A Multinational, Phase 2, Randomised, Adaptive Protocol to Evaluate Immunogenicity and Reactogenicity of Different COVID-19 Vaccines Administration in Older Adults (≥75) Already Vaccinated Against SARS-COV-2 (EU-COVAT-1_AGED)
Phase: PHASE2
Conditions: Prevention of COVID-19
Sponsor: Oliver Cornely, MD

Universität zu Köln 
TRIAL PROTOCOL 
A MULTINATIONAL, PHASE 2, RANDOMISED, ADAPTIVE PROTOCOL TO EVALUATE IMMUNOGENICITY AND 
REACTOGENICITY OF DIFFERENT COVID-19 VACCINES ADMINISTRATION IN OLDER ADULTS (≥75) ALREADY 
VACCINATED AGAINST SARS-COV-2 
(EU-COVAT-1_AGED) 
Sponsor 
University of Cologne 
Albertus-Magnus-Platz 
50923 Köln 
Germany 
Principal Coordinating Investigator: 
Prof. Dr. Oliver A. Cornely 
Department I of Internal Medicine  
University Hospital Cologne 
Kerpener Strasse 62 
50937 Cologne 
Germany 
Trial protocol code: uni-koeln-4602 
EudraCT number: 2021-004526-29 
Version of July 27, 2022, Version V06_0 
Please note: This trial (“EU-COVAT-1_AGED“) is a sub-protocol embedded within the 
EU-COVAT master protocol. 
The information in this trial protocol is strictly confidential. It is for the use of the sponsor, principal investigator, 
trial personnel, ethics committee, the authorities, and trial subjects only. This trial protocol may not be passed 
on to third parties without the expressed agreement of the sponsor or the Principal Coordinating Investigator 
(PCI, “Leiter der klinischen Prüfung (LKP)”). This trial protocol is written based on using a template drafted by 
the University of Cologne, which is subject to the UVM licence for unprotected content 
(http://www.ifross.de/Lizenzen/LizenzFuerFreieInhalte.html). 
SIgnatures have been removed prior to upload on clinicaltrials.gov.

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 3 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
II. Synopsis 
Sponsor 
University of Cologne 
Represented by: 
Prof. Dr. med. Oliver Cornely 
(Principal Coordinating Investigator, PCI) 
Department for Internal Medicine I  
University Hospital Cologne 
Kerpener Strasse 62 
50937 Cologne 
Germany 
Principal 
Coordinating 
Investigator 
See above 
National representatives are detailed in a separate list for this multinational 
trial. 
Title of the clinical 
trial 
A Multinational, Phase 2, Randomised, Adaptive Protocol to Evaluate 
Immunogenicity and Reactogenicity of Different COVID-19 Vaccines 
Administration in Older Adults (≥75) already Vaccinated Against SARS-CoV-
2 (EU-COVAT-1 AGED) 
Indication 
COVID-19 vaccination 
Phase 
 
 
 
 
 
 
 
Phase ll clinical trial 
 
 
 
 
 
 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 4 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Type of trial, trial 
design, 
methodology 
Please note: This trial (“EU-COVAT-1_AGED“) is a sub-protocol 
embedded within the EU-COVAT master protocol. 
 
PLEASE NOTE: 
This protocol refers to Part B of the clinical trial in which new accruals are 
randomized to a 4th vaccination (second booster) with either BNT162b2 
or mRNA-1273. 
Part A of the present trial in which individuals received a 3rd vaccination 
(first booster) is closed to further recruitment as of January 13, 2022. 
With the massive roll-out of booster campaigns throughout Europe, Part 
A was abandoned because of a poor recruitment rate. 
Individuals in Part A are followed-up as specified in protocol version 
V04_0 and analyzed descriptively, the statistical analysis plan will be 
adapted accordingly. 
 
This is a randomised controlled, adaptive, multicentre Phase II protocol 
evaluating different booster strategies in individuals aged 75 years and 
older already vaccinated against SARS-CoV-2. Part B of this trial foresees 
testing of different vaccines as a 4th vaccination dose (second booster) for 
comparative assessment of their immunogenicity and safety against SARS-
CoV-2 wild-type and variants in the elderly, a usually neglected population.  
Additional vaccines and extended follow-up visits can be added through 
amendments of this sub-protocol. As stated in the EU-COVAT master 
protocol, this trial, i.e., the EU-COVAT-1_AGED study, implements a specific 
safety monitoring strategy (see below). 
Randomisation in Part B 
Subjects who - prior to study entry - got a primary vaccination series and 
3rd vaccination dose of either 
• 
BNT162b2 + BNT162b2 + BNT162b2 or 
• 
BNT162b2 + BNT162b2 + mRNA-1273 or 
• 
mRNA-1273 + mRNA-1273 + mRNA-1273 or 
• 
mRNA-1273 + mRNA-1273 + BNT162b2 or 
• 
ChAdOx-1-S + ChAdOx-1-S + BNT162b2 or 
• 
ChAdOx-1-S + ChAdOx-1-S + mRNA-1273 or 
will receive a 4th vaccination dose with an allocation ratio of 1:1 to either 
BNT162b2 or mRNA-1273. Accordingly, there are 6 cohorts (equalling 12 
arms).   All individuals who were randomized to BNT162b2 represent 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 5 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Group 1, all individuals who were randomized to mRNA-1273 represent 
Group 2. 
Cohorts and arms can be withdrawn or added as deemed necessary 
according to the criteria specified in this protocol. 
 
Blinding 
No blinding is foreseen in this trial. 
Number of 
subjects 
The number needed has been calculated at 550 for Part B. 
 
Sample size calculation with multiplicity adjustment within each cohort 
When the sample size is 250 per randomized group (Group 1, Group 2) in 
Part B (275 without dropouts, i.e., assuming 8-10% dropouts), two-sided 
simultaneous 95% confidence intervals (with Bonferroni adjustment for 2 
simultaneous confidence intervals within a cohort) for a proportion using 
the large sample normal approximation will extend no more than ±7.1% 
(percentage points) from the observed proportion. E.g., if the observed 
proportion is 50% (where the confidence interval is widest), the confidence 
interval ranges from about 42.9% to 57.1%. 
Primary trial 
objective  
(Part B) 
• To compare the immune response between treatment arms after a 4th 
vaccination dose against SARS-CoV-2. 
Safety objective 
(Part B) 
• To assess the safety of a 4th vaccination dose against SARS-CoV-2 in the 
study population. 
 
 
 
 
 
 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 6 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Secondary trial 
objectives 
(Part B) 
• To compare the humoral response against wild-type SARS-CoV-2 
between treatment arms after a 4th vaccination dose against SARS-CoV-
2. 
• To evaluate descriptively the humoral response against SARS-CoV-2 
variants of concern between treatment arms after a 4th vaccination dose 
against SARS-CoV-2. 
 
• To evaluate descriptively the long-term humoral immune response of 4th 
vaccination dose against SARS-CoV-2. 
Exploratory 
objectives 
(Part B) 
• To investigate the cellular immune response after a 4th vaccination dose, 
virus neutralizing capacity against newly emerging variants in bio-banked 
samples and correlates of interest. 
Study endpoints 
(Part B) 
Primary endpoint: 
• Rate of 2-fold antibody titre increase 14 days after a 4th vaccination dose 
measured by quantitative enzyme-linked immunosorbent assay (Anti-
RBD-ELISA) against wildtype virus. (Part B) 
Safety endpoints: 
• Unsolicited AEs until the end of trial. 
• Solicited AEs for 7 days after a 4th vaccination dose. 
• Rate of serious adverse events (SAEs) Grade ≥3 according to the National 
Cancer Institute Common Toxicity Criteria up to three months after a 4th 
vaccination dose. 
Secondary endpoints: 
• Change in neutralizing antibody titre (Virus Neutralisation Assay) against 
wild-type 14 days after a 4th vaccination dose, to be determined in a 
subgroup only. 
• Change in neutralizing antibody titre (Virus Neutralisation Assay) against 
variants of concern 14 days after a 4th vaccination dose, to be 
determined in a subgroup only. 
 
• Antibody titre level at 12 months after a 4th vaccination dose measured 
by a quantitative enzyme-linked immunosorbent assay (anti-RBD-ELISA 
assay). 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 7 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• Neutralizing antibody titre (Virus Neutralisation Assay) against wild-type 
SARS-CoV-2 at 12 months after a 4th vaccination dose, to be determined 
in a subgroup only. 
• Neutralizing antibody titre (Virus Neutralisation Assay) against variants 
of concern at 12 months after a 4th vaccination dose, to be determined in 
a subgroup only. 
 
Exploratory endpoints: 
• Change in cellular immune response (CD4+ and CD8+ T cell response) 
measured by qPCR 14 days after 4th vaccination dose, to be determined 
in a subgroup only. 
• Neutralizing antibody titre (Virus Neutralisation Assay) against newly 
emerging variants in bio-banked samples after 4th vaccination dose, to be 
determined in a subgroup only. 
• Correlates of humoral immune response, cellular immune response and 
viral neutralising capacity against SARS-CoV-2 variants of concern (VOCs), 
to be determined in a subgroup only.  
 
Diagnosis and 
Principal inclusion 
and exclusion 
criteria (Part B) 
Medical condition or disease to be investigated: 
Prevention of COVID-19 infection. 
Principal inclusion criteria: 
• 
Subject is ≥75 years old. 
• 
Prior to study entry the subject was vaccinated with one of the 
following vaccination regimens (1st + 2nd + 3rd dose): 
 
o BNT162b2 + BNT162b2 + BNT162b2 
o BNT162b2 + BNT162b2 + mRNA-1273 
o mRNA-1273 + mRNA-1273 + mRNA-1273 
o mRNA-1273 + mRNA-1273 + BNT162b2 
o ChAdOx-1-S + ChAdOx-1-S + BNT162b2 
o ChAdOx-1-S + ChAdOx-1-S + mRNA-1273  
 
• 
The last dose of the above listed vaccinations must have been 
administered at least 1 month prior to study entry. Vaccination status 
should be documented in the source data and will be captured in the 
eCRF. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 8 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• 
Written informed consent from subject has been obtained. 
 
Principal exclusion criteria: 
• 
Prior to study entry the subject got vaccinated with a regimen not 
included in the list given above. 
• 
Last anti-SARS-CoV-2 vaccine dose administered less than one month 
prior to study entry. 
• 
Vaccination against a disease other than COVID-19 within 2 weeks 
prior to study entry. Only exception: Influenza vaccination which is 
allowed at any time. 
• 
Subjects with any significant or uncontrolled disease posing a risk due 
to vaccination as judged by the investigator. 
• 
Current immunosuppressive therapy, for example continuous 
glucocorticosteroid treatment equivalent to >10 mg/day prednisolone. 
• 
Subject simultaneously participates in another clinical trials or has 
participated in the past 30 days. 
• 
Subjects unable to report solicited adverse events. 
• 
Subject with any contraindications to the vaccines in the trial. A list of 
contraindications as listed in the Summary of medicinal Product 
Characteristics (SmPC, the Fachinformation in Germany), if 
appropriate. 
Name of 
investigational 
medicinal product 
(IMP) 
• BNT162b2 (Comirnaty®) including any VOC-modified vaccine product 
• mRNA-1273 (Spikevax®) including any VOC-modified vaccine product 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 9 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Investigational 
medicinal product 
– dosage and 
method of 
administration 
 
Intervention in Part A:    _no longer active - for information only_   
Cohort 
Vaccination prior 
to study entry 
Arm 
Study intervention:  
3rd vaccination dose 
Part A  
with Cohorts 1 to 3 
closed to further 
recruitment as of 
January 13, 2022 
Cohort 1 
BNT162b2 + 
BNT162b2 
1 
BNT162b2 
2 
mRNA-1273 
 
Cohort 2 
mRNA-1273 + 
mRNA-1273 
3 
BNT162b2 
 
4 
mRNA-1273 
 
Cohort 3 
ChAdOx-1-S +  
ChAdOx-1-S 
5 
BNT162b2 
 
6 
mRNA-1273 
 
Control 
Control arm of the EU-COVAT subprotocol EudraCT 
no. 2021-004889-35, a separate sub-protocol 
embedded within the EU-COVAT master protocol, 
will be used for a descriptive comparison. 
 
