination on Day 29 to continue to determine
eligibility.
9.3.6 
Vital Signs and Physical Examination
At all trial visits (see Table 1 and Table 2), vital signs (body temperature, systolic/diastolic
blood pressure and pulse) will be recorded in a standardized manner after the subject has
rested in the sitting position for 5 minutes.


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At the first trial visit on Day 1 and at the end of trial visit for all subjects in Trial CV-NCOV-
005 (see Table 1 and Table 2), a complete physical examination will be performed,
including examination of general appearance, eyes/ears/nose/throat, head/neck/thyroid,
lymph node areas, cardiovascular system, lung/chest and abdomen, extremities and
neurological examination, skin examination, measurement of weight and height. At all
other trial visits, a symptom-directed physical examination will be performed at the
discretion of the investigator and should include measurement of O2 saturation.
9.3.7 
Medical and Surgical History
All significant findings and pre-existing conditions present in a subject prior to enrollment
must be reported on the relevant medical history/current medical conditions screen of the
eCRF.
Information should be provided on medical and surgical history and concomitant medical
conditions specifying those ongoing on Day 1.
9.3.8 
Monitoring Committees
9.3.8.1 Data and Safety Monitoring Board (DSMB)
An independent DSMB will be convened to i) oversee the safety of subjects participating
in this trial, CV-NCOV-005; ii) to assess the progress and conduct of the trial; iii) to review
the cumulative safety data from the trial; iv) to perform an ongoing review of AEs of
potential safety concern (see Section 5.5.2); and v) to make recommendations to the
Sponsor whether to continue, modify, or pause the trial (see Section 5.5.2).
The DSMB will have regularly scheduled meetings to perform these responsibilities.
During these meetings, the DSMB will also be informed of the safety data being generated
in other ongoing clinical trials of CVnCoV. As described in Section 5.5.2, to further ensure
subject safety on an ongoing basis, a listing of AEs of potential safety concern will be
routinely monitored by the Chair of the DSMB (or designee) at regular intervals. As
described in Section 7.3.2, the DSMB may request unblinding of an individual subject or
a specific dataset at any time during the trial.
In addition to safety data, the DSMB will be asked to review efficacy data at the interim
analysis or possibly at other time points during the trial for a continued assessment of the
risk-benefit of the trial. As part of the risk-benefit analysis, the DSMB will periodically
monitor COVID-19 cases for signals of VDE.
The DSMB Charter will describe in detail the composition and objectives of the DSMB; the
responsibilities of the DSMB, CureVac, and CRO; the schedule and conduct of the DSMB
meetings; and the datasets to be reviewed. The Charter will contain the SAP for the
DSMB.
9.3.8.2 Adjudication Committee
An independent Committee of clinicians will be formed which might adjudicate COVID-19
cases for assessment of the secondary efficacy endpoint. The Committee will be blinded
to the treatment assignment of the subject. The cases might be adjudicated by the
members with respect to the questions presented in Section 9.2.1.4. The schedule of the
meetings and approach to adjudication of cases will be defined in the Charter. The
Committee Chair will attend the DSMB meetings as an ad-hoc member.


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9.4 Immunogenicity Assessments
For subjects participating in the Immunogenicity/Reactogenicity Subset in Trial
CV-NCOV-005, the timing of blood sample collection for immunogenicity assessments
post-vaccination is provided in Table 1, indicating no further immunogenicity assessments
after trial unblinding. Subjects in the Immunogenicity / Reactogenicity Subset who have
received an authorized vaccine, will continue according to table 2 with no further
immunogenicity assessments. After trial unblinding, placebo subjects will also continue
according to table 2 with no further immunogenicity assessments.
For all subjects participating in the Trial CV-NCOV-005, the timing of blood sample
collection for the determination of serology status to natural SARS-CoV-2 infection at
baseline and during the trial is provided in Table 1 and Table 2.
the laboratory performing the assays will keep the results in strict confidence. An
unblinded person, named at the start of the trial and independent of the conduct of the
trial, will periodically review the quality of the immunogenicity data. This person will
maintain the results in strict confidence.
9.4.1 
Antibody Responses to CVnCoV Vaccination (RBD of S Protein
and Viral Neutralizing Antibodies)
Antibody responses to CVnCoV vaccination will only be evaluated for 250 subjects (200
verum 
subjects, 
i.e. 
100 
per 
lot 
/ 
50 
placebo 
subjects) 
in 
the
Immunogenicity/Reactogenicity Subset at the following time points. Baseline, Day 29 and
Day 43.
The immune response induced by vaccination with CVnCoV will be evaluated by 2 assays:
 
Binding antibodies to the SARS-CoV-2 RBD of the S protein measured in serum by
immunoassay.
Viral neutralizing antibodies directed against SARS-CoV-2 measured in serum by a
functional activity assay.
9.4.2 
Antibody Responses to SARS-CoV-2 (N Protein)
Antibody responses to SARS-CoV-2 will be evaluated 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 Table 2, and will be
performed by immunoassay.
As a measure of prior infection with SARS-CoV-2, serological status to the N protein will
be used for the following:
1. To determine, retrospectively, if subjects were naïve or non-naïve to SARS-CoV-2
infection at trial entry and on Day 43. For evaluation of the efficacy of a 2-dose
schedule of CVnCoV in naïve subjects, subjects would have to be seronegative to the
N protein at both time points.
2. To determine if vaccination with a 2-dose schedule of CVnCoV can reduce
asymptomatic infection with SARS-CoV-2 by measuring seroconversion to the N


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protein in seronegative subjects during the trial period. As described above, these
subjects would have to be seronegative to the N protein at baseline and Day 43.
Measurements of the binding antibodies to the SARS-CoV-2 N protein will not be
conducted for the timepoint Day 393.
N-antibody testing was foreseen in this trial in order to detect asymptomatic infections as
a component of the analysis of vaccine efficacy. This analysis became obsolete due to
inconclusive efficacy further to different approved vaccines administered at different
timepoints in all treatment groups.
9.4.3 
Cell-mediated Immunity
CMI was planned to be evaluated in the CMI Subset including 120 subjects of the
Immunogenicity/Reactogenicity Subset: 40 subjects who receive lot 1, 40 subjects who
receive lot 2 of CVnCoV; and 40 subjects who receive placebo.
This exploratory analysis was planned to understand the cellular component of the
immune response to CVnCoV and association to antibody response and vaccine efficacy.
Given the very low number of subjects (n=~10) in this trial potentially eligible for the
analysis due to the fact that the majority of subjects received an authorized vaccine, these
data would not add value to the result seen in previous trials or to further understanding
of vaccine efficacy. Therefore this analysis is considered futile and not planned any longer.
9.5 Testing for SARS-CoV-2 Infection
9.5.1 
Virological Confirmation of COVID-19 Disease
See Flow Diagrams in Appendix 6 and Appendix 7.
During the trial, subjects clinically suspected of having COVID-19 disease or with a
positive result in a test for SARS-CoV-2 performed outside of the trial context will undergo
testing for the SARS-CoV-2 virus as described below. Sample collection for the tests may
be performed at the site or at a home visit by trial staff. Ideally, samples should be collected
within 5 days of symptom onset or the positive result. The tests results will be documented
on the appropriate eCRF page.
 
The nasopharyngeal swab sample collected will be used to perform a SARS-CoV-2
specific RT-PCR test at the site. The RT-PCR test result will be considered definitive
for SARS-CoV-2 infection. In the unlikely event that only 1 sample can be collected
from the subject, the sample should be tested by RT-PCR. For positive RT-PCR tests
performed, the same swab might be used to sequence the viral genome for the SARS-
CoV-2 S protein to identify variants and mutations in this protein.
 
If the RT-PCR test is negative, but COVID-
exposure history and clinical presentation, another nasopharyngeal swab sample
should be taken as soon as feasible for RT-PCR testing. The RT-PCR retest result will
be considered definitive for SARS-CoV-2 infection.


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9.5.2 
Confirmation of a Positive Test for SARS-CoV-2 Infection
Performed Outside of the Site
See Section 9.2.1.1.2 and Section 9.2.2 for follow-up of subjects who report a positive test
for SARS-CoV-2 infection performed outside of the site.
For subjects (symptomatic or asymptomatic) who report a positive test for SARS-CoV-2
infection which was performed outside of the site, regardless of the type of test, the subject
should be retested as soon as feasible to confirm the result. A nasopharyngeal swab
sample should be collected for RT-PCR testing at the site for confirmation. The retest
result will be considered definitive.


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10 STATISTICAL CONSIDERATIONS
10.1 Sample Size Determination
10.1.1 
Primary Safety Objective
While solicited vaccine reactions are expected, AEs that would limit product development
may arise. Table 5 below indicates the probability of observing at least 1 AE in the trial
when the true incidence of the AE with CVnCoV is 1:1000, 5:1000 or 1:100.
With a total of 1,680 subjects receiving CVnCoV (840 for each lot), AEs with a true
incidence of 1:1000 will likely be observed in this trial with a 81.4% probability of observing
at least one. Additionally, observation of 0 AE in 1,680 subjects would be associated with
a 95% confidence that the true incidence rate of this AE is below 1.8:1000.
With a total of 840 subjects included in the Immunogenicity/Reactogenicity subset and
receiving CVnCoV (420 for each lot), solicited/unsolicited AEs with a true incidence of
5:1000 will likely be observed in this trial with a 98.5% probability of observing at least
one. Observation of 0 AE in 840 subjects would be associated with a 95% confidence that
the true incidence rate of this AE is below 3.6:1000.
Table 5
Probability of Observing at least one Adverse Event Given a True
Incidence Rate
Number of subjects receiving CVnCoV
True AE incidence
All subjects
Pooled lots
(N=1,680)
Subset for
solicited/unsolicited
AE
By lot
(N=420)
Subset for
solicited/unsolicited
AE
Pooled lots
(N=840)
1:1000
81.4%
34.3%
56.8%
5:1000
100.0%
87.8%
98.5%
1:100
100.0%
98.5%
100.0%
AE: Adverse Event
10.1.2 
Primary Immunogenicity Objective
The primary analysis for SARS-CoV-2 RBD of S protein antibody response performed on
Days 1, 29 and 43 will be done for 250 subjects (200 on verum, i.e. 100 per lot and 50 on
placebo) in the PPI.
.
10.2 Populations for Analyses
10.2.1 
Safety Analysis Set
The Safety Analysis Set (SAS) will include all subjects randomized in the trial who received
at least 1 dose of any lot of CVnCoV or placebo vaccine.
The SAS will be the primary population for safety endpoints collected on all subjects
(i.e. medically-attended AEs, AESI, AEs leading to vaccine withdrawal or trial
discontinuation and SAEs) and a supportive population for efficacy endpoints.


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For safety analyses on the SAS, subjects will be analyzed in the group of treatment they
For efficacy analyses on the SAS, subjects will be analyzed in the group of treatment to
.
10.2.2 
Safety Analysis Subsets
The Safety Analysis Subset (SAS 2) will include all subjects of the SAS who belong to the
Immunogenicity/Reactogenicity Subset and will be used for unsolicited AEs analysis.
The SAS 2 for solicited AEs analysis (SASsol) population will include all subjects of the
SAS who belong to the Immunogenicity/Reactogenicity Subset with at least 1 diary
collection indicating the occurrence or lack of occurrence of solicited AEs and will be used
for solicited AEs analysis.
In SAS 2 and SASsol, subjects will be analyzed in the group of treatment they actually
10.2.3 
Per Protocol Immunogenicity Subset
The PPI will include 250 subjects who belong to the Immunogenicity/Reactogenicity
Subset (200 verum subjects, i.e. 100 per lot and 50 placebo subjects) and who:
 
Received both doses as randomized and within the windows defined in the protocol.
 
Have no major protocol deviations expecting to impact the immunogenicity outcomes
as specified in the SAP.
 
Have not received medical treatments (such as blood products, immunoglobulin
therapy) that may interfere with 1 or both of the proposed immunogenicity
measurements.
 
Have a blood sample collected 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.
For assessment of seroconversion rates, the analyses will be restricted to PPI subjects
who are naïve at baseline to SARS-CoV-2 RBD of S protein antibody or to SARS-CoV-2
viral neutralizing antibody depending on the endpoint analyzed.
The lot-to-lot consistency analysis on SARS-CoV-2 RBD of S protein antibody titers will
be done on the PPI subjects who received 2 doses of CVnCoV vaccine coming from the
same lot and who have a negative SARS-CoV-2 RBD of S protein antibody titer at
baseline.
Subjects to be excluded from the PPI will be identified and reviewed at the Blinded Data
Review Meeting held before unblinding of the trial. Major protocol deviations will be listed
and summarized.
10.2.4 
Efficacy Analysis Set
The EAS will include all subjects of the SAS who:


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Received both trial doses (2 doses of the same lot of CVnCoV or 2 doses of placebo)
according to their randomization.
 
Had not developed a virologically-confirmed case of COVID-19 before trial entry
(based on exclusion criteria 1) or before 15 days following the second vaccination.
 
Had not stopped the trial before 15 days following the second vaccination.
 
Were SARS-CoV-2 naïve at trial entry and at Day 43 (i.e. at all the testing time points
before 15 days after the second vaccination) based on seronegativity to N protein.
The EAS will be the primary analysis population for all efficacy endpoints.
The analysis of the efficacy endpoint related to seroconversion to the N protein of
SARS-CoV-2 (asymptomatic infections) will be performed on the EAS population for whom
at the Day 211
-second vaccination is available
for analysis.
10.2.5 
Summary of Analysis Sets
Table 6 below provides a summary of primary and supportive populations planned for
analysis of each endpoint. Other analysis populations may be defined in the SAP.
Table 6
Primary and Supportive Populations for the Analysis of Each
Endpoint
Endpoints
Primary Population
Supportive
Population
Primary Safety Endpoints:
 Solicited AEs
SASsol
-
 Unsolicited AEs
SAS 2
-
 SAEs, AESI, medically-attended
AEs, AE leading to vaccine
withdrawal
SAS
-
Primary Immunogenicity Endpoints:
 SARS-CoV-2 RBD of S protein
antibody titers
PPI
-
 Seroconversion to SARS-CoV-2 S
protein antibody responses
PPI (RBD of S protein
antibodies naïve
subjects)
-
Secondary Efficacy Endpoints:
 Any severity COVID-19
EAS
SAS
 Severity of COVID-19
EAS
SAS
 BoD scores
EAS
-
Secondary Immunogenicity Endpoints:


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 SARS-CoV-2 viral neutralizing
antibody
PPI
-
 Seroconversion to SARS-CoV-2 viral
neutralizing antibody
PPI (neutralizing
antibodies naïve
subjects)
-
 Lot-to-lot consistency on
SARS-CoV-2 RBD of S protein
antibody titers
PPI (CVnCoV subjects)
-
Exploratory Efficacy Endpoint:
 Second episode of COVID-19
EAS
SAS
EAS: Efficacy Analysis Set; PPI: Per Protocol Immunogenicity set; SAS: Safety Analysis Set;
SAS 2: Safety Analysis Subset; SASsol: SAS 2 for solicited adverse events analysis.
10.3 Statistical Analyses
10.3.1 
General Considerations
Two analyses are planned: the interim (triggered by regulatory requirements to obtain
early conditional approval in Europe, and the advancement of the accrual of a pre-defined
number of COVID-19 cases in Trial CV-NCOV-004) and the final (on all data up to Day 393
visit). A SAP for both analyses will be prepared and finalized at the latest prior to database
locks. 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.
10.3.2 
 Demographic, Medical History, and Other Baseline aracteristics
Data will be summarized with respect to demographic and baseline characteristics
(e.g., age, sex, height, weight) medical history, baseline immune status, and all safety
measurements using descriptive statistics (quantitative data) and contingency tables
(qualitative data) for pooled CVnCoV lots, for each CVnCoV lot separately, for placebo
and overall.
10.3.3 
Trial Vaccine Administration
The administrations of CVnCoV or placebo will be listed and the number of subjects
actually receiving the vaccination doses will be summarized by group (each lot, pooled lot
and placebo).
10.3.4 
Concomitant Medication and Vaccinations
Concomitant medication/vaccination after the start of the trial will be listed and
summarized by Anatomical Therapeutic Chemical term, overall and by group (each lot,
pooled lot and placebo).
10.3.5 
Safety Analysis
No formal statistical testing of safety data is planned.
Safety endpoints will be described for each CVnCoV lot separately, for pooled lots, for
placebo and overall.


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Solicited AEs: The frequencies and percentages of subjects experiencing each solicited
local and systemic AE within 7 days after each vaccination will be presented by intensity
and overall. For subjects with more than 1 episode of the same AE within 7 days after a
vaccination, the maximum intensity will be used for tabulations. Similar tabulations will be
performed for solicited systemic AEs by relationship to trial vaccination. Solicited local AEs
will be by definition considered as related to the trial vaccine. Time to onset (in days) and
duration (in days) will also be summarized for each solicited local and systemic AEs.
Summary tables showing the occurrence of at least 1 local or systemic solicited AE within
7 days after each vaccination will also be presented.
Unsolicited AEs: Unsolicited AEs including SAEs and AESIs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA) by SOC and PT.
The frequency and percentage of subjects reporting at least 1 unsolicited AE within the 28
days after each vaccination and overall will be tabulated globally and for each SOC and
PT levels.
Similar tables will be provided for: related unsolicited AE, Grade 3 or higher unsolicited
AE, medically-attended AEs that occur within 6 months after the second trial vaccination,
SAE, related SAE, AESI, related AESI, AEs leading to withdrawal or trial discontinuation
and SAE resulting in death through 1 year after the second trial vaccination.
When an AE occurs more than once for a subject within the 29 days post 1 vaccination,
the maximal severity and strongest relationship to the vaccine group will be counted.
Only AE post first vaccination will be considered in the summary tables. AE starting prior
to the first vaccination will only be listed.
Data listings of fatal and SAEs will be provided by subject.
Vital signs will be summarized by descriptive statistics at each visit including change from
baseline and a listing will be provided.
10.3.6 
Immunogenicity Analysis
No formal hypothesis on immunogenicity will be tested. Descriptive statistics for the
immunogenicity endpoints will be provided for a subset of subjects for each CVnCoV lot
separately (n = 100 per lot), for pooled lots and for a subset of subjects in the placebo
group (n = 50) on Days 1, 29 and 43.
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) / geometric mean titers (GMT) by group will
be summarized with their 95% CI at blood sampling time points Day 1, Day 29 and
Day 43 for 250 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 GMFC by group will be displayed with their 95% CI at the Day 29 and Day 43
blood sampling time point.
 
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


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sampling time point after baseline until Day 43 with exact 95% CI. Seroconversion is
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.
To assess lot-to-lot consistency, the two-sided 95% CI of the ratio of GMCs of
SARS-CoV-2 RBD of S protein antibodies between subjects receiving 2 different lots of
CVnCoV will be computed for Day 43.
Additional immunogenicity analyses including graphs will be described in SAP as
applicable.
10.3.7 
Efficacy Analyses
10.3.7.1
Secondary Efficacy Endpoint Analysis
Secondary Efficacy Analysis
The number of subjects reporting at least 1 episode of COVID-19 of any severity (meeting
the case definition for the efficacy analysis), will be presented for pooled CVnCoV lots and
placebo group with the attack rates.
The VE, defined as the percent reduction in the frequency of COVID-19 cases (according
to the case definition) in vaccinated subjects (pooled lots) compared with subjects who
received placebo, will be calculated as follows
VE = 1- RR = 1 - (ARV/ARP) = 1 - (p / r (1-p))
where
ARV = attack rate in vaccinated group (pooled lots) = nv/Nv = number of subjects reporting
at least 1 COVID-19 episode in the CVnCoV groups / total follow-up time of evaluable
subjects in the CVnCoV groups (number of person-month).
ARP = attack rate in placebo group = np/Np = number of subjects reporting at least 1
COVID-19 episode in the Placebo group / total follow-up time of evaluable subjects in the
Placebo group (number of person-month).
RR = relative risk = ARV/ARP
p = proportion of COVID-19 cases (according to the case definition) coming from the
CVnCoV groups among all cases = nv/(nv+np).
r = ratio of total follow-up time of evaluable subjects in the CVnCoV groups over total
follow-up time of evaluable subjects in the placebo group = Nv/Np.
The VE will be presented with exact 95% CI computed using Clopper-Pearson method for
interval around the proportion p.
The same analysis as described above will be done to describe the efficacy in the
prevention or reduction of asymptomatic infection by SARS-CoV-2 as measured by
seroconversion to the N protein of the virus.


