A Multi-center Phase Ib Trial to Assess the Safety, Tolerability and Immunogenicity of the Candidate Vaccine MVA-SARS-2-ST in Adults
Phase: PHASE1
Conditions: Covid19
Sponsor: Universitätsklinikum Hamburg-Eppendorf



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SIGNATURES 
 
Sponsor Signature  
This protocol has been approved by University Medical Center Hamburg-Eppendorf. 
 
 
Sponsor signature 
 
Date 
 
 
 
 
Sponsor name 
 
 
 
 
 
Coordinating investigator Signature  
I hereby confirm that I have acknowledged the protocol and agree to conduct the clinical trial in compli-
ance with the protocol. 
 
 
Coordinating investigator signature 
 
Date 
 
 
 
 
Coordinating investigator name 
 
 
 
 
Statistician signature  
I hereby confirm that I have acknowledged the protocol and agree to conduct the clinical trial in compli-
ance with the protocol. 
 
 
Statistician signature 
 
Date 
 
 
 
 
Statistician name 
 
 
 
 
 
 
Prof. Dr. Antonia Zapf
06 Oct 2021

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Part B with mRNA vaccinated subjects added and therefore update of primary and secondary ob-
jectives, inclusion and exclusion criteria, administered doses, duration of treatment. Phase IIa part 
of the study was deleted. 
02 
05-OCT-2021 
Study schedules 
Brief description of change: 
Footnote m added to all parts: COVID-19 antigen test results may be used if test was performed 
within 4h before screening. 
 
Study schedule Part B added. 
 
Detailed time and events: Update of details for assessments at time point 0 hours after dose ad-
ministration. 
 
02 
05-OCT-2021 
7.1 Background information and rationale 
Brief description of change: 
Update of numbers of infections and cases of death.  
02 
05-OCT-2021 
7.4 Risk-benefit considerations 
Brief description of change: 
Amount of blood collected from participants of Part B added and reference to Phase IIa deleted. 
02 
05-OCT-2021 
8.1 Primary objective 
Brief description of change: 
Alignment of wording of primary objective in Part A with exclusion criteria: Subjects are SARS-CoV-
2 seronegative.  
Primary objective for Part B added. 
Reference to Phase IIa deleted. 
02 
05-OCT-2021 
8.2 Secondary objectives 
Brief description of change: 
Alignment of wording of secondary objectives in Part A with exclusion criteria: Subjects are SARS-
CoV-2 seronegative.  
Secondary objective for Part B added. Reference to Phase IIa deleted. 
02 
05-OCT-2021 
9.1 Overall study design and plan-description 
Brief description of change: 
Update of numbers of participants: Part A reduced to 8 subjects in each dose level, B with 12 sub-
jects in each dose level. Reference to Phase IIa deleted. Figure 1 Overall study design updated 
accordingly. 
02 
05-OCT-2021 
9.2 Discussion of study design, including the 
choice of control groups 
Brief description of change: 
Study population of Part B added. Reference to Phase IIa deleted. 
02 
05-OCT-2021 
9.3 Selection of study population 
Brief description of change: 
Study population of Part B added. Reference to Phase IIa deleted. 
02 
05-OCT-2021 
9.3.1 Inclusion criteria   
Brief description of change: 
Inclusion criterion for Part B added. Reference to Phase IIa deleted. 
02 
05-OCT-2021 
9.3.2 Exclusion criteria 
Brief description of change: 
Update for distinction between Part A and Part B. Reference to Phase IIa deleted. 
02 
05-OCT-2021 
9.3.3 Reproductive potential 
Brief description of change: 
Contraception requirements not applicable for females with exclusively same-sex sex partners. 

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05-OCT-2021 
9.4.1 Treatments administered 
Brief description of change: 
Part B added. Reference to Phase IIa deleted. 
02 
05-OCT-2021 
9.4.7.2 Participant identification 
Brief description of change: 
Numbering for Part B added. 
Clarification added: Assignment to Part A and Part B will be in parallel. 
02 
05-OCT-2021 
9.4.5 Blinding 
Brief description of change: 
Reference to unblinding was deleted. 
02 
05-OCT-2021 
9.4.7.3 Screening, confinement and regular visits  
Brief description of change: 
Updated according to the study schedules. 
02 
05-OCT-2021 
9.7.2.12 Reactogenicity 
Brief description of change: 
Instructions for use of subject diary corrected. 
02 
05-OCT-2021 
9.11 Statistical methods planned in the protocol 
and determination of sample size 
Brief description of change: 
Adaption of the Part B and deletion of the Phase IIa. 
02 
05-OCT-2021 
11 Safety Steering Committee (SSC) 
Brief description of change: 
Safety steering committee instead of LSB/DSMB added. Section was renamed. 
 
 
 

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1 
SYNOPSIS 
 
Name of sponsor/company: 
University Medical Center Ham-
burg-Eppendorf 
Individual study table 
referring to part 
of the dossier 
 
 
Volume: 
 
 
Page: 
(For national authority use only) 
Name of finished product: 
MVA-SARS-2-ST 
Name of active ingredient: 
MVA-SARS-2-ST 
Title of study: 
A multi-center, phase Ib trial to assess the safety, tolerability and immu-
nogenicity of the candidate vaccine MVA-SARS-2-ST in adults 
Coordinating investigator 
Prof. Dr. med. M. Addo  
Sponsor 
University Medical Center Hamburg-Eppendorf 
CRO 
CTC North GmbH & Co. KG, Hamburg 
Study centers: 
2 to 5 study sites in Germany 
 
Protocol-No. 
UKE-SARS-COV-2-ST 
EudraCT-No. 
2021-000548-23 
Study period 
Period will last for approx. 7 months per participant (screening to fol-
low-up).  
Study Timelines: 
Total study duration (FPFV to LPLV) approx. 10 months  
FPFV JUL 2021 
LPFV NOV 2021 
LPLV MAY 2022 
Phase of development: 
Phase Ib 
Objectives: 
Primary objectives 
• 
To evaluate the safety, tolerability and reactogenicity of two intra-
muscular dose administrations of three dose levels of the candidate 
MVA-SARS-2-ST vaccine in healthy SARS-CoV-2 seronegative 
adults aged 18-64 years (Part A).  
• 
To evaluate the safety, tolerability and reactogenicity of one intra-
muscular dose administration of three dose levels of the candidate 
MVA-SARS-2-ST vaccine in healthy adults previously vaccinated 
against COVID-19 aged 18-64 years (Part B).  
• 
 
Secondary objectives 
• 
To evaluate SARS-CoV-2-S1-binding and SARS-CoV-2 neutralizing 
antibodies in healthy SARS-CoV-2 seronegative adults induced by 
three dose levels after two administrations of MVA-SARS-2-ST vac-
cine (Part A). 
• 
To evaluate SARS-CoV-2-S1-binding and SARS-CoV-2 neutralizing 
antibodies in healthy adults vaccinated against COVID-19 induced 
by three dose levels after one administration of MVA-SARS-2-ST 
vaccine (Part B). 

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Exploratory objectives 
• 
To investigate Th1 and Th2 immune responses following vaccina-
tion. 
• 
To investigate the occurrence of antibody-dependent enhancement 
and vaccine-associated enhanced respiratory disease. 
• 
To identify and immunologically characterize cases of COVID-19. 
• 
To evaluate the rate of natural infection of SARS-CoV-2 during the 
clinical trial by monitoring antibodies against SARS-CoV-2 N protein. 
• 
To investigate sex differences in immunity to MVA-SARS-2-ST vac-
cination. 
• 
To investigate age-related immune responses to MVA-SARS-2-ST 
vaccination. 
• 
To examine vaccine-induced humoral immune responses and anti-
body functions, including vector-immunity, neutralizing and non-
neutralizing antibody functions. 
 
• 
To evaluate MVA-SARS-2-ST-specific cellular immune responses 
after administration of MVA-SARS-2-ST vaccine. 
• 
To evaluate MVA-SARS-2-ST-induced B- and T-cell memory re-
sponses. 
• 
To evaluate innate immune responses induced by MVA-SARS-2-ST 
vaccine. 
• 
To evaluate early gene expression signatures induced by MVA-
SARS-2-ST vaccine. 
• 
To evaluate pre-existing humoral and cellular immunity to corona-
viruses. 
• 
To identify potential biomarkers and gene signatures of innate im-
mune responses to MVA-SARS-2-ST vaccine and their correlation 
to dose, reactogenicity, and immune response. 
Study design 
Multi-center, phase Ib study, open-label, 2 parts to evaluate SARS-CoV-
2 seronegative and previously SARS-CoV-2-vaccinated individuals. 
 
 
 

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Methodology: 
This will be a phase Ib, multi-center study in approximately 60 adults 
aged 18 years and older. 
PART A (24 seronegative subjects) 
• 
low dose ≥ 1 x 107 IU (N=8) 
• 
middle dose ≥ 5 x 107 IU (N=8) 
• 
high dose ≥ 1 x 108 IU (N=8) 
 
PART B (36 previously vaccinated subjects) 
• 
low dose ≥ 1 x 107 IU (N=12) 
• 
middle dose ≥ 5 x 107 IU (N=12) 
• 
high dose ≥ 1 x 108 IU (N=12) 
For safety reasons dose administration in each dose level for both Parts 
will be performed in at least three groups. 1st participant of each dose 
level will be vaccinated 24 hours before the next 3 participants and the 
rest of the participants will be vaccinated 24 hours after the second 
group of the respective dose level. 
Dose levels will commence in a staggered fashion. The next dose level 
of each Part will start at least 48 hours after all participants of the prior 
dose level of the respective Part have been vaccinated. 
Each participant will receive two single injections, 28 days apart (Part A) 
or one single injection (Part B). 
All participants will be followed up for safety until D 168. 
 
Part A and Part B will commence in parallel. 
 
 
Number of participants: 
60 
Homogeneous sex distribution of no less than 25% of one sex is tar-
geted.  
Main criteria for inclusion: 
Key inclusion criteria  
1. Written informed consent. 
2. Healthy male and female adults aged 18 – 64 at time of informed 
consent.  
3. Body mass index 18.5 - 32.0 kg/m2 and weight > 50 kg at screening. 
4. Female participants: non-pregnant, non-lactating with negative 
pregnancy test.   
5. Females who agree to comply with the applicable contraceptive re-
quirements of the protocol.  
 
6. ≥ 6 months fully vaccinated with a (conditionally) licensed mRNA 
vaccine against COVID-19 (Part B only). 
 

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Key exclusion criteria  
1. Receipt of any vaccine from 4 weeks prior to each trial vaccination 
(8 weeks for live vaccines) to 6 weeks after each trial vaccination. 
2. Previous rMVA immunization. 
3. Previous immunization with investigational vaccine against COVID-
19. 
4. Previous immunization with EUA/conditionally licensed vaccine 
against COVID-19 (not applicable to part B). 
5. Evidence of active SARS-CoV-2 infection (positive SARS-CoV-2 an-
tigen test followed by a confirmatory positive PCR test). 
6. Known allergy to the components of the MVA-SARS-2-ST vaccine 
product or history of life-threatening reactions to vaccine containing 
the same substances. 
7. Known history of anaphylaxis to vaccination or any allergy likely to 
be exacerbated by any component of the trial vaccines. 
8. Evidence in the participant's medical history or in the medical exam-
ination that might influence either the safety of the participant or the 
absorption, distribution, metabolism or excretion of the investiga-
tional product. 
9. Clinically relevant findings in ECG or significant thromboembolic 
events in medical history. 
10. Any confirmed or suspected immunosuppressive or immunodefi-
cient condition, cytotoxic therapy in the previous 5 years, and/or un-
controlled diabetes (HbA1c ≥ 7.0). 
11. Any known chronic or active neurologic disorder, including seizures 
and epilepsy, excluding a single febrile seizure as a child. 
Test product, dose and mode of 
administration: 
Test product:  MVA-SARS-2-ST 
Dose:  
Part A: Participants will receive 2 single doses of ≥ 1x107 
IU,  ≥ 5 x 107 IU, or ≥ 1 x 108 IU MVA-SARS-2-ST in 0.5 mL (total in-
jected volume 1 mL). 
Part B: Participants will receive 1 single dose of ≥ 1x107 IU,  ≥ 5 x 107 IU, 
or ≥ 1 x 108 IU MVA-SARS-2-ST in 0.5 mL (total injected volume 
0.5 mL). 
Dose administration on day 0 (Part A and B) and day 28 (Part A) for 
each participant.  
Mode of administration: 
Intramuscular (i.m.) 
 
Duration of treatment: 
Part A: 
Participants will receive two single vaccine injections. First injection on 
day 0; second injection on day 28.  
Part B: 
Participants will receive one single vaccine injection on day 0.  
Reference therapy, dose and 
mode of administration, batch 
number: 
None  

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Criteria for evaluation: 
 
Primary endpoints:  
The nature, frequency and severity of adverse events associated with 
MVA-SARS-2-ST vaccine will be collected and measured as follows: 
• 
Occurrence of solicited local reactogenicity signs and symptoms 
for 7 days after vaccination. 
• 
Occurrence of solicited systemic reactogenicity signs and symp-
toms for 7 days after vaccination. 
• 
Occurrence of unsolicited adverse events (AE) for 28 days after 
vaccination. 
• 
Change from baseline of safety laboratory measures.  
• 
Occurrence of serious adverse events (SAE) throughout the 
study period. 
Secondary endpoints: 
Immunogenicity 
• 
Humoral immunity: Amount of anti-SARS-CoV-2-S1-binding 
antibodies as measured by ELISA and detection of antibodies 
that neutralize SARS-CoV-2 (Part A & B). 
• 
Percentage of participants who seroconverted: The seroconver-
sion measured by ELISA is defined as the detection of SARS-
CoV-2-S1-specific antibodies if the baseline value was negative, 
or as an increase in the antibody titer by a factor of 4 or more 
compared to the baseline value (Part A).  
• 
Percentage of participants who showed an increase of  the level 
of binding and neutralizing antibodies to baseline (Part B). 
Safety: 
Safety data (AEs, SAEs and vital signs) will be collected at all study vis-
its. 
Laboratory safety tests (biochemistry, hematology and dipstick urinaly-
sis) will be performed at screening, pre-dose and at defined study follow-
up visit. 
It is planned to enroll all participants in a longitudinal follow-up study after 
end of study and have an additional 6-month follow-up for safety assess-
ment. 
Statistical methods: 
Metric data will be summarized using descriptive statistics (number, 
mean, standard deviation, minimum, Q25, median, Q75 and maximum). 
Categorical data will be summarized by using frequency Tables (fre-
quency and percent). Data will be analyzed in the entire study population 
as well as in subgroups. It is not planned to test any hypotheses in a 
confirmatory sense. 