 
Intervention in Part B:    4th vaccination dose 
 
Cohort 
Vaccination prior 
to study entry 
Arm 
Study intervention:  
4th vaccination dose* 
Cohort 4 
BNT162b2 + 
BNT162b2 + 
BNT162b2 
7 
BNT162b2 
8 
mRNA-1273 
Cohort 5 
BNT162b2 + 
BNT162b2 + 
mRNA-1273 
9 
BNT162b2 
10 
mRNA-1273 
Cohort 6 
mRNA-1273 + 
mRNA-1273 + 
mRNA-1273 
11 
BNT162b2 
12 
mRNA-1273 
Cohort 7 
mRNA-1273 + 
mRNA-1273 + 
BNT162b2  
13 
BNT162b2 
14 
mRNA-1273 
Cohort 8 
ChAdOx-1-S + 
ChAdOx-1-S + 
BNT162b2 
15 
BNT162b2 
16 
mRNA-1273 
Cohort 9 
ChAdOx-1-S + 
ChAdOx-1-S + 
mRNA-1273 
17 
BNT162b2  
18 
mRNA-1273 
* administered at least 1 month after the 3nd pre-study vaccination. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 10 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
IMP or therapy 
used as a 
comparator – 
dosage and 
method of 
administration 
No vaccination in the control group of the EU-COVAT subprotocol EudraCT 
no. 2021-004889-35, a separate sub-protocol embedded within the EU-
COVAT master protocol (applies to Part A of the trial, in Part B this is an 
option only). 
Duration of 
treatment 
(Part B) 
Treatment consists of a single 4th dose of each vaccine foreseen in this 
protocol. Follow up of subject included will last for 12 months. 
Time plan 
(Part A and B) 
 
 
 
First patient first visit (FPFV): 
November 2021 
Last patient first visit (LPFV): 
September 2022 
Last patient last visit (LPLV): 
September 2023 
Analysis 
October 2022 (Primary endpoint analysis) 
End of study definition 
The end of study will be on the day of 
database lock. 
End of trial 
November 2023 
Final study report: 
December 2023 
Statistician 
Assoc. Prof. Priv.-Doz. Dr. Franz König 
Center for Medical Statistics, Informatics and Intelligent Systems 
Medical University of Vienna 
Spitalgasse 23 
1090 Vienna 
Austria 
Statistical methods 
(Part B) 
Firstly, the rates of 2-fold increase in antibody titre with multiplicity 
adjusted 95% confidence intervals (adjusted for arms within each cohort) 
will be reported for both randomized groups 1 and 2 in Part B. 
Secondly, Cohorts of study participants are defined by the different pre-
vaccination series eligible for part B of this trial. We compare the 4th 
vaccination doses of BNT162b2 and mRNA-1273 and compute a two-sided 
confidence interval. Based on these, we test for equivalence of one of the 
4th vaccination doses (based on the equivalence margin as outlined in the 
Reflection Paper of EMA). 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 11 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Thirdly, we compare groups 1 and 2 based on homologous boosting (pre-
study 3rd vaccine and on-study 4th vaccine identical) vs. heterologous 
boosting (pre-study 3rd vaccine and on-study 4th vaccine different). Further 
exploratory analyses will be performed based on different pre-vaccination 
series. 
 
The primary endpoint analysis will be triggered as soon as for all patients 
the primary endpoint (14 days after the 4th vaccination dose) has been 
observed. 
Safety analysis. 
All clinical safety data will be listed by participant, time from vaccination 
dose and treatment arm. Continuous variables will be summarised using 
sample size (N), mean, standard deviation, median, minimum, and 
maximum. Frequency counts will be reported for categorical data. 
A Data and Safety Monitoring Committee (DSMC) will review data for 
decisions on arms incorporation and withdrawal and will ensure the 
appropriate oversight and monitoring in conducting the clinical trial.  
Interim analysis 
An interim analysis will be performed as soon as 50% of participants have 
been recruited within Part B. 
GCP compliance 
The present trial will be conducted in accordance with the valid versions of 
the trial protocol and the internationally recognised Good Clinical Practice 
Guidelines (ICH-GCP), including archiving of essential documents. 
Financing 
European Commission 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 12 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
III. Table of contents 
I. 
Signatures 
2 
II. 
Synopsis 
3 
III. 
Table of contents 
12 
III.a) 
List of tables 
17 
III.b) 
List of figures 
17 
IV. 
Abbreviations 
18 
1. 
Introduction 
20 
2. 
Objectives of the clinical trial 
21 
2.1. 
Rationale for the clinical trial 
21 
2.2. 
Primary objective (Part B) 
22 
2.3. 
Safety objective (Part B) 
22 
2.4. 
Secondary objectives (Part B) 
22 
2.5. 
Exploratory objectives (Part B) 
22 
3. 
Organisational and administrative aspects of the trial 
23 
3.1. 
Sponsor 
23 
3.2. 
Principal Coordinating Investigator 
23 
3.3. 
Statistics 
23 
3.4. 
Data Monitoring Committee 
23 
3.5. 
Central Coordinating Office (CCO) 
24 
3.6. 
Regional/Country specific Coordinating Centre (RCC) 
25 
3.7. 
Local Clinical Centres (LCC) 
25 
3.8. 
Steering Committee 
25 
3.9. 
Advisory Committee 
26 
3.10. 
Study laboratories and other technical services 
26 
3.11. 
Central organisation units 
27 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 13 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
3.12. 
Principal investigators and trial sites 
28 
3.13. 
Requirements for principal investigators and trial sites 
28 
3.14. 
Financing 
29 
4. 
Trial conduct 
30 
4.1. 
General aspects of trial design 
30 
4.1.1. 
Time schedule 
32 
4.2. 
Discussion of trial design 
32 
4.3. 
Risk-Benefit Assessment. 
33 
4.3.1. 
Known Potential Risks 
33 
4.3.2. 
Known Potential Benefits 
34 
4.3.3. 
Assessment of Potential Risks and Benefits 
34 
4.4. 
Selection of trial population 
35 
4.4.1. 
Inclusion criteria 
37 
4.4.2. 
Exclusion criteria 
37 
4.5. 
Withdrawal of trial subjects after trial start 
38 
4.6. 
Closure of trial sites/Premature termination of the clinical trial 
38 
4.6.1. 
Closure of trial sites 
38 
4.6.2. 
Premature termination of trial 
39 
4.7. 
Treatment 
39 
4.7.1. 
Treatments to be given 
39 
4.7.2. 
Description of investigational medicinal product 
41 
4.7.2.1. Manufacture of the investigational medicinal product 
42 
4.7.2.2. Labelling of investigational medicinal product 
42 
4.7.3. 
Storage of investigational medicinal product 
43 
4.7.4. 
Compliance with treatment/Dispensing and return of investigational medicinal product 43 
4.7.5. 
Assignment of trial subjects to treatment groups 
43 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 14 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4.7.6. 
Selection of dosage of investigational medicinal product 
44 
4.7.6.1. Justification of the 0.5 ml (100 µg) booster dose of Moderna's Spikevax COVID-19 vaccine 
(mRNA-1273) 
44 
4.7.7. 
Time of administration and adjustments to dosage of the investigational medicinal product 
in the individual trial subject 
46 
4.7.8. 
Blinding 
46 
4.7.8.1. Unblinding 
46 
4.7.9. 
Previous and concomitant medication 
46 
4.7.9.1. Rescue therapy for emergencies 
47 
4.7.10. 
Continuation of treatment after the end of the clinical trial 
47 
4.8. 
Efficacy and safety endpoints 
47 
4.8.1. 
Measurement of efficacy and safety endpoints in Part B 
47 
4.8.1.1. Primary endpoints 
47 
4.8.1.2. Safety endpoints 
47 
4.8.1.3. Secondary endpoints 
48 
4.8.1.4. Exploratory endpoints 
48 
4.8.1.5. Safety data in Part B 
48 
4.9. 
Description of visits 
50 
4.9.1. 
Rationale for assessment procedures 
53 
4.9.2. 
Pharmacokinetics/Determination of drug levels 
53 
4.9.3. 
Biobanking 
53 
4.9.4. 
Ethics for accessing and using biobank samples 
53 
4.10. 
Data quality assurance 
54 
4.10.1. 
Monitoring 
54 
4.10.2. 
Audits/Inspections 
55 
4.11. 
Documentation 
55 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 15 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4.11.1. 
Data management 
56 
4.11.2. 
Archiving 
57 
5. 
Ethical and regulatory aspects 
58 
5.1. 
Ethics committee 
58 
5.2. 
Applicable laws and regulations and ethical considerations 
58 
5.3. 
Legislation and guidelines 
59 
5.4. 
Notification of the authorities, approval and registration 
59 
5.5. 
Obtaining informed consent from trial subjects 
59 
5.6. 
Insurance of trial subjects 
60 
5.7. 
Data protection 
60 
6. 
Statistical methods and sample size calculation (Part B) 
62 
6.1. 
Statistical and analytical plan 
62 
6.1.1. 
Analysis populations 
62 
6.1.2. 
Description of trial subject groups 
63 
6.1.3. 
Primary analysis 
63 
6.1.3.1. Analysis time point for primary endpoint 
64 
6.1.4. 
Secondary analyses 
64 
6.1.5. 
Exploratory analyses 
64 
6.1.6. 
Multiplicity adjustment 
65 
6.1.7. 
Subgroup analyses 
65 
6.1.8. 
Interim Analysis 
65 
6.2. 
Safety Analysis 
65 
6.3. 
Sample size calculation 
66 
7. 
Safety 
68 
7.1. 
Definitions of adverse events and adverse drug reactions 
68 
7.1.1. 
Adverse event 
68 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 16 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
7.1.1.1. Pregnancy 
68 
7.1.2. 
Adverse drug reaction 
68 
7.1.3. 
Serious adverse events and serious adverse reactions 
68 
7.1.4. 
Unexpected adverse drug reaction 
69 
7.1.5. 
Suspected unexpected serious adverse reactions 
69 
7.1.6. 
Adverse events of special interest 
70 
7.1.7. 
Solicited Adverse Events 
70 
7.2. 
Documentation and follow-up of adverse events 
71 
7.2.1. 
Documentation of adverse events and adverse drug reactions 
71 
7.2.1.1. Exceptions from AE documentation 
72 
7.2.2. 
Severity of the adverse event 
72 
7.2.3. 
Causal relationship between adverse event and investigational medicinal product 
73 
7.2.3.1. Related 
74 
7.2.3.2. Unrelated 
74 
7.3. 
Reporting of serious adverse events, adverse events of special interest, pregnancy and 
changes in risk-benefit assessment 
74 
7.3.1. 
Reports from the investigator to the sponsor 
75 
7.3.2. 
Assessment of SAEs by the sponsor 
75 
7.3.3. 
Unblinding for SUSAR when treatment is blinded 
75 
7.3.4. 
Notification of ethics committee and competent authority 
76 
7.3.4.1. Fatal and life-threatening SUSARs 
76 
7.3.4.2. SUSARs that are not fatal or life-threatening 
76 
7.3.5. 
Review and reporting of changes in the risk-benefit ratio 
76 
7.3.6. 
Informing the Data Monitoring Committee 
77 
7.3.7. 
Informing the investigators 
77 
7.3.8. 
Informing the marketing authorisation holder 
77 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 17 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
7.4. 
Annual safety report (DSUR) 
78 
8. 
Trial results and publication 
79 
8.1. 
Reports 
79 
8.1.1. 
Interim reports 
79 
8.1.2. 
Final report 
79 
8.2. 
Publication 
79 
9. 
Amendments to the trial protocol 
81 
10. 
References 
82 
 
III.a) List of tables 
Table 1: Time schedule of the trial 
32 
Table 2: Treatments of the trial 
41 
Table 3: Visit schedule of the trial 
51 
 
III.b) List of figures 
Figure 1: Layout of the trial design 
31 
 
 
 
 
 
Please note: 
This trial (“EU-COVAT-1_AGED“) is a sub-protocol embedded within the 
EU-COVAT master protocol. 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 18 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
IV. Abbreviations 
Abbreviation 
Meaning 
AE 
Adverse Event 
CA 
Competent authority (BfArM, PEI) 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
EMA 
European Medicines Agency 
ISF 
Investigator Site File 
IMP 
Investigational Medicinal Product 
PBMC 
Peripheral blood mononuclear cells 
PCI 
Principal Coordinating Investigator (Leiter der klinischen Prüfung, LKP) 
PI 
Principal Investigator 
PEI 
Paul-Ehrlich-Institut 
SAE 
SmPC 
Serious Adverse Event 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
VOC(s)s 
Variant(s) of concern 
 
 
Please note: 
This trial (“EU-COVAT-1_AGED“) is a sub-protocol embedded within the 
EU-COVAT master protocol. 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 19 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
 
 
 
PLEASE NOTE: 
 
 
This protocol refers to Part B of the clinical trial in which new accruals  
 
are randomized to a 4th vaccination (second booster) with either  
 
BNT162b2 or mRNA-1273. 
 
 
Part A of the present trial in which individuals received a 3rd vaccination  
 
(first booster) is closed to further recruitment as of January 13, 2022.  
 
With the massive roll-out of booster campaigns throughout Europe,  
 
Part A was abandoned because of a poor recruitment rate. 
 
 
Individuals in Part A are followed-up as specified in  
 
protocol version V04_0 and analyzed descriptively, the statistical  
 
analysis plan will be adapted accordingly. 
 