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The severity of COVID-19 cases will be described by presenting the number and
percentage of subjects with mild, moderate, severe, and moderate to severe COVID-19
episode meeting the case definition in each group (pooled lots and placebo).
In order to consider incidence and severity of COVID-19 disease, a VE measure based
on the BoD scores (VEBoD) will be derived. VEBoD is defined as the relative reduction in the
BoD score in the CVnCoV groups compared to the placebo group and is calculated as 1
minus the relative risk (RR; the BoD score in the vaccinated groups divided by the BoD
score in the placebo group).
VEBoD = 1- RR = 1 - (SV/SP)
where
SV = mean BoD score in vaccinated group (pooled lots) / mean follow-up time (months)
of evaluable subjects in the CVnCoV groups.
SP = mean BoD score in placebo group / mean follow-up time (months) of evaluable
subjects in the Placebo group.
The 95% CI of the VEBoD will be based on the normal distribution.
All efficacy endpoints will be analyzed descriptively without success criteria testing on the
EAS.
A supportive analysis will be done on the SAS including all subjects whatever their
serological status at baseline and considering all events occurring at any time after the
first trial vaccination.
Sensitivity Analysis
As a sensitivity analysis, the time to first-occurrence of virologically-confirmed COVID-19
cases (according to the case definition) may be analyzed.
The Kaplan-Meier curves will display the estimated probabilities of not developing
COVID-19 and log-rank test will be performed.
The time to first-occurrence of virologically-confirmed COVID-19 (date of symptoms onset)
will start 15 days after the second vaccination.
Subjects who do not develop COVID-19 will be censored at the date of trial termination or
cut-off date for analysis whichever comes first.
An additional sensitivity analysis may include a Cox proportional hazards regression
model adjusted for relevant baseline covariates specified in the SAP.
More details on the analysis methods will be described in the SAP.
10.3.7.2
Exploratory Efficacy Endpoints Analyses
The number and percentage of subjects who developed a second episode of COVID-19
of any severity will be displayed by group (pooled lots and placebo) in naïve evaluable
subjects (complying with the definition of EAS) having presented a first episode of
COVID-19 meeting the case definition.


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10.3.8 
Interim Analysis
An interim analysis will be performed before the trial end based on the regulatory
requirements to obtain early conditional approval in Europe, and the advancement of the
accrual of a pre-defined number of COVID-19 cases in Trial CV-NCOV-004.
10.3.9 
Missing Data
Analysis of vaccination variables will be done on a valid case basis, i.e., for missing
observations, no imputation for missing data, such as last observation carried forward, will
be applied.
For SARS-CoV-2 RBD of the S protein antibodies and neutralizing antibodies,
concentration/titer values marked as below the LLOQ will be set to 0.5*LLOQ.
No imputation of missing values will be done for any analysis (except the imputation for
missing partial dates of AEs and concomitant medication as specified in the SAP).
Currently no replacement of drop-out subjects is foreseen.


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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
All data entered into the eCRF must be verifiable against source documents at the 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
The Sponsor or the CRO will check eCRF entries against source documents according to
the guidelines of Good Clinical Practice (GCP). The consent form will include a statement
by which subjects allow the Sponsor or designee, as well as authorized regulatory
agencies, to have direct access to source data that support data of the eCRF (e.g., subject
medical files, appointment books, original laboratory records, etc.). The Sponsor or
designee, bound by secrecy, will not disclose subject identities or personal medical
information.
11.2 Audit and Inspection
The site also may be subject to quality assurance audits by the Sponsor or designees. In
this circumstance, the Sponsor-designated auditor will contact the site in advance to
arrange an auditing visit. The auditor may ask to visit the facilities where laboratory
samples are collected, where the vaccine is stored and prepared, and any other facility
used during the trial. In addition, there is the possibility that this trial may be inspected by
regulatory agencies, including those of local or foreign governments. If the 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
 eCRF. Data collection must be
completed for each subject who signs an informed consent form (ICF). For subjects who
failed to meet the eligibility criteria, only demographic data and reason for failure will be
documented.
In accordance with GCP, and regulatory requirements, the trial monitor will carry out
source document verification at regular intervals to ensure that the data collected in the
eCRF are accurate and reliable. The frequency of monitoring visits will be determined by
the rate of subject recruitment. In case of travel restrictions and / or prolonged lockdowns
due to the COVID-19 pandemic, remote source data verification may be performed.


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The compliance with the protocol will be examined with regard to inclusion and exclusion
criteria, therapies leading to elimination and timing and availability of planned
assessments. Protocol deviations will be monitored on an ongoing basis during the trial
and closed before database lock. Protocol deviations will be classified as minor, major, or
critical deviations. The detailed definitions of important protocol deviations leading to
elimination of subjects from analysis will be provided in the final version of the SAP and/or
in the final signed minutes of the data review meeting.
The monitoring visits also provide the Sponsor with the opportunity to ensure the
Technical Requirements for Pharmaceuticals for Human Use (ICH) and regulatory
requirements are being met.
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 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 each country.
11.4 Data Management and Coding
All data derived from the trial will remain the property of the Sponsor. The Sponsor
assumes accountability for actions delegated to other individuals, e.g., the CRO. Data
include setting up a relevant database and data transfer mechanisms, along with
appropriate validation of data and resolution of queries. Data generated within this clinical
trial will be handled according to the data management plan and SAP or the relevant SOPs
of the data management and biostatistics departments of the CRO.
Trial sites will enter data in the eCRF. Access to the eCRF will be strictly password
protected and limited to personnel directly participating in the trial. All data entered into
the eCRF must be verifiable against source documents at the site (see Section 11.3). This
may include electronic source document verification. Data entered into the eCRF will be
validated as defined in the data validation plan.
Medical coding will use MedDRA for concomitant diseases and AEs and WHO Drug
Dictionary for medications.
Missing or inconsistent data will be queried to the Investigators for clarification.
Subsequent modifications to the database will be documented.


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


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The Investigator or designated personnel will inform the subject of the objectives,
methods, anticipated benefits, and potential risks and inconveniences of the trial. The
subject should be given every opportunity to ask for clarification of any points he does not
understand and if necessary, ask for more information. At the end of the interview, the
subject will be given ample time to consider the trial. Subjects will be required to sign and
date the ICF. After signatures are obtained, the ICF will be kept and archived by the
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.
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 site of
when these documents no longer need to be retained. The Investigator must contact the
Sponsor before destroying any trial-related documentation. In addition, all subject medical
records and other source documentation will be kept for the maximum time required by
the hospital, institution, or medical practice and in accordance with the national
requirements. If an Investigator moves, withdraws from the trial, or retires, the
responsibility for maintaining the records may be transferred to another person who will
accept responsibility. Notice of transfer must be made to and agreed by the Sponsor.
In this trial processing of personal data will be carried out on behalf of Sponsor by CRO/the
data processor, governed by a contract and strictly according and subject to the General
Data Protection Regulation (GDPR) and any applicable data protection rules and
regulations. The Sponsor and the CRO/data processor implement appropriate technical
and organizational measures to ensure a level of security appropriate to the risk, taking
into account the state of the art, the costs of implementation and the nature, scope, context
and purposes of processing as well as the risk of varying likelihood and severity for the
rights and freedoms of natural persons. Quality control will occur at each stage of data
handling to ensure that all data are reliable and have been processed correctly. The
Sponsor will ensure oversight of any trial-related duties and functions carried out on its
behalf, including trial-related duties and functions that are subcontracted to another party
by the CRO.
This trial will be registered on ClinicalTrials.gov in accordance with applicable laws or
publication policy and may also be registered on other publicly accessible websites as
necessary.
13.1 Data Protection
All information generated in this trial is considered highly confidential and must not be
disclosed to any person or entity not directly involved with the trial unless prior written
consent is gained from the Sponsor. However, authorized regulatory officials, IRB/IEC
personnel, the Sponsor, and its authorized representatives are allowed full access to the
records. All personal details will be treated as confidential by the investigator and staff at
the CRO. Prior to the processing, the Sponsor performs an assessment of the impact of
the envisaged processing operations on the protection of personal data (according to
Article 35 of the GDPR).
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or
datasets that are transferred to the Sponsor will contain the identifier only; subject names
or any information which would make the subject identifiable will not be transferred. All
personal identifiers according to applicable regulations (e.g., name, phone number) must
be redacted permanently by the site personnel and replaced with the subject
identification number in all records and data before transfer to the Sponsor (or designee).


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


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13.4 Clinical Trial Report
The Sponsor is responsible for preparing and providing the appropriate regulatory
authorities with the clinical trial report according to the applicable regulatory requirements.
The Sponsor should ensure that this report meets the standards of the ICH Guideline for
Structure and Content of Clinical Study Reports (ICH E3).
13.5 Publication Policy
Any publication or scientific communication related to this trial can only take place once
the manuscript has been reviewed by the Sponsor and once a written agreement between
the Sponsor and the Investigators has been reached. The Sponsor will comply with the
requirements for publication of trial results. In accordance with standard editorial and
ethical practice, the Sponsor will generally support publication of multicenter trials only in
their entirety and not as individual site data. In this case, a Coordinating Investigator will
be designated by mutual agreement. Authorship will be determined by mutual agreement
and in line with International Committee of Medical Journal Editors authorship
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15 APPENDICES
Appendix 1 
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the
applicable local laws and regulations.
The Investigator agrees to assume the following responsibilities:
1. Conduct the trial in accordance with the protocol ICH-E6 (R2), and all the applicable
local laws and regulations.
2. Personally conduct or supervise the staff who will assist with the protocol.
3. Ensure that trial-related procedures including trial specific (non-routine/non-standard
panel) screening assessments are NOT performed on potential subjects, prior to the
receipt of written approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the trial are
informed of these obligations.
5. Secure prior approval of the trial and any changes by an appropriate IEC and
competent authority.
6. Ensure that the IEC will be responsible for initial review, continuing review, and
approval of the protocol.
7. Ensure that requirements for informed consent, as outlined in ICH-E6 (R2) 4.8 and
local regulations, are met.
8. Obtain valid informed consent from each subject and document the date of consent in
approved by the IEC. Each informed consent form should contain a subject
authorization section that describes t
information (including personal health information) that will take place in connection
with the trial. If an informed consent form does not include such a subject authorization,
then the Investigator must obtain a separate subject authorization form from each
subject.
9. Prepare and maintain adequate case histories of all persons entered into the trial,
including eCRFs, hospital records, laboratory results, etc., and maintain these data for
a minimum of 2 years following notification by the Sponsor that all investigations have
been discontinued or that the Regulatory Authority has approved the marketing
application. The Investigator should contact and receive written approval from the
Sponsor before disposing of any such documents.
10. Ensure that clinical data is entered into the eCRFs on the visit day during the staggered
enrollment phase and within 5 days post-visit for all other visits.
11.  Allow possible inspection and copying by the Regulatory Authority of GCP-specified
source documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-
supplied vaccines, and return all unused Sponsor-supplied vaccines to the Sponsor.
13.  In the event of an SAE, AESI or overdose notify the CRO within 24 hours via
SAE/AESI/overdose/misuse report form signed by the Investigator.
14.  Review and provide a signature as approval of the content of the clinical trial report.


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CureVac AG
COVID-19 mRNA Vaccine
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CONFIDENTIAL
Page 111 of 132
Appendix 2 
Emergency Procedures
cipation 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 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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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 112 of 132
Appendix 3  Definition of Severe COVID-19 Disease
Severe COVID-19 cases are defined by any 1 of the following:
 Clinical signs at
level or PaO2/FIO2 < 300 mm Hg)
 SpO2 should be adjusted according to altitude.
 Respiratory failure (defined as needing high flow-oxygen, noninvasive ventilation,
mechanical ventilation or ECMO)
 Evidence of shock (SBP < 90mm Hg, DBP < 60 mmHg, or requiring vasopressors)
 Significant renal, hepatic, or neurologic dysfunction
 Admission to ICU
Death
FDA Development and Licensure of Vaccines to Prevent COVID-19 guidance [33].


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CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 113 of 132
Appendix 4  Definition of Moderate and Mild COVID-19 Disease
Moderate COVID-19 cases are defined by any 1 of the following:
 Shortness of breath or difficulty breathing
 Abnormal SpO2 but still > 93% on room air at sea level*
*SpO2 should be adjusted according to altitude
 Clinical or radiographic evidence of lower respiratory tract disease
 Radiologic evidence of deep vein thrombosis (DVT)
Mild COVID-19 cases are defined by the following:
 Symptomatic AND
 No shortness of breath or difficulty breathing AND
 No hypoxemia
*SpO2 should be adjusted according to altitude
 Does not meet the case definition of moderate or severe COVID-19 disease








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CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 117 of 132
Appendix 8  Potential Immune-Mediated Diseases
Current list of pIMDs:
Gastrointestinal disorders:
o Celiac disease
o Crohn's disease
o Ulcerative colitis
o Ulcerative proctitis
Liver disorders:
o Autoimmune cholangitis
o Autoimmune hepatitis
o Primary biliary cirrhosis
o Primary sclerosing cholangitis
Metabolic diseases:
o Addison's disease
o Autoimmune thyroiditis (including Hashimoto thyroiditis)
o Diabetes mellitus type I
o Grave's or Basedow's disease
Musculoskeletal disorders:
o Antisynthetase syndrome
o Dermatomyositis
o Juvenile chronic arthritis (including Still's disease)
o Mixed connective tissue disorder
o Polymyalgia rheumatic
o Polymyositis
o Psoriatic arthropathy
o Relapsing polychondritis
o Rheumatoid arthritis
o Scleroderma, including diffuse systemic form and CREST syndrome
o Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter's
Syndrome) and undifferentiated spondyloarthritis
o Systemic lupus erythematosus
o Systemic sclerosis
Neuro-inflammatory disorders:
o Acute disseminated encephalomyelitis, including site specific variants (e.g., non-
infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis)
o Cranial nerve disorders, including paralyses/paresis (e.g., Bell's palsy)
o Guillain-Barré syndrome, including Miller Fisher syndrome and other variants
o Immune-mediated peripheral neuropathies, Parsonage-Turner syndrome and
plexopathies, including chronic inflammatory demyelinating polyneuropathy,
multifocal motor neuropathy, and polyneuropathies associated with monoclonal
gammopathy
o Multiple sclerosis
o Narcolepsy
o Optic neuritis
o Transverse Myelitis


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 118 of 132
Skin disorders:
o Alopecia areata
o Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis
herpetiformis
o Cutaneous lupus erythematosus
o Erythema nodosum
o Morphoea
o Lichen planus
o Psoriasis
o Sweet's syndrome
o Vitiligo
Vasculitides:
o Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and
temporal arteritis
o Medium sized and/or small vessels vasculitis including: polyarteritis nodosa,
Kawasaki's disease, microscopic polyangiitis, Wegener's granulomatosis, Churg-
Strauss syndrome (allergic granulomatous angiitis), Buerger's disease
thromboangiitis obliterans, necrotizing vasculitis and anti-neutrophil cytoplasmic
antibody (ANCA) positive vasculitis (type unspecified), Henoch- Schonlein purpura,
Behcet's syndrome, leukocytoclastic vasculitis
Others:
o Antiphospholipid syndrome
o Autoimmune hemolytic anemia
o Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis
rapidly progressive, membranous glomerulonephritis, membranoproliferative
glomerulonephritis, and mesangioproliferative glomerulonephritis)
o Autoimmune myocarditis/cardiomyopathy
o Autoimmune thrombocytopenia
o Goodpasture syndrome
o Idiopathic pulmonary fibrosis
o Pernicious anemia
o Raynaud's phenomenon
o Sarcoidosis
o Sjögren's syndrome
o Stevens-Johnson syndrome
o Uveitis


Clinical Trial Protocol
CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 119 of 132
Appendix 9  Adverse Events of Special Interest (AESIs) for SARS-CoV-2 Vaccines
Current list of AESIs {
Emergency vACcines (SPEAC) Project}:
Immunological disorders:
o Anaphylaxis
o Vasculitides
o Enhanced disease following immunization
o Multisystem inflammatory syndrome in children
Respiratory disorders:
o Acute Respiratory Distress Syndrome
o COVID-19 disease
Cardiac disorders:
Acute cardiac injury including:
o Microangiopathy
o Heart failure and cardiogenic shock
o Stress cardiomyopathy
o Coronary artery disease
o Arrhythmia
o Myocarditis, pericarditis
Hematological disorders:
o Thrombocytopenia
Coagulation disorder:
o Deep vein thrombosis
o Pulmonary embolus
o Cerebrovascular stroke
o Limb ischemia
o Hemorrhagic disease
Renal disorders:
o Acute kidney injury
Gastrointestinal disorders
o Liver injury
Neurological disorders:
o Generalized convulsion
o Guillain-Barré Syndrome
o Acute disseminated encephalomyelitis
o Anosmia, ageusia
o Meningoencephalitis
Dermatologic disorder:
o Chilblain-like lesions
o Single organ cutaneous vasculitis
o Erythema multiforme
Other:
o Serious local/systemic AR following immunization
















Clinical Trial Protocol
CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 127 of 132
Appendix 11 
Protocol Amendment History
The trial was initiated using protocol version 1.0.
Protocol version 2.0: 19 March 2021
Section # and
Name
Description of Important Change
Brief Rationale
Throughout
Clarification
Throughout
Subjects who report to have
COVID-19 symptoms will only be
followed-up if the Investigator
considers the symptoms could
potentially indicate a COVID-19 case.
Clarification
Throughout
Subjects who tested positive for
SARS-CoV-2 outside of the trial
context (RT-PCR) are to be
considered for active surveillance for
COVID-19 (see Appendix 6).
Completeness
Throughout
Unblinding will be allowed in the case
a subject becomes eligible to receive
an authorized/licensed vaccine.
Several vaccine candidates
have been approved for
emergency use since the
original protocol
Synopsis
Inclusion of information on authorized
vaccine availability.
Update
Synopsis and
6.2 Exclusion
Criteria
History of pIMD separated from
history of angioedema or
anaphylactic reaction.
Clarification
Synopsis,
9.2.1.1.1 Routine
Surveillance for
COVID-19, and
9.5.1 Virological
Confirmation of
COVID-19 Disease
Instructions added to state that viral
RNA of SARS-CoV-2 should be
sequenced at a Sponsor-designated
laboratory to identify S protein
variants in subjects with positive
RT-PCR tests.
To identify mutations in this
protein


Clinical Trial Protocol
CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 128 of 132
Section # and
Name
Description of Important Change
Brief Rationale
5.1 Overall Design
and 6.3 Vaccine
Delay
Recommendations
Guidance added that subjects may
receive the second trial vaccine dose
if they develop COVID-19 between
the first and second doses
(after being symptom-free for
2 weeks).
Clarification
9.3.3 Adverse
Events
Inclusion of instructions that
COVID-19 illness and its
complications/sequelae are to be
reported as an AESI, according to
Appendix 9.
Clarification
9.3.6 Vital Signs
and Physical
Examination
Exclusion of the genitourinary system
examination from the complete
physical examination. Inclusion of O2
saturation measurement at the
discretion of the investigator.
Correction
Throughout
Minor editorial and document
formatting revisions.
-


Clinical Trial Protocol
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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 129 of 132
Protocol Version 3.0: 23 July 2021
Section # and
Name
Description of Important Change
Brief Rationale
1 Synopsis,
2 Schedule of
activities,
3.2.3 Assessment
of potential risk and
benefits,
4.2.3 Exploratory
endpoints,
7.3.3.2 Authorized/
licensed vaccine,
7.6.2 Prohibited
medications/
vaccines during the
Trial, and
9.1 Schedule of
Trial assessments
and procedures
Introduced the summary of CVnCoV
final efficacy analysis of the HERALD
trial and, following that, the
unblinding of all blinded subject and
subsequent change on the schedules
of activities to guarantee safety follow
up of all the subjects exposed to
CVnCoV and access to information
on the HERALD final analysis results
for all the subjects.
Update following availability of
the final efficacy analysis results
of the HERALD trial.