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Table 3 Detailed time and events 
Study 
day 
Time after dose ad-
ministration 
(hours) 
 
Vaccination 
Vital 
signs 
Temperature 
Adverse 
events/ 
con Med 
Injection site/ 
systemic reac-
tion/ Events as-
sessment 
0 
01 
√ 
√1 
√1 
Update 
Medical 
History 
√ (within 5 
minutes after 
vaccination 
0 
1 (±15 minutes) 
 
√ 
√ 
√ 
√ 
28 
01 
√ 
√1 
√1 
√1 
√ (within 5 
minutes after 
vaccination 
28 
1 (±15 minutes) 
 
√ 
√ 
√ 
√ 
1Events must be completed within 30 minutes before vaccination. 
 

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3 
TABLE OF CONTENTS 
 
1 
SYNOPSIS ....................................................................................................................................... 6 
2 
STUDY SCHEDULES .................................................................................................................... 11 
3 
TABLE OF CONTENTS ................................................................................................................. 16 
3.1 
List of Tables ......................................................................................................................... 17 
3.2 
List of Figures ........................................................................................................................ 17 
4 
LIST OF ABBREVIATIONS ............................................................................................................ 18 
5 
ETHICS AND LEGAL ASPECTS ................................................................................................... 21 
5.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ........................... 21 
5.2 
Ethical conduct of the clinical trial ......................................................................................... 21 
5.3 
Participant information and consent ..................................................................................... 21 
5.4 
Confidentiality ........................................................................................................................ 21 
5.5 
Insurance .............................................................................................................................. 21 
5.6 
Publication policy .................................................................................................................. 22 
5.7 
Qualification of the investigator ............................................................................................. 22 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .............................................. 23 
7 
INTRODUCTION ............................................................................................................................ 25 
7.1 
Background information and rationale .................................................................................. 25 
7.2 
Preclinical results .................................................................................................................. 25 
7.3 
Clinical studies ...................................................................................................................... 26 
7.4 
Risk-benefit considerations ................................................................................................... 26 
8 
STUDY OBJECTIVES .................................................................................................................... 27 
8.1 
Primary objective................................................................................................................... 27 
 
Primary endpoints .......................................................................................................... 27 
8.2 
Secondary objectives ............................................................................................................ 27 
 
Secondary endpoints ..................................................................................................... 28 
8.3 
Exploratory objectives ........................................................................................................... 28 
9 
INVESTIGATIONAL PLAN ............................................................................................................. 28 
9.1 
Overall study design and plan-description ............................................................................ 28 
9.2 
Discussion of study design, including the choice of control groups ...................................... 29 
9.3 
Selection of study population ................................................................................................ 30 
 
Inclusion criteria ............................................................................................................. 30 
 
Exclusion criteria ........................................................................................................... 30 
 
Reproductive potential ................................................................................................... 31 
 
Removal of participants from vaccination or assessment ............................................. 32 
9.4 
Treatments ............................................................................................................................ 34 
 
Treatments administered ............................................................................................... 34 
 
Identity of investigational medicinal products ................................................................ 35 
 
Method of assigning participants to treatment groups .................................................. 36 
 
Selection of doses in the study ...................................................................................... 36 
 
Blinding and unblinding ................................................................................................. 36 
 
Prior and concomitant therapy ...................................................................................... 36 
 
Treatment compliance ................................................................................................... 36 
9.5 
Protocol deviations (PD) ....................................................................................................... 40 
9.6 
Methods and timing of safety measurement ......................................................................... 41 

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9.7 
Appropriateness of measurements ....................................................................................... 41 
 
Screening procedures ................................................................................................... 41 
 
Study examinations ....................................................................................................... 41 
 
Safety variables ............................................................................................................. 48 
9.8 
Definition of adverse events, period of observation, recording of adverse events ............... 48 
 
Severity categorization .................................................................................................. 52 
 
Relationship categorization ........................................................................................... 54 
 
Outcome categorization................................................................................................. 55 
 
Clinical laboratory evaluations ....................................................................................... 55 
 
Procedures in case of pregnancy .................................................................................. 56 
 
Abuse, misuse, overdose, and medication error ........................................................... 56 
9.9 
Serious adverse event (SAE) and AESI procedures ............................................................ 56 
 
Reporting procedures .................................................................................................... 56 
 
Serious adverse event (SAE) definition ......................................................................... 57 
 
AE/ SAE onset and stop dates ...................................................................................... 57 
 
Fatal outcome ................................................................................................................ 57 
 
Serious adverse reaction (SAR) .................................................................................... 57 
 
Suspected unexpected serious adverse reaction (SUSAR) .......................................... 57 
 
Regulatory agency, independent Ethics Committee, and investigative site reporting .. 57 
9.10 
Data quality assurance ......................................................................................................... 58 
 
Quality assurance system ............................................................................................. 58 
 
Monitoring ...................................................................................................................... 58 
 
Documentation and data collection ............................................................................... 58 
 
Data management ......................................................................................................... 59 
 
Archival of documents ................................................................................................... 59 
9.11 
Statistical methods planned in the protocol and determination of sample size .................... 59 
 
Statistical and analytical plan ........................................................................................ 59 
10 
CHANGES IN THE CONDUCT OF THE CLINICAL TRIAL OR PLANNED ANALYSIS ................ 61 
11 
SAFETY STEERING COMMITTEE (SSC) .................................................................................... 61 
12 
REPORTS ...................................................................................................................................... 61 
12.1 
Clinical study report .............................................................................................................. 61 
12.2 
Additional reports .................................................................................................................. 62 
13 
REFERENCES ............................................................................................................................... 63 
ANNEX I INVESTIGATOR PROTOCOL ACKNOWLEDGMENT .......................................................... 64 
ANNEX II DEFINITION OF COVID-19 DISEASE IN THE STUDY ........................................................ 65 
3.1 
List of Tables 
Table 1 Study schedule Part A .............................................................................................................. 11 
Table 2 Study schedule Part B .............................................................................................................. 13 
Table 3 Detailed time and events .......................................................................................................... 15 
Table 4 Toxicity grading scale for local adverse events........................................................................ 52 
Table 5 Toxicity grading scale for physical observations and vascular disorders ................................ 53 
Table 6 Toxicity grading scale for systemic AEs ................................................................................... 54 
3.2 
List of Figures 
Figure 1 Overall study design ................................................................................................................ 29 
 

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4 
LIST OF ABBREVIATIONS 
 
ADEM 
Acute disseminated encephalomyelitis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AEFI 
Adverse Event Following Immunization 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase Level 
ALT 
Alanine amino transferase 
AST 
Aspartate amino transferase 
BP 
Blood pressure 
cm 
Centimeter 
CoV 
Coronavirus 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
DRM 
Data review meeting 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EDTA 
Ethylene Diamine Tetra-acetic Acid 
ELISA 
Enzyme-linked Immunosorbent Assay 
EliSpot 
Enzyme-linked Immunosorbent Spot 
ER 
Emergency room 
EU 
European Union 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FPFV 
First Participant First Visit 
GBS 
Guillain Barré Syndrome 
GCP 
Good Clinical Practice 
GCP-V 
Regulations on the implementation of Good Clinical Practice in the con-
duct of clinical trials on medicinal products for human use (GCP Ver-
ordnung) 
GeoCV 
Geometric coefficient of variation 
GeoM 
Geometric mean 
GGT 
gms 
Gamma-glutamyl transferase 
grams 
H 
Hour 
HBsAg 
HBV surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HD 
High Dose 

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HIV 
Human Immunodeficiency Virus 
i.m. 
Intramuscular 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
IU 
Infectious Units 
IMP 
Investigational Medicinal Product 
kg 
Kilogram 
LD 
Low Dose 
LDH 
Lactate dehydrogenase 
LPFV 
Last participant first visit 
LPLV 
LSB 
Last participant last visit 
Local Safety Board 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MDRD 
Creatinine clearance 
Mean 
Arithmetic mean 
Med 
Median 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome 
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
MVA 
Modified Vaccinia Virus Ankara 
N 
Number 
NIBSC 
National Institute for Biological Standards and Control 
NOAEL 
PBMC 
No Observed Adverse Event Level 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PD 
PFU 
Protocol deviation 
Plaque Forming Units 
PI 
Principal investigator 
PR 
Pulse rate 
PRNT 
PP 
Plaque Reduction Neutralization Test 
Per Protocol 
QAU 
UMR 
Quality Assurance Unit 
University Marburg 
RBC 
Red blood cells 
RNA 
Ribonucleic acid 
RKI 
Robert Koch-Institut 
rMVA 
Recombinant Modified Vaccinia Virus Ankara 

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SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SCR 
Screening 
SD 
Standard deviation 
SOP 
Standard Operating Procedure 
SPEAC 
Safety Platform for Emergency vACcines 
SUSAR 
Suspected unexpected Serious Adverse Reaction 
Th1 
T helper cell 1 
Th2 
T helper cell 2 
TMF 
Trial Master File 
VNT 
Virus Neutralization Test 
WBC 
White blood cells 
WHO 
World Health Organization 
WNL 
WOCBP 
Within normal limits 
Women of Childbearing Potential 

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5 
ETHICS AND LEGAL ASPECTS 
5.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
This study will be planned and performed in accordance with  
• 
The Declaration of Helsinki in its version of Fortaleza, 2013; 
• 
EU Directive 2001/20/EC; 
• 
EU Directive 2001/83/EC; 
• 
ICH Guideline Good Clinical Practice E6(R2), of 9 November 2016; 
• 
EMA Guideline on clinical evaluation of vaccines  
• 
EMA Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pan-
demic in its most current version 
• 
Ergänzende Empfehlungen des BfArM und des PEI zur Europäischen Guidance on the Man-
agement of Clinical Trials during the COVID-19 (Coronavirus) pandemic in its most current ver-
sion 
and other applicable laws. 
5.2 
Ethical conduct of the clinical trial  
The sponsor authorizes CTC North for all necessary applications. 
CTC North will submit all required documents according to local law to the responsible Ethics Commit-
tees (EC), as well as the Competent Authorities (CA) for approval. Approval by these authorities must 
be obtained prior to the start of the study in the respective study sites.  
Copies of the original submission and approval documents will be sent to the sponsor and will be in-
cluded in the Clinical Study Report (CSR). A list of the members of the EC will also be provided with the 
CSR. 
5.3 
Participant information and consent 
Before any study specific procedures can take place, an investigator will explain to the participants the 
nature, significance and implications of the clinical trial. He/she will explain all methods, rules of conduct, 
and any restrictions which may apply. Possible effects and side effects will be discussed. Participants 
will be informed that they are free to withdraw from the clinical trial at any time, without giving any reason 
for doing so. They must be able to understand the full implications of their decision.  
All participants will date and sign an informed consent form as evidence of consent. The investigator will 
also date and sign the informed consent form. The participant information sheet and the informed con-
sent form of each participant will be filed in the investigator site file (ISF). A copy of the dated and signed 
consent form and the information sheet will be handed to participant after signature and before enroll-
ment.  
If new information about the vaccine that could be relevant for the willingness to continue participation 
of the study becomes available the participant will be informed by an investigator. 
5.4 
Confidentiality 
The principal investigator (PI) at each study site must assure that participants’ anonymity will be strictly 
maintained and that their identities are protected from unauthorized parties. Only an identification code 
(i.e., consisting of an identification number, sex and year of birth) should be recorded on any form or 
biological sample submitted to the laboratory, sponsor, competent authority or EC. The PI must keep a 
participant identification log showing codes and names for all participants screened and for all partici-
pants enrolled in the trial.  
5.5 
Insurance 
The sponsor is responsible for the appropriate insurance coverage for the participants. 

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5.6 
Publication policy 
The sponsor has to publish the result of this study considering applicable requirements of the BMBF. It 
is at the discretion of the sponsor to lead the publication activities. The trial will be registered at clinical-
trials.gov. 
5.7 
Qualification of the investigator 
The PI and the deputy for each study site fulfill the requirements of applicable national law. Curriculum 
vitae of both will be filed in the trial master file (TMF). 
For conducting the clinical trial, the respective PI may delegate tasks to investigators (or other qualified 
staff). This is to be documented properly. The PI is responsible for the adequate training and supervision 
of all delegates. No clinical trial related procedure must be performed by personnel which is not properly 
trained and delegated. 
In the present document the mere term “investigator” refers to the PI or the deputy/deputies or investi-
gators. 