 
 
 
 
 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 20 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
1. Introduction 
The novel SARS-2 Coronavirus (SARS-CoV-2) was identified in December 2019 as a cause of severe 
pneumonia, acute respiratory distress syndrome (ARDS) and potential multiorgan failure in humans. 
The disease known as COVID-19 has since turned into a pandemic affecting nearly all countries in the 
world where it has caused widespread mortality and morbidity. 
A huge research effort on prevention and treatment of COVID-19 has been ongoing globally. As of 
February 16, 2021, almost 5,000 trials related with COVID-19 have been registered. Vaccination 
against COVID-19 started on December 27, 2020, across the European Union. So far, four vaccines 
have been granted conditional marketing authorisation by the European Commission: mRNA vaccine 
BNT162b2 (BioNTech and Pfizer - COMIRNATY), mRNA vaccine CX-024414 (Moderna - SPIKEVAX), 
adenovirus vaccine ChAdOx1-S (AstraZeneca - VAXZEVRIA) and adenovirus vaccine Ad26.Cov2.S 
(Janssen-Cilag International NV). These vaccines are indicated for active immunisation to prevent 
COVID-19 caused by SARS-CoV-2 in individuals 12 or 18 years of age and older. 
Clinical trials performed for marketing authorisation have demonstrated high efficacy in terms of 
preventing moderate and severe cases of COVID-19. However, there is low evidence on the efficacy 
of COVID-19 vaccines in special populations. An effectiveness study from Israel showed that 
participants aged 60 and older who were vaccinated with two doses of the Pfizer/BioNTech vaccine 
had a lower number of cases and hospitalisations compared to younger individuals and no more 
severe side effects.11,12,  
This trial aims to evaluate immune response against wild-type SARS-CoV-2 of further vaccine doses as 
booster strategy in individuals aged 75 or older already fully vaccinated against SARS-CoV-2. This 
investigation will likely provide useful information for vaccination programs in Europe and elsewhere. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 21 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
2. Objectives of the clinical trial 
2.1. Rationale for the clinical trial 
Recent data suggest that immunisation with any of the currently approved vaccines may not provide 
long-term or life-long protection.13, 14 Therefore, additional follow-up vaccination (booster) doses are 
indicated at some point in time after full vaccination, especially so in subjects of advanced age and 
with regard to emerging variants of concerns (VOCs) of SARS-CoV-2. 
Booster immunizations will be critical to substantially improve the immune response against 
emerging VOCs especially the Omicron (B.1.1.529) variant. The Omicron variant is causing high 
infection incidences all over the globe. Current monoclonal antibodies tested in studies show a 
strongly reduced neutralizing activity against the predominating Omicron variant and will limit 
treatment options for Omicron-induced COVID-19 disease. However, a recent study has shown, that 
a single dose (3rd dose) of BNT162b2 induced a remarkable increase in neutralizing serum activity one 
month after vaccination in individuals after primary vaccination series and in convalescent 
individuals.  Since titres were nearly similar to those observed against Wu01 after first vaccination 
series in this study, booster vaccinations with already available vaccines still seem to be the most 
effective step in the prevention of (re)infection. With regard to the Omicron variant vaccination 
schedules, vaccination intervals will be kept tight in future to keep immunity levels high.18,19,21,16,17   
In the elderly, adaptive immune response is reduced and therefore shorter intervals between 
booster doses may be warranted for satisfactory protection against SARS-CoV-2 infection.20 Right 
now, there are no data on the optimal timing of booster doses in elderly subjects after a full 
vaccination schedule. Also, in the age group above 75 years no robust clinical evidence exists on the 
immune response using heterologous strategies for such boosting. Therefore, this trial aims to assess 
the impact of different mRNA-based vaccines as booster doses in the elderly aged 75 years and older. 
This will likely provide useful information for vaccination programs in Europe (and elsewhere) for this 
high-risk population. Time points for booster (i.e., 3rd and 4th) vaccinations in Part A and B of this trial 
are based on current vaccination policies in the EU, i.e., there is a minimum interval of 1 month since 
the last (2nd or 3rd) vaccination, with longer intervals as per local regulation or practice. 
 
For a detailed assessment of potential risks and benefits see section 4.3. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 22 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
2.2. Primary objective (Part B) 
• To compare the immune response between treatment arms after a 4th vaccination dose against 
SARS-CoV-2. 
 
2.3.  Safety objective (Part B) 
• To assess the safety of a 4th vaccination dose against SARS-CoV-2 in the study population. 
 
2.4.  Secondary objectives (Part B) 
• To compare the humoral response against wild-type SARS-CoV-2 between treatment arms after a 
4th vaccination dose against SARS-CoV-2. 
 
• To evaluate descriptively the humoral response against SARS-CoV-2 variants of concern between 
treatment arms after a 4th vaccination dose against SARS-CoV-2. 
 
• To evaluate descriptively the long-term humoral immune response of a 4th vaccination dose 
against SARS-CoV-2. 
2.5. Exploratory objectives (Part B) 
• To investigate the cellular immune response after a 4th vaccination dose, virus neutralizing 
capacity against newly emerging variants in bio-banked samples and correlates of interest. 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 23 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
3. Organisational and administrative aspects of the trial 
3.1. Sponsor 
Sponsor: 
University of Cologne 
Represented by: 
Prof. Dr. med. Oliver A. Cornely 
Dep. I for Internal Medicine 
University Hospital of Cologne 
Kerpener Strasse 62 
50937 Cologne 
Germany 
3.2. Principal Coordinating Investigator 
Principal Coordinating 
Investigator (PCI): 
Prof. Dr. med. Oliver A. Cornely 
 
see above 
3.3. Statistics 
Statistician: 
Assoc. Prof. Priv.-Doz. Dr. Franz König 
Center for Medical Statistics, Informatics and Intelligent Systems 
Medical University of Vienna 
Spitalgasse 23 
1090 Vienna 
Austria 
3.4. Data Monitoring Committee 
According to section 3.4 of the accompanying master protocol: 
A Data Monitoring Committee of independent experts will be set up. It consists of two physicians and 
a statistician who are not involved in the conduct of the trial and who are independent from the 
sponsor. The task of the DMC is to monitor the safety of the trial subjects in the clinical trial by 
periodically assessing the safety and efficacy of the trial therapy, and to monitor the integrity and 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 24 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
validity of the data collected and the conduct of the clinical trial. Details with list of members will be 
described in the DMC charter. 
Throughout this process of surveillance, the DMC provides the sponsor with recommendations on 
trial continuation (including termination, temporary suspension or modification) based on the data 
collected. The data necessary for the DMC to fulfil this function is provided by the sponsor as 
determined in the DMC charter. Amongst other datasets, these must include listings providing 
information on serious adverse events and further variables that the DMC considers necessary. The 
frequency of the committee data review meetings and other working procedures will be detailed in a 
separate charter. The independent Data Monitoring Committee is responsible for: 
a) Reviewing unblinded interim results of trials according to the protocols under the master 
protocol. 
b) Advising the Steering Committee if, in their view, the randomised data provide evidence that 
may warrant a change in the protocol (e.g., modification or cessation of one or more of the 
treatment arms). 
The DMC will hold meetings at pre-defined times. Meetings of the DMC will be conducted through 
video conference, by phone, or in-person as deemed necessary by the DMC. If scheduling problems 
prevent a timely meeting, review and comment may alternatively be conducted by e-mail. One 
member will be appointed chair of the DMC and be responsible for summarising DMC meetings and 
informing the Principal Coordinating Investigator and sponsor about meetings and recommendations 
for adaptation and/or operational setting of the trial in writing. 
3.5. Central Coordinating Office (CCO) 
According to section 3.5 of the accompanying master protocol: 
The CCO is responsible for the overall coordination of the study, including: 
i. 
Study planning and organisation of Steering Committee meetings; 
ii. 
Ensuring necessary regulatory and ethics committee approvals; 
iii. 
Development of Standard Operating Procedures and computer systems; 
iv. 
Monitoring overall progress of the study; 
v. 
Provision of study materials to regional or local coordinating centres (RCCs/LCCs); 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 25 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
vi. 
Monitoring and reporting safety information in line with the protocol and regulatory 
requirements; 
vii. 
Dealing with technical, medical, and administrative queries from LCCs. 
3.6. Regional/Country specific Coordinating Centre (RCC) 
Refer to section 3.6 of the accompanying master protocol for details: 
The RCCs are responsible for: 
i. 
Ensuring necessary regulatory and ethics committee approvals; 
ii. 
Provision of study materials to LCCs; 
Dealing with technical, medical, and administrative queries from LCCs. 
3.7. Local Clinical Centres (LCC) 
Refer to section 3.7 of the accompanying master protocol: 
The LCC lead investigator and LCC clinic staff are responsible for: 
i. 
Obtaining all relevant local permissions (assisted by the CCO); 
ii. 
All trial activities at the LCC, including appropriate training and supervision for clinical staff; 
iii. 
Conducting trial procedures at the LCC in line with all relevant local policies and procedures; 
Dealing with enquiries from participants and others. 
3.8. Steering Committee 
According to section 3.8. of the accompanying master protocol: 
A Steering Committee (SC) will be set up to continuously monitor the progress of the trial. The Trial 
Steering Committee is responsible for: 
i. 
Agreement of the final protocol and protocols under the master protocol and the data 
analysis plans; 
ii. 
Reviewing progress of the trials under the master protocol and ensuring that the appropriate 
oversight and monitoring in conducting the clinical trials under the master protocol; 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 26 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
iii. 
Deciding on incorporation of new trials to the master protocol and approval of the new 
protocols; 
iv. 
Deciding on protocol changes of trials under the master protocol, which includes adding or 
removing arms as necessitated by the adaptive nature of the trials; 
v. 
Review and approval of study publications and sub-study proposals. 
A list of the members of the Steering Committee is given in a separate Steering Committee Manual 
and is constituted by the VACCELERATE Coordination Board. 
3.9. Advisory Committee 
According to section 3.9. of the accompanying master protocol: 
An Advisory Committee will be set up to provide guidance and advice on the planning, the 
development of the trial and the evaluation of results. This committee will include external experts in 
the field and patient representatives. 
A list of the members of the Advisory Committee is given in a separate Advisory Committee Manual 
and is constituted by the VACCELERATE Ethical and Scientific Advisory Board. 
3.10. Study laboratories and other technical services 
Anti-RBD, anti-N and neutralising antibody samples will be analysed in a central lab in Ireland 
(Europe): 
UCD Centre for Experimental Pathogen Host Research (CEPHR) 
University College 
Belfield 
Dublin 4 
Ireland 
 
Cellular immunity by qPCR will be analysed in a central lab in Spain (Europe): 
Laboratorio de Referencia en Inmunologia 
Modular 79, 1er piso 
Instituto de Salud Carlos III 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 27 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Cara Majadahonda-Pozuelo km2 
Majadahonda, Madrid, 28220  
Spain 
 
Samples for biobanking will be stored at a facility in Belgium (Europe): 
BIOBANK ANTWERP 
with legal entity part of University Hospital Antwerp 
Drie Eikenstraat 655 
B-2650 Edegem 
Belgium 
 
A laboratory manual will specify preparation, handling, storage and shipment of samples. 
 
3.11. Central organisation units 
Project management: 
Clinical Trials Centre Cologne (in conjunction with Division of 
Infectious Disease II, Department I of Internal Medicine, University 
Hospital Cologne) 
Monitoring: 
Clinical Trials Centre Cologne (Germany), ECRIN (other countries) 
Data management: 
Clinical Trials Centre Cologne 
Safety management: 
Clinical Trials Centre Cologne 
Scientific advice: 
VACCELERATE Consortium 
represented by its Coordination Office 
Herderstraße 52 
D-50935 Cologne 
Germany 
Tel.:  
+49 221 478 85523 
Fax: 
+49 221 478 32702 
E-mail: 
info@vaccelerate.eu 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 28 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
3.12. Principal investigators and trial sites 
According to section 3.12. of the accompanying master protocol: 
VACCELERATE is a clinical research network for the coordination and conduct of COVID-19 vaccine 
trials. The network is comprised of academic institutions from all over Europe: The consortium is led 
by the University of Cologne, Germany, and currently includes 26 national partners in 16 EU-member 
states & 5 countries associated to the EU Horizon 2020 research programme. 
VACCELERATE conducts capacity mapping of new clinical trial sites & laboratories with standardised 
methods and protocols, and provides standardised educational measures, training and quality 
management for harmonised vaccine trials. It already holds information more than 400 clinical trial 
sites in 32 European countries (EUVAP: https://euvap.eu/ as of 12th July 2021). Harmonisation of data 
acquisition across all network sites enables open data exchange for valid data analysis. 
The network aims to address research questions of interest, such as vaccine efficacy in virus variants, 
trials in children, pregnant women, immuno-compromised patients, trials on combination of 
different vaccines etc. 
Specific to this trial: 
This clinical trial will be conducted as a multicentre trial in up to 24 sites in up to 8 countries in 
Europe (approx. 3 sites per country). A separate country and site listing will be provided. If necessary, 
further qualified sites may be recruited. A list of the trial sites with names of the principal 
investigators is given separately. The listing of trial sites, principal investigators and sub-investigators 
and further trial staff, will be kept and continuously updated in a separate list, independent from the 
trial protocol. The final version of this list will be attached to the final report of the clinical trial. 
 Time points for booster vaccinations in this trial (i.e., 3rd and 4th vaccination in Part A and B 
respectively) are based on current vaccination policies in the EU, i.e., there is a minimum interval of 1 
month since the last (2nd or 3rd) vaccination, with longer intervals as per local regulation or practice. 
3.13. Requirements for principal investigators and trial sites 
According to section 3.13. of the accompanying master protocol: 
For each clinical trial under the master protocol and depending on the prerequisites and needs of 
each protocol, the appropriate number of centres and countries will be selected. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 29 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
All principal investigators and trial sites participating in the trials under the master protocol are 
required to have previous experience with the conduct of clinical trials with vaccines, to have 
experience in the regulatory process of their respective country, adequate facilities, sufficient 
dedicated and trained staff, access to target population and COVID-19 testing available on site. The 
documents for the qualification of the clinical trial team are filed in the sponsor´s Trial Master File 
(TMF) as well as in the Investigator Site File at the local site (ISF). 
Centres selected will be validated by the VACCELERATE network according to approved standardised 
validation procedures. 
Specific to this trial: 
All principal investigators and trial sites participating in this trial are required to have previous 
experience with the conduct of clinical trials with vaccines, to have experience in the regulatory 
process of their respective country, adequate facilities, sufficient dedicated and trained staff, access 
to target population and COVID-19 testing available on site. The documents for the qualification of 
the clinical trial team are filed in the sponsor´s Trial Master File (TMF) as well as the local trial site´s 
Investigator Site File (ISF). 
3.14. Financing 
According to section 3.13. of the accompanying master protocol for further details: 
A detailed financial plan does not form part of the trial protocol. The financial plan is archived 
separately; it may be needed to gain approvals or to accompany contracts or it may be requested for 
submission to the ethics committee. However, all sources of financing must be listed there. 
 