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 130 of 132
Protocol Version 4.0: 11 August 2021
Section # and
Name
Description of Important Change
Brief Rationale
1 Synopsis and
3.2.3 Assessment
of potential risk and
benefits
Clarification that the Study Physician
will be responsible for providing study
results to subjects.
Clarification
9.4.3 Antibody
Responses to
CVnCoV
Vaccination in
Subjects Who
Develop a Case of
COVID-19
Subjects receiving authorized
SARS-CoV-2 vaccines will not be
included in the antibody response.
See Table 2
Clarification
Throughout
Minor editorial and document
formatting revisions.
-


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CV-NCOV-005
CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 131 of 132
Protocol Version 5.0: 22 December 2021
Section # and Name
Description of Important
Change
Brief Rationale
Protocol Approval Signatures 
New Medical Responsible
Person
Change of responsibility
SAE Hotline and Medical
Monitor Contact
Added e-mail address for post-
trial safety reporting
Change of safety reporting
e-mail address after end of
trial
Synopsis
Trial will remain blinded until
approval of study protocol
version 3.0.
Clarification
Synopisis /
Schedule of Trial
Assessments Table 1, 2 and
3
3.1.4 Trial Rationale
4.1.2 Secondary Endpoints
4.2 Endpoints
4.3 Estimands
5.1 Overall Design
5.2 Scientific Rationale for
Trial Design
9.1.1.10; 9.1.2.7 End of Trial
Visit
9.2.1.1.1 Routine
Surveillance for COVID-19
9.4 Immunogenicity
Assessments
10 Statistical Considerations
Assessment of cell mediated
immune (CMI) response
cancelled.
Comparison of efficacy by
pooling of results with study
COVID19-5-P-002 cancelled.
Limitation of immunogenicity
analyses to 100 CVnCoV
subjects per lot and 50 placebo
subjects and to the following
time points: Baseline, Day 29
and Day 43.
Assessment of seroconversion
to the N-protein of SARS-CoV-
2 at Day 393 cancelled.
Assessment of efficacy of
CVnCoV in the prevention or
reduction of asymptomatic
infections cancelled.
Analyses no longer
required.


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CureVac AG
COVID-19 mRNA Vaccine
Version 5.0 (22 December 2021)
CONFIDENTIAL
Page 132 of 132
Measurement of antibody
responses for all Covid-19
cases that occur in the trial
cancelled.
For positive RT-PCR tests, viral
RNA 
of 
the 
SARS-CoV-2
sequencing to identify S protein
variants no longer required.
1. Synopsis
5.1 Overall Design
9.2.1.3 COVID-19 Case
Definition for the Efficacy
Analysis
9.2.1.4 Adjudication of
COVID-19 Cases
9.3.8.2 Adjudication
Committee
Efficacy cases must no longer
be confirmed by adjudication
Confirmation no longer
required
9.3.3.2 Safety Assessments
for All Subjects
Appendix 12 Adverse Events:
Definitions and Procedures
for Recording, Evaluating,
Follow-up, and Reporting
AE recording only to be done
for criteria defined in section
9.3.2
Clarification
8 Discontinuation /
Withdrawal Criteria
Withdrawal procedure for
placebo subjects added
Clarification
11.3 Monitoring
Option for remote source data
verification included
Implementation of Guidance
on the Management of
Clinical Trials during the
Covid-19 (Coronavirus)
Pandemic

SAP_001.pdf: 
Protocol Number: CV-NCOV-005 
 
Official Title: COVID-19: A Phase 3, Randomized, Observer-Blinded, Placebo-Controlled Clinical 
Study Evaluating the Safety and Immunogenicity of Investigational SARS-CoV-2 mRNA Vaccine 
CVnCoV in Adult Health Care Workers in Mainz (Germany) 
NCT Number: NCT04674189 
 
Document Date: 08 April 2022 








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• 
Section 9.5.2 Added that Subjects who received an alternate / licensed / 
authorized vaccine prior to 15 days after the second vaccination will be 
excluded from IS. 
• 
Section 9.5.5:  
o 
Reworded the EAS definition to make it clearer.  
o 
Added unblinding and alternate / licensed / authorized vaccine 
receipt.  
o 
Added use of adjudication data. 
• 
Section 9.5.6: Modified EASS definition to not exclude subjects after 
unblinding. 
• 
Section 10.6.1: Added serology status at baseline and serology status at Visit 
Day 43 definition. 
• 
Section 10.7.4: Corrected formula for Symptom onset ≥ 15 days after second 
trial vaccination. 
• 
Section 10.11: Added date of alternate / licensed / authorized vaccine + 1 to 
the censoring date formula. 
• 
Section 10.12: Added section regarding age groups. 
• 
Section 11:  
o 
Removed planned interim analysis.  
o 
Added possible ad-hoc analyses around early conditional approval 
in Europe. 
• 
Section 12.1:  
o 
Screen failures were removed.  
o 
Description of tables was adapted to match the required outputs. 
o 
Summary of censored subjects was added. 
o 
Summary of stratification and treatment errors was added. 
• 
Section 12.2: Added combined (adjudication + EDC) serology status variable 
• 
Section 12.3:  
o 
Adapted analysis description of medical/surgical history to match 
required analyses. 
o 
Added co-morbidities analysis. 
• 
Section 12.5: Added subject- and site-level for protocol deviations. 
• 
Section 12.6.1.1 Re-arranged solicited and unsolicited AE analysis 
descriptions to reflect the required analyses, added Section 12.6.1.3. 
• 
Section 12.7: Added that no “Total” summaries will be provided for 
immunogenicity. 
• 
Section 12.8.1.1: Added usage of adjudication data for serostatus at baseline 
and Visit Day 43. 
• 
Section 12.8.1.4: Added sensitivity analysis for one secondary endpoint. 
• 
Appendix 2:  
o 
Removed Multisystem inflammatory syndrome in children from 
AESI list 
o 
Removed COVID-19 disease from AESI list 
4.0 / 08 Apr 2022 
• 
Section 1.0: Updated signatories details 
• 
Section 6.0: Added info that main stakeholders are unblinded at time of SAP 
update 
• 
Section 6.1: Changes from protocol were updated 


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• 
Section 7.2.1: Secondary efficacy objective on asymptomatic cases was 
deleted. 
• 
Section 7.2.2: Secondary immunogenicity objective on lot-to-lot consistency 
was deleted. 
• 
Section 7.3: All exploratory objectives were deleted. 
• 
Section 8.2: Added EOT wording for placebo subjects after study unblinding. 
• 
Section 8.5.2: Adapted Sample information on primary immunogenicity 
objective to new analysis scope. 
• 
Section 8.6: Updated unblinding information according to protocol 3.0 and 
study development. 
• 
Section 9.1.2: Reduced timepoints for immunogenicity analyses to Days 1, 
29 and 43. 
• 
Section 9.2.1: Reduced secondary efficacy endpoints according to scope 
reduction in EOT delivery. 
• 
Section 9.2.2: Reduced timepoints for immunogenicity analyses to Days 1, 
29 and 43. Reduced secondary immunogenicity endpoints according to 
scope reduction in EOT delivery. 
• 
Section 9.3: Deleted all exploratory endpoints. 
• 
Section 9.4: Updated “Estimands” table to match study. 
• 
Section 9.5.2: Updated IS definition to not exclude subjects who had received 
an AV prior to 15 days after 2nd vaccination. 
• 
Section 9.5.4: Reduced PPI Set to 250 subjects. 
• 
Section 9.5.6: Mentioned that EASS is not further applicable. 
• 
Section 9.5.7: Updated and corrected Summary of Analysis Sets 
• 
Section 10.5.5: Corrected AESI definition 
• 
Section 10.5.8: Added Section defining overreported AEs. 
• 
Section 10.6, and 10.6.1: Updated wording according to protocol v 3.0 and 
for clarity reasons 
• 
Section 10.6.2.3 and 10.6.3: Deleted Sections on seroconversion to N protein 
antibodies and CMI. 
• 
Section 10.7.1.1 and 10.7.2 and 10.7.5: Provided for a local instead of a 
central laboratory being used 
• 
Section 10.10: Added unblinding column to censoring table. 
• 
Section 10.11: Updated overview table to match analysis updates. 
• 
Section 11.0: Updated IA info to match study development. 
• 
Section 12.0 and 12.2 and 12.4.2 and 12.6.1.2: Updated to match study 
development and reduced EOT analysis. 
• 
Section 12.6.1.4: Added section on repeats of AE analyses without censoring 
• 
Section 12.6.7: Added section on adapting the safety analyses to the 
requirements of extensive unblinding 
• 
Section 12.7 and 12.7.1: Reduced timepoints for immunogenicity analyses to 
Days 1, 29 and 43. 
• 
Section 12.7.2 and 12.8.1.1 –  12.8.1.4: Adapted to account for reduced EOT 
analyses. 
• 
Section 12.7.3 and 12.8.2: Deleted to account for endpoint deletion. 
 
 
 


Statistical Analysis Plan (SAP) 
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 Table of Contents 
 Approvals ................................................................................................................................................ 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents .................................................................................................................................... 5 
 Purpose ................................................................................................................................................... 8 
 Scope ...................................................................................................................................................... 8 
 Introduction ............................................................................................................................................. 8 
6.1 Changes from Protocol .................................................................................................................... 8 
 Trial Objectives ....................................................................................................................................... 9 
7.1 Primary Objectives: .......................................................................................................................... 9 
7.1.1 Primary Safety Objective ....................................................................................................... 9 
7.1.2 Primary Immunogenicity Objective ........................................................................................ 9 
7.2 Secondary Objectives: ..................................................................................................................... 9 
7.2.1 Secondary Efficacy Objectives .............................................................................................. 9 
7.2.2 Secondary Immunogenicity Objectives ............................................................................... 10 
 Trial Design ........................................................................................................................................... 10 
8.1 Overall Design ............................................................................................................................... 10 
8.2 Interim Analysis .............................................................................................................................. 10 
8.3 End of Trial ..................................................................................................................................... 10 
8.4 Independent Data Safety Monitoring Board ................................................................................... 11 
8.5 Sample Size Considerations .......................................................................................................... 11 
8.5.1 Sample Size Considerations for the Primary Safety Objective ........................................... 11 
8.5.2 Sample for the Primary Immunogenicity Objective ............................................................. 11 
8.6 Randomization and Blinding .......................................................................................................... 12 
 Trial Endpoints ...................................................................................................................................... 12 
9.1 Primary Endpoints .......................................................................................................................... 12 
9.1.1 Primary Safety Endpoints .................................................................................................... 12 
9.1.2 Primary Immunogenicity Endpoints ..................................................................................... 13 
9.2 Secondary Endpoints ..................................................................................................................... 13 
9.2.1 Secondary Efficacy Endpoints ............................................................................................. 13 
9.2.2 Secondary Immunogenicity Endpoints ................................................................................ 13 
9.3 Exploratory Endpoints .................................................................................................................... 14 
9.3.1 Exploratory Efficacy Endpoint .............................................................................................. 14 
9.3.2 Exploratory Immunogenicity Endpoints ............................................................................... 14 
9.3.3 Exploratory Efficacy Endpoints (pooled analysis of trial COVID19-5-P-002 and trial CV-
NCOV-005) ................................................................................................................................... 14 


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9.4 Estimands ...................................................................................................................................... 14 
9.5 Population Sets .............................................................................................................................. 16 
9.5.1 Safety Analysis Set .............................................................................................................. 16 
9.5.2 Immunogenicity/Reactogenicity Subset............................................................................... 17 
9.5.3 Safety Analysis Subsets (SAS 2 and SASsol) .................................................................... 17 
9.5.4 Per Protocol Immunogenicity (PPI) Set ............................................................................... 17 
9.5.5 Efficacy Analysis Set (EAS) ................................................................................................. 17 
9.5.6 Efficacy Analysis Set for Seroconversion for N Protein Antibodies (EASS) ........................ 18 
9.5.7 Summary of Analysis Sets to be Used per Analysis ........................................................... 18 
 Conventions and Derivations .............................................................................................................. 19 
10.1 Baseline and Change from Baseline ........................................................................................... 19 
10.2 Trial Day ....................................................................................................................................... 19 
10.3 Missing Data ................................................................................................................................ 19 
10.4 Prior and Concomitant Medications ............................................................................................. 20 
10.5 AEs ............................................................................................................................................... 20 
10.5.1 Treatment Emergent Adverse Events (TEAE) .................................................................. 21 
10.5.2 Solicited AEs ...................................................................................................................... 21 
10.5.3 Duration and Time of Onset for Solicited AEs ................................................................... 23 
10.5.4 Unsolicited AEs .................................................................................................................. 23 
10.5.5 Adverse Events of Special Interest .................................................................................... 24 
10.5.6 Medically Attended AEs ..................................................................................................... 24 
10.5.7 Adverse Events Related to Standardized and Customized MedDRA Queries ................. 24 
10.5.8 Overreported AEs .............................................................................................................. 25 
10.6 Immunogenicity Assessments ..................................................................................................... 25 
10.6.1 SARS-CoV-2 Serology Status ........................................................................................... 25 
10.6.2 Seroconversion .................................................................................................................. 26 
10.7 COVID-19 Cases ......................................................................................................................... 26 
10.7.1 Case Detection .................................................................................................................. 27 
10.7.2 Definition of Virologically-Confirmed COVID-19 Case and Onset Date ............................ 27 
10.7.3 Definition of Mild, Moderate and Severe COVID-19 Cases .............................................. 28 
10.7.4 COVID-19 Case Definition for Efficacy Analysis ............................................................... 29 
10.7.5 Adjudication of COVID-19 Cases ...................................................................................... 29 
10.8 Definition of Asymptomatic Cases of SARS-CoV-2 Infection and Onset Date ............................ 30 
10.9 Burden of Disease ....................................................................................................................... 30 
10.10 Censoring Rules for Unblinded Subjects and/or Treated with AV ............................................. 30 


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10.11 Event Dates, Follow-Up Time, Time to Event Calculation and Censoring ................................ 32 
10.12 Age Group .................................................................................................................................. 33 
 Interim Analyses .................................................................................................................................. 33 
 Statistical Methods .............................................................................................................................. 33 
12.1 Subject Disposition ...................................................................................................................... 34 
12.2 Demographic and Baseline Characteristics ................................................................................. 34 
12.3 Medical and Surgical History ....................................................................................................... 35 
12.4 Trial Treatment ............................................................................................................................. 35 
12.4.1 Trial Vaccine Exposure ...................................................................................................... 35 
12.4.2 Prior and Concomitant Medications and Vaccinations ...................................................... 35 
12.5 Important Protocol Deviations ...................................................................................................... 35 
12.6 Safety Analyses ........................................................................................................................... 36 
12.6.1 Adverse Events .................................................................................................................. 36 
12.6.2 Deaths and Serious Adverse Events ................................................................................. 39 
12.6.3 Laboratory Data ................................................................................................................. 39 
12.6.4 Vital Signs .......................................................................................................................... 39 
12.6.5 Physical Examinations, ECGs, and Other Observations Related to Safety ...................... 39 
12.6.6 Sensitivity Analysis on Safety Outputs .............................................................................. 39 
12.6.7 Adapting the Safety Analyses to the Requirements of Extensive Unblinding ................... 39 
12.7 Immunogenicity Analyses ............................................................................................................ 40 
12.7.1 Primary Immunogenicity Analyses .................................................................................... 40 
12.7.2 Secondary Immunogenicity Analyses ................................................................................ 40 
12.7.3 Exploratory Immunogenicity Analyses............................................................................... 41 
12.8 Efficacy Analyses ......................................................................................................................... 41 
12.8.1 Secondary Efficacy Endpoint Analysis .............................................................................. 41 
 References .......................................................................................................................................... 42 
 Glossary of Abbreviations ................................................................................................................... 43 
 Appendices ......................................................................................................................................... 45 
Appendix 1 
Potential Immune-Mediated Diseases ........................................................................ 45 
Appendix 2 
AESIs for SARS-CoV-2 Vaccines* .............................................................................. 47 
Appendix 3 
Terms for Selected Standardised and Customized MedDRA Queries ....................... 48 
Appendix 4 
List of TFLs .................................................................................................................. 70 
Appendix 5 
Identification of Protocol Deviations Leading to Exclusion from Analysis Sets........... 70 
 


Statistical Analysis Plan (SAP) 
Version Date: 4.0 08-Apr-2022  
 
Sponsor: CureVac AG 
 
Protocol no: CV-NCOV-005 
 
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 Purpose 
The  Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under CureVac AG Protocol CV-NCOV-005. 
 Scope 
The SAP outlines the following: 
• 
Trial Objectives 
• 
Trial Design 
• 
Trial Endpoints and Assessments 
• 
Analysis Sets 
• 
Conventions and Definitions 
• 
Applicable Trial Definitions 
• 
Statistical Methods 
 Introduction 
The SAP describes the statistical methods to be used during the reporting and analyses of data collected 
under CureVac AG Protocol CV-NCOV-005. 
The SAP should be read in conjunction with the trial protocol version 5.0 dated 22-Dec-2021 and Case 
Report Form (CRF) v4.0 dated 10-Jun-2021. 
This SAP describes the statistical methods used for the final analysis. The SAP v1.0 is approved prior to 
the first relevant delivery1. Changes following approval of the first version of the SAP are tracked in the SAP 
Change Log and the last final SAP version is approved prior to final database lock.  
Each version of the SAP requires approval by the Sponsor. 
It must be noted that all main stakeholders from the combined Sponsor and designated Contract Research 
Organization (CRO) (PRA/ICON) study team have been unblinded between approval of SAP versions 3.0 
and 4.0. As a consequence, the SAP version 4.0 is created and approved by an unblinded 
authorship/approval team.  
6.1 Changes from Protocol 
1) Addition of sensitivity analysis on Safety outputs for Safety Interim Analysis (IA) to account for 
censoring rules in main analyses (Section12.6.6) 
2) Inclusion of Adverse Events (AEs) Related to Standardized and Customized Medical Dictionary for 
Regulatory Activities (MedDRA) Queries (CMQs)  
3) The planned IA to obtain early conditional approval in Europe was removed. 
4) An early immunogenicity delivery and related unblinding of PRA/ICON was added. 
5) Update to analysis sets (Section 9.5) to account for unblinding and/or Authorized Vaccine (AV) 
application. 
6) Protocol deviations are classified in site- and subject-level protocol deviations. 
7) A sensitivity analysis on a secondary endpoint was added, according to what was done in the 
CV-NCOV-004 study. 
 
1 This was the safety delivery for the rolling submission when subjects randomized by (including) 11-Feb-
2021 had reached 6 weeks post 2nd dose. 


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8) Multisystem inflammatory syndrome in children was removed from Adverse Event of Special 
Interest (AESI) list  
9) The Efficacy Analysis Set (EAS) excludes subjects who were unblinded prior to 15 days after the 
second vaccination or received an AV prior to 15 days after the second vaccination  
10) In the protocol synopsis the definition of the efficacy endpoint does no longer require the subject to 
be N negative. This is considered an erroneous deletion and is ignored. 
11) “Non-serious intercurrent medical conditions that may affect the immune response to vaccination 
will also be collected throughout the trial.” is taken out of the AESI definition. 
12) The secondary immunogenicity endpoint lot to lot consistency is not to be analyzed. 
13) From the secondary efficacy endpoint “Occurrence of first episodes of virologically-confirmed (RT-
PCR positive) symptomatic cases of COVID-19 meeting the case definition for the efficacy analysis 
by severity (mild, moderate, severe and moderate to severe COVID-19)” only the mild cases are 
analyzed . 
14) No repeat of any of the secondary efficacy analyses on the Safety Analysis Set (SAS) is done. 
15) Protocol Section 10.3.7.1 requires the secondary efficacy analyses of prevention or reduction of 
asymptomatic infections as measured by seroconversion to the N protein to be performed, although 
this was deleted from all other sections in the protocol. This is considered an oversight and 
therefore this analysis is not performed. 
16) The Vaccine Efficacy (VE) analysis of Burden of Disease (BoD) is not performed. 
17) The sensitivity analysis by Kaplan-Meier (KM) curves for the time to first occurrence of virologically-
confirmed COVID-19 case of any severity is not performed. No sensitivity analysis of this endpoint 
on the SAS is performed either. 
 Trial Objectives 
7.1 Primary Objectives: 
7.1.1 Primary Safety Objective 
• 
To evaluate the safety (in all subjects) and reactogenicity (in a subset of subjects) of CVnCoV 
administered as a 2-dose schedule to adults 18 years of age or older. 
7.1.2 Primary Immunogenicity Objective 
• 
To assess antibody responses to the receptor-binding domain (RBD) of S protein of SARS-CoV-2 after 
1 and 2 doses of CVnCoV in adults 18 years of age or older included in a subset of subjects.   
7.2 Secondary Objectives: 
7.2.1 Secondary Efficacy Objectives 
• 
To assess the efficacy of a 2-dose schedule of CVnCoV in the prevention of first episodes of 
virologically-confirmed symptomatic cases of COVID-19 of any severity in SARS-CoV-2 naïve subjects. 
• 
To describe the severity of first episodes of virologically-confirmed symptomatic cases of COVID-19 in 
SARS-CoV-2 naïve subjects, receiving a 2-dose schedule of CVnCoV compared to those administered 
placebo. 
• 
To assess the efficacy of a 2-dose schedule of CVnCoV in reducing the BoD from COVID-19.  