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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Sponsor 
University Medical Center Hamburg-Eppendorf 
Martinistr. 52 
20246 Hamburg, Germany 
 
Coordinating investigator 
Prof. Marylyn M. Addo, MD, PhD, MSc, DTM&H 
University Medical Center Hamburg-Eppendorf 
I. Department of Medicine 
Division of Infectious Diseases 
Martinistr. 52, 20246 Hamburg, Germany 
 
  
 
 
 
 
Medical monitor 
Dr. Olaf Degen 
University Medical Center Hamburg-Eppendorf 
MVZ Fachbereich Infektiologie 
Martinistr, 52,20246 Hamburg, Germany 
 
 
  
 
 
CRO 
CTC North GmbH & Co. KG 
at the University Medical Center Hamburg-Eppendorf  
Martinistr. 64, 20251 Hamburg, Germany 
 
Responsibilities 
Project management, regulatory submission, monitoring, data man-
agement, safety management 
 
Overall project lead 
Dr. Saskia Borregaard 
  
 
  
 
 
Project manager 
Laura Kaltenberg 
  
 
  
 
 
Statistics 
Prof. Dr. Antonia Zapf 
Institute of Medical Biometry and Epidemiology 
University Medical Center Hamburg-Eppendorf 
Martinistr. 52, 20246 Hamburg, Germany 
 
 
 
 
 
 
 

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7 
INTRODUCTION 
7.1 
Background information and rationale 
SARS-CoV 2 and the need for a SARS-CoV-2 Vaccine 
SARS-CoV-2 first emerged in December 2019 in Wuhan, China and quickly spread over the whole world 
with currently more than 213 million confirmed cases of primary infection leading to more than 4.4 million 
deaths in 192 countries [1]. The World Health Organization (WHO) declared the outbreak a “Public 
Health Emergency of International Concern” on 30th of January 2020 and, only 41 days later, on 11th of 
March, a pandemic [2]. 
Coronaviruses (CoV) are a large family of viruses that cause illness ranging from common cold to more 
severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory 
Syndrome (SARS). SARS-CoV-2 is the causative agent of coronavirus disease 2019 (COVID-19), which 
is an infectious respiratory disease. Typical symptoms can include fever, cough, fatigue, shortness of 
breath, loss of smell and taste and diarrhea [3]. While most cases only report mild symptoms or are 
even asymptomatic, a severe form of pneumonia including acute respiratory distress syndrome, multi-
organ failure, septic shock and blood clots can occur that can lead to death [4]. The overall infection 
fatality rate is currently estimated to be significantly lower compared to SARS and MERS. SARS-CoV-
2 is easily transmitted by human-to-human contact.  
MVA-SARS-2-ST represents a replication-deficient vector vaccine built on the recombinant Modified 
Vaccinia virus Ankara (MVA) platform. A first-in-human (FIH) trial (NCT04569383) with the a predeces-
sor vaccine candidate, MVA-SARS-2-S, which expresses a non-stabilized full-length spike (S) glycopro-
tein of SARS-CoV-2, started in Hamburg in October 2020 (University Medical Center Hamburg-Eppen-
dorf & CTC North GmbH & Co. KG) (see chapter 7.3). While the interim results of this study show that 
the vaccinations were well tolerated by subjects in both dose cohorts and no serious adverse events 
(SAEs) occurred, the immunogenicity analysis, however, showed that humoral immunity was lower than 
expected and, therefore, suboptimal. Vaccine candidates with pre-fusion-stabilized full-length spike gly-
coprotein of SARS-CoV-2 have recently shown remarkable efficacy while retaining a favourable safety 
profile, both in large phase III clinical trials as well as in real world scenarios [5, 6, 7]. 
The new vaccine candidate to be tested in this trial, MVA-SARS-2-ST, has been optimized to express a 
pre-fusion stabilized full-length spike (S) glycoprotein of SARS-CoV-2. Spike antigen is functionally im-
plicated in virus cell entry and the target of naturally occurring neutralizing antibodies to coronaviruses. 
Multiple lines of evidence support the choice of S glycoprotein as vaccine target as described in detail 
below. The MVA vector platform, due to its replication-deficiency, is considered a safe, well-tolerated 
and immunogenic vaccine platform capable of inducing a multimodal humoral and cell-based immuno-
logical antigen response. MVA in its dozens of different clinical stage explorations in thousands of pa-
tients has never been associated with vaccine-related serious adverse events. The licensed 
IMVAMUNE®/IMVANEX® smallpox vaccine product line by Bavarian Nordic is based upon this platform. 
7.2 
Preclinical results 
The experimental vaccine MVA-SARS-2-ST is currently being studied in mice and Syrian hamsters as 
outlined in the investigator’s brochure [8]. Animals were immunized using up-to-full-human-dose equiv-
alents (1 x 108 plaque forming units [PFU]) in a prime-boost vaccination scheme via the intramuscular 
route. MVA-SARS-2-ST was well tolerated and led to the production of S antigen-specific CD8+ T cells 
and neutralizing antibodies. 
Preclinical testing of the predecessor vaccine candidate MVA-SARS-2-S harboring the native SARS-
CoV-2 S antigen sequence was done in mice, ferrets and Syrian hamsters. A combined preclinical proof-
of-concept and safety study was performed in female BALB/c mice to obtain primary pharmacology and 
toxicology data for this construct. Animals were immunized in a prime-boost vaccination scheme using 
1 x 107 or 1 x 108 PFU MVA-SARS-2-S via the intramuscular route. No evidence for a potential toxicity 
of the full human dose of MVA-SARS-2-S was observed. The repeated vaccination was well tolerated 
and caused no adverse events. A No Observed Adverse Event Level (NOAEL) was established for 
MVA-SARS-2-S of repeat i.m. administration of 1 x 108 PFU. Furthermore, MVA-SARS-2-S was shown 
to elicit humoral and cellular immune responses against SARS-CoV-2 (data unpublished).  
Challenge experiments conducted with MVA-SARS-2-S in SARS-CoV-2 naturally susceptible hamsters 
and BALB/c mice transduced with the human ACE2 receptor demonstrated the protective capacity of 
MVA-SARS-2-ST. The knowledge gained from the experiments promise a benefit in respect to protec-
tion from COVID-19. 

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7.3 
Clinical studies 
The MVA platform is a promising vaccine platform, as multiple clinical trials against a variety of infectious 
diseases revealed a safe and immunogenic profile for MVA-based vaccines. Clinical trials showed the 
induction of multimodal humoral and cellular immune responses to the target antigen. More than 370 
clinical trials testing MVA were published in PubMed.  
From 2017 to 2019, a first-in-human trial (NCT03615911) with an MVA-MERS-S vaccine was performed 
in Hamburg (University Medical Center Hamburg-Eppendorf and CTC North GmbH & Co. KG) in 
23 healthy adults using the same prime-boost regime as in this trial. Immunizations with MVA-MERS-S 
revealed a benign safety profile with only transient mild-to-moderate reactogenicity. The safety profile 
was similar after prime and boost immunization. Participants experienced no severe or serious adverse 
events. Local reactions, headache and fatigue were the most common AEs. All AEs resolved swiftly and 
without sequelae. Following booster immunization, 87% of all vaccines and 100% of high-dose vaccine 
recipients showed seroconversion using an S1-ELISA. Antibody titers measured by ELISA correlated 
well with MERS-S-specific neutralizing antibodies. MERS-CoV-S-specific T-cell responses were de-
tected in 91% of all vaccine recipients. A dose-effect relationship was observed for reactogenicity but 
not for immunogenicity [9]. 
The first-in-human (FIH) trial (NCT04569383) with the predecessor vaccine candidate MVA-SARS-2-S 
included 30 healthy adults who were vaccinated with either a low dose (1 x 107  0.5 log IU; N=15) or a 
high dose (1 x 108  0.5 log IU; N=15) of the vaccine, using the same dosages and prime-boost regimen 
as in the MVA-MERS-S trial (days 0 and 28). The interim results of this study show that the vaccinations 
were well tolerated by subjects in both dose cohorts and no serious adverse events (SAEs) occurred. 
The majority of AEs were expected (local vaccine reactions, headache, fatigue/malaise, arthralgias, 
myalgias, gastrointestinal complaints, fever, and chills). Examinations of vital signs, temperature, and 
blood analyses including clinical chemistry and hematology (time points defined in the study protocol) 
also revealed no safety-relevant abnormalities.  
7.4 
Risk-benefit considerations 
The participation in a phase Ib study will not be of direct benefit to the participants. Known risks related 
to the pharmacological properties of the investigational compound and/or study modalities are possible. 
To our best knowledge and judgement and based on the data available to date, the vaccine appears to 
be safe and no severe side effects and no unacceptable adverse drug reactions (ADR) are expected 
with this study. The used MVA vaccine vector has been extensively studied in clinical trials for other 
infectious diseases encompassing >6500 individuals, including children, cancer patients and immuno-
compromised hosts. The vaccine vector has had an excellent safety profile and unexpected adverse 
reactions conferred by the antigenic insert are not anticipated. A phase I study testing MVA-MERS-S by 
the coordinating investigator did not show any SAE and preliminary data from an ongoing MVA-SARS-
2-S phase I clinical trial (NCT04569383) has only revealed mild to moderate adverse events in both 
dose groups. 
All relevant preclinical studies required for the start of clinical development have been conducted. Pre-
clinical data suggest a favorable safety and tolerability profile. Based on available information and the 
design of the study, the sponsor and the coordinating investigator consider the trial to be ethically ac-
ceptable. The duration of confinement, the medical surveillance and the chosen study design for the 
sequential dosing in all dose groups are considered adequate to ensure safety of the participants. Spe-
cial consideration was given to frequent safety assessments as mandated and recommended by the 
Regulatory Authorities. 
The selection of vaccine dose levels for this trial are based on preclinical data and data derived from 
previous clinical trials with the recombinant MVA vector technology. Vaccine dose levels of 1 x 107 IU 
and 1 x 108 IU have been found to be both safe and immunogenic. The rate of seroconversion was 
higher in the higher dose group in a previous small trial related to MVA-MERS-S. The current trial aims 
at contributing to dose finding for later phase clinical trials. 
The vaccine recipients may benefit from protection against SARS-CoV-2 during the current COVID-19 
pandemic. However, this trial is the first trial of MVA-SARS-2-ST in humans. Therefore, to date the risks-
benefit ratio remains unknown. Participants will be strongly advised to not consider themselves pro-
tected against SARS-CoV-2 after vaccination at this stage of vaccine development. 
Serious allergic reactions including anaphylaxis may occur and for this reason participants will be inoc-
ulated in a clinical area where advanced life support trained physicians, equipment and drugs are im-
mediately available for the management of any serious adverse reactions. Participants will be closely 

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monitored and evaluated for AEs for at least 1 h after administration of vaccine with appropriate medical 
treatment readily available in case of a rare anaphylactic reaction. 
In summary, preclinical and clinical data indicate a favorable safety and tolerability profile. So far, clinical 
trials with MVA vectors, including a phase 1 trial with MVA-SARS-2-S, have reported transient and 
spontaneously resolving adverse events and no serious adverse reactions. The duration of confinement 
and the medical surveillance are considered adequate to ensure maximal safety of the participants and 
have been established with guidance of the CA. Thus, considering the safety measures to minimize 
risks for study participants, the exposure of healthy participants with the MVA-SARS-2-ST vaccine is 
justified, since the potential risks and disadvantages for study participants are outweighed by the poten-
tial benefits for medical research, medical practice and eventually for individuals at risk of SARS-CoV-2 
infection. 
The total amount of blood collected from a participant will not exceed a maximum of 600 mL for partici-
pants of the Part A and 500mL for the participants in Part B over 7 months. These blood volumes should 
not endanger the otherwise healthy volunteers and do not exceed the volumes of voluntary blood dona-
tions. There may be slight bruising, local sensitivities, presyncopic symptoms associated with venipunc-
ture or phlebitis, which may later lead to superficial vein thrombosis. 
More detailed information about the known and expected benefits, risks and reasonably expected AEs 
of MVA-SARS-2-ST may be found in the IB [8]. 
Risk Assessment of conducting the clinical trial during the COVID-19 pandemic: 
The sponsor and coordinating investigator carefully reviewed the feasibility, risk and benefits of starting 
a new clinical trial during the ongoing pandemic. Given the fact that MVA-SARS-2-ST represents a 
vaccine for the current COVID-19 pandemic, there is an immediate necessity to continue the MVA-
SARS-2-ST vaccine development program. The safety of the trial participants is of primary importance, 
and all measures will be taken to minimize the risk to trial participants and prioritize trial participant safety 
and data validity. 
8 
STUDY OBJECTIVES 
8.1 
Primary objective 
Part A: 
This study is designed to evaluate the safety, tolerability and reactogenicity of two intramuscular dose 
administrations of three dose levels of the candidate MVA-SARS-2-ST vaccine in healthy SARS-CoV-2 
seronegative adults aged 18-64 years. 
Part B: 
This study is designed to evaluate the safety, tolerability and reactogenicity of one intramuscular dose 
administration of three dose levels of the candidate MVA-SARS-2-ST vaccine in healthy adults previ-
ously vaccinated against COVID-19 aged 18-64 years. 
 
Primary endpoints  
The nature, frequency and severity of adverse events associated with MVA-SARS-2-ST vaccine will be 
collected and measured as followed: 
• 
Occurrence of solicited local reactogenicity signs and symptoms for 7 days after vaccination. 
• 
Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days after vaccina-
tion. 
• 
Occurrence of unsolicited adverse events (AE) for 28 days after vaccination. 
• 
Change from baseline of safety laboratory measures.  
• 
Occurrence of serious adverse events (SAE) throughout the study period. 
 
8.2 
Secondary objectives 
Part A: 

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To evaluate SARS-CoV-2-S1 binding and SARS-CoV-2 neutralizing antibodies in healthy SARS-CoV-2 
seronegative adults induced by three dosage levels after two administrations of MVA-SARS-2-ST vac-
cine. 
Part B: 
To evaluate SARS-CoV-2-S1 binding and SARS-CoV-2 neutralizing antibodies in healthy adults previ-
ously vaccinated against COVID-19 induced by three dosage levels after one administration of MVA-
SARS-2-ST vaccine. 
 