This clinical trial receives full financial support through a grant from the European Commission. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 30 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4. Trial conduct 
4.1. General aspects of trial design 
According to section 4.1 of the accompanying master protocol: 
This is a randomised, adaptive, multicentre, Phase II master protocol evaluating different booster 
strategies in individuals against SARS-CoV-2. This protocol allows testing of different booster 
strategies to assess their immunogenicity and safety against SARS-CoV-2 and its variants. Different 
trial populations, different vaccines, additional doses and vaccination time points, and extended 
follow-up visits can be added throughout amendments of the master protocol. The master protocol 
contains a common control group that does not receive a 3rd nor a 4th vaccination, i.e., no booster 
dose at all. This control group is used for exploratory comparison as applicable. The trial implements 
a specific safety monitoring strategy for this control group. 
Specific to this trial: 
This is a randomised controlled, adaptive, multicentre Phase II protocol evaluating the 
immunogenicity and reactogenicity of different strategies of a 3rd (Part A) and 4th (Part B) 
vaccination dose ("boosters") in individuals ≥75 years after a primary vaccination series against 
SARS-CoV-2. This trial foresees testing of different vaccines as a 3rd or 4th vaccination dose (also 
referred to as booster vaccinations) for comparative assessment of their immunogenicity and safety 
against SARS-CoV-2 wild-type and variants in the elderly, a usually neglected population. Additional 
vaccines and extended follow-up visits can be added by means of amendments to this sub-protocol. 
As stated in the master protocol, this trial implements a specific safety monitoring strategy for the 
control group (see below). 
Subjects in each cohort will be randomised to one of the arms planned in an equal allocation ratio. 
In each cohort, the number of arms foreseen at this moment is 2; therefore, the allocation ratio 
within in each cohort will be 1:1. 
Arms can be withdrawn or added as deemed necessary according to the criteria specified in this 
protocol. 
Figure 1 shows a schematic flow chart of the trial design. 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 31 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Figure 1: Flow chart of the trial design, 4th vaccination dose in Part B 
 
 
A: AstraZeneca vaccine ChAdOx-1-S   B: BioNTech vaccine Comirnaty®   M: Moderna vaccine Spikevax® 
D14: day 14 
M3/6/12: month 3/6/12 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 32 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4.1.1. 
Time schedule 
The time schedule of this trial is detailed in table 1. 
Table 1: Time schedule of the trial (Part A and Part B) 
 
End of study will be on the day of database lock, as planned 30 days after the last patient last visit. 
4.2. Discussion of trial design 
According to section 4.2 of the accompanying master protocol: 
Trials under the master protocol allow testing of different booster strategies to assess their 
immunogenicity and safety against SARS-CoV-2 and its variants. Different trial populations, different 
vaccines, additional doses and vaccination time points, and extended follow-up visits can be added 
throughout amendments of the master protocol or trials under the master protocol. 
Specific to this trial: 
This trial is a sub-protocol embedded within the master protocol EU-COVAT: A Randomised, 
Controlled, Adaptive, Multicentre, Phase II Master Protocol Evaluating Different Booster Strategies in 
Individuals Already Vaccinated Against SARS-CoV-2. 
This is a randomised controlled, adaptive, evaluator-blinded multicentre Phase II protocol evaluating 
immunogenicity and reactogenicity of different booster strategies in individuals 75 years and older 
after a primary vaccination series against SARS-CoV-2. This trial foresees testing of different vaccines 
as a 3rd (Part A) or 4th (Part B) vaccination dose (for details see Section 4.7.1, Tables 2.1 and 2.2) for 
comparative assessment of their immunogenicity and safety against SARS-CoV-2 wild-type and 
variants in the elderly, a usually neglected population. Different vaccines and extended follow-up 
visits can be added by means of amendments to this trial. As stated in the master protocol, this trial 
implements a specific safety monitoring strategy for a control group as implemented in the EU-
COVAT subprotocol with the EudraCT no.: 2021-004889-35, a separate sub-protocol embedded 
First patient first visit (FPFV): 
November 2021 
Last patient first visit (LPFV): 
September 2022 
Last patient last visit (LPLV): 
September 2023 
Analysis 
October 2022 (Primary endpoint analysis) 
End of study definition 
The end of study will be on the day of database lock. 
End of trial 
November 2023 
Final study report: 
December 2023 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 33 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
within the EU-COVAT master protocol (see below). This control group is used for exploratory 
comparison. 
Vaccines used in this trial will be those already marketed and in their commercial presentation. In 
Part B the sample size planned is adequate for a precise enough estimation of the immune response 
after a 4th vaccination dose.  
4.3. Risk-Benefit Assessment 
4.3.1. 
Known Potential Risks 
According to section 4.3.1 of the accompanying master protocol: 
The risks will be based on the SmPC of each vaccine and any risk described in the literature. 
Specific to this trial, Part B: 
Side effects that have been reported with the Pfizer-BioNTech Comirnaty and Moderna Spikevax 
vaccine include: 
• 
Headache, diarrhoea, nausea, vomiting, abdominal pain 
• 
Arthralgia, myalgia 
• 
Injection site pain, fatigue, chills, pyrexia 
• 
injection site swelling, injection site redness 
• 
Injection site pruritus 
• 
Lymphadenopathy 
• 
Hypersensitivity reactions (e.g. rash, pruritus, urticaria, angioedema), including anaphylaxis 
• 
Decreased appetite, insomnia, lethargy, asthenia, malaise, dizziness 
• 
Acute peripheral facial paralysis, paraesthesia, hypoaesthesia 
• 
Myocarditis, pericarditis 
• 
Hyperhidrosis, night sweats 
• 
Erythema multiforme 
• 
Pain in vaccinated extremity 
• 
Extensive swelling of vaccinated limb, facial swelling 
These may not be all of the possible side effects of Pfizer-BioNTech's BNT162b2 (Comirnaty®) and 
Moderna mRNA-1273 (Spikevax®) vaccines. Possible hitherto unknown side effects that cannot be 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 34 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
excluded when combinations of different vaccines are used, although there is a sufficient lag period 
between 2nd, 3rd and 4th vaccination doses as per enrolment criteria so that no overlap of acute side 
effects is expected. Serious and unexpected side effects may occur. Both vaccines are still being 
studied in clinical trials. 
Respective potential risks will be described for other vaccines that may be included in the trial at a 
later stage. 
4.3.2. 
Known Potential Benefits 
According to section 4.3.2 of the accompanying master protocol, modified for Part B: 
At present, the level and duration of protection against SARS-CoV-2 infection provided by the 
available vaccines and authorised vaccination schedules are not known, especially in the context of 
newly emerging VOCs. Therefore, 4th vaccine dose as an additional (i.e. second) booster may be 
needed to provide and/or maintain immunity against SARS-CoV-2 and, thus, may provide a benefit to 
subjects. Also, this protection may probably differ between age strata and the need for and the 
timing of administering a booster vaccination dose is unknown. Evaluation of the immune response 
to booster doses in different populations and at different timepoints after primary vaccination series 
will provide a rationale for further phase III trials and vaccination programs. Trial-specific benefits will 
be described in the respective sub-protocol. 
Specific to this trial: 
Older subjects are at very high risk of severe disease and death due to SARS-CoV-2 infection. 
Furthermore, the duration and grade of protection provided by the currently available vaccines, 
especially in the elderly above 75 years of age, is not known but immune response to vaccines of 
older subjects may indeed be low. We know that the vaccines presently available induce a strong 
immune response and there is evidence that this is related to the level of prevention of moderate 
and severe COVID-19. The use of booster doses may be needed to maintain immunity against SARS-
CoV-2 and may therefore provide a benefit to subjects receiving booster vaccination doses. 
4.3.3. 
Assessment of Potential Risks and Benefits 
According to section 4.3.3 of the accompanying master protocol: 
While the efficacy and safety profile of the approved COVID-19 vaccines are subject to investigation 
when used as homologous or heterologous boost regimen, it is not expected that risks associated to 
booster vaccination doses of a COVID-19 vaccine will increase compared to the standard, i.e., 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 35 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
authorised, vaccine administration. Therefore, participants volunteering for this trial are not 
considered to be at additional risk related to the administration of the COVID-19 vaccines available. 
Any contraindication or precaution of use of any of the vaccines included in the trials under the 
master protocol will be considered and included in participant’s selection criteria of each sub-
protocol. A risk-benefit assessment will be performed in each protocol under the master protocol. 
Participants in this study are exposed to some general risks. The participants may be subjected to 
additional blood sampling without representing any relevant harm or discomfort. Collection of other 
samples, like oropharyngeal or nasal swabs, or urine sampling, are considered not to cause any 
significant harm. 
Participants’ identities will be protected, and personal health information (PHI) held securely. No 
directly identifiable data will be stored in the clinical trial database, and the participant lists will be 
stored separately and secured at the local study sites. The risk of unauthorised persons accessing 
participant’s PHI will be kept to a minimum, and measures will be taken to keep PHI confidential in 
accordance with legal requirements. 
Specific to this trial: 
Benefits and risks of COVID-19 vaccination are well known and are described in sections 4.3.1 and 
4.3.2. Although there is only limited published information on the administration of booster doses 
after standard vaccination, it is expected that risks posed by subsequent doses are similar to those 
observed with the standard vaccination regimen. On the contrary, administration of booster doses 
may confer a higher and longer protection against COVID-19 in this vulnerable population and some 
protection against VOCs. 
Potential benefit/risk balance will be assessed prior to the addition of other vaccines in the trial. 
4.4. Selection of trial population 
According to section 4.4 of the accompanying master protocol: 
VACCELERATE has established a European volunteer registry for vaccine trials. A continuously 
growing number of interested individuals have expressed their interest in this registry. This will allow 
for fast and efficient recruitment of trial participants. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 36 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Subjects to be recruited in the trials under the master protocol will be those already fully 
vaccinated(all-comers) with no contra-indication against any of the vaccine products in the trial at 
the moment of inclusion and as specified in respective sub-protocol. 
Within each trial, subjects will be stratified (as applicable and specified per sub-protocol) by: 
• 
Gender (female/male). 
• 
Vaccine product used for primary vaccination (BNT162b2; mRNA-1273; ChAdOx-1-S; other) 
• 
Immune status (competent, immunocompromised). 
Documented history of prior COVID-19 infection. 
Reasons for gender distribution 
Subjects included in this trial are expected to be similar to subjects that have been vaccinated within 
the vaccination programs in each country. Therefore, gender distribution in the present trial is 
expected to be similar to that of the general vaccinated population and no restrictions will be made 
with relation to biological sex, unless included in the selection criteria. 
Specific to this trial, Part B: 
Subjects included in this trial are expected to be similar to subjects that have been vaccinated within 
the vaccination programs in each country. Gender distribution will be therefore similar to that of the 
population vaccinated so far. Accordingly, Part B (for details see section 4.7.1, Tables 2.1 and 2.2) will 
include 550 subjects that are randomised 1:1 to either BNT162b2 or mRNA-1273. Recruitment of 
cohorts will be closed when the pre-planned number for each cohort is reached. Stratification is 
planned according to the pre-study vaccination series eligible for Part B (primary vaccination plus 3rd 
vaccine dose (= first booster), gender (female/male), documented history of prior COVID-19 infection 
(yes/no)), as applicable and defined also by enrolment criteria. 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 37 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
 
4.4.1. 
Inclusion criteria 
• 
Subject is ≥75 years old. 
• 
For study entry in Part B the subject was vaccinated with one of the following vaccination 
regimens (1st + 2nd + 3rd dose): 
o BNT162b2 + BNT162b2 + BNT162b2 
o BNT162b2 + BNT162b2 + mRNA-1273  
o mRNA-1273 + mRNA-1273 + mRNA-1273 
o mRNA-1273 + mRNA-1273 + BNT162b2 
o ChAdOx-1-S + ChAdOx-1-S + BNT162b2 
o ChAdOx-1-S + ChAdOx-1-S + mRNA-1273  
 