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7.2.2 Secondary Immunogenicity Objectives  
• 
To assess SARS-CoV-2 virus neutralizing antibody responses after 1 and 2 doses of CVnCoV in adults 
18 years of age or older included in a subset of subjects. 
 Trial Design 
8.1 Overall Design 
Trial CV-NCOV-005 is conducted as a randomized, observer-blinded, and placebo-controlled trial. Subjects 
18 years of age or older previously enrolled in the non-interventional trial performed at the Mainz University, 
Germany (COVID19-5-P-002), other health care workers (HCW) and potentially students in clinical training 
are enrolled. Subjects receive a 2-dose schedule, 28 days apart, of either one of two lots of CVnCoV at a 
dose level of 12 µg mRNA or placebo (normal saline [0.9% NaCl] for injection) in a 1:1:1 ratio. Approximately 
2,520 subjects (840 per randomization group) are enrolled. 
The safety, reactogenicity and immunogenicity of a 2-dose schedule of CVnCoV in HCWs is assessed 
descriptively.  
The primary safety objective is to expand the safety database that demonstrates the safety profile of 
CVnCoV. The safety and reactogenicity of a 2-dose schedule of CVnCoV is assessed in detail by measuring 
the frequency and severity of solicited local and systemic AEs (on the day of vaccination and for the 
following 7 days after each vaccination) and unsolicited AEs on the day of vaccination and for the following 
28 days after each vaccination, both in a subset of subjects (Immunogenicity/Reactogenicity Subset i.e. the 
first 1,260 subjects enrolled). Medically-attended AEs through 6 months after the second trial vaccination 
and AESIs, Serious Adverse Events (SAEs) and AEs leading to vaccine withdrawal or trial discontinuation 
for 1 year after the second trial vaccination are collected for all subjects. 
An independent Data Safety Monitoring Board (DSMB, see Section 8.4) performs a review of the available 
safety data of both CV-NCOV-004 and CV-NCOV-005 at regular meetings.     
The immunogenicity of CVnCoV after 1 and 2 doses is evaluated in a subset of subjects 
(Immunogenicity/Reactogenicity Subset, the first 1,260 subjects enrolled) by measuring:  
• 
binding antibodies to the SARS-CoV-2 RBD of S protein  
• 
viral neutralizing antibodies directed against SARS-CoV-2  
 
During the trial, subjects undergo active surveillance for COVID-19. Subjects suspected of having COVID-
19 undergo testing for SARS-CoV-2 virus.  
8.2 Interim Analysis 
No formal IA is done. In August 2021 a first immunogenicity delivery is provided. PRA/ICON who is to create 
that analysis is unblinded on that occasion. 
8.3 End of Trial 
A subject is considered to have completed the trial when he/she has completed all visits, procedures, and 
tests applicable for the group to which he/she was randomized to at trial entry. Exception: Placebo subjects 
discontinue the trial once study protocol version 3.0 and 4.0 are approved. The corresponding wording from 
the protocol is as follows: “After trial unblinding, i.e. after approval of study protocol version 3.0 and 4.0, all 
placebo subjects should be withdrawn at the earliest possible timepoint, if their originally planned End of 
Trial visit is later than February 2022 and will undergo the same procedures as for the End of Trial visit at 
their withdrawal visit. If a withdrawal visit cannot be scheduled for placebo subjects due to the pandemic 
setting, the end of trial assessment, i.e. collection of final safety data, can also be done by phone. In the e-




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8.6 Randomization and Blinding 
The trial is randomized, observer-blinded, and placebo-controlled. The difference in appearance of the 
investigational CVnCoV vaccine and placebo requires the trial to be conducted in an observer-blinded 
manner. 
The pharmacist/personnel preparing the trial vaccine at the site is not blinded to the identity of the trial 
vaccine being administered to the subject. However, the vaccinator, investigator and all site personnel 
involved in the conduct of the trial are blinded to trial vaccine and subject treatment assignments. To 
maintain the blinding of the vaccinator, the unblinded pharmacist/site personnel  provide the dose of trial 
vaccine to the vaccinator prefilled in a syringe with a label covering the liquid contents so that it is not visible. 
All personnel at PRA/ICON and Sponsor directly involved in the conduct of the trial is also blinded. There 
are certain individuals at PRA/ICON and Sponsor whose function requires them to be unblinded during the 
trial (e.g., unblinded monitoring for trial vaccine accountability in the pharmacy; unblinded independent 
statistician assisting the DSMB; review of immunogenicity data). These unblinded individuals are identified 
and their responsibilities documented. 
As the immunogenicity results would unblind the subject’s treatment assignment, an independent laboratory 
performing the assays keep the results in strict confidence. An unblinded person, named at the start of the 
trial and independent of the conduct of the trial, has the responsibility of reviewing the quality of the 
immunogenicity data as it is being generated. This person maintains the results in strict confidence. To 
maintain the blind, the immunogenicity data is only merged with the clinical database at CDISC level 
following unblinding of the trial. 
The first immunogenicity analysis is scheduled for August 2021. PRA/ICON who is to perform this analysis 
is unblinded on that occasion. 
Approximately 2,520 subjects 18 years of age or older are enrolled at the site at Mainz University, Germany 
and are randomized in a 1:1:1 ratio (840 per randomization group) to receive either one of two different lots 
of a 2-dose schedule of CVnCoV or placebo. The randomization is performed centrally and stratified by age 
group (18 to 60 and ≥61 years of age). 
The randomization scheme is generated and maintained by an independent statistical group at PRA/ICON. 
Subjects are enrolled into the trial online and randomized using an  Interactive Web Response System 
(IWRS). The first 1,260 subjects enrolled are planned to be included in the Immunogenicity/Reactogenicity 
Subset. 
See Section 10.10 for handling of cases where a subject becomes eligible to receive an AV during the 
course of the trial. 
In Study Protocol 3.0 the following decision regarding unblinding was added: “Since the efficacy results 
from the HERALD study for CVnCoV are available and all subjects in the CV-NCOV-005 study are currently 
eligible to receive an authorized vaccine, all subjects in this CV-NCOV-005 study will be unblinded.” This 
unblinding is performed on a by-subject level via IWRS and therefore does not require any additional 
programmatic or planning attention. 
In July 2021, on the occasion of Herald CV-NCOV-004 study primary efficacy analysis delivery, selected 
members from the Sponsor and PRA/ICON study teams (i.e. both Biostatistics teams) were unblinded for 
CV-NCOV-005. In December 2021 the full Sponsor and PRA/ICON study teams were unblinded. 
 Trial Endpoints 
9.1 Primary Endpoints 
9.1.1 Primary Safety Endpoints 
• 
Occurrence, intensity and relationship of medically-attended AEs collected through 6 months after the 
second trial vaccination in all subjects. 


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• 
Occurrence, intensity and relationship of SAEs and AESIs collected through EOT Visit in all subjects. 
• 
Occurrence of fatal SAEs through EOT Visit in all subjects. 
• 
Occurrence of AEs leading to vaccine withdrawal or trial discontinuation through EOT Visit in all 
subjects. 
• 
Occurrence, intensity and duration of each solicited local AE within 7 days after each trial vaccination 
in a subset of subjects. 
• 
Occurrence, intensity, duration of each solicited systemic AE within 7 days after each trial vaccination 
in a subset of subjects. 
• 
Occurrence, intensity and relationship of unsolicited AEs occurring within 28 days after each trial 
vaccination in a subset of subjects.  
9.1.2 Primary Immunogenicity Endpoints 
SARS-CoV-2 RBD of the S protein antibody responses on Days 1, 29 and 43 in a subset of 250 subjects 
(Per Protocol Immunogenicity Set (PPI)) : 
• 
Serum antibodies to SARS-CoV-2 RBD of the S protein  
• 
Occurrence of seroconversion to SARS-CoV-2 RBD of S protein.  
Thereby, seroconversion is defined as detectable SARS-CoV-2 RBD of S protein antibodies in the 
serum of subjects who tested seronegative at Day 1 (Baseline), see Section 10.6.2.1 and Section 10.6.1 
for details.  
9.2 Secondary Endpoints 
9.2.1 Secondary Efficacy Endpoints 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) symptomatic cases of 
COVID-19 of any severity meeting the case definition for the efficacy analysis. 
• 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) symptomatic mild cases of 
COVID-19 meeting the case definition for the efficacy analysis as defined in Section 10.7.3. 
• 
BoD scores calculated based on first episodes of virologically-confirmed (RT-PCR positive) cases of 
COVID-19 of any severity meeting the case definition for the efficacy analysis. 
o 
BoD #1 – no disease (not infected or asymptomatic infection) = 0; mild or moderate disease = 
1; severe disease = 2.  
o 
BoD #2 – no disease (not infected or asymptomatic infection) = 0; disease without 
hospitalization = 1; disease with hospitalization = 2; death = 3.  
9.2.2 Secondary Immunogenicity Endpoints 
• 
SARS-CoV-2 viral neutralizing antibody responses on Days 1, 29 and 43 in the PPI subset of 250 
subjects: 
o 
Serum viral neutralizing antibodies to SARS-CoV-2 virus, as measured by a virus neutralizing 
assay. 








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9.5.2 Immunogenicity/Reactogenicity Subset 
The 
Immunogenicity/Reactogenicity 
Subset 
is 
defined 
as 
all 
subjects 
from 
the 
immunogenicity/reactogenicity cohort as indicated on the CRF (i.e. the first 1260 subjects enrolled into the 
study). 
9.5.3 Safety Analysis Subsets (SAS 2 and SASsol) 
• 
The SAS 2 includes all subjects of the SAS who belong to the Immunogenicity/Reactogenicity cohort.  
• 
The SASsol includes all subjects of the SAS who belong to the Immunogenicity/Reactogenicity cohort 
with at least 1 diary collection indicating the occurrence or lack of occurrence of solicited AEs (see 
Section 10.5.2). 
9.5.4 Per Protocol Immunogenicity (PPI) Set 
The PPI set 
includes 250 subjects (100 per lot and 50 placebo subjects) 
from the 
Immunogenicity/Reactogenicity Subset who: 
• 
Received both doses as randomized and within the windows defined in the protocol. 
• 
Have no major protocol deviations expected to impact the immunogenicity outcomes as specified 
in Section 12.5. 
• 
Have not received medical treatments (such as blood products, immunoglobulin therapy) that may 
interfere with one or both of the proposed immunogenicity measurements. 
• 
Have at least one blood sample collected at baseline and at 14 days (Day 43) post-second 
vaccination available for analysis.  
Subjects who have been tested positive for COVID-19 have their data included up to the point of a positive 
test result. 
Subjects to be excluded from the PPI set are identified and reviewed at the Blinded Data Review Meeting 
held before any formal analysis (interim or final). See Section 12.5 for further details.  
The selection of the 250 applicable subjects is performed by the Sponsor and communicated at the Blinded 
Data Review Meeting performed before the EOT analysis.  
9.5.5 Efficacy Analysis Set (EAS) 
The EAS includes all subjects of the SAS who: 
• 
Received both trial doses according to their randomization (two doses of the same lot of CVnCoV 
if randomized to that lot or two doses of placebo if randomized to placebo). 
• 
Had not developed a virologically-confirmed case of COVID-19 before trial entry (based on 
exclusion criteria 1, see Trial Protocol)  
• 
Had not developed a virologically-confirmed case of COVID-19 (definition in Section 10.7.2) or an 
asymptomatic case of SARS-CoV-2 (definition in Section 10.8) before 15 days after the second 
vaccination. 
• 
Had not stopped the trial before 15 days after the second vaccination.  
• 
Were SARS-CoV-2 naïve at baseline (Visit Day 1) and Visit Day 43 (based on seronegativity to N 
protein in the blood sample). 
• 
Were not unblinded or in receipt of AV prior to 15 days after the second vaccination (See Section 
10.10) 
Where available the information assessed by the independent adjudication Committee of clinicians (Section 
10.7.5) is used. 




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 Conventions and Derivations 
10.1 Baseline and Change from Baseline 
Unless otherwise stated, baseline is defined as the last non-missing measurement at Visit 1 (Day 1), prior 
to administration of the first dose of trial vaccine. 
Change from baseline at any post baseline timepoint is defined as: 
Change from baseline =  Observed Value at post baseline timepoint −Observed value at baseline. 
10.2 Trial Day 
Throughout this trial, trial days are defined as follows: 
• 
Day 1 is the day of first trial vaccination. 
• 
For days after first trial vaccination, trial day is calculated as 
𝑇𝑟𝑖𝑎𝑙 𝐷𝑎𝑦= 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑎𝑦−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑣𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑖𝑜𝑛+ 1 . 
• 
For days before first trial vaccination, trial day is calculated as 
𝑇𝑟𝑖𝑎𝑙 𝐷𝑎𝑦= 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑎𝑦−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑣𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑖𝑜𝑛. 
10.3 Missing Data 
In general, no imputation of missing values is done except for the following: 
• 
Imputation of missing onset date for confirmed COVID-19 cases as specified in Section 10.7.2. 
• 
For SARS-CoV-2 RBD of S protein antibodies, and viral neutralizing antibodies, concentration 
values marked as below the lower limit of quantification (LLOQ) are set to 0.5*LLOQ for 
computation purposes. 
• 
Imputation of (partially) missing AE start dates: 
o 
If start date year value is missing, the date uncertainty is too high to impute a rational date. 
Therefore, if year value is missing, the imputed AE start date is set to missing.  
o 
If start date year value is before the vaccination start date year value, then the AE started 
before the vaccination. Therefore:  
▪ 
If month is missing, the imputed start date is set to the mid-year point (i.e., 
01JULYYYY).  
▪ 
If month is not missing, the imputed start date is set to the mid-month point (i.e., 
15MONYYYY).  
o 
If start date year value is equal to the vaccination start date year value, the start date month 
needs to be compared against the vaccination start date month, to determine the 
imputation rule to apply. Therefore:  
▪ 
If month is missing, the imputed month and imputed day is the same as start of 
vaccination 
▪ 
If month is lower than vaccination start date month and start date day is missing, 
the imputed start date is set to the mid-month point (i.e. 15MONYYYY). 
▪ 
If month is equal to the vaccination start date month and start date day is missing, 
the start day is set to the start day of vaccination. 
▪ 
If month is greater than the vaccination start date month and start date day is 
missing, the imputed start date is set to the beginning of the month (i.e., 
01MONYYYY). 
o 
If start date year value is greater than the vaccination start date year value, the AE started 
after vaccination. Therefore:  


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▪ 
If month is missing, the imputed start date is set to the year start point (i.e., 
01JANYYYY).  
▪ 
If start date month is not missing and start date day is missing, the imputed start 
date is set to the beginning of the month (i.e., 01MONYYYY).  
o 
If after imputation of start and resolution date (see below) a start date is after the resolution 
date (for example if a missing day of a start date is set to 15 and the resolution date is 
before the 15th of the same month and year) then the start date is set to the resolution date. 
• 
Imputation of (partially) missing AE end dates:  
o 
If date of resolution is completely missing, and it is assumed that it resolved at the date of 
the end of the trial, the date of the end of the trial is used as the AE end date.  
o 
If year is present, it is assumed that it resolved on 31 December of that year (i.e., 
31DECYYYY), or at the end of the trial if this is earlier and in the same year.  
o 
If year and month are present, it is assumed that it resolved on the last day of that month, 
or at the end of the trial if this is earlier and in the same month/year.  
• 
Imputation of missing AE start times: 
o 
If the (recorded or imputed) AE start date is equal to the vaccination start date, then the 
AE start time is the time of vaccination start. 
o 
In all other cases, AE start time is imputed as 00:00.  
If not stated otherwise, the original or incomplete data is presented in listings rather than the imputed one.  
10.4 Prior and Concomitant Medications 
Medications are categorized as prior medication or concomitant medication based on the following rules: 
• 
Any medication taken prior to trial start (informed consent signature) as recorded by the investigator 
is considered prior medication. 
• 
Any medication not taken prior to trial start as recorded by the investigator is considered 
concomitant medication. 
• 
Any medication taken prior to trial start as recorded by the investigator and for which “Ongoing” is 
ticked as “Yes” or “Unknown” is considered concomitant medication. 
Note: A medication can be both prior and concomitant if it starts prior to trial start and is ongoing.  
10.5 AEs 
An AE is any untoward medical occurrence in a subject which does not necessarily have to have a causal 
relationship with the investigational product. In this trial, confirmed cases of COVID-19 and 
complications/sequelae are not considered as AEs as they are captured on the CRF pages for COVID-19 
illness which are expected outcomes of the trial and are analyzed as efficacy endpoints. 
In this trial, for subjects in the Immunogenicity/Reactogenicity Subset, information on solicited local and 
systemic AEs occurring within 7 days after each vaccination and on unsolicited AEs occurring within 28 
days after each vaccination are collected. 
For all trial subjects, information on medically attended AEs through 6 months after second vaccination and 
SAEs, AESIs and AEs leading to vaccine withdrawal or trial discontinuation through EOT are recorded. 
Non-serious intercurrent medical conditions that may affect the immune response to vaccination are also 
collected as AEs throughout the trial.  
No other AEs require recording in the CRF.  








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Unsolicited AEs are assigned to first or second dose based on the (reported or imputed) AE date. 
Unsolicited AEs occurring before dose 2 are assigned to dose 1. Unsolicited AEs occurring after dose 2, 
are assigned to dose 2. Unsolicited AEs occurring on the day of dose 2 are assigned to either dose 1 or 
dose 2 as per the following rules:  
• 
If the AE occurred on the day of dose 2 but before vaccination with dose 2, the AE is assigned to 
dose 1  
• 
If the AE occurred on the day of dose 2 but on or after vaccination with dose 2, it is assigned to 
dose 2.  
• 
If the AE occurred on the day of dose 2 and it cannot be determined whether it occurred before, on 
or after vaccination with dose 2, it is assigned to dose 2.  
10.5.5 Adverse Events of Special Interest 
The following events are considered and collected as AESI throughout the trial: 
• 
AEs with a suspected immune-mediated etiology (pIMDs, see Appendix 1) 
• 
Other AEs relevant to SARS-CoV-2 vaccine development or the target disease (see Appendix 2)  
AESI are identified as recorded by the investigator in the eCRF (electronic CRF). No additional 
programming is performed to identify (potential) AESIs.  
10.5.6 Medically Attended AEs 
Up to 6 months after second vaccination (or up to EOT, whatever is earlier), subjects are asked to confirm 
if they sought medical attention for an AE. Medically attended AEs are defined as AEs with medically-
attended visits that are not routine visits for physical examination or vaccination, such as visits for 
hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel 
(medical doctor) for any reason. The start of a medically attended AE is defined by its start date, irrespective 
of the date medical attention was sought. A medically attended AE is considered as occurring up to 6 
months after second trial vaccination if 
Start Date of AE −(Scheduled) date of second vaccination + 1 ≤180 days. 
I.e. one month is defined as 30 days and the date of the scheduled second vaccination (Day 29) is used in 
case a subject only received the first vaccination.  
10.5.7 Adverse Events Related to Standardized and Customized MedDRA Queries 
Subjects’ AEs are filtered with Standardized MedDRA Queries (SMQs) and Customized MedDRA Queries  
(CMQs) for the following SMQs/CMQs: 
• 
Anaphylactic reaction (SMQ) 
• 
Convulsions (SMQ) 
• 
Embolic and thrombotic events 
• 
Hypersensitivity (SMQ) 
• 
Immune-mediated/autoimmune disorders (SMQ)  
• 
Liver related investigations, signs and symptoms (Sub-SMQ) 
• 
Paraesthesia, Hypoaesthesia, Hyperaesthesia (CMQ) 
• 
Taste and smell disorders (CMQ) 
The related terms for MedDRA Version 23.1 are listed in Appendix 3.  