Secondary endpoints 
Immunogenicity:  
• 
Humoral immunity: Amount of anti-SARS-CoV-2-S1-binding antibodies as measured by ELISA 
and detection of antibodies that neutralize SARS-CoV-2 (Part A & B). 
• 
Percentage of participants who seroconverted. The seroconversion measured by ELISA is de-
fined as the detection of SARS-CoV-2-S1-specific antibodies if the baseline value was negative, 
or as an increase in the antibody titer by a factor of 4 or more compared to the baseline value 
(Part A). 
• 
Percentage of participants who showed an increase of  the level of binding and neutralizing 
antibodies to baseline (Part B). 
8.3 
Exploratory objectives 
• 
To investigate Th1 and Th2 immune responses following vaccination. 
• 
To investigate antibody-dependent enhancement and vaccine-associated enhanced respira-
tory disease. 
• 
To identify and characterize cases of COVID-19. 
• 
To evaluate the rate of natural infection of SARS-CoV-2 during the clinical trial by monitoring 
antibodies against SARS-CoV-2 N protein. 
• 
To investigate sex differences in immunity to MVA-SARS-2-ST vaccination. 
• 
To investigate age-related immune responses to MVA-SARS-2-ST vaccination. 
• 
To examine vaccine-induced humoral immune responses and antibody functions, including 
vector-immunity, neutralizing and non-neutralizing antibody functions. 
• 
To evaluate MVA-SARS-2-ST-specific cellular immune responses after administration of MVA-
SARS-2-ST. 
• 
To evaluate MVA-SARS-2-ST-induced B- and T-cell memory responses. 
• 
To evaluate innate immune responses induced by MVA-SARS-2-ST. 
• 
To evaluate early innate immunity gene expression signatures induced by MVA-SARS-2-ST. 
• 
To evaluate pre-existing humoral and cellular immunity to coronaviruses. 
• 
To identify potential biomarkers and gene signatures of innate immune responses to MVA-
SARS-2-ST and their correlation to dose, reactogenicity, and immune response. 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall study design and plan-description  
This will be a phase Ib multi-center study in approximately 60 adults consisting of the following two parts:  
 
Part A  
24 healthy SARS-CoV-2 seronegative adults aged 18-64 years will receive: 
o 
≥ 1 x 107 IU MVA-SARS-2-ST (low dose, LD) (N= 8) or 
o 
≥ 5 x 107 IU MVA-SARS-2-ST (middle dose, MD) (N= 8) or 

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o 
≥ 1 x 108 IU MVA-SARS-2-ST (high dose, HD) (N= 8) 
Each participant will receive two single injections, 28 days apart (day 0 and 28). 
Part B  
36 healthy adults, previously vaccinated with a (conditionally) licensed mRNA vaccine aged 18-64 years 
will receive: 
o 
≥ 1 x 107 IU MVA-SARS-2-ST (low dose, LD) (N= 12) or 
o 
≥ 5 x 107 IU MVA-SARS-2-ST (middle dose, MD) (N= 12) or 
o 
≥ 1 x 108 IU MVA-SARS-2-ST (high dose, HD) (N= 12) or 
Each participant will receive one single injection (day 0). 
 
 
A schematic overview of study design is represented in the below  
Figure 1 Overall study design. 
 
 
  
 
Figure 1 Overall study design 
9.2 
Discussion of study design, including the choice of control groups  
In close coordination with the national Regulatory Authorities, the study design, including doses and 
schedule has been optimized to safely investigate the MVA-SARS-2-ST vaccine candidate. The study 
will be a phase Ib study in SARS-CoV-2 seronegative and fully with a (conditionally) licensed vaccine 
against COVID-19 vaccinated participants. In this phase Ib trial the primary focus will be on safety, 
tolerability and reactogenicity.  

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9.3 
Selection of study population 
In total, 60 male and female adults will be enrolled in this clinical trial. Participants will be recruited from 
the study centers’ pool and public advertisement. Eligible participants will be allocated to one of the 
three dose cohorts [Parts A and B]. 
Homogeneous sex distribution of no less than 25% of one sex is targeted. 
 Inclusion criteria 
The participant must not be enrolled before all inclusion criteria (including test results) are confirmed.  
1. Ability to understand the participant information and to personally name, sign and date the in-
formed consent to participate in the study. 
2. Provided written informed consent. 
3. Healthy male and female adults aged 18 – 64 at time of informed consent. 
4. Chronic medical condition should be stable for the last 8 weeks (no hospitalization, no emer-
gency room, no need for supplemental oxygen).  
5. Participant may be on chronic or as needed medications if, in the opinion of the investigator 
they pose no additional risk to participant safety or assessment of reactogenicity and immuno-
genicity and do not indicate worsening of medical condition.  
6. Body weight is defined in relation to height. Body mass index 18.5 – 32.0 kg/m2 and weight 
> 50 kg at screening. 
7. Non-pregnant, non-lactating female with a negative pregnancy test at screening and on dosing 
days (prior to vaccination). 
8. Females of child-bearing potential who agree to comply with the applicable contraceptive re-
quirements of the protocol (section 9.3.3) from at least 14 days prior to vaccination until day 56 
or females who are permanently sterilized (at least 6 weeks post-sterilization). 
9. The participant is co-operative and available for the entire study. 
10. Part B: ≥ 6 months fully vaccinated with a (conditionally) licensed mRNA vaccine against 
COVID-19. 
 
 Exclusion criteria 
Participants are excluded from the study if any of the following criteria are met at screening and/or on 
dosing days: 
1. Receipt of any vaccine from 4 weeks prior to each trial vaccination (8 weeks for live vaccines) 
to 6 weeks after each trial vaccination. 
2. Prior rMVA immunization. 
3. Previous immunization with investigational vaccine against COVID-19. 
4. Part A: Previous immunization with EU/conditionally licensed vaccine against COVID-19. 
5. Evidence of an active SARS-CoV-2 infection (positive SARS-CoV-2 antigen test followed by a 
confirmatory positive PCR test).  
6. Prior history of SARS-CoV-2 infection (documented by positive PCR test) according to medical 
history and/or antibody test (Part A only) at screening. 
7. Known allergy to the components of the MVA-SARS-2-ST vaccine product or history of life-
threatening reactions to vaccine containing the same substances. 
8. Known history of anaphylaxis to vaccination or any allergy likely to be exacerbated by any com-
ponent of the trial vaccines. 
9. Participation in a clinical trial or use of an investigational product within 30 days or five times the 
half-life of the investigational product - whichever is longer - prior to receiving the first dose 
within this study. 

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10. Evidence in the participant's medical history or in the medical examination that might influence 
either the safety of the participant or the absorption, distribution, metabolism or excretion of the 
investigational products.  
11. Clinically relevant findings in ECG or significant thromboembolic events in medical history. 
12. Any positive result for HIV1/2, HCV antibody or HBs antigen testing. 
13. Any confirmed or suspected immunosuppressive or immunodeficient condition, cytotoxic ther-
apy in the previous 5 years, and/or uncontrolled diabetes (HbA1c > 7.0). 
14. Participants with inflammatory, infectious and neuroinflammatory underlying disease which 
could cause an expected impairment of the blood brain barrier such as meningitis, multiple scle-
rosis, epilepsy, or Alzheimer’s disease. 
15. Any known chronic or active neurologic disorder, including seizures and epilepsy, excluding a 
single febrile seizure as a child. 
16. Known history of Guillain-Barré Syndrome. 
17. Active malignancy or history of metastatic or hematologic malignancy. 
18. Suspected or known severe alcohol or illicit drug abuse within the past 5 years.  
19. Moderate or severe illness and/or fever >38 °C within 1 week prior to vaccination. 
20. Administration of immunoglobulins and/or any blood products within the 120 days preceding 
study entry or planned administration during the study period. 
21. History of blood donation within 60 days of enrollment or plans to donate within the study. 
22. Receipt of chronic (defined as more than 14 days) immune suppressants or other immune-mod-
ifying drugs within 6 months of screening. 
• 
For corticosteroids, this will mean prednisone, or equivalent, greater than or equal 
to 0.5 mg/kg/day. 
• 
Intranasal and inhaled steroids are allowed. Topical steroids are permitted provided they 
are not required to be applied to injection site. 
23. Participants with skin lesions close to the injection site will be excluded. 
24. Thrombocytopenia, contraindicating intramuscular vaccination based on investigator's judg-
ment. 
25. Participants with a significant infection or known inflammation. 
26. Participants who are known or suspected not to comply with the study directives. 
27. Any other significant finding or underlying medical condition, that in the opinion of the investiga-
tor, would increase the risk of the individual having an adverse outcome from participating in 
this study. 
28. Investigator or employee of the study site or sponsor with direct involvement in the proposed 
study, or identified as an immediate family member (i.e., parent, natural or adopted child) of the 
investigator or employee with direct involvement in the proposed study. 
 Reproductive potential 
The study population includes women of childbearing potential (WOCBP). WOCBP have to agree to 
comply with the applicable contraceptive requirements of the protocol as named below for the duration 
of the study. This does not apply for females who are permanently sterilized (at least 6 weeks post-
sterilization) or are post-menopausal. Post-menopausal is defined as no menses for 12 months without 
alternative medical cause and ≥ 47 years. 
Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year 
when used consistently and correctly and when applicable, in accordance with the product label, for 
example: 
• 
Oral contraceptives, either combined or progesterone alone; 
• 
Injectable progesterone;  
• 
Implants of etonogestrel or levonorgestrel; 

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• 
Estrogen vaginal ring;  
• 
Percutaneous contraceptive patches;  
• 
Intrauterine device or intrauterine system;  
• 
Male partner sterilization at least 6 months prior to the female participant’s entry into the study, 
and a monogamous relationship; 
• 
Male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository); 
• 
Male condom combined with a female diaphragm, either with or without a vaginal spermicide 
(foam, gel, film, cream, or suppository); 
• 
Sexual abstinence (from at least 14 days prior first vaccination until end of study): acceptable 
only if it is the participant’s preferred and usual form of birth control/lifestyle choice; 
• 
Bilateral tubal occlusionVasectomised partner; 
Condoms are to be used with the mentioned acceptable contraceptives.  
Not applicable for females with exclusively same-sex sex partners. 
 
Removal of participants from vaccination or assessment  
The study in its entirety may be discontinued prematurely by the sponsor at any time (see below) for 
safety reasons. Individual participants may terminate their participation prematurely, or have their par-
ticipation be terminated by the investigator. 
Participants in Part A will not receive the second immunization if: 
• 
A clinically significant acute illness occurs before vaccination. Minor illnesses (e.g. diarrhea or 
mild upper respiratory tract infection) do not affect second immunization; 
• 
Fever (body temperature ≥ 38.0°C) within 24 hours prior to the planned time of vaccination; 
• 
Allergic/anaphylactic reaction after the 1st vaccination considered as related to the trial vaccine; 
• 
SARS-CoV-2 infection during day 0 to 28*; 
In case any of the events occur before the first immunization, immunization may be postponed provided 
the screening window will not be exceeded. 
* in case participant does not receive day 28 vaccination, no ambulatory visits on day 29 and day 35 will 
take place 
9.3.4.1 
Withdrawal of participants from the clinical trial 
The circumstances that may lead to discontinuation of the study by an individual participant who will 
then be recorded as a drop-out include, but are not limited to, the following: 
• 
Withdrawal for personal reasons; 
• 
Circumstances in which the health of the participant would be endangered upon continued par-
ticipation in the study; 
• 
Participant non-compliance with study requirements; 
• 
An AE, which requires discontinuation of the study involvement or results in inability to continue 
to comply with study procedures; 
• 
Significant protocol violation; 
• 
Lost-to follow-up; 
• 
Pregnancy; 
• 
Other (must be specified). 
The reason for withdrawal will be recorded in the electronic case report form (eCRF). If withdrawal is 
due to an AE, appropriate follow-up visits or medical care will be arranged, with the agreement of the 
participant, until the AE has resolved, stabilized or a non-trial related causality has been assigned. The 
SSC may also recommend withdrawal of participants.  

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At least 3 documented attempts must be made within 2 weeks to contact any participant lost to follow-up 
at any time point prior to the last scheduled office visit. One of the documented attempts must include a 
written communication (e.g. post mail, courier) with acknowledgement of receipt requested (e.g. certified 
mail, registered mail) sent to the participant’s last known address, requesting that they return any re-
quired material (e.g. diary) and return to the study site for final safety evaluations. 
9.3.4.2 Handling of participants with premature study discontinuation 
In the absence of a medical contraindication or significant protocol violation, every effort will be made 
by the investigator to keep the participant in the study (if participant received at least one vaccination). 
If a participant has to be withdrawn, all efforts will be made to complete and report the trial observations 
as thoroughly as possible. If a participant needs to be withdrawn, all efforts shall be made to follow 
safety of the participant as per protocol.  
Participants who withdraw or are withdrawn from the study prior to the first injection (Part A and B) or 
participants who received the first vaccination but are withdrawn without medical reasons before the 
second vaccination will be replaced (Part A). An early termination visit will be performed for all drop-outs 
who received at least one vaccination. This visit may be a phone visit. 
When a participant withdraws from the study after the first vaccination and before the planned end of 
the study period, all investigations scheduled for the end-of-study visit should be performed if the par-
ticipant agrees. End-of-study evaluation will be completed at the time of the participant’s withdrawal, 
with an explanation of the reason for this entered onto the respective “end-of-study” section of the eCRF 
as follows: 
• 
Adverse event (specify); 
• 
Death (specify); 
• 
Protocol violation (specify); 
• 
Medical condition (specify); 
• 
Consent withdrawal, not due to AE; 
• 
Lost to follow-up; 
• 
Other (specify). 
9.3.4.2.1 
Replacement of participants 
In case a participant will be replaced, the replacement participant will be assigned to the participant 
number as described in section 9.4.7.2. In the phase Ib the replacement participant will be assigned to 
the same treatment sequence as the participant he/she replaces.  
9.3.4.3 Criteria for termination of the study (holding rules) 
Safety holding rules will apply throughout the entire study period. Should a holding rule be activated, the 
investigator will inform the medical monitor and the sponsor. Study evaluation will be discussed with the 
SSC. The sponsor has to inform the CAs and the EC within the timelines defined by national law. 
If the event(s) occur, the follow-up phase will continue. The discontinuation of a holding rule should be 
communicated to all entities in the same manner and timeframe as described above.  
The SSC safety review will consider:  
• 
The relationship of the AE to the IMP; 
• 
The relationship of the AE to the IMP dose, or other possible causes of the event; 
• 
If appropriate, additional screening or laboratory testing for other participants to identify those 
who may develop similar symptoms will be discussed. 
All vaccines will be followed for safety until resolution or stabilization (if determined to be chronic seque-
lae) of their AE. For further details on AE grading please refer to 9.8. 
The holding rules are as follows: 
• Solicited (expected) local adverse events: 

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o 
If more than 2 injections in at least 2 participants are followed by Grade 3 solicited 
swelling or pain or Grade 4 redness beginning within 3 days after injection and persist-
ing at Grade 3 (swelling or pain)/4 (redness) for > 48 hours 
• Solicited (expected) systemic adverse events:  
o 
If more than 2 injections in at least 2 participants are followed by Grade 3 solicited sys-
temic AE (or Grade ≥ 3 physical observations) beginning within 3 days after study in-
jection and persisting at Grade ≥ 3 for >48 hours 
• Unsolicited (unexpected) adverse events: 
o 
If more than 2 individuals develop a Grade ≥ 3 unsolicited AE (including laboratory AE 
and physical observations) that is considered probably or definitely related to injection 
and persists at Grade 3 for > 48 hours 
• Any treatment related SAE 
• A suspected unexpected serious adverse drug reaction (SUSAR) occurs that is life-threatening or 
results in death 
Or 
The sponsor may terminate the trial at any time or a Regulatory Authority may request the termination. 
In the case of study termination, investigators will be informed of the procedures to be followed to ensure 
adequate consideration is given to the protection of the participants’ safety. 
In case any holding or stopping rules apply, the sponsor needs to be informed within 24 hours. The 
sponsor has to inform the CAs and the EC within 15 days. 
9.4 
Treatments 
 
Treatments administered 
Part A 
All eligible participants will be assigned to one of the dose cohorts (low dose, middle dose or high dose) 
according to the assignment list. Each participant will receive two vaccine injections administered as 
i.m. injections in the deltoid region of the upper arm muscle preferably of the non-dominant arm.  
Part B 
All eligible participants will be assigned to one of the dose cohorts (low dose, middle dose or high dose) 
according to the assignment list. Each participant will receive one vaccine injection administered as i.m. 
injection in the deltoid region of the upper arm muscle preferably of the non-dominant arm.  
In case injection in the deltoid region of the upper arm muscle is not possible (e.g. due to medical or 
other contraindication), an alternative location can be used.   
For safety reasons dose administration in each dose level of both Parts will be performed in at least 
three groups. Dose administration for the first participant at each dose levels will occur 24 hours prior to 
the next 3 participants. Dose administration for the three participants of the second group at each dose 
levels will occur 24 hours prior to the other participants of this dose level. 
 