• 
The last dose of the above vaccinations must have been administered at least 1 month prior 
to study entry. Vaccination status should be documented in the source data and will be 
captured in the eCRF. 
• 
No contra-indication against any of the vaccine products in the trial. 
• 
Written informed consent from subject has been obtained. 
4.4.2. 
Exclusion criteria 
• 
Prior to study entry the subject got vaccinated with a regimen not included in the above list. 
• 
Last anti-SARS-CoV-2 vaccine dose administered less than one month prior to study entry. 
• 
Vaccination against a disease other than COVID-19 within 2 weeks prior to study entry. Only 
exception: Influenza vaccination which is allowed at any time. 
• 
Subjects with any significant or uncontrolled disease posing a risk due to vaccination as 
judged by the investigator. 
• 
Current immunosuppressive therapy, for example continuous glucocorticosteroid treatment 
equivalent to >10 mg/day prednisolone. 
• 
Subject simultaneously participates in another clinical trials or has participated in the past 30 
days. 
• 
Subjects unable to report solicited adverse events. 
• 
Subject participates or participated in Part A of this trial. 
• 
Subject with any contraindications to the vaccines in the trial. A list of contraindications as 
listed in the Summary of medicinal Product Characteristics (SmPC, the Fachinformation in 
Germany), if appropriate. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 38 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• 
Use of drugs with significant interaction with the investigational product according to the 
SmPC or similar documents. 
• 
Diseases or findings that may have a significant effect on the target variables and which may 
therefore mask or inhibit the therapeutic effect under investigation. 
• 
Subject had COVID-19 or tested positive for SARS-CoV-2 within the last 3 months.  
• 
Persons with any kind of dependency on the principal investigator or employed by the 
sponsor or principal investigator. 
• 
Legally incapacitated persons. 
• 
Persons held in an institution by legal or official order. 
4.5. Withdrawal of trial subjects after trial start 
According to section 4.5. of the accompanying master protocol: 
A participant may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioural, or compliance/adherence 
reasons. This is expected to be uncommon. When a participant withdraws before study completion, 
the reason for withdrawal is to be documented in the eCRF and in the source document. If the 
reason for withdrawal from the study is withdrawal of consent, then no additional assessments are 
allowed. The participant will be permanently discontinued from the study intervention and the study 
at that time. If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. If a 
participant withdraws from the study, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the study site records. 
4.6. Closure of trial sites/Premature termination of the clinical trial 
4.6.1. 
Closure of trial sites 
According to section 4.6.1 of the accompanying master protocol: 
Study sites will be closed upon study completion. A study site is considered closed when all required 
documents and study supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 39 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4.6.2. 
Premature termination of trial 
According to section 4.6.2. of the accompanying master protocol: 
The sponsor has the right to terminate the trial prematurely if there are any relevant medical or 
ethical concerns, or if completing the trial is no longer practicable. If such action is taken, the reasons 
for terminating the trial must be documented in detail. All trial subjects at the time of termination 
shall undergo a final examination which must be documented, if deemed necessary for patient 
safety. The sponsor must be informed without delay if any principal investigator has ethical concerns 
about continuation of the trial. 
Premature termination of the trial will be considered if: 
• 
The risk-benefit assessment for trial subjects changes markedly. 
• 
It is no longer ethical to continue treatment with the IMP. 
• 
The sponsor considers that the trial must be discontinued for safety reasons (e.g., on the 
advice of the DMC). 
• 
Results of other research show that one of the trial treatments is superior or inferior to 
another. 
• 
It is no longer practicable to complete the trial. 
The sponsor decides on whether to discontinue the trial in consultation with the PCI, DMC, SC, 
Advisory Board and trial statistician, as applicable. 
4.7. Treatment 
4.7.1. 
Treatments to be given 
According to section 4.7.1. of the accompanying master protocol: 
Vaccines to be evaluated in sub-protocols under the master protocol will be vaccines with marketing 
authorization at the time of each sub-protocol design and/or vaccines still in clinical development, 
i.e., pre-authorisation. Vaccines to be administered in the intervention and control arms will be 
defined in each sub-protocol depending on the hypothesis and the booster strategies tested. 
Subjects allocated to control arms could receive a 3rd vaccine dose or not receive a 3rd vaccine dose. 
Specific to this trial, Part B: 
Study vaccines will be given as a 4th dose in subjects already vaccinated with defined prior 
vaccination strategies (with BNT162b2, mRNA-1271 or ChAdOx-1-S) as per eligibility criteria. The 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 40 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
vaccines to be evaluated as 4th vaccination (second booster) dose will be BNT162b2 (Comirnaty®) and 
mRNA-1273 (Spikevax®). For a detailed overview of all cohorts and arms in this study please refer to 
Tables 2.1 and 2.2 below. 
In Part B there is a minimum interval of 1 month between the on-study 4th vaccination dose and 
the 3rd pre-study vaccination, with longer intervals as per local regulation or practice. 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 41 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Table 2.1: Intervention in Part A _no longer active - for information only_   
Cohort 
Vaccination prior 
to study entry 
Arm 
Study intervention: 
3rd vaccination dose 
Part A  
with Cohorts 1 to 3 
closed to further 
recruitment as of 
January 13, 2022 
Cohort 1 
BNT162b2 + 
BNT162b2 
1 
BNT162b2 
2 
mRNA-1273 
 
Cohort 2 
mRNA-1273 + 
mRNA-1273 
3 
BNT162b2 
 
4 
mRNA-1273 
 
Cohort 3 
ChAdOx-1-S +  
ChAdOx-1-S 
5 
BNT162b2 
 
6 
mRNA-1273 
 
Control 
Control arm of the EU-COVAT subprotocol EudraCT 
no. 2021-004889-35, a separate sub-protocol 
embedded within the EU-COVAT master protocol, 
will be used for a descriptive comparison. 
 
 
Table 2.2: Intervention in Part B - 4th vaccination dose 
Cohort 
Vaccination prior 
to study entry 
Arm 
Study intervention:  
4th vaccination dose* 
Cohort 4 
BNT162b2 + 
BNT162b2 + 
BNT162b2 
7 
BNT162b2 
8 
mRNA-1273 
Cohort 5 
BNT162b2 + 
BNT162b2 + 
mRNA-1273 
9 
BNT162b2 
10 
mRNA-1273 
Cohort 6 
mRNA-1273 + 
mRNA-1273 + 
mRNA-1273 
11 
BNT162b2 
12 
mRNA-1273 
Cohort 7 
mRNA-1273 + 
mRNA-1273 + 
BNT162b2  
13 
BNT162b2 
14 
mRNA-1273 
Cohort 8 
ChAdOx-1-S + 
ChAdOx-1-S + 
BNT162b2 
15 
BNT162b2 
16 
mRNA-1273 
Cohort 9 
ChAdOx-1-S + 
ChAdOx-1-S + 
mRNA-1273 
17 
BNT162b2  
18 
mRNA-1273 
* administered at least 1 month after the 3nd pre-study vaccination. 
 
 
4.7.2. 
Description of investigational medicinal product 
Trade name: Comirnaty® 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 42 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
INN (International Nonproprietary Name)/active substance: 
COVID-19 mRNA vaccine(nucleoside-modified). 
ATC-Code: J07BX 
Presentation: vaccine shot for intramuscular injection. 
Dose: 30 µg (0.3 mL after dilution). 
Manufacturer (or marketing authorisation holder if applicable): Pfizer-BioNTech. 
Already approved for the following indication: Protection against COVID-19 infection. 
Please note: Can be modified in composition to address emerging VOCs. 
 
Trade Name: Spikevax® 
ATC-code: J07BX03 
Presentation: Dilution, vaccine shot for intramuscular injection. 
Dose: 100 µg (0.5 mL after dilution); please note that the 50 µg (0.25 mL) dose is not used in this 
trial - see dose justification further down below. 
Manufacturer: Moderna. 
Already approved for the following indication: Protection against COVID-19 infection. 
Please note: Can be modified in composition to address emerging VOCs. 
 
4.7.2.1. 
Manufacture of the investigational medicinal product 
Not applicable. 
4.7.2.2. 
Labelling of investigational medicinal product 
Vaccines to be administered in this trial are already marketed. Therefore, labelling is carried out as 
approved in each country. Preparation of the dose of each vaccine will be done according to the 
respective SmPC. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 43 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4.7.3. 
Storage of investigational medicinal product 
All study vaccines must be stored in a secured location with no access for unauthorised personnel 
and at controlled temperatures as indicated on the commercial labels and manufacturer instructions. 
If study vaccine is exposed to temperatures outside the specified temperature range according to 
SmPC as per market authorization, then the affected supplies will be destroyed in line with locally 
regulated procedures and replaced with new supplies. 
Instructions for the preparation, handling and storage will be those described in the SmPC of 
COMIRNATY and SPIKEVAX approved by Regulatory Authorities. The investigator is responsible for 
ensuring that all study vaccines received at the site is inventoried and accounted for throughout the 
study. The study vaccine administered to the participant must be documented on the vaccine (drug) 
accountability form. All study vaccine will be stored and disposed of according to the manufacturer’s 
instructions. Destruction of vaccines will be recorded on appropriate drug destruction logs. 
4.7.4. 
Compliance with treatment/Dispensing and return of investigational medicinal product 
This study will be conducted within hospitals and/or experienced commercial clinical trial sites. 
Treatment is administered at site and participants will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered in 
the clinic will be recorded in the source documents and captured in the eCRF. Deviation(s) from the 
trial-specific dosage regimen as given in section 4.7.2 are not permitted. Dates of intervention will 
also be recorded. 
4.7.5. 
Assignment of trial subjects to treatment groups 
According to section 4.7.5 of the accompanying master protocol: 
Subject fulfilling selection criteria will be randomised to the different treatment arms in the trial 
through a central procedure. Randomisation will be stratified according to: 
• 
Vaccine product used for primary vaccination (detailed in the concerned sub-protocol). 
• 
Trial Site. 
• 
Gender (female/male). 
• 
Immune status (competent, immunocompromised as applicable in the concerned sub-
protocol). 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 44 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• 
Documented history of prior COVID-19 infection (none, asymptomatic, symptomatic/pre-
vaccination or post-vaccination). 
The participants are randomised into the study arms as defined in each sub-protocol. Randomisation 
will be implemented by a 24/7-Internet service (ALEA 17.1, FormsVision BV, Abcoude, NL) and 
prepared centrally by the Institute of Medical Statistics and Computational Biology (IMSB) at the 
University of Cologne. 
Specific to this trial, Part B: 
Subjects fulfilling selection criteria will be randomised to 4th dose through a central procedure. 
Subjects will be randomised in a 1:1 ratio to one of the two treatment groups: 
• 
4th vaccination with BTN162b2 (Comirnaty®), including modified vaccine product. 
• 
4th vaccination with mRNA-1273 (Spikevax®), including modified vaccine product. 
Randomisation will be stratified as described below:  
Stratification is planned according to the pre-study vaccination series eligible for Part B (primary 
vaccination plus 3rd vaccine dose (= first booster), gender (female/male), documented history of prior 
COVID-19 infection (yes/no), as applicable and defined also by enrolment criteria. 
In this trial, there is no stratification in the randomisation 
• 
according to the status of immune competency of the trial subject. 
• 
according to trial site. 
 
4.7.6. 
Selection of dosage of investigational medicinal product 
Treatment will be given as a single shot using the approved dose and mode of administration of each 
vaccine included in this trial. 
4.7.6.1. Justification of the 0.5 ml (100 µg) booster dose of Moderna's Spikevax COVID-
19 vaccine (mRNA-1273) 
In the present EU-COVAT-1_AGED study, subjects aged 75 years or older receive a booster dose of 
0.5 ml (100 µg) mRNA-1273. This investigational booster dose of mRNA-1273 is identical with the 
first and second mRNA-1273 dose administered in the primary vaccination series. 22,23 
Under the jurisdictions of both FDA and EMA, mRNA-1273 is approved for a booster dose (3rd 
vaccination) of 0.25 ml (50 µg) six months after completion of the primary vaccination series in 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 45 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
individuals 18 years of age or older.22,23 An mRNA-1273 dose of 0.5 ml (100 µg) one month after the 
primary vaccination series is approved in severely immunocompromised individuals, such as after 
organ transplantation or at an equivalent level of immunocompromise. 22,23 
The rationale for the lower booster dose of 0.25 ml (50 µg) was provided by Moderna, Inc. as follows: 
"- Goal was to use optimal effective dose for boosting. 
  - Lower booster doses than those used for primary series of other vaccines [was] shown to    
     reactivate immune memory. 
  - Lower booster dose increases worldwide vaccine supply of mRNA-1273." 24 
Safety, especially with regard to a potential myocarditis risk of the booster, was not a driver in 
choosing the 0.25 ml (50 µg) booster dose instead of 0.5 ml (100 µg). However, myocarditis/ 
pericarditis is indeed a concern in individuals of male sex aged under 30 years receiving either of the 
currently approved mRNA COVID-19 vaccines. Surveillance studies showed that myocarditis reporting 
rates were 40.6 cases per million second doses of mRNA COVID-19 vaccines administered to males 
aged 12−29 years and 2.4 per million second doses administered to males aged ≥30 years; reporting 
rates among females in these age groups were 4.2 and 1.0 per million second doses, respectively.25,26 
In comparison to the Pfizer/BioNTech BNT162b2 mRNA vaccine, there are 21.5 excess cases of 
myocarditis (including pericarditis) per million doses of the Moderna vaccine in males aged 18 to 39 
years 0 to 7 days after the second dose25. Accordingly, the FDA Fact Sheet provides the following 
information for mRNA-1273: "Postmarketing data demonstrate increased risks of myocarditis and 
pericarditis, particularly within 7 days following the second dose. The observed risk is higher among 
males under 40 years of age than among females and older males. The observed risk is highest in 
males 18 through 24 years of age."22 
As outlined above, the target population of the present EUCOVAT-1_AGED study (75 years or 
older) does not fall into the at-risk group for an increased level of myocarditis/pericarditis after 
vaccination with mRNA-1273. Besides, there is further reassuring information available regarding 
the potential myocarditis/pericarditis risk of a booster dose (3rd dose) as compared to the second 
dose of an mRNA vaccine: "Extrapolation from [Israeli surveillance] data obtained with the Pfizer-
BioNTech COVID-19 vaccine […] suggests that the risk of myocarditis for the Moderna COVID-19 
Vaccine following a third dose several months following the primary vaccination series is not 
associated with an unacceptable risk of myocarditis/pericarditis. […] … the risk of 
myocarditis/pericarditis appears to be more similar after the administration of the third dose to the 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 46 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
risk observed after the first dose." 27 Of note, vaccinees with the Pfizer/BioNTech vaccine BNT162b2 
receive identical doses for the booster as for the first and second administrations28. 
With a booster dose of mRNA-1273 identical to the doses of the primary vaccination series very old 
individuals (> 75 years) with assumed immunosenescence29 may thus benefit from increased 
immunogenicity while not being exposed to a currently detectable increased risk of 
myocarditis/pericarditis. 
Meanwhile, Moderna Tx. has communicated data that demonstrate markedly increased levels of 
Omicron neutralizing antibodies after the 100 µg mRNA-1271 booster (3rd) dose as compared to the 
50 µg dose30. 
A full booster (3rd) dose (0.5 ml, 100 µg) of mRNA-1273 was administered in two subgroups of the 
COV-BOOST trial, either following primary vaccination series with twice ChAdOx1-S or twice 
BNT162b2. The median age in the ChAdOx1-S subgroup (n=112) was 70.2 years and 65.0 years in the 
BNT162b2 group (n=111)31. Data on a full dose mRNA-1273 booster in the very old above 75 years of 
age is thus still missing. 
 