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10.5.8 Overreported AEs 
The definition of overreported AEs consists of the following 6 items: 
No overreporting restrictions exist for: 
1. (Treatment emergent) AESIs 
2. (Treatment emergent) SAEs 
3. (Treatment emergent) non-serious intercurrent medical condition that may affect the immune 
response to vaccination 
4. (Treatment emergent) AEs leading to vaccine withdrawal or trial discontinuation 
Overreporting restrictions: 
5. Medically attended TEAEs not matching any of the above 4 categories that have started later than 
6 months after 2nd dose 
6. TEAEs not matching any of the above 5 categories that have started later than 28 days after any 
dose. (I.e. An AE starting between Day 29 and 49 when dose 2 was given on Day 50 is also an 
overreported AE.) 
In the output, overreported AEs are displayed in listings but are not included in tables. 
10.6 Immunogenicity Assessments 
Immunogenicity assessments are only performed in subjects from the Immunogenicity/Reactogenicity 
Subset to assess the immune response induced by vaccination with CVnCoV and are evaluated in 2 ways: 
• 
Binding antibodies to the SARS-CoV-2 RBD of the S protein (IgG) measured in serum by 
immunoassay. 
• 
Viral neutralizing antibodies directed against SARS-CoV-2 (MN 25 TCID50) measured in serum by 
a functional activity assay. 
Results from the two assays are quantitative. Measures below the LLoQ are presented as half the LLoQ in 
the data. 
Further assessments for serology status to natural SARS-CoV-2 infection (SARS-CoV-2 N protein) are 
performed in all subjects by immunoassay. The N protein is not a component of the CVnCoV vaccine, but 
is measured to determine the serostatus of subjects to the SARS-CoV-2 virus and the occurrence of 
SARS-CoV-2 infections during the trial (see also Section Error! Reference source not found.). Data 
provided is qualitative (positive/negative). 
As the immunogenicity results would potentially unblind the subject’s treatment assignment, the laboratory 
performing the assays keeps the results in strict confidence. The SARS-CoV-2 N protein data is not 
considered unblinding information. 
After approval of protocol v3.0 immunogenicity assessments are no longer performed.  
10.6.1 SARS-CoV-2 Serology Status 
In all trial subjects, measurement of binding antibodies to the SARS-CoV-2 N protein is performed by 
immunoassay. Blood samples are taken on Day 1 (pre-vaccination baseline), Day 43 and Day 211 of the 
trial.  
The (retrospective) SARS-CoV-2 serology status is defined based on levels of antibodies to the 
SARS-CoV-2 N protein. Subjects are defined as naïve to SARS-CoV-2 infection at baseline and Day 43, if 
there are no detectable SARS-CoV-2 N protein antibodies in the blood samples taken at baseline and 
Day 43, respectively. 


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Serology status at baseline is based on blood samples taken at Clinic Visit 1 (Visit Day 1) up to 2 days after 
1st vaccination. The baseline definition for serology status is differing from the general baseline definition in 
this study (see Section 10.1). 
Serology status at Visit Day 43 is based on blood samples taken at Clinic Visit 3 (Visit Day 43) 14 days 
after 2nd vaccination +/- 3 days. 
For safety analyses, N antibody serostatus at baseline is used to define the seronegative and seropositive 
safety populations.  
For the efficacy analyses, the subject must be seronegative/naïve to N protein at baseline and Day 43 to 
be considered naïve when COVID-19 cases are being counted ≥ 15 days after second trial vaccination. For 
endpoints where cases are counted at any time after the 1st trial vaccination, these subjects only have to 
be seronegative/naive at baseline.    
The same definition as given above is applied to assess the SARS-CoV-2 serology status of subjects at 
any other timepoint where a respective blood sample was taken; to measure infections with SARS-CoV-2 
during the course of the trial. 
Nota bene: Although the N antibody serostatus is to be considered an immunogenicity assessment, these 
values are not censored due to AV receipt. 
10.6.2 Seroconversion 
Seroconversion is defined by a relevant increase in antibody titer compared to baseline. The titer is the 
highest dilution factor that still yields a positive reading for the antibodies, i.e. larger titers correspond to 
larger concentration of antibodies. Depending on the type of antibodies and previous exposure of a subject 
to SARS-CoV-2 (as measured by antibodies to the SARS-CoV-2 N protein), different definitions of 
seroconversion apply: 
10.6.2.1 SARS-CoV-2 RBD of S Protein Antibodies 
In subjects who tested seronegative to the N protein for SARS-CoV-2 at baseline (see Section 10.6.1), 
seroconversion is defined as a fold increase above 1 in antibody titer against SARS-CoV-2 RBD of S 
protein.  
In subjects who tested seropositive to the N protein for SARS-CoV-2 at baseline (see Section 10.6.1), the 
definition for seroconversion is a fold increase above 2 in antibody titer against SARS-CoV-2 RBD of S 
protein versus baseline. 
10.6.2.2 SARS-CoV-2 Neutralizing Antibodies 
In subjects who tested seronegative to the N protein for SARS-CoV-2 at baseline (see Section 10.6.1), 
seroconversion is defined as a fold increase above 1 in SARS-CoV-2 neutralizing antibody titer.  
In subjects who tested seropositive to the N protein for SARS-CoV-2 at baseline (see Section 10.6.1), the 
definition for seroconversion is a fold increase above 2 in SARS-CoV-2 neutralizing antibody titer versus 
baseline. 
10.7 COVID-19 Cases 
COVID-19 case detection begins with the identification of subjects reporting at least one symptom from a 
standardized list of symptoms. Based on a scripted phone interview with trial staff, subjects suspected of 
having COVID-19 undergo testing for SARS-CoV-2 virus. Details of the tests performed and, in case of 
confirmed COVID-19 cases, details on the COVID-19 cases are recorded on the CRF. 


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10.7.1 Case Detection 
10.7.1.1 Routine Surveillance 
During all clinic visits and phone calls, subjects are reminded to contact the trial site if they have any of the 
following symptoms [1]: 
• 
Fever or Chills 
• 
Shortness of breath or difficulty breathing 
• 
New loss of smell or taste 
• 
Cough 
• 
Fatigue 
• 
Muscle or body aches 
• 
Headache 
• 
Sore throat 
• 
Congestion or runny nose 
• 
Nausea or vomiting 
• 
Diarrhea  
In addition, subjects are messaged up to twice a week to provide a yes or no response to having COVID-19 
symptoms.  
Those who report symptoms either at the clinic visit or by phone call, or respond “yes” to having symptoms 
by messaging are contacted by trial staff for a follow-up interview(s) to determine the probability of the 
subject having COVID-19. If the subject is suspected of having COVID-19 illness, he/she undergoes testing 
for SARS-CoV-2 infection, consisting of a molecular-based RT-PCR test performed at a designated local 
laboratory.  
The result of the local RT-PCR test is recorded on the CRF as positive or negative. 
10.7.1.2 Non-Routine Surveillance for COVID-19 (Positive Test Outside of Trial Site) 
Subjects are reminded to contact the trial site immediately if he/she has a positive SARS-CoV-2 test 
performed outside of the trial site, whether or not they were symptomatic (COVID-19 illness) or 
asymptomatic at the time of the test. 
The subject should be retested as soon as feasible to confirm the result. The RT-PCR test result is 
considered definitive as a virologically-confirmed case of COVID-19. If the subject is not 
virologically-confirmed by RT-PCR testing, he/she returns to routine surveillance for COVID-19  as a subject 
who is naïve to SARS-CoV-2 infection (unless determined otherwise by a seropositive test to the N protein).    
If the subject was symptomatic, trial staff uses the scripted interview to collect information about the 
subject’s COVID-19 symptoms and medical condition.   
10.7.2 Definition of Virologically-Confirmed COVID-19 Case and Onset Date 
A virologically-confirmed case of COVID-19 is defined as a positive SARS-CoV-2 specific RT-PCR test 
performed at the designated local laboratory in a person with clinically symptomatic disease consisting of 
one or more of the symptoms listed in Section 10.7.1. 
The onset date of a virologically confirmed COVID-19 case (identified during routine surveillance or outside 
of the trial) is defined as the date of symptom onset as recorded on the CRF. If the date of symptom onset 
is partially or completely missing, the following imputation rules are applied: 


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1. If the date is present but incomplete and it can be confirmed, based on the available date parts, 
that the onset was before first vaccination, then the missing date parts are imputed as the earliest 
possible date. 
2. If a present but incomplete date is still incomplete after checking point 1, and it can be confirmed, 
based on the available date parts, that the onset was before 15 days after second vaccination, 
the missing date parts are imputed with the earliest possible date on or after first vaccination. 
3. If a present but incomplete date is still incomplete after checking points 1 and 2, it is imputed with 
the earliest possible date ≥ 15 days after second vaccination. 
4. If the symptom onset date is completely missing, the date of first positive RT-PCR test is used 
instead. 
a) If the first positive RT-PCR test is incomplete then points 1-3 above should be applied on 
the first positive RT-PCR test date.  
10.7.3 Definition of Mild, Moderate and Severe COVID-19 Cases 
Mild COVID-19 cases are defined as virologically (RT-PCR) confirmed cases fulfilling all of the following: 
• 
Symptomatic, 
• 
No shortness of breath or difficulty breathing, 
• 
No hypoxemia, i.e. Oxygen saturations in arterial blood (SpO2) saturation ≥ 95% on room air at 
sea level; SpO2 should be adjusted according to altitude. 
• 
Does not meet the case definition of moderate or severe COVID-19  
Moderate COVID-19 cases are defined as virologically (RT-PCR) confirmed cases fulfilling any of the 
following criteria: 
• 
Shortness of breath or difficulty breathing 
• 
Respiratory rate ≥ 20 to < 30 breaths per minute 
• 
Abnormal SpO2, but still > 93% on room air at sea level; SpO2 should be adjusted according to 
altitude. 
• 
Clinical or radiographic evidence of lower respiratory tract disease 
• 
Radiologic evidence of Deep Vein Thrombosis 
Severe COVID-19 cases are defined as virologically (RT-PCR) confirmed cases fulfilling any of the 
following: 
• 
Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 per minute, heart 
rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or  Arterial Oxygen Partial Pressure 
/Fractional Inspired Oxygen (PaO2/FIO2) < 300 mmHg); SpO2 should be adjusted according to 
altitude. 
• 
Respiratory failure (defined as needing high flow-oxygen, noninvasive ventilation, mechanical 
ventilation or Extracorporeal membrane oxygenation (ECMO)) 
• 
Evidence of shock (systolic blood pressure (SBP) < 90 mmHg, diastolic blood pressure (DBP) < 60 
mmHg, or requiring vasopressors) 
• 
Significant renal, hepatic, or neurologic dysfunction 
• 
Admission to  Intensive Care Unit (ICU) 
• 
Death 
A fourth category of “moderate to severe” cases is further defined, combining cases of moderate severity 
and cases of severe severity. 


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10.7.4 COVID-19 Case Definition for Efficacy Analysis 
A case of COVID-19  meeting the case definition for efficacy analysis is defined as follows: 
• 
Virologically-confirmed case of COVID-19 (of any severity) defined as a positive SARS-CoV-2 
specific RT-PCR test in a person with clinically symptomatic COVID 19, see Section 10.7.2. 
• 
Symptom onset ≥ 15 days after second trial vaccination, i.e. 
𝑆𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑠𝑦𝑚𝑝𝑡𝑜𝑚𝑠−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑠𝑒𝑐𝑜𝑛𝑑 𝑣𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑖𝑜𝑛 ≥15 𝑑𝑎𝑦𝑠. 
See Section 10.7.2 for further details on definition of symptom onset. 
• 
First episode of virologically-confirmed COVID-19, i.e. the subject must not have a history of 
virologically-confirmed COVID-19 illness at enrollment or have developed a case of virologically-
confirmed COVID-19 before 15 days after the second trial vaccination. 
• 
Subject is SARS-CoV-2 naïve at baseline and Day 43 (defined as seronegative to N protein in the 
blood samples collected at baseline and Day 43). See Section 10.6.1 for further details. 
10.7.5 Adjudication of COVID-19 Cases 
An independent Committee of clinicians is formed to adjudicate some COVID-19 cases, and asymptomatic 
cases of SARS-CoV-2 infections (Section 10.8). The Committee is blinded to the treatment assignment of 
the subject. The cases are adjudicated by the members with respect to the following questions: 
• 
Is the case a virologically-confirmed case of COVID-19 defined as a positive SARS-CoV-2 specific 
RT-PCR test in a person with clinically symptomatic COVID-19 with one or more of the symptoms 
listed in Section 10.7.1?  
• 
Was the RT-PCR test performed at the CureVac designated central laboratory? 
• 
Was the symptom onset of the case ≥ 15 days following the second vaccination? Or did it occur 
before 15 days following the second trial vaccination?  
• 
Was the subject naïve or non-naïve to SARS-CoV-2 at baseline and Day 43? (defined as being 
seronegative or seropositive to the SARS-CoV-2 N protein at baseline and Day 43).  
• 
Was the subject 18 to 60 years of age or ≥ 61 years of age?  
• 
Was the subject asymptomatic? If asymptomatic, was the RT-PCR test positive ≥ 15 days following 
the second vaccination or before?   
• 
Was it a mild, moderate, or severe case of COVID-19 based on the provided clinical definitions? 
• 
Did the subject require supplemental oxygenation? What type of oxygen support did the subject 
receive? 
• 
Was the subject hospitalized? Was the subject admitted to the ICU?  
• 
Did the subject die? Due to COVID-19 or other cause? 
 
NB: The Adjudication questionnaire uses the term “CureVac designated central laboratory” although in this 
study the local laboratory had been designated by CureVac to perform the RT-PCR test. 
COVID-19 case summary data as provided by the Adjudication Committee is used for all relevant definitions 
and analyses, i.e. especially all efficacy cases have to be confirmed by the Adjudication Committee. Where 
the adjudicated data conflicts with other data recorded on the CRF (e.g. severity of the event, or baseline 
serology status), the adjudication data generally overrules the other data available. This applies to both 
COVID-19 cases and asymptomatic cases of SARS-CoV-2 infections. 
 


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Exceptions: 
1. For the analysis of COVID-19 cases by age group, the age at trial entry as recorded on the CRF 
rather than the age at onset (as assessed by the Adjudication Committee) is used. 
2. The case onset date is also taken from the CRF, irrespective from the onset date recorded on the 
Adjudication Form.  
10.8 Definition of Asymptomatic Cases of SARS-CoV-2 Infection and Onset Date 
There is no active surveillance in this trial for asymptomatic SARS-CoV-2 infections. Subjects are reminded 
to contact the trial site immediately if he/she had a positive SARS-CoV-2 test performed outside of the trial 
site, whether or not they were symptomatic (COVID-19 illness) or asymptomatic at the time of the test.  
If the subject was asymptomatic, trial staff contacts the subject immediately to collect information about the 
positive SARS-CoV-2 test the subject reported. The subject should be retested as soon as feasible to 
confirm the result. A positive RT-PCR test result is considered definitive as a virologically-confirmed case 
of SARS-CoV-2 infection. 
If the subject is confirmed to have SARS-CoV-2 infection, the subject is followed by trial staff for at least 2 
weeks for the development of any COVID-19 symptoms, to ensure that this is an asymptomatic infection. 
If the subject develops COVID-19, he/she is followed up as a COVID-19 case. If the subject is confirmed 
to be an asymptomatic infection, information is collected by the trial staff and documented on the 
appropriate CRF page. 
The onset date of an asymptomatic infection is defined as the date of the positive RT-PCR test result 
performed by a central laboratory.  
10.9 Burden of Disease 
Two different BoD scores are calculated for each subject, based on their first episode of virologically 
confirmed COVID-19 case meeting the case definition for efficacy analysis. 
BoD Score #1 is assigned as follows (considering only first episodes): 
• 
No disease (i.e. not infected or only asymptomatic infection): Score = 0 
• 
Mild or moderate disease (as defined in Section 10.7.3): Score = 1 
• 
Severe disease (as defined in Section 10.7.3): Score = 2 
BoD Score #2 is assigned as follows (considering only first episodes): 
• 
No disease (i.e. not infected or only asymptomatic infection): Score = 0 
• 
Disease without hospitalization: Score = 1 
• 
Disease with hospitalization: Score = 2 
• 
Death: Score = 3.  
10.10 Censoring Rules for Unblinded Subjects and/or Treated with AV 
If during the conduct of study CV-NCOV-005 an AV becomes available to subjects, these subjects can 
request to be unblinded from the study treatment to decide whether they would like to receive the AV. The 
following censoring rules are applied to these subjects to avoid any study bias. Further inclusion/exclusion 
rules are specified in the relevant analysis populations (See Section 9.5). 
• 
Subjects who are unblinded are censored for the safety and efficacy endpoints at the first day 
after unblinding. However any related follow-up data that is collected from censoring time point 
forward is included in the listings output. 








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In general, all data summaries are presented overall and by vaccine group. Thereby, the CVnCoV data is 
presented for pooled CVnCoV lots and split by lot. Efficacy outputs are not split by lot and do not have an 
overall column presented. Selected outputs are additionally presented using further subsetting of the data. 
This is specified explicitly in the respective sections.  
If not stated otherwise, p-values from statistical tests are two-sided and CIs are calculated using a 95% 
confidence level.  
Age group is used as a factor for stratification of randomization. The efficacy analyses are in general not 
adjusted for this factor.  
No imputation of missing data other than that described in Section 10.3 is performed. 
All data collected during this trial is displayed in data listings, unless otherwise specified. Screening failures 
are excluded from all listings and tables if not otherwise stated. Listings include all relevant 
assigned/derived variables. If not explicitly stated, listings do not show imputed data, but  present data as 
reported.  
All data summaries and tabulations are prepared using SAS® Version 9.4 or higher. 
In agreement with the sponsor it was decided to not perform some of the analyses in the EOT analysis. 
Therefore some of the below analyses were never performed. For details, please refer to Appendix 4 
12.1 Subject Disposition 
The number and percentage of subjects who prematurely withdraw from treatment, prematurely withdraw 
from the trial and a breakdown of the corresponding reasons for treatment withdrawal and early trial 
discontinuation is provided. Reasons for withdrawal are listed for subjects who prematurely withdraw from 
treatment or prematurely withdraw from the trial. 
The number and percentage of subjects randomized and treated is presented with the number and 
percentage of subjects included in each analysis set. Reasons for exclusion from each analysis set are not 
tabulated, but are listed.  
Subjects whose data is censored due to unblinding for AV treatment being available, are summarized for 
unblinding and / or AV use before dose 2 and after dose 2 for SAS and randomized subjects. A separate 
listing is provided indicating the date a subject was unblinded / received an AV. Subjects who have received 
an AV without being unblinded are also included in that listing.  
The number and percentage of subjects who were not stratified correctly is presented along with the number 
of subjects who received an incorrect vaccine at first and/or second vaccination. The summary is done for 
all randomized subjects. Subjects are also listed accordingly.  
12.2 Demographic and Baseline Characteristics 
The following demographic data collected at baseline is summarized for the SAS (and PPI at the 
Immunology IA): 
• 
Age at first informed consent (years), 
• 
Age group (18 to 60 years / ≥ 61 years), 
• 
Gender (Female / Male / Undifferentiated / Unknown), 
• 
Ethnicity (Hispanic or Latino / Not Hispanic or Latino / Not Reported / Unknown), 
• 
Race (American Indian or Alaska Native / Asian Indian/ Black or African American / Chinese / 
Filipino / Japanese / Korean / Native Hawaiian or Pacific Islander / Vietnamese / White / Other / 
Not reported / Unknown), 
• 
Baseline and Visit Day 43 serology status (Seronegative / Seropositive), see Section 10.6.1 for 
details. 