 
 
 
 
 
 
 
   Part A  
 
 
 
Part B 
 
01
24h
02
03
24h
05
06
04
07
08
09
10
11
12

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Vaccination in the next dose level can start 48 hours after all participants of the previous dose level of 
the respective Part received their 1st vaccination. 
Dosing events are supervised by an investigator. 
 
 
Identity of investigational medicinal products 
Test-IMP:  
Name: 
 
 
MVA-SARS-2-ST 
Dosage form: 
 
Suspension for injection 
Active substances:  
MVA-SARS-2-ST 
Route: 
 
 
i.m. injections 
Manufacturer: 
 
IDT Biologika GmbH, Dessau  
 
Additional information can be found in the investigator’s Brochure [8].  
An investigator or a delegated member of the study team will administer the IMP.  
9.4.2.1 Packaging & labeling 
IDT Biologika GmbH, Dessau, will supply the MVA-SARS-2-ST for the study. MVA-SARS-2-ST is la-
beled in accordance with the applicable laws and GCP guidelines.  
9.4.2.2 Storage 
The PI at each study site has the responsibility for ensuring that study medication is stored under ap-
propriate conditions in a secure, limited-access location. Study medication is distributed by the phar-
macy or by a nominated member of the unblinded study team. 
MVA-SARS-2-ST must be stored in accordance with labeled storage conditions according to the phar-
macy manual. Temperature monitoring is required at the storage location to ensure that the study med-
ication is maintained within an established temperature range.  
The PI is responsible for ensuring that the temperature is monitored throughout the total duration of the 
clinical trial and that records are maintained; the temperature must be monitored continuously such that 
at least minimum and maximum temperatures over a specific time period can be recorded and retrieved 
as required. 
The sponsor has to be informed by the clinical trial site of any excursion from the established range as 
soon as the PI becomes aware of an excursion. The sponsor has then to confirm the stability of the 
vaccine before further use. Relevant temperature excursions will require site investigation as to cause 
and remediation. The sponsor will determine the ultimate impact of excursions on the vaccine and will 
provide supportive documentation as necessary. 
9.4.2.3 Shipment 
The vaccine will be provided by IDT on behalf of the sponsor in sufficient quantity to the study sites. 
9.4.2.4 Drug accountability 
The PI at each study site has the overall responsibility for administering the IMP. The IMP must be 
administered in the manner specified in the study protocol and the pharmacy manual. 
The investigator or a designee at the study sites will acknowledge receipt of the study medication doc-
umenting shipment content and condition. Damaged supplies will be replaced. Accurate records of all 
study medication received, dispensed, used, returned or destroyed must be maintained. No study med-
ication may be destroyed or returned from the investigational site without prior knowledge and written 
consent by the sponsor. If such transfer is authorized by the sponsor, all applicable local, state and 
national laws must be adhered to for the transfer. 
All administrations will be documented in the site’s drug accountability log or other study drug record. 
The PI is responsible for assuring the retrieval of all dispensed study supplies from participants. 

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The sponsor or its representatives must be permitted access to review the supplies storage and distri-
bution procedures and records. 
As instructed by the sponsor all unused stocks and empty used boxes are sent to a nominated contractor 
or will be destroyed at the study site on behalf of the sponsor. Study medication being returned or de-
stroyed must be counted and verified by PI or a designee. All certificates of delivery/drug receipts should 
be signed by the site representative to confirm contents of shipment. Shipment return forms must be 
signed prior to shipment by the study site. The sponsor must give authorization to return or destroy any 
study medication prior to shipment or destruction. Shipment of all returned study medication must com-
ply with local, state, and national laws. 
Based on the entries in the site drug accountability logs, it must be possible to reconcile study medication 
delivered with those used and returned. One hundred percent of the study medication must be ac-
counted for and all discrepancies investigated and documented. 
 
Method of assigning participants to treatment groups 
Participants willing and eligible to participate in this study will be assigned to a dose cohort according to 
the assignment list. Assignment to the 2nd dose cohort will start after all participants for the 1st dose 
cohort are enrolled and assignment to the 3rd dose cohort will start after all participants for the 2nd dose 
cohort are enrolled.  
 
Selection of doses in the study 
The doses selected in this study represent dose levels with optimal immunogenicity and safety profile 
as observed in prior clinical trials using MVA-vector-based vaccines. 
 
Blinding and unblinding  
As this is an open-label study, no blinding procedures are necessary. 
 
Prior and concomitant therapy 
As outlined in Table 1 and Table 2Fehler! Verweisquelle konnte nicht gefunden werden. participants 
will be asked about concomitant use of medication.  
All other concomitant therapies and change on pre-existing therapies must be recorded if administered 
in conjunction with an adverse event. 
Prestudy therapies administered up to 30 days before the first dose of study vaccine must be recorded 
at screening. 
Concomitant medication with a possible impact on study results such as corticosteroids, antihistamines, 
and vaccinations must not be used from first vaccination until day 56. Otherwise this has to be discussed 
with the PI, so that a decision about the further participation of the participant can be made.  
For symptomatic management of flu-like symptoms/solicited AEs, the use of anti-pyretic drugs (e.g. 
paracetamol/ibuprofen) in the recommended daily dose is permitted. 
Vaccination with a (conditionally) licensed COVID-19 vaccine is permitted 6 weeks or later after the 2nd 
immunization. 
 
Treatment compliance  
9.4.7.1 Admission to the clinical trial 
Admission to the study will be effective upon the participant's arrival at the study ward. A participant will 
only be admitted to the study if the Informed Consent Form has been signed and all inclusion and none 
of the exclusion criteria are met. Should there be any doubts as to the state of health, a participant will 
not be admitted to the study.  
Participants who fail to make themselves available upon commencement of the study or who cannot 
participate for personal reasons will be considered as not admitted to the study. They will be replaced 
by back-up participants who will be screened in surplus. 
9.4.7.2 Participant identification 
The PI of each site will keep a record relating the patient numbers and the names of all participants that 
have given their informed consent, to allow easy checking of data in patient files, when required. This 

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record will also include the date of the participant`s enrollment and completion, as well as participant 
who could not be included in the study for whatever reason.  
Ascending screening numbers are to be assigned sequentially to all participants as they consent to take 
part in the study. The screening number will be a 4-digit number starting at 0001 following the site num-
ber (e.g. 01-0001).  
The participant number is assigned to participants when they are enrolled into the study in order of 
appearance of the participants. This will be a 4-digit number starting at 1001 following the site number 
(e.g. 01-1001) for subjects in Part A and a 4-digit number starting at 5001 following the site number (e.g. 
01-5001).  
For screening failures, the screening number will be the identifying number used throughout the docu-
mentation.  
For the Phase Ib participants who will replace a participant e.g. a withdrawn participant, will receive a 
screening number according to the above described scheme. In difference to the described participant 
number assignment, replacement participant will receive a 4-digit participant number which will consist 
of the old participant number (of the subject which should be replaced) plus 1000. 
Participants who replace a participant will receive a screening number according to the above described 
scheme.  
For the phase Ib allocation to a certain participant number will be done in successive order following 
screening and based on the participants’ availability. Enrollment to Part A and Part B will be in parallel. 
9.4.7.3 Screening, confinement and regular visits  
9.4.7.3.1 Screening (day -28 to day -1) Part A and B 
On the screening visit the following events will be performed: 
• 
Informed consent 
• 
Inclusion/exclusion criteria 
• 
Medical history/ demographics 
• 
Physical examination 
• 
Height and weight 
• 
Vital signs 
• 
12-lead ECG  
• 
Temperature 
• 
Safety laboratory blood (clinical chemistry, hematology) 
• 
Urine pregnancy test 
• 
Urine drug screen 
• 
Safety urinalysis 
• 
HIV/HBV/HCV serology 
• 
COVID-19 antigen test (If COVID-19 antigen test was performed within 4 hours before the 
screening visit and if the test result is suitable to be used as source data for the clinical trial, e.g. 
a test done by the study site as part of the hygiene concept, the test does not need to be re-
peated at screening and the available test results can be used.) 
• 
PCR for SARS-CoV-2 (only if required) 
• 
SARS-CoV-2 antibody test (Part A only) 
9.4.7.3.2 Pre-vaccination visit (day -1*) Part A and B 
• 
Safety laboratory blood (clinical chemistry, hematology)  
• 
Serum pregnancy test 

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• 
Safety urinalysis 
*only applicable if screening visit is between day -28 and day -2, last antigen test to be performed 
within 2 days before the first vaccination. 
9.4.7.3.3 Vaccination visits (day 0 and 28) Part A 
• 
Update of inclusion/exclusion criteria (day 0 only) 
• 
Update of medical history (day 0 only)  
• 
Physical examination (symptom-targeted) 
• 
Vaccination 
• 
Training & dispensing of diary (day 0 only) 
• 
Review & collection diary (day 28 only) 
• 
COVID-19 antigen test  
• 
PCR for SARS-CoV-2 (only if required) 
• 
Urine drug screen 
• 
Safety laboratory blood (clinical chemistry, hematology) (day 28 only) 
• 
Serum pregnancy test (day 28 only) 
• 
Safety urinalysis (day 28 only) 
• 
Humoral responses 
• 
RNA blood sample  
• 
PBMC freezing and plasma aliquots  
Before drug administration and one hour after dosing the following events will be performed at 0 and 
1 h (±15 minutes). 
• 
Vital signs (at 0 h before dose administration, and at 1 h [±15 minutes] ) 
• 
Temperature (at 0 h before dose administration, and at 1 h [±15 minutes]) 
• 
Adverse events/ concomitant medication (at 1 h ±15 minutes after first dose administration and 
at 0 h before dose administration and 1 h ±15 minutes after dose administration on day 28) 
• 
Injection site/ systemic events/reactions assessment (within 5 minutes and at 1 h ±15 minutes 
after dose administration). 
9.4.7.3.4 Regular ambulatory visits Part A 
Participants will return to the study ward for regular ambulatory visits on study day 1, 3, 7 (±1), 14 (±3), 
29, 35 (±1), 42 (±3), 56 (±7) and 84 (±7).  
 
On the ambulatory visits the following events will be performed: 
• 
Temperature  
• 
Vital signs  
• 
Injection site & systemic events/reactions assessment  
• 
Review & collection diary: only on day 1, 3, 7 (±1), 14 (±3), 29, 35 (±1), 42 (±3), and 56 (±7)  
• 
Adverse events & concomitant medication assessment  
• 
COVID-19 antigen test (only if required) 
• 
PCR for SARS-CoV-2 (only if required) 
• 
Safety lab blood (clinical chemistry, hematology) only on day 1, 3, 7 (±1), 29, 35 (±1), 42 (±3), 
56 (±7) and 84 (±7) 

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• 
Humoral responses only on day 7 (±1), 14 (±3), 35 (±1), 42 (±3), 56 (±7) and 84 (±7) 
• 
RNA blood sample only on day 1, 3, 7 (±1), 29 and 35 (±1) 
• 
PBMC freezing and plasma aliquots  
9.4.7.3.5 Vaccination visit (day 0) Part B 
• 
Update of inclusion/exclusion criteria  
• 
Update of medical history  
• 
Physical examination (symptom-targeted) 
• 
Vaccination 
• 
Training & dispensing of diary  
• 
COVID-19 antigen test  
• 
PCR for SARS-CoV-2 (only if required) 
• 
Urine drug screen 
• 
Humoral responses 
• 
RNA blood sample  
• 
PBMC freezing and plasma aliquots  
Before drug administration and one hour after dosing the following events will be performed at 0 and 
1 h (±15 minutes). 
• 
Vital signs (at 0 h before dose administration, and at 1 h [±15 minutes]) 
• 
Temperature (at 0 h before dose administration, and at 1 h [±15 minutes]) 
• 
Adverse events/ concomitant medication (at 1 h ±15 minutes after first dose administration and 
at 0 h before dose administration  
• 
Injection site/ systemic events/reactions assessment (within 5 minutes after and at 1 h ±15 
minutes after dose administration). 
9.4.7.3.6 Regular ambulatory visits Part B 
Participants will return to the study ward for regular ambulatory visits on study day 1, 3, 7 (±1), 14 (±3), 
28 (±2), and 56 (±7).  
 