4.7.7. 
Time of administration and adjustments to dosage of the investigational medicinal 
product in the individual trial subject 
Not applicable. 
4.7.8. 
Blinding 
No blinding is foreseen in this trial. 
4.7.8.1. 
Unblinding 
Not applicable. 
4.7.9. 
Previous and concomitant medication 
According to section 4.7.8. of the accompanying master protocol: 
There are no previous or concomitant medication prohibited in this protocol. Any medication at the 
time of enrolment or received during the study must be recorded along with: 
• 
Reason for use. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 47 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• 
Date of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
4.7.9.1. 
Rescue therapy for emergencies 
For any adverse drug reaction that is deemed an emergency (e. g. severe allergic reactions), rescue 
therapy according to standard of care will be applied and the trial subject be followed up until full 
resolution of the adverse drug reaction. 
4.7.10. 
Continuation of treatment after the end of the clinical trial 
Not applicable. 
4.8. Efficacy and safety endpoints 
According to section 4.8 of the accompanying master protocol: 
Main overarching immunogenicity variables to be included in the sub-protocols are those standard 
tests showing the immune response to SARS-CoV-2 vaccines, as described below. 
Overarching safety variables of interest include unsolicited and solicited adverse events day 14, as 
applicable, after a 4th vaccination dose administration and severe adverse events for the duration of 
the trial. 
Specific to Part B of this clinical trial: 
This trial aims to evaluate immunogenicity and safety of a 4th vaccination dose of COVID-19 vaccines 
in older (≥75) subjects having received a primary vaccination series plus a 3rd vaccine dose > 1month 
ago at the time of enrolment. 
4.8.1. 
Measurement of efficacy and safety endpoints in Part B 
4.8.1.1. 
Primary endpoints 
According to section 4.8.1.1 of the accompanying master protocol: 
• Rate of 2-fold antibody titre increase 14 days after the 4th vaccination dose measured by 
quantitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wild-type virus. 
4.8.1.2. 
Safety endpoints 
• Unsolicited AEs until the end of trial. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 48 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• Solicited AEs for 7 days after a 4th vaccination dose. 
• Rate of severe adverse events (AEs) Grade ≥3 according to the National Cancer Institute Common 
Toxicity Criteria up to three months after a 4th vaccination dose (Note: Adverse events Grade ≥3 
must be reported as SAE by using study specific SAE reporting process, see section 7.3). 
4.8.1.3. 
Secondary endpoints 
• Change in neutralizing antibody titre (Virus Neutralisation Assay) against wild-type 14 days after 
a 4th vaccination dose, to be determined in a subgroup only. 
 
• Change in neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern 14 
days after a 4th vaccination dose, to be determined in a subgroup only. 
 
• Antibody titre level 12 months after a 4th vaccination dose measured by a quantitative enzyme-
linked immunosorbent assay (anti-RBD-ELISA assay). 
 
• Neutralizing antibody titre (Virus Neutralisation Assay) against wild-type SARS-CoV-2 at 12 
months after a 4th vaccination dose, to be determined in a subgroup only. 
 
• Neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern at 12 months 
after a 4th vaccination dose, to be determined in a subgroup only. 
4.8.1.4. 
Exploratory endpoints 
• Change in cellular immune response measured by qPCR 14 days after 4th booster dose, to be 
determined in a subgroup only. 
• Neutralising capacity measured by neutralising activity against newly emerging variants in bio-
banked samples after a 4th vaccination dose, to be determined in a subgroup only. 
• Correlates of humoral immune response, cellular immune responses and viral neutralising 
capacity against SARS-CoV-2 variants of concern (VOCs), to be determined in a subgroup only. 
 
Please note that the size of the above-mentioned subgroups (sections 4.8.1.3 and 4.8.1.4) is 
targeted to be 200 subjects each. Analysis will be performed in all samples if additional funding 
becomes available. 
4.8.1.5. 
Safety data in Part B 
• 
Solicited AEs (as defined in section 7.1.7) for 7 days after an on-trial 4th vaccination dose will 
be collected by using a diary (electronic or paper-based). Information collected will be 
entered into the eCRF by designated study site personnel. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 49 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• 
Unsolicited adverse events will be collected during visits up to the end of trial upon an open 
question by the investigator to the participant. Those unsolicited AEs graded as severe by the 
subject will be evaluated by the investigator to define the relationship with administered 
vaccines. Only those considered related will be accounted for and reported. Serious adverse 
events (SAEs) will be collected through an open question. 
• 
SADRs will be collected and reported during the visits 3 to 5, reported spontaneously by the 
subject or elicited after an open question about any event of interest since the previous visit. 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
 
 
 
 
 
Page 50 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
  
 
 
University of Cologne 
4.9. Description of visits 
Patient visits are carried out at the following timepoints (see table 3.1). Subjects will be followed for 1 year after on-study vaccine administration. 
 
 
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
 
 
 
 
 
Page 51 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
  
 
 
University of Cologne 
Table 3.1: Visit schedule in Part B 
Visit number 
1 
2 
3 
4 
5 
Procedure 
Screening, enrolment, 
baseline 4th dose 
Immune response 
evaluation 
Follow up 
Follow up 
End of study 
Day ± window 
0 
14 ±2 days 
after 4th dose 
3 months ± 3 days 
after 4th dose 
6 months ± 3 days 
after 4th dose 
12 months ± 3 days 
after 4th dose 
Screening for eligibility 
Informed consent a 
X 
 
 
 
 
Demographics and  
medical historyf 
X 
 
 
 
 
Eligibility check  
X 
 
 
 
 
Baseline procedures 
 
 
 
 
 
Concomitant medication 
review  
X 
X 
 
 
 
Physical exam 
X 
Xb 
 
 
 
Vital signs 
X 
Xb 
 
 
 
Immunogenicity 
 
 
 
 
 
Anti-RBD & anti-N IgG 
(ELISA) 
X 
X 
 
 
X 
Neutralising activity 
(wildtype) c 
X 
X 
 
 
X 
Neutralising activity 
(VOC) c 
X 
X 
 
 
X 
Cellular response (qPCR 
assay) c 
X 
X 
 
 
 
Biobanking d 
X 
X 
X 
X 
X 
IMP administration 
 
 
 
 
 
Vaccination§ 
X 
 
 
 
 
Safety 
 
 
 
 
 
AE/SAE e 
X 
X 
X 
X 
X 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
 
 
 
 
 
Page 52 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
  
 
 
University of Cologne 
AE, adverse events; SAE, serious adverse event 
a: Informed consent must be obtained before obtaining consent for biobanking and secondary data use, and any other procedure to be undertaken. 
b: will be performed at visit 2 only upon SAE 
c: samples taken from all subjects, analysis performed in a subgroup only. Analysis will be performed in all samples if additional funding becomes available. 
d: for secondary use defined in informed consent; also optional at visit 1 and visit 2: at trial site and upon agreement of trial participant additional blood collection 
for biobanking of peripheral blood mononuclear cells (PBMC) as per informed consent 
e: solicited AEs are recorded by trial participant till Day 7 and records will be collected at visit 2 (Day 14) by trial staff and captured in eCRF; unsolicited AEs are 
recorded by trial investigator until the end of trial as described in this protocol. 
f: medical history includes information on prior SARS-CoV-2 infection and COVID-19 disease if applicable; name of SARS-CoV-2 variant should be documented if 
known. 
§Administration of 4th vaccination dose after blood sampling for immunogenicity and cellular immunity during visit 1. Trial participant is observed for any adverse 
reaction for at least 15 min or according to standard of care upon vaccination. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 53 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4.9.1. 
Rationale for assessment procedures 
Monitoring of immunogenicity at 14 days has been a standard time-point for COVID-19 vaccines and 
the immunogenicity test performed at 3, 6 and 12 months are considered adequate for evaluating 
the duration of immunity in this population vaccinated against COVID-19. 
Subjects will be evaluated for reactogenicity events during the first 14 days after 4th dose 
administration (solicited AEs until Day 7; unsolicited AEs up to Day 14 and until the end of trial) and 
thereafter every 3 months after 4th vaccination dose according to visit schedule (see Table 3) for SAEs 
reported. This is considered sufficient for safety monitoring of already marketed vaccines.  
4.9.2. 
Pharmacokinetics/Determination of drug levels 
Not applicable. 
4.9.3. 
Biobanking 
Serum, plasma, immune cell activation and optional isolation of peripheral blood mononuclear cells 
(PBMCs) will be prepared from whole blood collection. Samples will be used for determining the 
primary and secondary endpoints. Samples will be centrally collected and stored at the determined 
biobank – see section 3.10. The biobank will distribute samples to determined central laboratories 
(section 3.10) and store the samples for additional research. Trial subjects are informed in detail 
about the use of bio-banked samples in the informed consent form. The preparation, storage 
conditions and logistics of the samples for biobanking are described in a separate laboratory manual. 
4.9.4. 
Ethics for accessing and using biobank samples 
Scientists wishing to access biobank samples collected from this trial must obtain a positive vote 
from their concerned ethical committee in accordance with the Declaration of Helsinki (2013) prior 
to undertaking an intended research project. This positive vote must be provided to the sponsor 
and/or their representative before release of the samples for the intended research projects by the 
sponsor. The final decision about releasing biobank sample request lies with the sponsor and/or their 
representative. Further details about request, access and usage of biobank samples are provided in a 
separate biobanking concept. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 54 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4.10. Data quality assurance 
4.10.1. 
Monitoring 
According to section 4.10.1 of the accompanying master protocol: 
The trial sites will be monitored to ensure the quality of the data collected. The objectives of the 
monitoring procedures are to ensure that the trial subject’s safety and rights as a study participant 
are respected, that accurate, valid and complete data are collected, and that the trial is conducted in 
accordance with the trial protocol, the principles of GCP and local legislation. 
The exact extent of the monitoring procedures is described in a separate monitoring manual. 
Monitoring will follow a risk-adapted on-site monitoring strategy (Brosteanu et al). 
All principal investigators agree that the monitor regularly visits the trial site and assure that the 
monitor will receive appropriate support in their activities at the trial site, as agreed in separate 
contracts with each trial site. The declaration of informed consent (see section 5.5) includes a 
statement allowing the monitor to compare the case report forms (CRFs) with the trial subject’s 
medical records (doctor’s notes, ECGs, laboratory printouts etc.). 
The principal investigator will secure access for the monitor to all necessary documentation for trial-
related monitoring. The aims of the monitoring visits are as follows: 
• 
To check the declarations of informed consent. 
• 
To monitor trial subject safety (occurrence and documentation/reporting of AEs and SAEs). 
• 
To check the completeness and accuracy of entries on the CRFs. 
• 
To validate the entries on the CRFs against those in the source documents (source data 
verification, SDV). 
• 
To perform drug accountability checks. 
• 
To evaluate the progress of the trial. 
• 
To evaluate compliance with the trial protocol. 
• 
To assess whether the trial is being performed according to GCP at the trial site. 
• 
To discuss with the principal investigator aspects of trial conduct and any deficiencies found. 
A monitoring visit report is prepared for each visit describing the progress of the clinical trial and any 
problems. The principal investigator will reasonably consider the corrective and preventive measures 
suggested by the monitor. All participant data relating to the study will be recorded on electronic 
CRFs. The investigator is responsible for verifying that data entries are accurate and correct by 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 55 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
electronically signing the CRF. Guidance on completion of eCRFs will be provided in the Trial Master 
File. The investigator must permit study-related monitoring, audits, REC/NCA review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and processes 
(e.g., risk-based initiatives in operations and quality such as risk management and mitigation 
strategies and analytical risk-based monitoring), methods, responsibilities, and requirements, 
including handling of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the monitoring plan. The sponsor or designee is responsible for the data 
management of this study, including quality checking of the data. The sponsor assumes 
accountability for actions delegated to other individuals (e.g., contract research organisations). 
 