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• 
Baseline and Visit Day 43 serology status, overruled by independent committee adjudication if 
available (Seronegative / Seropositive), see Section 10.7.5 for details. 
• 
Height (cm), 
• 
Weight (kg), 
• 
Body Mass Index (kg/m2). 
12.3 Medical and Surgical History 
Medical/surgical history is coded using the MedDRA Version 23.1 or higher. Medical/surgical history is 
listed for the SAS. 
The number and percentage of subjects with any co-morbidity and a breakdown of the corresponding co-
morbidities are provided for the SAS.  
12.4 Trial Treatment 
12.4.1 Trial Vaccine Exposure 
A summary of doses administered, including reasons for doses not administered is provided for the SAS.  
12.4.2 Prior and Concomitant Medications and Vaccinations 
Prior and concomitant medications and vaccinations are coded using World Health Organization Drug 
Dictionary (WHODRUG), Version September 2020 Global B3 or higher. Concomitant medications are 
summarized based on the SAS. .  
Concomitant medications/vaccinations (see Section 10.4) are summarized by Anatomical Therapeutic 
Chemical (ATC) level 1 WHODRUG PN as the number and percentage of subjects taking at least one 
medication within each medication group and subgroup. 
Prior medications/vaccinations (see Section 10.4) are provided in a data listing along with the concomitant 
medications/vaccinations.  
12.5 Important Protocol Deviations 
Per PRA/ICON processes, protocol deviations data is entered into PRA/ICON system of record (PSO). The 
trial team and the Sponsor conduct on-going reviews of the deviation data from PSO and the resulting set 
of evaluable subjects throughout the trial, adjusting the deviation criteria as seems appropriate.  
Protocol deviation data is reviewed prior to each formal analysis (i.e. interim analyses or final analyses) and 
important deviations leading to elimination of subjects from analysis sets are identified. Detailed definitions 
and further guidance on programmatic approaches for identification of protocol deviations and/or other 
criteria leading to exclusion from the analysis sets are provided in a separate Appendix to the SAP (see 5). 
The detailed definitions of important protocol deviations leading to exclusion of subjects from analysis sets 
are provided in the final version of the SAP and/or in the final signed minutes of the data review meetings 
prior to each formal analysis and prior to database lock. 
A summary of important subject-level protocol deviation data is created based on the SAS, displaying the 
number and percentage of subjects with any important protocol deviations and broken down by type of 
deviations.  
Site- and subject-level protocol deviation data is listed.  


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12.6 Safety Analyses 
12.6.1 Adverse Events 
Unsolicited AEs, including SAEs, and AESIs and solicited AEs integrated to or recorded on the CRF are 
coded using MedDRA Version 23.1 or higher by SOC and PT.  
Only TEAEs as defined in Section 10.5.1 are included in AE summaries. In AE listings, all AEs are included. 
Solicited AEs occurring on the day of vaccination and the following 7 days are generally included in 
summaries if not otherwise stated.  
Summaries of medically attended AEs only include those AEs that started up to 6 months after the second 
trial vaccination, see Section 10.5.6 for further details.  
Note that for all summaries by SOC and PT, counting is by subject, not event and subjects are only counted 
once within each SOC and PT. However, if not stated otherwise, all summaries of unsolicited AEs include 
the number of AEs reported in each category and all events of a subject are then counted. 
All AE summary tables are provided overall, by vaccine group (placebo, pooled CVnCoV lot, and split by 
lot), and are repeated separately in subjects seronegative at baseline and in subjects seropositive at 
baseline for SARS-CoV-2 N protein antibody levels (see Section 10.6.1). 
In general, percentages are based on the number of subjects in the respective analysis set. In summary 
tables for AEs after the second vaccination, percentages are based on the number of subjects in the 
respective analysis set who have received the second vaccination.  
12.6.1.1 Analysis of Unsolicited AEs 
The following summaries of unsolicited AEs by SOC and PT are further provided, separately for AEs 
occurring within the first 28 days after each vaccination, within 28 days after any vaccination, and all 
reported AEs (including those reported later than 28 days after any vaccination):  
• 
Occurrence of unsolicited AEs  
• 
Occurrence of related unsolicited AEs  
• 
Occurrence of unsolicited AEs by maximum severity (mild / moderate / severe) 
• 
Occurrence of related unsolicited AEs by maximum severity (mild / moderate / severe) 
Additionally, a summary of unsolicited AEs (excluding solicited AEs) occurring within the first 28 days after 
each vaccination and within 28 days after any dose that have a frequency of > 5% in at least one treatment 
arm (on PT level) by SOC and PT is provided. The summary is repeated for all reported AEs (including 
those reported later than 28 days after any vaccination). 
Summaries of unsolicited AEs occurring within 28 days after each vaccination and within 28 days after any 
vaccination are provided based on the SAS 2. Summaries of all reported unsolicited AEs (including those 
reported later than 28 days after any vaccination) are provided based on the SAS. 
Listings of unsolicited AEs and related unsolicited AEs are produced. These listings exclude solicited AEs 
and flag treatment emergent event.  
12.6.1.2 Analysis of Solicited AEs 
The following summaries of solicited AEs within 7 days after each trial vaccination and within 7 days after 
any trial vaccination are planned: 
• 
Summary of local and systemic AEs, overall and by maximum grade (mild / moderate / severe) 
o 
Are also provided by gender (female/male) for any vaccination, vaccination 1, and 
vaccination 2.  


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• 
Occurrence of local AEs, overall and by maximum grade (mild / moderate / severe) 
• 
Occurrence of systemic AEs, overall and by maximum grade (mild / moderate / severe) 
• 
Occurrence of related systemic AEs, overall and by maximum grade (mild / moderate / severe) 
• 
Duration (days) of local AEs, overall and for grade 3 events  
• 
Duration (days) of systemic AEs, overall and for grade 3 events  
• 
Duration (days) of related systemic AEs, overall and for grade 3 events 
• 
Daily summary of local AEs overall and by maximum grade (mild/moderate/severe) (only for each 
dose) 
• 
Daily summary of systemic AEs overall and by maximum grade (mild/moderate/severe) (only for 
each dose) 
• 
Daily summary of related systemic AEs overall and by maximum grade (mild/moderate/severe) 
(only for each dose) 
• 
Summary of time of onset (Day) overall and for grade 3 solicited AEs, any solicited AEs, local, 
systemic AEs, and related systemic AEs 
• 
Time of onset (Day) of local AEs, overall and for grade 3 events  
• 
Time of onset (Day) of systemic AEs, overall and for grade 3 events.  
• 
Time of onset (Day) of related systemic AEs, overall and for grade 3 events 
All analyses of solicited AEs are provided based on the SASsol. 
In agreement with the sponsor was decided to not provide any analyses on solicited AEs in the EOT 
analysis. Therefore some of the above analyses are never performed. For details, please refer to 
Appendix 4. 
12.6.1.3 Analysis of AEs (Combined Unsolicited and Solicited) 
An overall summary of unsolicited AEs, SAEs, intercurrent medical conditions affecting immune response, 
AESIs, medically attended AEs, AEs leading to vaccine withdrawal, AEs leading to withdrawal from trial 
and AEs with fatal outcome is prepared for AEs occurring within 28 days after each vaccination, within 28 
days after any vaccination, and all reported AEs (including those reported at more than 28 days after any 
vaccination), presenting the number and percentage of subjects with  
• 
any unsolicited AEs ,  
• 
related unsolicited AEs,  
• 
grade 3 (severe) unsolicited AEs  
• 
grade 3 (severe) related unsolicited AEs  
• 
SAEs (includes solicited AEs),  
• 
related SAEs (includes solicited AEs),  
• 
intercurrent medical conditions affecting immune response (includes solicited AEs), 
• 
AESIs (includes solicited AEs), 
• 
related AESIs (includes solicited AEs), 
• 
medically attended AEs (includes solicited AEs),  
• 
related medically attended AEs (includes solicited AEs),  


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• 
AEs leading to vaccine withdrawal (includes solicited AEs), 
• 
AEs leading to withdrawal from trial (includes solicited AEs), 
• 
AEs with fatal outcome (includes solicited AEs),  
• 
related AEs with fatal outcome (includes solicited AEs).  
The overall summary is also provided by gender (male/female) for any vaccination, vaccination 1 and 
vaccination 2. 
The following summaries of AEs by SOC and PT are further provided, separately for AEs occurring within 
the first 28 days after each vaccination, within the 28 days after any vaccination, and all reported AEs 
(including those reported at more than 28 days after any vaccination):  
• 
Occurrence of SAEs, 
• 
Occurrence of related SAEs, 
• 
Occurrence of SAEs by maximum severity (mild / moderate / severe), 
• 
Occurrence of related SAEs by maximum severity (mild / moderate / severe), 
• 
Occurrence of intercurrent medical conditions affecting immune response, 
• 
Occurrence of AESIs, 
• 
Occurrence of related AESIs, 
• 
Occurrence of medically attended AEs, 
• 
Occurrence of related medically attended AEs, 
• 
Occurrence of AEs leading to vaccine withdrawal, 
• 
Occurrence of AEs leading to withdrawal from trial, 
• 
Occurrence of AEs with fatal outcome, 
• 
Occurrence of related AEs with fatal outcome, 
• 
Occurrence of SMQs and CMQs (as specified in Section 10.5.7). (The SMQ/CMQ tables are only 
provided for all reported AEs, not by vaccination 1 and vaccination 2 separately and only by PT, 
not by SOC.) 
All summaries and listings above are provided based on the SAS.  
A listing of all SAEs and all SAEs with fatal outcome is further provided by subject, including both unsolicited 
and solicited AEs.  
Further AE listings supporting the AE tables described above  include both relevant solicited and unsolicited 
AEs.  
12.6.1.4 Repeats of AE Analyses without Censoring 
In the EOT analysis the following outputs are repeated without applying any censoring rules due to subject 
unblinding or AV receipt: 
o 
Overall summary of unsolicited AEs occurring through 28 days after any dose 
o 
Unsolicited AEs, SAEs, unsolicited AESIs and AEs with fatal outcome, by SOC and PT 
occurring through EOT Visit 
 


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12.6.2 Deaths and Serious Adverse Events 
Description of analyses of SAEs and fatal AEs are included in Section 12.6.1.1. 
12.6.3 Laboratory Data 
A urine sample for pregnancy testing is taken from women of childbearing potential on Day 1 prior to trial 
vaccination to establish eligibility. A urine pregnancy test is also performed before the second trial 
vaccination on Day 29 to continue to determine eligibility. Urine pregnancy test result data is listed only. 
No other standard laboratory tests are performed.  
12.6.4 Vital Signs 
Vital signs are recorded at each clinic visit (i.e. Day 1, Day 29, Day 43, Day 57 
[Immunogenicity/Reactogenicity Subset only], Day 120 [Immunogenicity/Reactogenicity Subset only], Day 
211, and Day 393 / EOT). Body temperature (°C), SBP/DBP (mmHg) and pulse (beats per minute) at 
baseline and each post-baseline timepoint as well as change from baseline at each post-baseline timepoint 
is summarized. 
Vital Signs data is summarized based on the SAS. 
12.6.5 Physical Examinations, ECGs, and Other Observations Related to Safety 
General physical examinations are performed at Day 1 and Day 393 / EOT. Symptom-directed 
examinations are performed Day 29, Day 43, Day 57, Day 120, and Day 211. Physical examination data is 
listed only. 
12.6.6 Sensitivity Analysis on Safety Outputs 
For the safety delivery when the first 1037 subjects are 6 weeks post 2nd vaccination all safety outputs are 
repeated without applying any censoring due to AV-prone subject use or unblinding.  
12.6.7 Adapting the Safety Analyses to the Requirements of Extensive Unblinding 
If not explicitly exempted, all safety analyses described in Sections 12.6.1 – 12.6.6 are performed under 
the conditions of data censoring (described in Section 10.10).  
In order to maximally maintain the previous analysis setup while nevertheless aiming at optimally evaluating 
the collected data the following approach is introduced regarding safety analyses. 
1. The above-mentioned analyses (Sections 12.6.1 – 12.6.6) remain unchanged, regardless of 
extensive unblinding. All definitions still correctly apply and analyses are conducted as originally 
planned and described above. 
2. Additional outputs are planned to account for the massive loss of data due to censoring. The 
concerned analyses are explicitly listed at the end of this Section 12.6.7. 
a. These additional outputs are closely following the above mentioned safety analyses. 
b. As far as possible, endpoint definitions and analysis sets are maintained as described in 
Sections 12.6.1 – 12.6.6. 
c. No censoring due to unblinding and/or AV receipt is performed.  
d. AEs/vital sign values are divided into 4 groups: Placebo-only, CVnCoV-only, CVnCoV-AV, 
AV-only. 
AEs/vital sign values are allocated to treatment groups as follows:  
• 
Placebo-only: Only placebo has been administered before AE start date / vital signs 
date. No CVnCoV and no AV must have been administered until then. 


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• 
CVnCoV-only: At least one dose of CVnCoV and no AV has been administered before 
AE start date / vital signs date. Placebo might have been administered as well.  
• 
CVnCoV-AV: At least one dose of CVnCoV and at least one dose of AV has been 
administered before AE start date / vital signs date. Placebo might have been 
administered as well. 
• 
AV-only: At least one dose of AV and no CVnCoV has been administered before AE 
start date / vital signs date. Placebo might have been administered as well. 
Treatments are considered “as received”, not “as randomized”. 
The following analyses are repeated as described above. All repeat analyses are based on the SAS.  
o 
Overall summary of unsolicited AEs occurring through EOT Visit 
o 
Unsolicited AEs, SAEs, unsolicited AESIs and AEs with fatal outcome, by SOC and PT 
occurring through EOT Visit 
12.7 Immunogenicity Analyses 
For subjects in the Immunogenicity/Reactogenicity Subset, blood samples for SARS-CoV-2 viral 
neutralizing activity and antibody to SARS-CoV-2 RBD of S protein testing are collected on Day 1, Day 29 
and Day 43.  
In general, all analyses of SARS-CoV-2 RBD to S protein antibodies and SARS-CoV-2 viral neutralizing 
antibody levels are performed based on the PPI, for the pooled CVnCoV lots, split by lot and for placebo, 
and separately in subjects seronegative to the N protein at baseline and in subjects seropositive to the N 
protein at baseline (see Section 10.6.1). Summary statistics presented include the Geometric Mean (GM) 
with corresponding geometric SD and 95% CI, as well as the Median, Min, Max, Q1 and Q3.  
Total columns (or respective sections in graphs) are not provided for immunogenicity outputs. 
12.7.1 Primary Immunogenicity Analyses 
SARS-CoV-2 RBD of S protein antibodies (expressed as GMT) are summarized descriptively. Summaries 
are provided at baseline and each post-baseline sampling timepoint. The fold change (FC) from baseline 
is further computed and summarized for Day 29 and Day 43.  
For each post-baseline timepoint, the number and percentage of subjects seroconverting with any fold 
increase, a 2-fold increase and a 4-fold increase are presented together with the exact 95% Pearson-
Clopper CIs for the proportion of seroconverting subjects. This analysis is only done for subjects 
seronegative to the N protein at baseline. For a definition of seroconversion for subjects seronegative at 
baseline, see Section 10.6.2. 
GMTs of SARS-CoV-2 RBD of S protein antibody levels over time are presented in the following figures: 
• 
Line plot of GM FC from baseline and 95% CIs, 
• 
Line plot of GMTs with GM and 95% CIs, 
• 
Boxplots of GMTs with median, Q1 and Q3, and whiskers representing minimum and maximum by 
vaccine group. 
12.7.2 Secondary Immunogenicity Analyses  
The analyses described for the primary immunogenicity endpoints detailed above in Section 12.7.1, are 
repeated for the secondary immunogenicity endpoints related to viral neutralizing antibodies to 
SARS-CoV-2 (expressed as GMT).  


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The analysis to explore correlates of protective immunity induced by CVnCoV vaccination is described in a 
separate SAP. 
12.7.3 Exploratory Immunogenicity Analyses 
Exploratory immunogenicity endpoints were deleted from the study protocol from version 5.0 onwards. 
12.8 Efficacy Analyses 
All efficacy analyses are presented for pooled CVnCoV lots and Placebo. 
12.8.1 Secondary Efficacy Endpoint Analysis 
12.8.1.1 First Episodes of Covid-19 Cases 
Occurrence of first episodes of virologically-confirmed (RT-PCR positive) cases of COVID-19 of any 
severity meeting the case definition for the efficacy analysis is analyzed as follows: 
From the number of occurrences of respective cases (COVID-19 cases or seroconversion) in each vaccine 
group, the VE corresponding to each endpoint is calculated as follows: 
𝑉𝐸= 1 −
𝑝
1 −𝑝∗1
𝑟 
Thereby, p denotes the proportion of cases coming from the pooled CVnCoV group among all cases and r 
is the ratio of total follow-up time of subjects in the pooled CVnCoV group over the total follow-up time of 
subjects in the placebo group (see Section 10.11). 
An exact two-sided 95% Pearson-Clopper CI for p is calculated. From this, the Lower Limit (LL) and Upper 
Limit (UL) of the 95% CI for the VE is calculated from the UL and LL of the CI for p as: 
𝐿𝐿𝑉𝐸= 1 − 
𝑈𝐿𝑝
(1 −𝑈𝐿𝑝) ∗𝑟; 𝑈𝐿𝑉𝐸= 1 − 
𝐿𝐿𝑝
(1 −𝐿𝐿𝑝) ∗𝑟 
The following is presented for the analysis of these secondary efficacy endpoints: 
• 
Number and percentage of subjects with a respective case (COVID-19 case or seroconversion)  
• 
Total follow-up time (years) in each vaccine group, 
• 
Calculated proportion of cases coming from the pooled CVnCoV group among all cases (p), 
• 
Ratio of total follow-up time of subjects in the pooled CVnCoV group over the total follow-up time 
of subjects in the placebo group (r), 
• 
Estimated VE based on p and r, 
• 
95% CIs for p and VE  
This secondary efficacy analysis is performed on the EAS. 
For any analysis requiring the serostatus at baseline or Visit Day 43 the information of the adjudication of 
COVID-19 cases is used, if available (Section 10.7.5). Otherwise the information of the N protein blood 
samples taken at baseline and Visit Day 43 is used (Section 10.6.1). 
12.8.1.2 Severity Assessment of COVID-19 Cases 
All COVID-19 cases meeting the efficacy case definition are classified as mild, moderate or severe. An 
additional category “moderate to severe” is created, combining moderate and severe cases. The number 
and percentage of subjects with mild, moderate, severe and moderate to severe cases is summarized 
descriptively. 


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Additionally, VE efficacy is analyzed based on first occurrence of mild COVID-19 cases meeting the efficacy 
case definition in a similar way as for the analysis of first episodes of COVID-19 cases of any severity.  
The following is presented for these cases: 
• 
Number and percentage of subjects with a respective case,  
• 
Total follow-up time in each vaccine group (years), 
• 
Calculated proportion of cases coming from the pooled CVnCoV group among all cases (p), 
• 
Ratio of total follow-up time of subjects in the pooled CVnCoV group over the total follow-up time 
of subjects in the placebo group (r), 
• 
Estimated VE based on p and r, 
• 
95% CIs for p and VE. 
All summaries and analyses are provided based on the EAS. 
12.8.1.3 BoD Scores 
BoD scores are calculated based on first episodes of virologically-confirmed cases of COVID-19 of any 
severity meeting the case definition for the efficacy analysis (see Section 10.7.4). 
For both BoD endpoints, the number and percentage of subjects in each category is summarized 
descriptively for both of the two scores. 
These analysis is provided for the EAS. 
12.8.1.4 Sensitivity Analyses 
As a sensitivity analysis, the time to first occurrence of virologically-confirmed COVID-19 case of any 
severity according to the efficacy case definition is analyzed. Calculation of the time to first occurrence and 
censoring rules is applied according to Section 10.11.  
KM estimates for the probability of not developing COVID-19 (hereafter referred to as “survival”) are 
computed for each vaccine group (pooled CVnCoV and Placebo). Estimates for Q1, median and Q3 of the 
survival times are presented. Log rank test comparing the vaccine groups is performed. The summaries 
are provided by vaccine group. 
A Cox Proportional Hazard model is used to model the time to first occurrence of virologically-confirmed 
COVID-19 cases according to the efficacy case definition. The model includes the vaccine group (pooled 
CVnCoV or Placebo) as a factor and is adjusted for the stratification factor age at baseline (18 to 60 and 
≥61 years). The estimated Hazard Ratios for the CVnCoV vaccine group versus placebo and corresponding 
95% CI is presented. The CIs are derived based on the Wald test. 
These sensitivity analyses are performed on the EAS.  
 References 
[1] Development and Licensure of Vaccines to Prevent COVID-19, FDA Guidance for Industry, June 2020. 


