On the ambulatory visits the following events will be performed: 
• 
Temperature (only on day 1,3, 7 (±1) and 14 (±3)) 
• 
Vital signs (only on day 1,3, 7 (±1), and 14(±3)) 
• 
Injection site & systemic events/reactions assessment (only on day 1, 3, 7 (±1), and 14(±3)) 
• 
Review & collection diary: only on day 1, 3, 7 (±1), 14 (±3), 28 (±2) 
• 
Adverse events & concomitant medication assessment  
• 
COVID-19 antigen test (only if required) 
• 
PCR for SARS-CoV-2 (only if required) 
• 
Safety lab blood (clinical chemistry, hematology) (only on day 1,3 and 7 (±1)) 
• 
Humoral responses only on day 7 (±1), 14 (±3), 28 (±2), and 56 (±7) 
• 
RNA blood sample only on day 1, 3 and 7 (±1) 
• 
PBMC freezing and plasma aliquots  
 

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9.4.7.3.7 End of study / early termination visit Part A and B 
An end-of-study follow-up visit will be performed on day 168 (±14) or upon early termination. The follow-
ing events will be performed:  
• 
Physical examination 
• 
Weight 
• 
Vital signs 
• 
Injection site & systemic events/ reactions assessment  
• 
Temperature 
• 
COVID-19 antigen test (as required) 
• 
PCR for SARS-CoV-2 (only if required) 
• 
Adverse events & concomitant medication assessment 
• 
Safety lab blood (clinical chemistry, hematology) 
• 
Safety urinalysis 
• 
Urine pregnancy test 
• 
Humoral responses 
• 
PBMC freezing and plasma aliquots  
9.4.7.4  Unscheduled visit 
Unscheduled visits may be performed at any time during the study. Depending on the reason for the 
unscheduled visit (e.g. AE, abnormal laboratory values), appropriate assessments will be performed 
based on the judgment of the investigator. Results of the assessment and any changes in concomitant 
treatment will be recorded in the eCRF. Specifically, to assess for antibody dependent enhancement 
and vaccine-associated enhanced respiratory disease, unscheduled visits should occur in the case of 
SARS-CoV-2 infection or vaccination against COVID-19 with a vaccine as standard-of-care outside the 
study. After an unscheduled visit, the regular scheduled study visits must continue according to the 
planned visit and assessment schedule. 
9.4.7.5 Early termination 
All enrolled participants who complete the study or discontinue early from the study will have the follow-
up assessments and procedures completed for their safety as outlined in Table 1 and Table 2. Partici-
pants who discontinue early or withdraw from the phase Ib study will be replaced as outlined in section 
9.4.7.2. 
In some cases, it may be necessary for participants to return to the study ward for additional care, 
confinement, and/or follow-up. Circumstances in which this may be necessary are:  
• 
Follow-up on abnormal laboratory evaluations 
• 
Follow-up on an ongoing AE at the final visit 
All additional safety follow-up visits will be at the discretion of the PI/deputy and the sponsor. 
9.4.7.6 End of trial 
A participant is considered to have completed the study if he/she has completed the last follow-up visit 
(end of study visit). Last participant last visit is defined as end of trial. 
9.5 
Protocol deviations (PD) 
All PDs will be tracked and actions will be defined, as feasible. All PDs classified as major will be re-
viewed in Data Review Meetings for the interim analysis and the final analysis for assessment of their 
influence on the quality of the study analysis. Classification of PDs by the study site will be reviewed 
before the Data Review Meeting by the sponsor. 
Protocol deviations due to COVID-19 will be tracked and reported together with the other protocol devi-
ations in the CSR.   

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Major PD are defined as follows: 
• 
Informed consent procedure: ICF not signed and dated by participant/investigator 
• 
Violation of an in- or exclusion criterion 
• 
Incorrect use of vaccine (storage, preparation and administration) 
• 
Use of forbidden concomitant medication 
• 
Delayed reporting of serious adverse events 
• 
Unauthorized unblinding 
• 
Other deviations which might compromise the quality of the study analysis  
9.6 
Methods and timing of safety measurement  
Details regarding scheduled assessments and procedures to be conducted in this study are provided 
below. For detailed assessment of schedules refer to Table 1, Table 2, and Table 3. 
All relevant laboratories involved in this trial are accredited for the assays performed and copies of the 
accreditation certificates are to be filed in the TMF. Continuous compliance with legal requirements 
throughout the trial will be assured. 
9.7 
Appropriateness of measurements 
 Screening procedures 
Written, signed, and dated informed consent from the participant prior to the performance of any study 
related procedures must be obtained by an investigator. Participants will first have ample time to read 
the participant information before an investigator will start the information and informed consent process. 
The participant information/informed consent process will be performed according to the study site’s 
processes.  
A copy of the signed informed consent form must be given to the participants for their records. 
Screening procedures must be completed between 28 days and 1 day prior to receiving the first dose 
of study medication. See section 9.4.7.3.1 for a complete list of screening procedures to be performed. 
Re-checks may be performed for individual events as long as they are within the screening window.  
Only an authorized and trained investigator may decide on the eligibility of the participant. 
9.7.1.1 
Screening failure  
A screening failure is defined as a participant who has given informed consent and failed to meet at 
least one inclusion criterion or met at least one exclusion criterion or has not been enrolled. Enrollment 
is defined as first vaccination received. 
Eligible participants who meet all inclusion criteria and no exclusion criterion but are unable to participate 
in the study due to scheduling conflicts will not be considered screening failures. 
9.7.1.2 
Re-screening of participants 
Screening failures will not be enrolled into the study or vaccinated but may be re-screened based on 
investigator’s discretion and sponsor’s approval. In these cases, a new screening number must be as-
signed for each participant to be re-screened and a new informed consent form must be signed to con-
firm consent for study participation. 
 Study examinations 
Assessments are to be performed according to the schedule shown in Table 1 and Table 2 and depend 
on timepoint of vaccination. 
9.7.2.1 
Safety 
Safety will be evaluated by collecting reported adverse events at regular intervals throughout the study 
and by the assessment of physical examination findings, vital signs, and clinical laboratory parameters.  

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9.7.2.2 
Medical and medication history 
A complete medical and medication history as well as demographic information will be assessed at the 
time points indicated in Table 1 and Table 2. 
The medical history will be reviewed and recorded, including: 
Medical and Medication History 
• 
Recent ingestion of medication (30 days prior to entering the screening period) 
• 
History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, hematological, 
neurological, psychiatric, musculoskeletal and other diseases. 
Demographic information 
• 
Year of birth 
• 
Sex 
9.7.2.3 Physical examination  
A complete physical examination will be performed at the timepoints described in Table 1 and Table 2. 
The physical examination will include a review of the following body systems:  
• 
General appearance 
• 
Skin 
• 
Head, eyes, ears, nose and throat  
• 
Spine/Neck/Thyroid 
• 
Musculoskeletal 
• 
Respiratory 
• 
Cardiovascular 
• 
Neurological 
• 
Abdomen (including liver and kidneys). 
Any abnormalities or changes in intensity from the screening visit noted during the review of body sys-
tems have to be documented in the source documents. Clinically significant abnormal findings discov-
ered during a physical examination after screening will be documented either as part of medical history 
(participant forgot to mention an intermittent medical condition at screening) or documented as an ad-
verse event or part of an adverse event (up from the time after dose administration), if the discovered 
symptom is leading to a diagnosis. 
9.7.2.4 Electrocardiogram 
A 12-lead ECG will be performed at the timepoints described in Table 1 and Table 2. Actual ECG as-
sessment times will be documented. 
Participants must be resting in a supine position for at least 5 minutes prior to performing the ECG. At a 
minimum, the date and time of when the event was performed, the investigator’s assessment and the 
heart rate, RR, PR, QT, and QRS intervals are to be collected. All clinically significant abnormalities will 
be recorded on the appropriate source documents. 
9.7.2.5 Vital signs 
Blood pressure should be determined by cuff (using the same method and in the same position through-
out the study). Measurements of vital signs (systolic and diastolic blood pressure as well as pulse rate) 
will be performed after the participant has been in a sitting position for at least 5 minutes at the time 
points specified in Table 1 and Table 2. Actual vital sign assessment times will be recorded. 
All measurements of vital signs must be recorded in the appropriate source documents. 
9.7.2.6 Temperature 
Temperature will be measured using a digital thermometer (orally at the timepoints specified in Table 1 
and Table 2.  

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9.7.2.7 Height and weight 
Measurements of height and weight will be performed according to the schedule in Table 1 and Table 
2.  
Height is measured in centimeters (cm) and weight is measured in kilograms (kg). Measurements are 
to be taken in light clothing and socks (without shoes) with pockets emptied. The participant’s height is 
recorded to the nearest cm and weight is recorded to the nearest 0.1 kg. 
Height and weight will be measured and used to calculate the BMI using the following formula: 
BMI = 
 
9.7.2.8 Patient diary 
Participants must complete a patient diary on the timepoints specified in Table 1 and Table 2. Partici-
pants are asked to document local and systemic reactions, temperature, medication and other reactions 
or disease for 28 days after each vaccination. The diary must be reviewed by an investigator during the 
ambulatory study visits. 
9.7.2.9 Clinical laboratory evaluations 
All laboratory tests will be performed according to the normal procedures in the local laboratory. Refer-
ence ranges must be supplied by the laboratory and used to assess the laboratory data for clinical 
significance and out-of-range pathological changes. The investigator should assess out-of-range labor-
atory values for clinical significance, indicating if the value(s) is/are not clinically significant (NCS) or 
clinically significant (CS). Abnormal laboratory values that are unexpected or not explained by the par-
ticipant’s clinical condition may be, at the discretion of the physician, investigator or sponsor, repeated 
until confirmed, explained, or resolved as soon as possible. Additional laboratory tests may be per-
formed for assessment of AEs or other medical events based on the investigator’s judgment. 
The following laboratory assessments will be performed:  
Clinical chemistry 
Blood samples for biochemistry will be collected at the time points described in Table 1 and Table 2. 
The following parameters will be assessed:  
Sodium 
Aspartate transaminase (AST) 
Potassium 
Alanine transaminase (ALT) 
Calcium 
Alkaline phosphatase (ALP) 
Urea 
Gamma-glutamyl transferase (GGT) 
Creatine kinase (total) 
Total bilirubin 
Albumin 
Glucose  
Total protein 
Pancreas-specific amylase 
Creatinine 
Lactate dehydrogenase (LDH) 
Creatinine clearance (MDRD) (only at 
Screening) 
C-reactive protein (CRP) 
Hematology 
Blood will be drawn at the timepoints described in Table 1 and Table 2. The following parameters will 
be assessed: 
Hemoglobin 
Mean corpuscular hemoglobin concentration (MCHC) 
Hematocrit 
White blood cell (WBC) count; total and differential 
Red blood cells (RBC) 
Neutrophils 
Mean corpuscular volume (MCV) 
Lymphocytes  
2
])
[
(
]
[
m
height
kg
weight

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Monocytes  
Platelet count 
Eosinophils 
Mean corpuscular hemoglobin (MCH) 
Basophils 
Urine pregnancy test 
In all female participants a urine ß-HCG test will be performed on fresh midstream urine at the time 
points described in Table 1 and Table 2. 
Safety urinalysis 
The following parameters will be analyzed in fresh midstream urine at the timepoints described in 
Table 1 and Table 2.  
pH 
Ketones 
Specific gravity 
Bilirubin 
Protein 
Blood 
Glucose 
 
 
Microscopic examination will be conducted if blood is detected during urinalysis. The microscopic ex-
amination will comprise of RBC, WBC, casts, and bacteria.  
Serology 
During the screening period only, blood sample(s) will be drawn to test for the presence of HIV, HBsAg,  
HCV, and SARS-CoV-2 antibody. 
HIV testing (HIV I and HIV II) 
HCV antibody screen 
HBV testing (HBsAg) 
SARS-CoV antibody testing (not applicable for Phase Ib 
Part B) 
 
PCR for SARS-CoV-2  
For PCR for SARS-CoV-2 samples are taken from the nose, nose and throat or throat at timepoints 
described in Table 1 and Table 2.  
COVID-19 antigen test 
For COVID-19 antigen testing samples are taken from the nose, nose and throat or throat at timepoints 
described in Table 1 and Table 2. 
9.7.2.10 
Alternative measures with respect to the COVID-19 pandemic 
In case trial participants may not be able to come to the site for protocol-specified visits (e.g. due to the 
public health emergency related to COVID-19 or quarantine), safety assessments may be performed 
using alternative methods (e.g. phone contact, virtual visit, alternative location for assessment). This is 
in accordance with EMA’s Guidance on the Management of Clinical Trials during the COVID-19 (Coro-
navirus) pandemic Version 4.0 [10] which states that “in case the trial participant cannot reach the site 
to have these performed, it is acceptable that laboratory, imaging or other diagnostics test are done at 
local laboratory or relevant clinical facility authorized/certified (as legally required nationally) to perform 
such test routinely, if this can be done within local restrictions on social distancing”. There will likely be 
further updates to this guidance, and the sponsor will take these into consideration for decision-making 
during the course of the trial. 
All efforts should be made to collect blood samples for safety and humoral immune response assess-
ment via a home visit within the protocol-specified time window.  
Any participant with clinical suspicion of SARS-CoV-2 infection will undergo appropriate testing and 
referral within the local health care system as appropriate. 
The WHO/European Centre for Disease Prevention and Control case definition for a suspected case 
requiring diagnostic testing will be used.  