Specific details for this trial are outlined in a separate monitoring plan. 
4.10.2. 
Audits/Inspections 
According to section 4.10.2. of the accompanying master protocol:  
As part of quality assurance, the sponsor has the right to audit the trial sites and any other 
institutions involved in the trial. The aim of an audit is to verify the validity, accuracy and 
completeness of data, to establish the credibility of the clinical trial, and to check whether the trial 
subject’s rights and trial subject safety are being maintained. The sponsor may assign these activities 
to persons otherwise not involved in the trial (auditors). These persons are allowed access to all trial 
documentation (especially the trial protocol, case report forms, trial subjects’ medical records, drug 
accountability documentation, and trial-related correspondence). 
The sponsor and all trial sites involved undertake to support auditors and inspections by the 
competent authorities at all times and to allow the persons charged with these duties access to the 
necessary original documentation. 
All persons conducting audits will keep all trial subject data and other trial data confidential. 
4.11. Documentation 
According to section 4.11. of the accompanying master protocol: 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 56 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Principal Investigators will oversee and coordinate data collection, entry, and protection. 
Trial-specific data will be collected by the clinical trial staff using designated source documents. 
Standard GCP practices will be followed to ensure accurate, reliable, and consistent data collection. 
Any correction to source documentation needs to ensure a valid correction trail, including leaving 
original entries legible and signed or initialled dated corrections. If source documents involve 
electronic patient files, then an audit trail of changes to documentation must be available. 
All trial data must be verifiable to the source documentation. All source documents will be kept in a 
locked facility at the clinical site. Source documents include but are not limited to: 
• 
Informed Consent Forms; 
• 
Reported laboratory results; 
• 
Lists of adverse events; 
• 
Lists of concomitant medication; 
• 
Documentations of existing conditions. 
Medical records will be archived by the trial site as per local regulations. 
All data relevant to the trial are documented by the Principal Investigators (PI) or designees in 
corresponding electronic case report forms (eCRFs). All eCRFs and laboratory reports will be 
reviewed by the clinical team to ensure that they are accurate and complete. 
The Principal Investigators may authorise trial staff members to sign the eCRFs to confirm accuracy of 
the data. At the completion of the follow-up visits, final sign-off must be performed by the Principal 
Investigators. 
4.11.1. 
Data management 
According to section 4.11.1. in the accompanying master protocol: 
Data management activities will be conducted by CTCC (Clinical Trials Centre Cologne). 
The IT infrastructure and data management staff will be provided by the CTCC. The trial database will 
be developed and validated before data entry based on standard operating procedures at the CTCC. 
The data management system is based on commercial trial software and stores the data in a 
database. All changes made to the data are documented in an audit trail. The trial software has a 
user and role concept that can be adjusted on a trial-specific basis. The database is integrated into a 
general IT infrastructure and safety concept with a firewall and backup system. The data are backed 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 57 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
up daily. After completion and cleaning of data, the database is locked and the data are exported for 
statistical analysis. 
The data will be entered online at the trial sites via the Internet. Plausibility checks are run during 
data entry, thereby detecting many discrepancies immediately. The CTCC Data Management will 
conduct further checks for completeness and plausibility and will clarify any questions with the trial 
sites electronically via the trial software. These electronic queries have to be answered by the trial 
site without unreasonable delay. Further details will be specified in the data management manual. A 
guidance document and web-based training for data entry in the eCRF will be provided. 
All participant data relating to the study will be recorded on electronic CRFs unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data) via secure platform transfer or encrypted e-
mail. The investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the CRF. 
4.11.2. 
Archiving 
According to section 4.11.2. in the accompanying master protocol: 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 10 years after study completion unless local regulations or 
institutional policies require a longer retention period, this applies to both the investigator and 
sponsor part of the TMF. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Digitisation of paper-based documentation must meet regulatory requirements, especially 
concerning quality assurance, completeness and correctness. Paper-based documentation must not 
be destroyed after digitisation and must be archived according to applicable regulations. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 58 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
5. Ethical and regulatory aspects 
5.1. Ethics committee 
The clinical trial will not be started before favourable opinion of the competent ethics committee. 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus on ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines. 
• 
Applicable ICH Good Clinical Practice (GCP) guidelines dated July 1996 and its Addendum 
E6(R2) of June 2017. 
5.2. Applicable laws and regulations and ethical considerations 
The protocol, protocol amendments, ICF, SmPCs and other relevant documents (e.g., 
advertisements) must be submitted to a Research Ethics Committee (REC) and National Competent 
Authority (NCA) by the sponsor and reviewed and approved by the REC and NCA before the study is 
initiated. The present trial protocol and any amendments were and will be prepared in accordance 
with the principles of the Declaration of Helsinki. 
Protocols and any substantial amendments to the protocol will require National Competent 
Authority (NCA) approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The sponsor will be responsible for the following: 
• 
Providing written summaries of the status of the study to the REC/NCA annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
• 
Notifying the REC/NCA of SAEs or other significant safety findings as required by REC/NCA 
procedures. 
Providing oversight of the conduct of the study at the sites and adherence to requirements of ICH 
guidelines, the REC/NCA, European Directive 2001/20/EC and European Regulation 536/2014 for 
clinical trials on medicinal products, and all other applicable local regulations. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 59 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
5.3. Legislation and guidelines  
The present clinical trial will be conducted in accordance with the principles of the guidelines for 
Good Clinical Practice (ICH-GCP) and applicable legislation. All principal investigators and other staff 
involved in the trial will be informed that local and national competent authorities as well as 
competent authorities from foreign countries and authorised representatives of the sponsor have 
the right to review trial documentation and the trials subject´s medical records at any time under 
confidentiality (see also section 4.10.2). 
5.4. Notification of the authorities, approval and registration 
According to section 5.4. in the accompanying master protocol: 
Before the start of the clinical trial, all necessary documentation will be submitted to the responsible 
national competent authority for approval. Local authorities will be notified according to applicable 
regulations. 
Before the trial is started, it will be registered under a register approved by the World Health 
Organisation (WHO) (http://www.who.int/ictrp/en/). 
In addition, trials conducted at the University Hospital and the University of Cologne have to be 
registered at “Site Management System” (https://clinicalsite.org/). 
5.5. Obtaining informed consent from trial subjects 
The investigator or his/her representative will explain the nature of the study, including the risks and 
benefits, to the participant in a comprehensible language and answer all questions regarding the 
study. This includes consent to data access by representatives of the sponsors (e.g., monitors, 
auditors) and by the competent authorities. 
Participants must be informed that their participation is voluntary. Participants will be required to 
give a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and those of the ethics 
committee. Trial subjects will be informed that withdrawal of consent is possible at any time without 
giving reasons and without jeopardising the subject´s well-being. Subjects must not be enrolled into 
the trial unless they have given their informed consent in writing to participate in the study. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 60 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
The medical record must include a statement that written informed consent was obtained, before 
the participant was enrolled in the study, and the date on which the consent was obtained. The 
authorised person (investigator or sub-investigator) obtaining the informed consent must also sign 
the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their participation 
in the study if relevant. A copy of the ICF(s) must be provided to the participant. 
The ICF will contain a separate section that addresses the secondary use of data and of remaining 
samples for optional exploratory research. 
The investigator or authorised designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. The participant can 
opt to document their agreement to allow any data and remaining specimens to be used for 
secondary exploratory research. Participants who decline to participate in this optional research will 
not provide this separate signature. 
5.6. Insurance of trial subjects 
All trial subjects enrolled are insured in accordance with regulatory requirements. The insurer's 
name, contact details, and policy number will be provided in the participant’s information sheet. 
5.7. Data protection 
The provisions of data protection legislation will be observed. It is assured by the sponsor that all 
investigational materials and data will be pseudonymised in accordance with data protection 
legislation. 
Trial subjects will be informed that their pseudonymised data will be handled in accordance with 
applicable law. Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred. 
Sponsor staff that require access to personal data will agree to keep confidentiality. Data relevant to 
fulfil the objectives of the study will be collected only. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 61 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
The level of disclosure must also be explained to the participant who will be required to give consent 
for their data to be used as described in the informed consent. The participant must be informed 
that his/her medical records may be examined by Clinical Quality Assurance auditors or other 
authorized personnel appointed by the sponsor and by inspectors from regulatory authorities. Study 
participants have the right to request access to their personal data and the right to request 
rectification of incorrect or incomplete data. 
Exploratory research data will not be returned to participants or investigators, unless required by law 
or local regulations. Privacy and confidentiality of data generated in the future on stored samples will 
be protected by the same standards applicable to all other clinical data. 
Subjects who do not agree to data handling as described in the informed consent form will not be 
enrolled into the trial. 
The sponsor of each sub-protocol is responsible for data protection. Contact details for the sponsor’s 
data protection officer are described respectively in each sub-protocol and in the trial specific ICF. 
Data processing will be performed by the Clinical Trials Center Cologne at the University of Cologne 
(CTCC, Gleueler Str. 269, 50935 Cologne). 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 62 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
6. Statistical methods and sample size calculation (Part B) 
Below, the statistical analyses are outlined for the present trial. More details will be provided in the 
statistical analysis plan (SAP), which will be finalised before the first interim analysis. 
6.1. Statistical and analytical plan 
6.1.1. 
Analysis populations 
According to section 6.1.1 in the accompanying master protocol: 
The primary dataset for analysis is derived from the intention-to-treat (ITT; Full Analysis Set, FAS) 
population. This dataset includes all trial subjects enrolled into the trial and randomised. 
The evaluation is carried out strictly in accordance with the allocation by randomisation. 
The secondary dataset for analysis is derived from the per-protocol (PP) population. This dataset 
includes all trial subjects who were treated according to protocol and reached a defined endpoint in 
the trial. 
The tertiary dataset for analysis is the safety population. This population includes all trial subjects 
who received any IMP or other trial treatment. 
Details about analysis population are specified in the respective section of the concerned sub-
protocol. 
Specific to this trial: 
Primary Analysis Population 
The primary analysis population is a modified intention-to-treat population (mITT), consisting 
of all randomised subjects whose primary endpoint measurement is available. 
Safety Population 
The population for the safety analysis will be all randomised subjects that received the study 
vaccine. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 63 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
6.1.2. 
Description of trial subject groups 
For Part B, all statistical analyses described below will be performed separately from Part A of the 
trial. A full Statistical Analysis Plan (SAP) will be finalised for Part A and Part B separately before any 
analysis is performed. 
Subjects are randomised to one of the two intervention groups BNT162b2 (Comirnaty) and mRNA-
1273 (Spikevax). 
Patient demographics and baseline characteristics will be summarised on the modified ITT (mITT) set, 
overall and by treatment cohort and randomised treatment arms, by means of summary descriptive 
statistics. 
For qualitative variables (e.g., gender (biological sex)), absolute and relative frequencies will be 
calculated per treatment group. Data will be visualised by bar plots. For quantitative data (e.g., age), 
the number of valid observations, mean, standard deviation, standard error, median, minimum and 
maximum will be calculated for each treatment group and each time point separately. Data will be 
visualised by waterfall, boxplots and histograms. 
6.1.3. 
Primary analysis 
All primary analyses will be on the mITT set. The primary endpoint is the rate π of 2-fold antibody 
titre increase following the 4th vaccine dose measured by quantitative enzyme-linked 
immunosorbent assay (Anti-RBD-ELISA) against wildtype virus at 14 days after the 4th vaccine dose 
(versus immediately before vaccination). 
For the binary primary endpoint absolute and frequencies in percent will be calculated for each study 
part (Part A, Part B) and treatment group. For each study part and treatment group the 
corresponding rate together with simultaneous 95% confidence intervals will be calculated. Exact 
Clopper Pearson confidence intervals at Bonferroni adjusted level of (1-0.05/2) *100% will be 
provided. 
In additional supportive analysis, the primary endpoint will be performed in the same way for each 
cohort separately, i.e., further exploratory analyses will be performed based on different pre-
vaccination series. Especially, within each cohort the multiplicity adjustment will be implemented. 
The data will be visualised with bar charts. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 64 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
6.1.3.1. 
Analysis time point for primary endpoint 
For the second Part B (4th vaccination, cohorts 4-9), the primary endpoint analysis will be triggered as 
soon as for all patients the primary endpoint data (14 days after study vaccination) has been 
captured. 
Analysis time (planned): October 2022 (primary endpoint analysis). 
6.1.4. 
Secondary analyses 
The geometric mean titres (GMT) following and the 4th dose vaccination measured by quantitative 
enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wildtype virus at 14 days after the 4th 
dose will be compared between the boosters BNT162b2 and mRNA-1273 computing two-sided 95% 
confidence intervals for the GMR or differences of GMC on log scale (base 10). Based on the 
confidence intervals, an equivalence test will be performed. The equivalence margins are the 1.5 to 
0.67-fold change between the GMT in the two boost arms corresponding to a margin for the 
differences of GMC on log scale (base 10) which results in a margin ±0.174. This is suggested in 
Section 2.3.1 of the EMA/117973/2021 Reflection paper on the regulatory requirements for vaccines 
intended to provide protection against variant strain(s) of SARS-CoV-2.11 Because GMT are expected 
to have a skewed distribution, the log10 scaled GMT values will be compared using a linear model 
with factors booster (BNT162b2/mRNA-1273) as well as the stratification variables used in the 
randomisation. As this is a secondary analysis, no adjustment for multiplicity will be made. For Part B 
in further secondary analyses, it will be explored whether switching or keeping the same vaccination 
for the 4th vaccination (study intervention in B) compared to the 3rd vaccination will have an effect. In 
this model the interaction between cohort and study drug will be included as well. 
6.1.5. 
Exploratory analyses 
Different combinations of vaccines (1st, 2nd, 3rd and the on-study 4th vaccine dose) will be assessed for 
equivalence in terms of humoral and/or cellular immune response against VOC compared to 
approved homologous COVID-19 vaccination. The analysis strategy will be as described in 6.1.3 and 
6.1.4. Furthermore, exploratory comparisons of the primary endpoint as well as the humoral and/or 
cellular immune response against VOC will be performed between cohorts as well as between the 
treatment groups within cohorts. As an option only in Part B, it is planned to run comparisons with 
the control group from EU-COVAT subprotocol with the EudraCT no.: 2021-004889-35. The control 
group of EU-COVAT subprotocol EudraCT no. 2021-004889-35 will be only utilised if the sample size 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 65 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
in the age group of interest is sufficiently large. Otherwise, the data of the control group will be 
reported only descriptively. These analyses will be performed similar to the analysis described in 
6.1.4. 
6.1.6. 
Multiplicity adjustment 
The different pre-study vaccine combinations are considered as inferentially independent, as the 
prior vaccination strategy cannot be influenced and there will be no extrapolation from one cohort to 
another one for the primary analysis. Therefore, the multiplicity adjustment concerning the primary 
endpoint will be applied within each cohort, but there will be no further adjustment for having 
several cohorts within the accompanying master protocol. 
6.1.7. 
Subgroup analyses 
Subgroup analyses will be performed by gender and documented history of prior COVID-19 infection 
(yes/no), respectively. 
6.1.8. 
Interim Analysis 
An interim analysis will be performed as soon as 50% of participants have been recruited within Part 
B. In the interim analysis, Haybittle–Peto boundaries of 0.0001 will be used to calculate the 
confidence intervals for the primary analysis in each cohort. There will be no stopping because of 
differences in the primary endpoint analysis at interim analysis. 
If a treatment arm is dropped due to safety concerns, a sample size re-allocation to the remaining 
arms might be considered. However, in this case the overall sample is still fixed as initially planned, 
i.e., the total sample size over all cohorts in Part B is bounded by 550 patients in total. 
The interim analysis will allow for a sample size reassessment in the interim analysis, e.g., to re-
estimate the standard deviation. If a sample size reassessment is performed, the conditional error 
principle is implemented to control the FWER for the primary endpoint. 
Note: In case enrolment is impacted by the dynamics of the pandemic and/or by public vaccination 
policies, the interim analysis may be omitted. 
6.2. Safety Analysis 
Summaries and analysis of safety data will be presented for the Safety Analysis Population.  