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• 
Arterial bypass operation 
• 
Arterial bypass thrombosis 
• 
Arterial graft 
• 
Arterial occlusive disease 
• 
Arterial revascularisation 
• 
Arterial stent insertion 
• 
Arterial therapeutic procedure 
• 
Arterial thrombosis 
• 
Arteriogram abnormal 
• 
Arteriogram carotid abnormal 
• 
Arteriotomy 
• 
Atherectomy 
• 
Atherosclerotic plaque rupture 
• 
Atrial appendage closure 
• 
Atrial appendage resection 
• 
Basal ganglia infarction 
• 
Basilar artery occlusion 
• 
Basilar artery thrombosis 
• 
Blindness transient 
• 
Brachiocephalic artery occlusion 
• 
Capsular warning syndrome 
• 
Carotid angioplasty 
• 
Carotid arterial embolus 
• 
Carotid artery bypass 
• 
Carotid artery occlusion 
• 
Carotid artery stent insertion 
• 
Carotid artery thrombosis 
• 
Carotid endarterectomy 
• 
Cerebellar artery occlusion 
• 
Cerebellar artery thrombosis 
• 
Cerebral artery embolism 
• 
Cerebral artery occlusion 
• 
Cerebral artery stent insertion 
• 
Cerebral artery thrombosis 
• 
Cerebral hypoperfusion 
• 
Cerebrovascular insufficiency 
• 
Cerebrovascular stenosis 
• 
Coeliac artery occlusion 
• 
Coronary angioplasty 
• 
Coronary arterial stent insertion 
• 
Coronary artery bypass 
• 
Coronary artery embolism 
• 
Coronary artery occlusion 
• 
Coronary artery reocclusion 
• 
Coronary artery surgery 
• 
Coronary artery thrombosis 
• 
Coronary endarterectomy 
• 
Coronary revascularisation 
• 
Coronary vascular graft occlusion 
• 
Embolia cutis medicamentosa 
• 
Embolism arterial 
• 
Endarterectomy 
• 
Femoral artery embolism 
• 
Hepatic artery embolism 
• 
Hepatic artery occlusion 
• 
Hepatic artery thrombosis 
• 
Hypothenar hammer syndrome 
• 
Iliac artery embolism 
• 
Iliac artery occlusion 
• 
Internal capsule infarction 
• 
Intra-aortic balloon placement 
• 
Intraoperative cerebral artery occlusion 
• 
Ischaemic cerebral infarction 
• 
Ischaemic stroke 
• 
Lacunar infarction 
• 
Leriche syndrome 
• 
Mesenteric arterial occlusion 
• 
Mesenteric arteriosclerosis 
• 
Mesenteric artery embolism 
• 
Mesenteric artery stenosis 
• 
Mesenteric artery stent insertion 
• 
Mesenteric artery thrombosis 
• 
Myocardial infarction 
• 
Myocardial necrosis 
• 
Ophthalmic artery thrombosis 
• 
Papillary muscle infarction 
• 
Penile artery occlusion 
• 
Percutaneous coronary intervention 
• 
Peripheral arterial occlusive disease 
• 
Peripheral arterial reocclusion 
• 
Peripheral artery angioplasty 
• 
Peripheral artery bypass 
• 
Peripheral artery occlusion 
• 
Peripheral artery stent insertion 
• 
Peripheral artery surgery 
• 
Peripheral artery thrombosis 
• 
Peripheral embolism 
• 
Peripheral endarterectomy 






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• 
Cerebrovascular disorder 
• 
Cerebrovascular operation 
• 
Choroidal infarction 
• 
Collateral circulation 
• 
Coronary bypass thrombosis 
• 
Device embolisation 
• 
Device occlusion 
• 
Device related thrombosis 
• 
Diplegia 
• 
Directional Doppler flow tests abnormal 
• 
Disseminated intravascular coagulation 
• 
Disseminated intravascular coagulation 
in newborn 
• 
Embolic cerebellar infarction 
• 
Embolic cerebral infarction 
• 
Embolic pneumonia 
• 
Embolic stroke 
• 
Embolism 
• 
Eye infarction 
• 
Fluorescence angiogram abnormal 
• 
Foetal cerebrovascular disorder 
• 
Gastric infarction 
• 
Graft thrombosis 
• 
Haemorrhagic adrenal infarction 
• 
Haemorrhagic cerebral infarction 
• 
Haemorrhagic infarction 
• 
Haemorrhagic stroke 
• 
Haemorrhagic transformation stroke 
• 
Haemorrhoids thrombosed 
• 
Hemiparesis 
• 
Hemiplegia 
• 
Heparin-induced thrombocytopenia 
• 
Hepatic infarction 
• 
Hepatic vascular thrombosis 
• 
Implant site thrombosis 
• 
Incision site vessel occlusion 
• 
Infarction 
• 
Infusion site thrombosis 
• 
Injection site thrombosis 
• 
Inner ear infarction 
• 
Instillation site thrombosis 
• 
Intestinal infarction 
• 
Intracardiac mass 
• 
Intracardiac thrombus 
• 
Lambl's excrescences 
• 
Medical device site thrombosis 
• 
Mesenteric vascular insufficiency 
• 
Mesenteric vascular occlusion 
• 
Microembolism 
• 
Monoparesis 
• 
Monoplegia 
• 
Optic nerve infarction 
• 
Pancreatic infarction 
• 
Paradoxical embolism 
• 
Paraneoplastic thrombosis 
• 
Paraparesis 
• 
Paraplegia 
• 
Paresis 
• 
Peripheral revascularisation 
• 
Pituitary infarction 
• 
Placental infarction 
• 
Pneumatic compression therapy 
• 
Portal shunt procedure 
• 
Post procedural stroke 
• 
Postpartum thrombosis 
• 
Prosthetic cardiac valve thrombosis 
• 
Prosthetic vessel implantation 
• 
Quadriparesis 
• 
Quadriplegia 
• 
Renal infarct 
• 
Renal vascular thrombosis 
• 
Retinal infarction 
• 
Retinal vascular thrombosis 
• 
Revascularisation procedure 
• 
Shunt occlusion 
• 
Shunt thrombosis 
• 
Spinal cord infarction 
• 
Spinal stroke 
• 
Splenic infarction 
• 
Splenic thrombosis 
• 
Stoma site thrombosis 
• 
Stroke in evolution 
• 
Strokectomy 
• 
Surgical vascular shunt 
• 
Testicular infarction 
• 
Thalamic infarction 
• 
Thrombectomy 
• 
Thromboangiitis obliterans 




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• 
Application site vasculitis 
• 
Arthritis allergic 
• 
Aspirin-exacerbated respiratory disease 
• 
Atopic cough 
• 
Atopy 
• 
Blepharitis allergic 
• 
Blood immunoglobulin E abnormal 
• 
Blood immunoglobulin E increased 
• 
Bromoderma 
• 
Bronchospasm 
• 
Bullous haemorrhagic dermatosis 
• 
Catheter site dermatitis 
• 
Catheter site eczema 
• 
Catheter site hypersensitivity 
• 
Catheter site rash 
• 
Catheter site urticaria 
• 
Catheter site vasculitis 
• 
Chronic eosinophilic rhinosinusitis 
• 
Chronic 
hyperplastic 
eosinophilic 
sinusitis 
• 
Circulatory collapse 
• 
Circumoral oedema 
• 
Circumoral swelling 
• 
Conjunctival oedema 
• 
Conjunctivitis allergic 
• 
Contact stomatitis 
• 
Contrast media allergy 
• 
Contrast media reaction 
• 
Corneal oedema 
• 
Cutaneous vasculitis 
• 
Dennie-Morgan fold 
• 
Dermatitis 
• 
Dermatitis acneiform 
• 
Dermatitis allergic 
• 
Dermatitis atopic 
• 
Dermatitis bullous 
• 
Dermatitis contact 
• 
Dermatitis exfoliative 
• 
Dermatitis exfoliative generalised 
• 
Dermatitis herpetiformis 
• 
Dermatitis infected 
• 
Dermatitis psoriasiform 
• 
Device allergy 
• 
Dialysis membrane reaction 
• 
Distributive shock 
• 
Documented 
hypersensitivity 
to 
administered product 
• 
Drug eruption 
• 
Drug hypersensitivity 
• 
Drug provocation test 
• 
Drug reaction with eosinophilia and 
systemic symptoms 
• 
Eczema 
• 
Eczema infantile 
• 
Eczema nummular 
• 
Eczema vaccinatum 
• 
Eczema vesicular 
• 
Eczema weeping 
• 
Encephalitis allergic 
• 
Encephalopathy allergic 
• 
Eosinophilic 
granulomatosis 
with 
polyangiitis 
• 
Epidermal necrosis 
• 
Epidermolysis 
• 
Epidermolysis bullosa 
• 
Epiglottic oedema 
• 
Erythema multiforme 
• 
Erythema nodosum 
• 
Exfoliative rash 
• 
Eye allergy 
• 
Eye oedema 
• 
Eye swelling 
• 
Eyelid oedema 
• 
Face oedema 
• 
Fixed eruption 
• 
Giant papillary conjunctivitis 
• 
Gingival oedema 
• 
Gingival swelling 
• 
Gleich's syndrome 
• 
Haemorrhagic urticaria 
• 
Hand dermatitis 
• 
Henoch-Schonlein purpura 
• 
Henoch-Schonlein purpura nephritis 
• 
Heparin-induced thrombocytopenia 
• 
Hereditary angioedema 
• 
Hereditary 
angioedema 
with 
C1 
esterase inhibitor deficiency 
• 
Hypersensitivity 
• 
Hypersensitivity myocarditis 


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• 
Hypersensitivity pneumonitis 
• 
Hypersensitivity vasculitis 
• 
Idiopathic urticaria 
• 
Immediate post-injection reaction 
• 
Immune thrombocytopenia 
• 
Immune tolerance induction 
• 
Implant site dermatitis 
• 
Implant site hypersensitivity 
• 
Implant site rash 
• 
Implant site urticaria 
• 
Incision site dermatitis 
• 
Incision site rash 
• 
Infusion related hypersensitivity reaction 
• 
Infusion related reaction 
• 
Infusion site dermatitis 
• 
Infusion site eczema 
• 
Infusion site hypersensitivity 
• 
Infusion site rash 
• 
Infusion site recall reaction 
• 
Infusion site urticaria 
• 
Infusion site vasculitis 
• 
Injection related reaction 
• 
Injection site dermatitis 
• 
Injection site eczema 
• 
Injection site hypersensitivity 
• 
Injection site rash 
• 
Injection site recall reaction 
• 
Injection site urticaria 
• 
Injection site vasculitis 
• 
Instillation site hypersensitivity 
• 
Instillation site rash 
• 
Instillation site urticaria 
• 
Interstitial granulomatous dermatitis 
• 
Intestinal angioedema 
• 
Iodine allergy 
• 
Kaposi's varicelliform eruption 
• 
Kounis syndrome 
• 
Laryngeal oedema 
• 
Laryngitis allergic 
• 
Laryngospasm 
• 
Laryngotracheal oedema 
• 
Limbal swelling 
• 
Lip oedema 
• 
Lip swelling 
• 
Mast cell degranulation present 
• 
Medical device site dermatitis 
• 
Medical device site eczema 
• 
Medical device site hypersensitivity 
• 
Medical device site rash 
• 
Medical device site recall reaction 
• 
Medical device site urticaria 
• 
Mouth swelling 
• 
Mucocutaneous rash 
• 
Multiple allergies 
• 
Nephritis allergic 
• 
Nikolsky's sign 
• 
Nodular rash 
• 
Nutritional supplement allergy 
• 
Oculomucocutaneous syndrome 
• 
Oculorespiratory syndrome 
• 
Oedema mouth 
• 
Oral allergy syndrome 
• 
Oropharyngeal blistering 
• 
Oropharyngeal oedema 
• 
Oropharyngeal spasm 
• 
Oropharyngeal swelling 
• 
Palatal oedema 
• 
Palatal swelling 
• 
Palisaded neutrophilic granulomatous 
dermatitis 
• 
Palpable purpura 
• 
Pathergy reaction 
• 
Perioral dermatitis 
• 
Periorbital oedema 
• 
Periorbital swelling 
• 
Pharyngeal oedema 
• 
Pharyngeal swelling 
• 
Procedural shock 
• 
Pruritus allergic 
• 
Radioallergosorbent test positive 
• 
Rash 
• 
Rash erythematous 
• 
Rash follicular 
• 
Rash macular 
• 
Rash maculo-papular 
• 
Rash maculovesicular 
• 
Rash morbilliform 
• 
Rash neonatal 


Statistical Analysis Plan (SAP) 
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Protocol no: CV-NCOV-005 
 
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• 
Rash papulosquamous 
• 
Rash pruritic 
• 
Rash pustular 
• 
Rash rubelliform 
• 
Rash scarlatiniform 
• 
Rash vesicular 
• 
Reaction to azo-dyes 
• 
Reaction to colouring 
• 
Reaction to excipient 
• 
Reaction to food additive 
• 
Reaction to preservatives 
• 
Red man syndrome 
• 
Rhinitis allergic 
• 
Scleral oedema 
• 
Scleritis allergic 
• 
Scrotal dermatitis 
• 
Scrotal oedema 
• 
Serum sickness 
• 
Serum sickness-like reaction 
• 
Shock 
• 
Shock symptom 
• 
SJS-TEN overlap 
• 
Skin necrosis 
• 
Skin reaction 
• 
Skin test positive 
• 
Solar urticaria 
• 
Solvent sensitivity 
• 
Stevens-Johnson syndrome 
• 
Stoma site hypersensitivity 
• 
Stoma site rash 
• 
Swelling face 
• 
Swelling of eyelid 
• 
Swollen tongue 
• 
Symmetrical drug-related intertriginous 
and flexural exanthema 
• 
Therapeutic product cross-reactivity 
• 
Tongue oedema 
• 
Toxic epidermal necrolysis 
• 
Toxic skin eruption 
• 
Tracheal oedema 
• 
Type I hypersensitivity 
• 
Type II hypersensitivity 
• 
Type III immune complex mediated 
reaction 
• 
Type IV hypersensitivity reaction 
• 
Urticaria 
• 
Urticaria cholinergic 
• 
Urticaria chronic 
• 
Urticaria contact 
• 
Urticaria papular 
• 
Urticaria physical 
• 
Urticaria pigmentosa 
• 
Urticaria vesiculosa 
• 
Urticarial dermatitis 
• 
Urticarial vasculitis 
• 
Vaccination site dermatitis 
• 
Vaccination site eczema 
• 
Vaccination site exfoliation 
• 
Vaccination site hypersensitivity 
• 
Vaccination site rash 
• 
Vaccination site recall reaction 
• 
Vaccination site urticaria 
• 
Vaccination site vasculitis 
• 
Vaccination site vesicles 
• 
Vaginal ulceration 
• 
Vasculitic rash 
• 
Vernal keratoconjunctivitis 
• 
Vessel puncture site rash 
• 
Vessel puncture site vesicles 
• 
Vulval eczema 
• 
Vulval ulceration 
• 
Vulvovaginal rash 
• 
Vulvovaginal ulceration 
• 
Vulvovaginitis allergic 
Broad 
• 
Acute respiratory failure 
• 
Administration 
site 
photosensitivity 
reaction 
• 
Airway remodelling 
• 
Allergy to chemicals 
• 
Allergy to fermented products 
• 
Alpha tumour necrosis factor increased 
• 
Alveolitis 
• 
Antibody test abnormal 
• 
Antibody test positive 
• 
Anti-insulin antibody increased 
• 
Anti-insulin antibody positive 


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Protocol no: CV-NCOV-004 
 
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• 
Anti-insulin receptor antibody increased 
• 
Anti-insulin receptor antibody positive 
• 
Application site photosensitivity reaction 
• 
Asthma 
• 
Asthma late onset 
• 
Asthma-chronic obstructive pulmonary 
disease overlap syndrome 
• 
Asthmatic crisis 
• 
Auricular swelling 
• 
Blister 
• 
Blister rupture 
• 
Blood immunoglobulin A abnormal 
• 
Blood immunoglobulin A increased 
• 
Blood immunoglobulin D increased 
• 
Blood immunoglobulin G abnormal 
• 
Blood immunoglobulin G increased 
• 
Blood immunoglobulin M abnormal 
• 
Blood immunoglobulin M increased 
• 
Bronchial hyperreactivity 
• 
Bronchial oedema 
• 
Bullous impetigo 
• 
Caffeine allergy 
• 
Capillaritis 
• 
Charcot-Leyden crystals 
• 
Cheilitis 
• 
Childhood asthma 
• 
Choking 
• 
Choking sensation 
• 
Complement factor C1 decreased 
• 
Complement factor C2 decreased 
• 
Complement factor C3 decreased 
• 
Complement factor C4 decreased 
• 
Complement factor decreased 
• 
Conjunctivitis 
• 
Corneal exfoliation 
• 
Cough variant asthma 
• 
Cytokine release syndrome 
• 
Cytokine storm 
• 
Ear swelling 
• 
Eosinophil count abnormal 
• 
Eosinophil count increased 
• 
Eosinophil percentage abnormal 
• 
Eosinophil percentage increased 
• 
Eosinophilia 
• 
Eosinophilia myalgia syndrome 
• 
Eosinophilic bronchitis 
• 
Eosinophilic oesophagitis 
• 
Eosinophilic pneumonia 
• 
Eosinophilic pneumonia acute 
• 
Eosinophilic pneumonia chronic 
• 
Erythema 
• 
Flushing 
• 
Gastrointestinal oedema 
• 
Generalised oedema 
• 
Genital rash 
• 
Genital swelling 
• 
Haemolytic transfusion reaction 
• 
HLA marker study positive 
• 
Human anti-hamster antibody increased 
• 
Human anti-hamster antibody positive 
• 
Immune complex level increased 
• 
Immunoglobulins abnormal 
• 
Immunoglobulins increased 
• 
Immunology test abnormal 
• 
Implant site photosensitivity 
• 
Infusion site photosensitivity reaction 
• 
Injection site panniculitis 
• 
Injection site photosensitivity reaction 
• 
Interstitial lung disease 
• 
Laryngeal dyspnoea 
• 
Laryngeal obstruction 
• 
Leukotriene increased 
• 
Lip exfoliation 
• 
Localised oedema 
• 
Macrophage 
inflammatory 
protein-1 
alpha increased 
• 
Mechanical urticaria 
• 
Medical device site photosensitivity 
reaction 
• 
Mesenteric panniculitis 
• 
Monocyte 
chemotactic 
protein-2 
increased 
• 
Mouth ulceration 
• 
Mucocutaneous ulceration 
• 
Mucosa vesicle 
• 
Mucosal erosion 
• 
Mucosal exfoliation 
• 
Mucosal necrosis 
• 
Mucosal ulceration 