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9.7.2.11 
Procedures in case of occurrence of COVID-19 symptoms 
Participants will be instructed to report clinical evidence of COVID-19-like symptoms to the study site. 
The investigator decides on the strategy to secure a diagnosis according to the current recommenda-
tions of the Robert Koch-Institut (RKI) and local guidelines.   
Reporting of COVID-19-like symptoms might be facilitated by providing diary-like instructions indicating 
start and stop dates of specific symptoms, diagnostic information outside the study site, or information 
related to health care service contacts or hospitalizations.  
Diagnostic procedures to detect or rule out COVID-19 disease will be performed according to estab-
lished procedures at each study site but will be based for all cases on PCR diagnostics. Swabs for 
antigen tests might be performed using self-sampling devices or by health care provider (or both). Par-
ticipants will be provided with antigen self-test kits and instructions for handling and shipment after en-
rolment. In addition, participants will be asked to contact a test facility according to local requirements 
in case of COVID-19 symptoms. At least one antigen or  test result shall be performed at each occur-
rence in case of suspected of COVID-19-like symptoms, a second swab following a first negative result 
is encouraged for suspected cases based on the investigator’s decision.  
If the result of the test is positive the participant has to follow local quarantine requirements. If applicable, 
upcoming on-site study visits will be replaced by phone visits. Additional phone visits for follow-up until 
resolution of all COVID-19 symptoms may be scheduled. 
9.7.2.12 
Reactogenicity 
To assess reactogenicity after each immunization, body temperature and reaction are recorded once 
daily for at least 7 days after vaccination by the participant in the diary or longer in case of systemic 
adverse events until they have subsided. Fever is defined as at least one measured body temperature 
of ≥ 38 °C. If fever is detected, temperature should be measured twice a day (in the morning and even-
ing) until two consecutive measurements are < 38 °C. According to the defined time frames in the study 
schedules, recording might be shortened to less days. During the ambulatory visits at the study ward 
temperature, solicited injection site and systemic reactions will be assessed and recorded by a desig-
nated member of the study team. After dismissal participants are asked to maintain a diary to record 
daily temperature and injection site and systemic reactions for 7 days after each dosing and to record 
medical events for 28 days after each dosing. Participants will be trained on the thermometer and diary 
use.  
The following items will be recorded:  
• 
Daily temperature (oral);  
• 
Daily measurement of intensity grade of all other injection site and systemic reactions;  
• 
Action taken for each recorded event (none, medication taken, physician consulted, hospitali-
zation).  
9.7.2.13 
Local reaction assessments 
A local reaction is defined as any morphological or physiological change at or near the reaction site, not 
resulting from a generalized systemic reaction, i.e. urticaria or other distinct clinical entities, i.e. lym-
phadenopathy. Local reactions include, but are not limited to: pain, erythema, hematoma maculopapular 
eruptions, induration, pruritus, blistering, ulceration, cellulitis, phlebitis, necrosis or abscesses. 
Local reactions, occurring after vaccination, will be graded using the toxicity grading scale in section 
9.8.1. 
9.7.2.14 
Adverse events assessments 
Participants will be questioned in a general way to ascertain if AEs have occurred (e.g. “Have you had 
any health problems since the last time you came to the clinic/since you were last questioned?”). This 
open, standardized questioning should be done discretely in order to prevent participants from influenc-
ing each other. Spontaneous reports of AEs will also be recorded as well as AEs that are observed by 
an investigator or a staff member. 
All AEs will be reviewed, confirmed, and classified by a qualified, designated investigator. 
 

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Variety of techniques like e.g. flowcytometry, ELISA, 
Sequencing 
Characterization of innate and adaptive responses in-
duced by vaccination 
 
9.7.2.16 Shipment of samples 
After processing and aliquoting sera, samples will be stored at a minimum of -20°C. Analyses for sec-
ondary endpoints will be performed at the Philipps University Marburg (Prof. Stephan Becker):  
Prof. Stephan Becker 
Institute for Virology  
Philipps University Marburg 
Hans Meerweinstr. 2 
35043 Marburg, Germany 
 
 
 
 
Samples will be shipped to the collaborators named in section 6 (Immunogenicity Laboratories). 

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9.7.2.17 Future use of stored samples  
Left over blood samples may be used in the further evaluation of an adverse event or for the subsequent 
evaluation of additional parameters that are identified as important to the evaluation of an individual 
participant or to the study, or for further research regarding the immune response to the MVA-SARS-2-
ST vaccine. Any unused part of the blood samples will be securely stored at the sponsor Institution for 
15 years for analyses of exploratory objectives. Parts of the pseudonymized blood samples may be 
shipped to collaborators for further evaluation. 
 Safety variables 
Assessment of safety is performed for the safety collective.  
Safety data include: 
• 
Adverse events (including changes from baseline in physical examination findings)  
• 
Clinical laboratory results  
• 
Vital signs  
• 
Physical examination 
The safety evaluation will be based upon the review of the individual values (potentially clinically im-
portant abnormalities) and descriptive statistics (summary Tables, graphics).  
9.7.3.1 Adverse events 
The adverse events will be listed per participant using MedDRA (Medical Dictionary for Regulatory Ac-
tivities) terminology (and will be reported in Tables summarizing the frequency of participants with ad-
verse events and adverse events by treatment and body system, the number of adverse events and 
participants with adverse events by treatments and the characteristics of adverse events. 
For hematology, clinical laboratory and urine analysis, deviations from the reference ranges will be sum-
marized in frequency Tables. 
9.7.3.2 Clinical laboratory 
All relevant clinical laboratory variables obtained during screening, final examination or the clinical trial 
periods will be reported in appropriate Tables together with descriptive statistics. Clinical laboratory find-
ings outside of the reference range will be flagged. 
9.7.3.3 Vital signs 
For blood pressure and pulse rate descriptive statistics will be listed by sampling times (screening and 
follow-up) according to the data captured in the eCRF. 
9.7.3.4 ECG 
The results (normal or abnormal, and clinical significance) of the 12-lead ECG will be listed by sampling 
times (screening ) according to the data captured in the eCRF. 
9.8 
Definition of adverse events, period of observation, recording of adverse events  
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation participant admin-
istered an IMP and that does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
disease or exacerbation of a pre-existing condition temporally associated with the use of a medicinal 
(test) product, whether or not considered related to the medicinal product (ICH Guidance E2A 1995). 
In this clinical trial AEs will be collected from the time of first administration of the IMP until the last 
follow-up visit, regardless of the relationship to the investigational medicinal product. Following these 
specifications all AEs in this clinical trial fulfil the WHO’s definition of an Adverse Event Following 
Immunization (AEFI): An AEFI is any untoward medical occurrence which follows immunization and 
which does not necessarily have a causal relationship with the usage of the vaccine. The adverse event 
may be any unfavorable or unintended sign, abnormal laboratory finding, symptom or disease. 
Thus, the terms AE and AEFI are interchangeable. For better readability the common term AE will be 
used.  

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All AEs will be recorded on the appropriate source documents and subsequently will be entered into the 
AE module of the eCRF. Where possible, a diagnosis rather than a list of symptoms should be recorded. 
If a diagnosis has not been made each symptom should be entered as a separate AE. 
CAVE: Solicited AEs have to be documented separately as described below. Those must not be sum-
marized in a diagnosis. 
If an event fulfils the criteria for an AE and occurs after a study participant signed the informed consent 
but before the administration of the first vaccination it will be documented in the medical history. If the 
event occurs after the first immunization the event fulfils the definition AE. An AE will also be documented 
in case of a worsening of severity of a pre-dose event from the medical history. 
All AEs have to be recorded until the last trial visit of the participant according to the clinical trial protocol.  
A solicited AE is a predetermined event occurring within 7 days after application of vaccine, which may 
reflect safety concerns related to the investigational product. The solicited AEs for this study only in-
clude: 
• 
Local reaction (swelling, redness/ erythema, itching, warmth, induration, hematoma or pain at 
site of injection, tenderness)  
• 
Fever 
• 
Chills 
• 
Myalgia (described to the participant as generalized muscle aches) 
• 
Arthralgia (described to the participant as generalized joint aches) 
• 
Fatigue 
• 
Headache 
• 
Gastrointestinal symptoms (nausea, vomiting, abdominal pain, loose stool and/or diarrhea) 
• 
Malaise 

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 Procedures in case of pregnancy 
All pregnancies that occur during the trial in female trial participants should be followed up. Although 
pregnancy is not an SAE, information about any pregnancy should be reported promptly to CTC North 
Safety Department on the same timeline as an SAE (without undue delay but not later than within 
24 hours of the first awareness of the event) using the pregnancy form filed in the investigator site file. 
In case the pregnant woman gives her informed consent regarding the data collection, monitoring of the 
pregnant participant shall continue until the conclusion of the pregnancy. Study vaccination will be dis-
continued for the pregnant participant. Should pregnancy result in a congenital abnormality, birth defect, 
miscarriage, or medically indicated abortion an SAE must be submitted to sponsor using the SAE re-
porting procedures described in section 9.9.1. 
 Abuse, misuse, overdose, and medication error  
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor within 
24 hours after first awareness by sending an e-mail to pharmacovigilance@ctc-north.com and reporting 
a PD (please refer to section 9.5) whether or not they result in an AE/SAE.  
Misuse - Intentional or unintentional use of a study medication other than as directed or indicated at any 
dose, which is at or below the dose defined for overdose. (Note: this includes a situation where the study 
medication is not used as directed at the dose prescribed by the protocol.) 
Overdose - Intentional or unintentional intake of a dose of study medication higher than the protocol 
prescribed dose for each participant. 
Medication Error - A mistake made in prescribing, dispensing, administration, and/or use of the study 
medication.  
Administration of an expired product should be considered as a reportable medication error. 
Cases of participants missing doses of product are not considered reportable as medication errors. 
9.9 
Serious adverse event (SAE) and AESI procedures 
 Reporting procedures 
All initial SAE and AESIs from the time of first administration of the IMP until the last follow-up visit of 
the participant must be reported by the investigator to the CTC North Safety Department without undue 
delay but not later than within 24 hours of the first awareness of the event. All SAE follow-up reports 
must be reported in a timely manner. If the investigator becomes aware of a SAE considered related to 
the IMP after last visit of the participant, the investigator must report this event to the sponsor. This event 
has to be documented  in the safety database and if this event fulfils the criteria of a SUSAR, the event 
must be reported accordingly.  
The investigator must complete, sign, and date the SAE Form or AESI Form provided in the eCRF and 
verify the accuracy of the information recorded on the form with the corresponding source documents 
(Note: source documents are not to be sent unless requested) and send the form via the eCRF form to 
the sponsor delegated responsible Safety Department. The report will be sent by the eCRF system after 
an investigator signs the form by clicking the Review A button in the eCRF. All events should be followed 
up until closure via detailed follow-up reports that must be sent to the sponsor in a timely manner using 
the appropriate eCRF forms.  
In case the reporting via eCRF is not possible due to technical issues with the eCRF reporting system, 
reporting may be handled via E-mail (pharmacovigilance@ctc-north.com) or fax (+49 (0) 40 524719 
222). As soon as the technical issues are resolved all data has to recorded and transmitted additionally 
via eCRF. 
CTC North forwards all SAEs for review to the medical monitor of the sponsor. The medical monitor 
assesses SAEs causality and expectedness and returns the SAE documentation to the CTC North 
Safety Department.  
Additional information according to the Brighton Collaboration for severe AESIs only need to be captured 
in the safety database, not in the eCRF.  
In case an SAE is considered to be a SUSAR, on behalf of the sponsor CTC North has to inform the 
CA, the ECs and the PIs about the SUSAR according to the applicable law and within the appropriate 
timelines. 

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 Serious adverse event (SAE) definition 
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be related 
to IMP or not) that follows immunization and at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital abnormality/birth defect 
• 
Is an important medical event, i.e. an event that may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition  
Hospitalizations which are the result of elective or previously scheduled surgery for pre-existing condi-
tions which have not worsened after initiation of treatment should not be classified as SAEs. For exam-
ple, an admission for a previously scheduled ventral hernia repair would not be classified as an SAE. 
However, complication(s) resulting from a hospitalization for an elective or previously scheduled surgery 
that meets serious criteria must be reported as SAE(s). 
 AE/ SAE onset and stop dates 
The AE onset date is defined as the date on which an adverse event begins. The SAE onset date is 
defined as the date the event meets serious criteria. SAE stop date is defined as the date the event no 
longer meets serious criteria. The AE stop date is the date the symptoms are resolved or resolved with 
sequelae/event is no longer present. In the case of hospitalizations, the hospital admission and dis-
charge dates are considered the SAE onset and SAE stop dates, respectively. 
 Fatal outcome 
Any SAE that results in the participant’s death (i.e. the SAE was noted as the primary cause of death) 
should have fatal checked as an outcome and the date of death recorded as the stop date. For all other 
events ongoing at time of death that did not contribute to the participant’s death, the outcome should be 
considered not resolved, without a resolution date recorded. 
For any SAEs that results in the participant’s death or any ongoing events at the time of death, the action 
taken with the IMP should be recorded as “dose not changed” or “not applicable” (if the participant never 
received IMP).  
 Serious adverse reaction (SAR) 
An AE (expected or unexpected) that is both serious and, in the opinion of the reporting investigator or 
sponsor, believed that there is a reasonable possibility that the IMP caused the event, based on the 
information provided. 
 Suspected unexpected serious adverse reaction (SUSAR) 
Adverse events are SUSARs if the following three conditions are met: 
• 
The event must be serious; 
• 
There must be a reasonable possibility that one IMP caused the event, regardless of the ad-
ministered dose; 
• 
The adverse reaction must be unexpected, that is to say, the nature and severity of the adverse 
reaction are not in agreement with the safety information as recorded in the reference safety 
information of the IMPs. 
 Regulatory agency, independent Ethics Committee, and investigative site 
reporting 
The sponsor is responsible for SUSAR reporting to the relevant Regulatory Authorities/European Union 
(EU) central Independent ECs and investigators participating in the clinical trial.  

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The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the 
adverse reactions. For fatal or life-threatening cases, the term will be maximally 7 days for a preliminary 
report with another 8 days for completion of the report.  
9.10 
Data quality assurance 
 Quality assurance system 
Protocol development, case report form and trial master file, investigator site file, content of participant 
information and consent, application for Ethics approval, monitoring and data processing will follow the 
Standard Operating Procedures (SOP) of the CTC North. Statistics will follow sponsor SOPs.  
The quality management system of CTC North has been repeatedly audited by sponsors as well as by 
local authorities. 
Standard phases of the study may be subject to audits by the quality assurance unit (QAU) of the spon-
sor or the CTC North.  
 Monitoring 
During the study, the monitor/clinical research associate will visit the investigational site regularly to 
check the completeness of participant records, the accuracy of entries in the eCRF, the adherence to 
the protocol and to ICH-GCP, the progress of enrollment, and to ensure that study drug is being stored, 
dispensed, and accounted for according to specifications. Key trial personnel must be available to assist 
the monitor during these visits. The investigator must maintain source documents for each participant 
in the study, consisting of case and visit notes containing demographic and medical information, labor-
atory data and the results of any other tests or assessments. All information on eCRFs must be traceable 
to these source documents in the participant’s file. Data not requiring a written or electronic record will 
be defined before study start and will be recorded directly in the eCRFs, which will be documented as 
being the source data. The investigator must also keep the original of the signed informed consent form. 
The investigator must give the monitor access to all relevant source documents to confirm their con-
sistency with the eCRF entries. Monitoring standards require full verification for the presence of informed 
consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of data 
that will be used for all primary and safety variables.  
A combination of remote monitoring and regular on-site visits will be performed depending on the pos-
sibility for on-site visits due to the current COVID-19 pandemic. Close-out visits are planned as on-site 
visits. The frequency and kind of monitoring visits will depend on the current situation. The detailed 
extent of the monitoring and the risk-based approach considering the COVID-19 pandemic situation and 
its influence on the daily life and the health system will be defined in the monitoring plan. 
 Documentation and data collection 
An eCRF will be prepared to report all data required by the protocol.  
Site staff will transfer the study data from the source documents into the eCRF and will check eCRF 
entries for completeness. Completed eCRF modules will be electronically signed by an investigator in 
order to ensure data entry accuracy. 
Corrections to source data documents will be dated and initialed. Reasons for the corrections should be 
given. Corrections to eCRF entries must be electronically signed and reasons for the corrections must 
be provided. The date on which the correction was performed is automatically recorded by the system's 
audit trail.  
A study monitor will review source data and the eCRF data for consistency, completeness and accuracy 
during the monitoring visits (source data verification). The study monitor will point out discrepancies 
between source data and the data captured in the eCRF. The monitor will issue electronic queries to 
site staff in order to initiate discrepancy resolution. Discrepancies which require eCRF data corrections 
have to be resolved by authorized site personnel by answering the queries and changing the respective 
eCRF entries. These query management and query resolution activities are also automatically recorded 
by the system’s audit trail. 
If a participant is a screening failure (according to section 9.7.1.1), only baseline characteristic data of 
this participant may be entered in the eCRF and will not be analyzed in the CSR. 
Data generated by this study must be available for inspection and audits by representatives of other 
national and local Health Authorities and the sponsor, if appropriate. 

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Participants will be identified on eCRFs and other documents submitted to the sponsor or organizations 
working on behalf of the sponsor only by participant number, not by name or initials. Documents not to 
be submitted to the sponsor or organizations working on behalf of the sponsor that identify the participant 
(e.g., the signed informed consent) must be maintained in confidence at the study site. 
 Data management 
Data management will double check all eCRF entries as defined in the data management plan (DMP) 
and the data validation plan (DVP).  
Quality control and data validation procedures such as programmed automatic edit and consistency 
checks ensure data validity and accuracy immediately at the point of entry into the clinical database. 
The database application which is used to capture electronic study data is fully 21 CFR part 11 compli-
ant. Thus, it is access restricted, demands electronic signatures, maintains an electronic audit trail and 
provides appropriate backup functionalities. Details of the application and eCRF configuration and all 
further data management procedures will be described in the DMP. 
The database will only be locked after all queries and discrepancies that may occur during data entry 
are resolved. 
Upon request safety reports and interim analysis will be generated and provided to the respective mem-
bers of the SSC. 
After database lock, the data in the study database will be exported and SPSS datasets will be compiled 
for statistical analysis. The data will be exported in SPSS transport files or other SPSS-compatible for-
mat and transferred electronically to the responsible biometrician for statistical analysis. The locked 
SPSS database will be used to generate the participant listings, tabulations, and analyses. 
 Archival of documents 
The study site will maintain the trial documents and take measures to prevent accidental or premature 
destruction of these documents according to the respective SOPs. 
All documents related to the study will be retained by the sponsor until at least 15 years after the end of 
the study.  
The sponsor will receive an electronic copy of the eCRF for archival and study sites will receive and 
electronic copy of the site eCRF data for archival 
If documents shall be retained for a longer period, it is the responsibility of the sponsor to inform the 
study site when these documents no longer need to be retained. 
In case of any change concerning the archiving modalities the study site has to inform the sponsor 
immediately. 
9.11 
Statistical methods planned in the protocol and determination of sample size 
 Statistical and analytical plan 
Details for the statistical evaluation of the results will be given in a separate statistical analysis plan 
(SAP). 
9.11.1.1 Software to be used 
The data will be analyzed using SAS 9.4 or later, Stata 16.0 or later, or R 3.6.3 or later by a biometrician 
of the Institute of Medical Biometry and Epidemiology.  
9.11.1.2 Analysis populations 
Eligibility of participants will be determined within the data review meeting (DRM). The following popu-
lations will be investigated.  
- 
Safety population: All participants who received at least one vaccination will be part of the safety 
population.  
- 
Per-protocol population: All participants who received one vaccination (Part B) or two vaccina-
tions (Part A), respectively, and for whom no major protocol deviation was reported will be part 
of the per-protocol population. 

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All safety endpoints will be investigated in the safety population. Immune response endpoints will be 
investigated in the per-protocol population only.  
9.11.1.3 Statistical analyses 
All analyses will be conducted separately for the two study parts Part A and Part B. 
The primary objective of the study will be the assessment of safety, tolerability and reactogenicity fol-
lowing injection.  
All safety information will be listed by participant and by treatment group.  
Data will be summarized with respect to demographic and baseline characteristics, immune response, 
and safety data. Safety data comprises AEs, laboratory tests, vital signs, and physical examination. AE 
data will be reported tabulated by system organ class and preferred term using MedDRA coding. 
Exposure to study medication will be summarized by number of injections and dose intensity using 
descriptive statistics. Reasons for not giving all protocol required injections will be presented.  
Immunogenicity will be determined by levels of anti-SARS-CoV-2-S antibodies in response to vaccina-
tion.  
For continuous variables, mean, standard deviation (SD), coefficient of variation (CV), or geometric 
mean (GeoM) and geometric coefficient of variation (GeoCV), as appropriate, as well as minimum, max-
imum and median will be reported per treatment group.  
Unless otherwise specified, baseline is defined as the time point closest but prior to the first administra-
tion of the vaccine.  
Categorical variables will be summarized by treatment group in frequency tables (absolute and relative 
(%) frequencies).  
Number of related AEs between groups will be compared using descriptive statistics. For the total fre-
quency of adverse events by treatment group 95% Miettinen-Nurminen confidence intervals will be pre-
sented. Furthermore, humoral response based on number of responders, mean, and median of ELISA 
and virus neutralization assays will be compared between groups using descriptive statistics.  
Furthermore group comparisons might be performed using Student’s t-tests, ANOVA or baseline ad-
justed ANCOVA models for continuous variables and chi square tests for categorical variables. All p-
values resulting from statistical tests will be interpreted as descriptive measures only and hence, adjust-
ments for multiplicity are not considered. Log transformation is applied before evaluation if required. 
If deemed necessary, 95% Wald confidence intervals will be provided for means (metric variables) and 
proportions (categorical variables).  
The results will be summarized in a report according to the ICH E3 guideline. 
Further details regarding the analyses will be provided in the SAP. 
9.11.1.3.1 
Missing data 
Subjects who withdraw or are withdrawn from the study prior to the first vaccine injection (Parts A and 
B), or subjects who received the first injection but are withdrawn without medical reasons prior to the 
second injection (Part A only), will be replaced. When a subject withdraws or needs to be withdrawn 
from the study after the first vaccine injection and before the planned end of the study period, all efforts 
will be made to complete the end-of-study evaluation at the time of the subject’s withdrawal and to 
receive complete data regarding adverse events. For safety data (i.e. SAEs) we therefore do not expect 
a substantial amount of missing data (namely in more than 5% of participants) which justify any imputa-
tion methods. If there are missing values related to adverse events of subjects not lost to follow-up, they 
are considered as absence of the same. 
However, if there will be isolated missing values, the outcome of the SSC review of safety and immuno-
genicity data after day 42, on which the decision to move to Phase II of the study will be based, should 
not be affected. Therefore, no imputation or sensitivity analyses are planned in case of missing data. 
 

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9.11.1.3.2 
Determination of sample size 
For the FIH study, no formal criteria are available in order to determine the sample size. Nevertheless, 
most FIH trials involve a small number of healthy subjects (n<20 per arm) [11]. The MVA vaccine is 
licensed and has been tested in various clinical trials as listed in table 10 of the IB [8].  
With 8 subjects the 95% confidence interval can be estimated with a precision of at least 0.69 (in case 
of a rate of 50%) or 0.52 for the rarest events (1 event in 8 subjects) (Confidence Intervals for One 
Proportion, PASS 2008). 
With 12 subjects the 95% confidence interval can be estimated with a precision of at least 0.58 (in case 
of a rate of 50%) or 0.38 for the rarest events (1 event in 12 subjects) (Confidence Intervals for One 
Proportion, PASS 2008). 
 
10 
CHANGES IN THE CONDUCT OF THE CLINICAL TRIAL OR PLANNED ANALY-
SIS 
Modifications of the protocol are permitted only if they are authorized by the sponsor and the Coordinat-
ing investigator in writing.  
Deviations and changes to the study protocol will be classified by the sponsor and the study center as: 
Note-to-File: This refers to clarifications which are not considered changes of the protocol. 
Study protocol amendment: This refers to changes of the protocol. If they fulfill the criteria as set out in 
applicable law for definition as substantial amendment they need to be approved by the EC, the CA or 
both. Changes to the study protocol may also induce revision of the participant informed consent form. 
Accordingly, participants undergoing trial assessment procedures at the time of implementation of the 
change have to be given the amended version and have to be asked for consent to continue on this 
amended trial.  
A “substantial amendment” is defined as an amendment to the terms of the applicable regulations. 
All substantial amendments will be notified to the relevant authorities. 
11 SAFETY STEERING COMMITTEE (SSC) 
During the trial a SSC will be established.The SSC will review and judge the safety, tolerability, and 
immunogenicity after 50% of the subjects have been completed the first 2 weeks of the study.  
In addition, an SSC meeting will be conducted whenever safety relevant data occur that might have an 
influence on the trial.  
At a minimum the holding rules (criteria for termination of the study) specified in the protocol will au-
tomatically apply (if activated) for not proceeding with a higher dose.  
The decisions of the SSCmeeting will be briefly summarized by CTC North and signed by all members 
involved in the meeting and the decision. Relevant findings will be reported to the responsible authori-
ties. 
 
12 
REPORTS 
All reports to the sponsor will be in English. The sponsor will receive the original CSR.  
The CSR is the property of the sponsor. Publication of the report or of part of it may only be allowed 
when authorized by the sponsor. 
12.1 
Clinical study report 
All clinical, analytical and statistical results will be presented in a CSR. The outline of this report will 
accord to the ICH-GCP E3 document "Structure and Content of Clinical Study Reports" in its current 
version. Within a year upon completion of the clinical trial, a summary of the CSR will be sent to the ECs 
and CAs uploaded in the EU database as required by appropriate law(s). 

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12.2 
Additional reports 
Upon completion of the study, a short report will be sent to the ECs, stating any undesired event and 
indicating whether study objectives have been attained. Short reports to the authorities after study ter-
mination will be provided as required by law. An interims analysis may be performed. 

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13 
REFERENCES
1            https://gisanddata.maps.arcgis.com/apps/opsdashboard/in-
dex.html#/bda7594740fd40299423467b48e9ecf6 , accessed on 25AUG2021 
2  
Joint 
statement 
ICAO-WHO 
on 
COVID-19“(https://www.icao.int/Security/COVID-
19/Pages/Statements.aspx from 11 March 2020). 
3  
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet. 2020;395(10223):497-506. 
4  
Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and Thrombotic or Thromboembolic Dis-
ease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-
Art Review. J Am Coll Cardiol. 2020;75(23):2950-2973. 
5  
Baden et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 
2021 Feb 4;384(5):403-416. 
6  
Pollack et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 
2020 Dec 31;383(27):2603-2615 
7  
Dagan et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N 
Engl J Med. 2021 Apr 15;384(15):1412-1423 
8  
Investigators Brochure, Version 3.0, realease date 30.04.2021.  
9  
Koch T, Dahlke C, Fathi A, et al. Safety and immunogenicity of a modified vaccinia virus Ankara 
vector vaccine candidate for Middle East respiratory syndrome: an open-label, phase 1 trial. 
Lancet Infect Dis. 2020;20(7):827-838. 
10  
Guidance on the management of clinical trials during the covid-19 (coronavirus) pandemic. 
Version 4.0 04/02/2021. 
11  
https://www.fda.gov/media/87621/download 
                                                
 

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ANNEX I INVESTIGATOR PROTOCOL ACKNOWLEDGMENT 
 
 
I have read this protocol and hereby acknowledged the protocol and I agree to conduct the study in 
compliance with the protocol. I confirm that I will provide the study team with a copy of the protocol and 
will forward any protocol amendments that I acknowledge to any team members involved in the conduct 
of the trial. 
 
 
 
 
 
Name investigator 
 
 
 
 
Institution  
 
 
 
 
Date and Signature 
 
 
 
 
 

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ANNEX II DEFINITION OF COVID-19 DISEASE IN THE STUDY 
 
COVID-19-like symptoms include: fever1, cough, dyspnea, anosmia/ageusia, sore throat, di-
arrhea1, nausea/vomiting1, headache1, congested/runny nose. 
1 These symptoms will not be considered COVID-19 like within 7 days post vaccinations. 
Fever, chills, cough and dyspnea will be considered of any duration, all other symptoms should 
be present of at least 48 hours. 
1. Symptomatic COVID-19: Positive SARS-CoV-2 PCR result and at least 1 COVID-19-like 
symptom. 
2.  Asymptomatic COVID-19: Positive SARS-CoV-2 PCR result without clinical symptoms, 
or evidence of SARS-CoV-2 infection as documented by N-antigen seroconversion. 
3. SARS-CoV-2 infection: N-antigen seroconversion in an at baseline N-antibody negative 
participant.