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• 
Autoimmune aplastic anaemia 
• 
Autoimmune arthritis 
• 
Autoimmune blistering disease 
• 
Autoimmune cholangitis 
• 
Autoimmune colitis 
• 
Autoimmune demyelinating disease 
• 
Autoimmune dermatitis 
• 
Autoimmune disorder 
• 
Autoimmune encephalopathy 
• 
Autoimmune endocrine disorder 
• 
Autoimmune enteropathy 
• 
Autoimmune eye disorder 
• 
Autoimmune haemolytic anaemia 
• 
Autoimmune 
heparin-induced 
thrombocytopenia 
• 
Autoimmune hepatitis 
• 
Autoimmune hyperlipidaemia 
• 
Autoimmune hypothyroidism 
• 
Autoimmune inner ear disease 
• 
Autoimmune lung disease 
• 
Autoimmune 
lymphoproliferative 
syndrome 
• 
Autoimmune myocarditis 
• 
Autoimmune myositis 
• 
Autoimmune nephritis 
• 
Autoimmune neuropathy 
• 
Autoimmune neutropenia 
• 
Autoimmune pancreatitis 
• 
Autoimmune pancytopenia 
• 
Autoimmune pericarditis 
• 
Autoimmune retinopathy 
• 
Autoimmune thyroid disorder 
• 
Autoimmune thyroiditis 
• 
Autoimmune uveitis 
• 
Autoinflammation 
with 
infantile 
enterocolitis 
• 
Autoinflammatory disease 
• 
Axial spondyloarthritis 
• 
Basedow's disease 
• 
Behcet's syndrome 
• 
Bickerstaff's encephalitis 
• 
Birdshot chorioretinopathy 
• 
Butterfly rash 
• 
C1q nephropathy 
• 
Caplan's syndrome 
• 
Cardiac amyloidosis 
• 
Cardiac sarcoidosis 
• 
Central nervous system lupus 
• 
Central nervous system vasculitis 
• 
Cerebral amyloid angiopathy 
• 
Cholangitis sclerosing 
• 
Chronic autoimmune glomerulonephritis 
• 
Chronic cutaneous lupus erythematosus 
• 
Chronic gastritis 
• 
Chronic 
inflammatory 
demyelinating 
polyradiculoneuropathy 
• 
Chronic lymphocytic inflammation with 
pontine 
perivascular 
enhancement 
responsive to steroids 
• 
Chronic 
recurrent 
multifocal 
osteomyelitis 
• 
Clinically isolated syndrome 
• 
Coeliac disease 
• 
Cogan's syndrome 
• 
Cold type haemolytic anaemia 
• 
Colitis ulcerative 
• 
Collagen disorder 
• 
Collagen-vascular disease 
• 
Concentric sclerosis 
• 
Coombs positive haemolytic anaemia 
• 
CREST syndrome 
• 
Crohn's disease 
• 
Cryofibrinogenaemia 
• 
Cryoglobulinaemia 
• 
Cutaneous amyloidosis 
• 
Cutaneous lupus erythematosus 
• 
Cutaneous sarcoidosis 
• 
Cutaneous vasculitis 
• 
Cystitis interstitial 
• 
De novo purine synthesis inhibitors 
associated 
acute 
inflammatory 
syndrome 
• 
Demyelinating polyneuropathy 
• 
Dermatomyositis 
• 
Dialysis amyloidosis 
• 
Diffuse vasculitis 
• 
Digital pitting scar 
• 
Dressler's syndrome 
• 
Encephalitis allergic 
• 
Encephalitis autoimmune 


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Protocol no: CV-NCOV-004 
 
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• 
Encephalitis post immunisation 
• 
Endocrine ophthalmopathy 
• 
Enteropathic spondylitis 
• 
Eosinophilic fasciitis 
• 
Eosinophilic 
granulomatosis 
with 
polyangiitis 
• 
Eosinophilic oesophagitis 
• 
Evans syndrome 
• 
Felty's syndrome 
• 
Fibrillary glomerulonephritis 
• 
Gastrointestinal amyloidosis 
• 
Giant cell arteritis 
• 
Glomerulonephritis 
• 
Glomerulonephritis rapidly progressive 
• 
Goodpasture's syndrome 
• 
Granulomatosis with polyangiitis 
• 
Granulomatous dermatitis 
• 
Guillain-Barre syndrome 
• 
Haemophagocytic lymphohistiocytosis 
• 
Haemorrhagic vasculitis 
• 
Hashimoto's encephalopathy 
• 
Hashitoxicosis 
• 
Henoch-Schonlein purpura 
• 
Henoch-Schonlein purpura nephritis 
• 
Heparin-induced thrombocytopenia 
• 
Hepatic amyloidosis 
• 
Hypogammaglobulinaemia 
• 
IgA nephropathy 
• 
IgM nephropathy 
• 
Immune thrombocytopenia 
• 
Immune-mediated adverse reaction 
• 
Immune-mediated cholangitis 
• 
Immune-mediated cholestasis 
• 
Immune-mediated cytopenia 
• 
Immune-mediated encephalitis 
• 
Immune-mediated encephalopathy 
• 
Immune-mediated endocrinopathy 
• 
Immune-mediated enterocolitis 
• 
Immune-mediated gastritis 
• 
Immune-mediated hepatic disorder 
• 
Immune-mediated hepatitis 
• 
Immune-mediated hyperthyroidism 
• 
Immune-mediated hypothyroidism 
• 
Immune-mediated myocarditis 
• 
Immune-mediated myositis 
• 
Immune-mediated nephritis 
• 
Immune-mediated neuropathy 
• 
Immune-mediated pancreatitis 
• 
Immune-mediated pneumonitis 
• 
Immune-mediated renal disorder 
• 
Immune-mediated thyroiditis 
• 
Immune-mediated uveitis 
• 
Immunoglobulin G4 related disease 
• 
Inclusion body myositis 
• 
Inflammatory bowel disease 
• 
Injection site vasculitis 
• 
Insulin autoimmune syndrome 
• 
Interstitial granulomatous dermatitis 
• 
IPEX syndrome 
• 
Juvenile idiopathic arthritis 
• 
Juvenile polymyositis 
• 
Juvenile psoriatic arthritis 
• 
Juvenile spondyloarthritis 
• 
Kawasaki's disease 
• 
Keratoderma blenorrhagica 
• 
Laryngeal rheumatoid arthritis 
• 
Latent autoimmune diabetes in adults 
• 
Leukoencephalomyelitis 
• 
Lewis-Sumner syndrome 
• 
Limbic encephalitis 
• 
Linear IgA disease 
• 
Liver sarcoidosis 
• 
Lupoid hepatic cirrhosis 
• 
Lupus cystitis 
• 
Lupus encephalitis 
• 
Lupus endocarditis 
• 
Lupus enteritis 
• 
Lupus hepatitis 
• 
Lupus myocarditis 
• 
Lupus myositis 
• 
Lupus nephritis 
• 
Lupus pancreatitis 
• 
Lupus pleurisy 
• 
Lupus pneumonitis 
• 
Lupus vasculitis 
• 
Lymphocytic hypophysitis 
• 
MAGIC syndrome 
• 
Marburg's variant multiple sclerosis 


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• 
Marine Lenhart syndrome 
• 
Metastatic cutaneous Crohn's disease 
• 
Microscopic polyangiitis 
• 
Mixed connective tissue disease 
• 
Morphoea 
• 
Morvan syndrome 
• 
Multifocal motor neuropathy 
• 
Multiple sclerosis 
• 
Multiple sclerosis relapse 
• 
Multisystem inflammatory syndrome in 
children 
• 
Muscular sarcoidosis 
• 
Myasthenia gravis 
• 
Myasthenia gravis crisis 
• 
Myasthenia gravis neonatal 
• 
Myasthenic syndrome 
• 
Myelitis transverse 
• 
Neonatal Crohn's disease 
• 
Neonatal lupus erythematosus 
• 
Neuralgic amyotrophy 
• 
Neuromyelitis optica pseudo relapse 
• 
Neuromyelitis optica spectrum disorder 
• 
Neuropsychiatric lupus 
• 
Neurosarcoidosis 
• 
Nodular vasculitis 
• 
Noninfectious myelitis 
• 
Noninfective encephalitis 
• 
Noninfective encephalomyelitis 
• 
Ocular myasthenia 
• 
Ocular pemphigoid 
• 
Ocular sarcoidosis 
• 
Ocular vasculitis 
• 
Overlap syndrome 
• 
Palindromic rheumatism 
• 
Palisaded neutrophilic granulomatous 
dermatitis 
• 
Palpable purpura 
• 
Pericarditis lupus 
• 
Peritonitis lupus 
• 
Pernicious anaemia 
• 
POEMS syndrome 
• 
Polyarteritis nodosa 
• 
Polychondritis 
• 
Polyglandular autoimmune syndrome 
type I 
• 
Polyglandular autoimmune syndrome 
type II 
• 
Polyglandular autoimmune syndrome 
type III 
• 
Polymyalgia rheumatica 
• 
Postpericardiotomy syndrome 
• 
Primary amyloidosis 
• 
Primary biliary cholangitis 
• 
Primary progressive multiple sclerosis 
• 
Proctitis ulcerative 
• 
Progressive facial hemiatrophy 
• 
Progressive multiple sclerosis 
• 
Progressive relapsing multiple sclerosis 
• 
Psoriasis 
• 
Psoriatic arthropathy 
• 
Pulmonary renal syndrome 
• 
Pulmonary sarcoidosis 
• 
Pulmonary vasculitis 
• 
Pyoderma gangrenosum 
• 
Pyostomatitis vegetans 
• 
Radiologically isolated syndrome 
• 
Rasmussen encephalitis 
• 
Raynaud's phenomenon 
• 
Reactive 
capillary 
endothelial 
proliferation 
• 
Relapsing multiple sclerosis 
• 
Relapsing-remitting multiple sclerosis 
• 
Renal amyloidosis 
• 
Renal arteritis 
• 
Renal vasculitis 
• 
Retinal vasculitis 
• 
Retroperitoneal fibrosis 
• 
Reynold's syndrome 
• 
Rheumatic brain disease 
• 
Rheumatic disorder 
• 
Rheumatoid arthritis 
• 
Rheumatoid lung 
• 
Rheumatoid neutrophilic dermatosis 
• 
Rheumatoid nodule 
• 
Rheumatoid scleritis 
• 
Rheumatoid vasculitis 
• 
SAPHO syndrome 
• 
Sarcoidosis 
• 
Satoyoshi syndrome 
• 
Sclerodactylia 


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• 
Scleroderma 
• 
Scleroderma associated digital ulcer 
• 
Scleroderma renal crisis 
• 
Scleroderma-like reaction 
• 
Secondary amyloidosis 
• 
Secondary cerebellar degeneration 
• 
Secondary 
progressive 
multiple 
sclerosis 
• 
Segmented hyalinising vasculitis 
• 
Shrinking lung syndrome 
• 
Sjogren's syndrome 
• 
SLE arthritis 
• 
Stiff leg syndrome 
• 
Stiff person syndrome 
• 
Still's disease 
• 
Stoma site vasculitis 
• 
Subacute 
cutaneous 
lupus 
erythematosus 
• 
Subacute inflammatory demyelinating 
polyneuropathy 
• 
Susac's syndrome 
• 
Sympathetic ophthalmia 
• 
Systemic lupus erythematosus 
• 
Systemic lupus erythematosus rash 
• 
Systemic scleroderma 
• 
Systemic sclerosis pulmonary 
• 
Takayasu's arteritis 
• 
Terminal ileitis 
• 
Testicular autoimmunity 
• 
Thromboangiitis obliterans 
• 
Thrombocytopenic purpura 
• 
Thrombotic thrombocytopenic purpura 
• 
Tongue amyloidosis 
• 
Toxic oil syndrome 
• 
Tubulointerstitial nephritis and uveitis 
syndrome 
• 
Tumefactive multiple sclerosis 
• 
Type 1 diabetes mellitus 
• 
Type III immune complex mediated 
reaction 
• 
Ulcerative keratitis 
• 
Undifferentiated 
connective 
tissue 
disease 
• 
Vaccination site vasculitis 
• 
Vasculitic rash 
• 
Vasculitic ulcer 
• 
Vasculitis 
• 
Vasculitis gastrointestinal 
• 
Vasculitis necrotising 
• 
Vitiligo 
• 
Vogt-Koyanagi-Harada disease 
• 
Warm type haemolytic anaemia 
Broad 
• 
Acoustic neuritis 
• 
Acute febrile neutrophilic dermatosis 
• 
Acute flaccid myelitis 
• 
Acute macular outer retinopathy 
• 
Anosmia 
• 
Antiacetylcholine 
receptor 
antibody 
positive 
• 
Anti-actin antibody positive 
• 
Anti-aquaporin-4 antibody positive 
• 
Anti-basal ganglia antibody positive 
• 
Anti-cyclic citrullinated peptide antibody 
positive 
• 
Anti-epithelial antibody positive 
• 
Anti-erythrocyte antibody positive 
• 
Anti-exosome complex antibody positive 
• 
Anti-GAD antibody negative 
• 
Anti-GAD antibody positive 
• 
Anti-ganglioside antibody positive 
• 
Antigliadin antibody positive 
• 
Anti-glomerular basement membrane 
antibody positive 
• 
Anti-glycyl-tRNA synthetase antibody 
positive 
• 
Anti-HLA antibody test positive 
• 
Anti-IA2 antibody positive 
• 
Anti-insulin antibody increased 
• 
Anti-insulin antibody positive 
• 
Anti-insulin receptor antibody increased 
• 
Anti-insulin receptor antibody positive 
• 
Anti-islet cell antibody positive 
• 
Antimitochondrial antibody positive 
• 
Anti-muscle specific kinase antibody 
positive 


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• 
Anti-myelin-associated 
glycoprotein 
antibodies positive 
• 
Antimyocardial antibody positive 
• 
Anti-neuronal antibody positive 
• 
Antineutrophil 
cytoplasmic 
antibody 
increased 
• 
Antineutrophil 
cytoplasmic 
antibody 
positive 
• 
Anti-NMDA antibody positive 
• 
Antinuclear antibody increased 
• 
Antinuclear antibody positive 
• 
Antiphospholipid antibodies positive 
• 
Anti-platelet antibody positive 
• 
Anti-prothrombin antibody positive 
• 
Antiribosomal P antibody positive 
• 
Anti-RNA 
polymerase 
III 
antibody 
positive 
• 
Anti-saccharomyces 
cerevisiae 
antibody test positive 
• 
Anti-sperm antibody positive 
• 
Anti-SRP antibody positive 
• 
Anti-thyroid antibody positive 
• 
Anti-transglutaminase 
antibody 
increased 
• 
Anti-VGCC antibody positive 
• 
Anti-VGKC antibody positive 
• 
Anti-vimentin antibody positive 
• 
Anti-zinc transporter 8 antibody positive 
• 
Aortitis 
• 
Aplastic anaemia 
• 
Arteritis 
• 
Arteritis coronary 
• 
Arthritis 
• 
Atrophic thyroiditis 
• 
Autoantibody positive 
• 
Autonomic nervous system imbalance 
• 
Axonal 
and 
demyelinating 
polyneuropathy 
• 
Axonal neuropathy 
• 
Beta-2 glycoprotein antibody positive 
• 
Bulbar palsy 
• 
Capillaritis 
• 
Cardiolipin antibody positive 
• 
Cerebral arteritis 
• 
Chronic spontaneous urticaria 
• 
Cold agglutinins positive 
• 
Colitis 
• 
Colitis erosive 
• 
Colitis microscopic 
• 
Complement factor abnormal 
• 
Complement factor C1 decreased 
• 
Complement factor C2 decreased 
• 
Complement factor C3 decreased 
• 
Complement factor C4 decreased 
• 
Complement factor decreased 
• 
Cranial nerve disorder 
• 
Cranial nerve palsies multiple 
• 
Cranial nerve paralysis 
• 
CSF oligoclonal band present 
• 
Demyelination 
• 
Dermatitis 
• 
Dermatitis bullous 
• 
Dermatitis herpetiformis 
• 
Diabetes mellitus 
• 
Diabetic ketoacidosis 
• 
DNA antibody positive 
• 
Double stranded DNA antibody positive 
• 
Encephalitis 
• 
Encephalitis brain stem 
• 
Encephalitis haemorrhagic 
• 
Encephalomyelitis 
• 
Encephalopathy 
• 
Endocrine disorder 
• 
Enteritis 
• 
Enterocolitis 
• 
Erythema induratum 
• 
Erythema multiforme 
• 
Erythema nodosum 
• 
Expanded disability status scale score 
decreased 
• 
Expanded disability status scale score 
increased 
• 
Facial paresis 
• 
Fulminant type 1 diabetes mellitus 
• 
Glomerulonephritis 
membranoproliferative 
• 
Glomerulonephritis membranous 
• 
Glossopharyngeal nerve paralysis 
• 
Haemolytic anaemia 
• 
Hepatitis 


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• 
Histone antibody positive 
• 
Hyperthyroidism 
• 
Hypoglossal nerve paralysis 
• 
Hypoglossal nerve paresis 
• 
Hypothyroidism 
• 
Idiopathic interstitial pneumonia 
• 
Idiopathic pulmonary fibrosis 
• 
IIIrd nerve paralysis 
• 
IIIrd nerve paresis 
• 
Immunoglobulins abnormal 
• 
Infected vasculitis 
• 
Interstitial lung disease 
• 
Intrinsic factor antibody abnormal 
• 
Intrinsic factor antibody positive 
• 
IRVAN syndrome 
• 
IVth nerve paralysis 
• 
IVth nerve paresis 
• 
LE cells present 
• 
Lichen planopilaris 
• 
Lichen planus 
• 
Lichen sclerosus 
• 
Lupus-like syndrome 
• 
Mastocytic enterocolitis 
• 
Mesangioproliferative 
glomerulonephritis 
• 
Miller Fisher syndrome 
• 
Mononeuritis 
• 
Mononeuropathy multiplex 
• 
Myelitis 
• 
Myocarditis 
• 
Myositis 
• 
Narcolepsy 
• 
Nephritis 
• 
Neuritis 
• 
Neuritis cranial 
• 
Neuronal neuropathy 
• 
Neuropathy peripheral 
• 
Noninfective oophoritis 
• 
Oculofacial paralysis 
• 
Oesophageal achalasia 
• 
Optic neuritis 
• 
Optic neuropathy 
• 
Optic perineuritis 
• 
Oral lichen planus 
• 
Palmoplantar keratoderma 
• 
Pancreatitis 
• 
Panencephalitis 
• 
Paresis cranial nerve 
• 
Parietal cell antibody positive 
• 
Pemphigoid 
• 
Pemphigus 
• 
Pericarditis 
• 
Pityriasis lichenoides et varioliformis 
acuta 
• 
Pleuroparenchymal fibroelastosis 
• 
Polyglandular disorder 
• 
Polymyositis 
• 
Polyneuropathy idiopathic progressive 
• 
Premature menopause 
• 
Pulmonary amyloidosis 
• 
Pulmonary fibrosis 
• 
Radiculitis brachial 
• 
Retinopathy 
• 
Rheumatoid factor increased 
• 
Rheumatoid factor positive 
• 
Rheumatoid 
factor 
quantitative 
increased 
• 
Rheumatoid nodule removal 
• 
Scleritis 
• 
Silent thyroiditis 
• 
Smooth muscle antibody positive 
• 
Spondylitis 
• 
Spondyloarthropathy 
• 
Stevens-Johnson syndrome 
• 
Subacute endocarditis 
• 
Systemic lupus erythematosus disease 
activity index abnormal 
• 
Systemic lupus erythematosus disease 
activity index decreased 
• 
Systemic lupus erythematosus disease 
activity index increased 
• 
Thromboplastin antibody positive 
• 
Thyroid disorder 
• 
Thyroid 
stimulating 
immunoglobulin 
increased 
• 
Thyroiditis 
• 
Toxic epidermal necrolysis 
• 
Trigeminal nerve paresis 
• 
Trigeminal palsy 






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• 
Hypogeusia 
• 
Hyposmia 
• 
Parosmia 
• 
Taste disorder 


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Protocol no: CV-NCOV-005 
 
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Appendix 4 List of TFLs 
A complete list of all Tables, Figures and Listings (TFLs) is provided in a separate document CV-NCOV-
005 Statistical Analysis Plan – Appendix 4 List of TFLs. TFLs to be provided at the different interim and 
final delivery timepoints are indicated therein. The document is maintained outside of this SAP. 
Appendix 5 Identification of Protocol Deviations Leading to Exclusion from 
Analysis Sets 
Details on the identification of protocol deviations leading to exclusion of subjects from analysis sets are 
described in a separate document CV-NCOV-005 Statistical Analysis Plan – Appendix 5 Protocol 
Deviations Leading to Exclusion from Analysis sets. The document is maintained outside of this SAP.