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 66 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
An adverse event (AE) is any untoward medical occurrence in a trial subject administered an IMP. 
There does not necessarily have to be a causal relationship with this treatment. The adverse event 
may be, but is not restricted to: a new illness, worsening of a sign or symptom following trial-specific 
treatment (here 4th vaccination dose), the clinically significant abnormal results of an examination 
(e.g., laboratory findings, electrocardiogram) or deterioration of a pre-existing medical condition, or 
a combination of two or more of these factors, as applicable. 
AEs will be documented starting from baseline visit and until the last scheduled visit after the 4th 
vaccine dose unless otherwise defined in the sub-protocol specific visit schedule. 
 
The safety endpoints includes  
• 
Unsolicited AEs until the end of trial. 
• 
Solicited AEs for 7 days after a 4th vaccination dose. 
• 
Rate of serious adverse events (SAEs) Grade ≥3 according to the National Cancer Institute 
Common Toxicity Criteria up to three months after a 4th vaccination dose. 
Listing will be provided on a subject level reporting the severity and relationship to study vaccination 
(related / unrelated). Absolute and numbers in percent will be given per intervention group. 
Different types of AEs will be grouped. Additionally, the safety data will be reported descriptively for 
each intervention and cohort separately.  
6.3. Sample size calculation 
The number needed has been calculated at 550 for Part B (i.e., 600 overall for Part A and B, and 
including a potential dropout rate of 8-10% for Part B). 
 
Sample size calculation with multiplicity adjustment: 
Sample size calculation has been carried out for the primary endpoint for the rate π of 2-fold 
antibody titre increase following 4th dose vaccination. As two-sided simultaneous 95% confidence 
intervals for this rate should be calculated separately for each randomized group in Part B a 
Bonferroni adjustment was used in the sample size calculation accordingly.  
 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 67 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
When the sample size is 250 per randomized group, two-sided simultaneous 95% confidence 
intervals (with Bonferroni adjustment for 2 simultaneous confidence intervals in a cohort) for a 
proportion using the large sample normal approximation will extend no more than ±7.1% 
(percentage points) from the observed proportion. E.g., if the observed proportion is 50% (where 
the confidence interval is widest), the confidence interval ranges from about 42.9% to 57.1%. 
To adjust for potential dropouts in Part B of about 8-10%, the total sample size for Part B (=4th 
vaccination and Cohorts 4-9) was set to 550. 
In the table below the precision for the simultaneous two-sided 95%-confidence intervals (with the 
same assumptions as described above) is shown for varying sample sizes. This shows which 
precision could be achieved in the different cohorts based on the previous vaccination strategy (see 
also inclusion criteria for Part B). 
 
Sample Size, n 
250 
200 
150 
125 
90 
50 
40 
Expected Proportion, π 
0.500 
0.500 
0.500 
0.500 
0.5 
0.500 
0,5 
Distance from Proportion to Limit, ω 
0.071 
0.079 
0.092 
0.100 
0.118 
0.158 
0.177 
 
 
Software program(s): 
All statistical analyses will be conducted with statistical software like SAS 9.4. (or higher) and R 
3.6.3. (or higher). 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 68 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
7. Safety 
7.1. Definitions of adverse events and adverse drug reactions 
7.1.1. 
Adverse event 
According to section 7.1.1. in the accompanying master protocol: 
An adverse event (AE) is any untoward medical occurrence in a trial subject administered an IMP. 
There does not necessarily have to be a causal relationship with this treatment. The adverse event 
may be, but is not restricted to: a new illness, worsening of a sign or symptom following trial-specific 
treatment (here 4th vaccination dose), the clinically significant abnormal results of an examination 
(e.g., laboratory findings, electrocardiogram) or deterioration of a pre-existing medical condition, or 
a combination of two or more of these factors, as applicable. 
AEs will be documented starting from baseline visit and until the last scheduled visit after the 4th 
vaccine dose unless otherwise defined in the sub-protocol specific visit schedule. 
7.1.1.1. 
Pregnancy 
Since in this trial only adults ≥75 years of age are enrolled, pregnancies are excluded as female 
participants are considered post-menopausal. 
7.1.2. 
Adverse drug reaction 
According to section 7.1.2. in the accompanying master protocol: 
All adverse events judged by either the investigator or the sponsor as having a reasonable 
suspected causal relationship to an investigational medicinal product qualify as adverse drug 
reactions (ADR). 
7.1.3. 
Serious adverse events and serious adverse reactions 
According to section 7.1.3. in the accompanying master protocol: 
A serious AE (SAE) or serious ADR (SAR) is any untoward medical occurrence that at any dose: 
1. Results in death; 
2. Is life-threatening at the time of the event; 
3. Requires inpatient hospitalisation or prolongation of existing hospitalisation; 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 69 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
4. Results in persistent or significant disability/incapacity; 
5. Is a congenital anomaly or birth defect; 
6. Is any other medical important event in the opinion of the investigator. 
Additionally, those adverse events Grade ≥3 which are assessed as related to IMP by the investigator, 
will be reported as SAE by indicating “other medical important event“ as seriousness criterion on the 
SAE report form and eCRF, if no other seriousness criteria apply.  
Inpatient hospitalisation is defined as any stay in hospital that includes at least one night (midnight to 
06:00). Admission to hospital as an inpatient planned before the first admission of the IMP is not 
considered as SAE but must be documented in a proper manner in the trial subject’s medical records 
and CRF (see Section 7.1.1). 
EXCEPTIONS: the following events are not considered as SAE requiring immediate reporting to the 
sponsor: 
• 
The participant is formally admitted to a hospital for medical reasons with no seriousness 
criterion and does not require overnight hospitalisation. 
• 
Elective or previously scheduled surgery or medical treatment; hospitalisation for social or 
administrative reasons. 
• 
Pre-existing diseases or present conditions detected prior to start of study drug 
administration and which do not worsen. 
7.1.4. 
Unexpected adverse drug reaction 
According to section 7.1.4. in the accompanying master protocol: 
An unexpected ADR is an ADR of which the nature or severity, outcome or frequency is not 
consistent with the applicable product information available for the IMP. ADRs listed in the 
Investigator’s Brochure or Summary of Product Characteristics (SmPC, Information Sheet for Health 
Professionals) are not regarded as unexpected. 
7.1.5. 
Suspected unexpected serious adverse reactions 
According to section 7.1.5. in the accompanying master protocol: 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse event the nature or 
severity of which is not consistent with the product information available for the IMP (e.g., SmPC), 
is regarded as serious, and has at least a possible causal relationship with the IMP. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 70 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
7.1.6. 
Adverse events of special interest 
According to section 7.1.6. in the accompanying master protocol: 
An adverse event of special interest (AESI) is an adverse event that may not be serious but has special 
meaning or importance for the clinical trial. AESI will be recorded if considered described specifically 
in a sub-protocol under the master protocol. 
Specific to this trial: 
No AESI are considered in this trial, besides solicited adverse events. 
7.1.7. 
Solicited Adverse Events 
According to section 7.1.7. in the accompanying master protocol: 
Solicited adverse events are a list of events/symptoms that participants are specifically asked to 
record. Injectable drugs (i.e., vaccines) are associated with a number of well-characterised reactions 
referred to as ‘solicited adverse events’, including local and systemic manifestations. Solicited 
adverse events will be collected by the participants in an (electronic or paper-based) diary. 
 
Table 1: Solicited Adverse Events 
TYPE 
EVENT 
Local AEs 
(injection or infusion site)  
Injection site redness  
Injection site swelling 
Injections site pruritus  
Injection site urticaria  
Injection site pain 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 71 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Systemic Clinical AEs 
following injections / 
infusions  
Chills, hyperhidrosis, night sweats, pyrexia 
Asthenia, malaise, fatigue 
Myalgia, Arthralgia 
Pain in vaccinated extremity 
Paraesthesia, hypoaesthesia 
Extensive swelling of vaccinated limb, facial swelling 
Generalized rash 
Nausea, vomiting, diarrhoea, abdominal pain 
Generalized pruritus 
Headache 
Dizziness 
Insomnia 
Decreased appetite 
 
Intensity of solicited AEs will be graded by the trial participant as mild, moderate and severe 
according to CTCAE grading 1 to 3. When a solicited AE is reported by the participant in the diary, 
then the subject will contact the investigator as per instructions. 
7.2. Documentation and follow-up of adverse events 
According to section 7.2. in the accompanying master protocol: 
The sponsor ensures that all persons involved in the treatment of trial subjects are adequately 
informed of the responsibilities and actions required when AEs occur. Trial subjects will be asked at 
each visit whether they have experienced AEs or SAEs. AEs will be documented in the trial subject’s 
medical records and in the eCRF. 
For the procedure of SAE-reporting see section 7.2.2. and section 4.8.1.5 for safety data. 
7.2.1. 
Documentation of adverse events and adverse drug reactions 
According to section 7.2.1. in the accompanying master protocol: 
All AEs will be documented in the eCRF including all information listed below. 
AEs occurring within the following time frame will be documented: 
• 
between baseline visit and the last visit of the individual subject. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 72 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
The AE is documented in the eCRF including the following information: 
• 
AE verbatim; 
• 
Date and time of onset and resolution; 
• 
Severity; 
• 
Causal relationship with IMP/study treatment; 
• 
Seriousness; 
• 
Action taken; 
• 
Outcome. 
If a causal relationship between the AE and the IMP is suspected, trial subjects who develop adverse 
events must be monitored until all symptoms have been subsided, pathological laboratory values 
have returned to pre-event levels, a plausible explanation is found for the AE, the trial subject has 
died, or the study has been terminated for the trial subject concerned, as applicable. AEs are 
followed up for up to 30 days after last visit of the trial subject, if applicable. 
7.2.1.1. 
Exceptions from AE documentation 
According to section 7.2.1.1. in the accompanying master protocol: 
Pre-existing diseases (before administration of the IMP) are not documented as adverse events but 
as concomitant diseases. New diseases and pre-existing diseases that worsen during the trial are 
documented as AEs. 
7.2.2. 
Severity of the adverse event 
According to section 7.2.2. in the accompanying master protocol: 
The CTCAE (Common Terminology Criteria for Adverse Events) grading table (v5.0) will be used by 
trial investigators to classify adverse events. It comprises the following categories: 
• 
Grade 1: Mild. 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
• 
Grade 2: Moderate. 
Minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental 
activities of daily living* (ADL). 
• 
Grade 3: Severe or medically significant but not immediately life-threatening. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 73 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• 
Grade 4: Life-threatening consequences. 
Urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
(Apart from grading methods each death is to be assessed as grade 5). 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
7.2.3. 
Causal relationship between adverse event and investigational medicinal product 
According to section 7.2.3 in the accompanying master protocol: 
The investigator will assess therefore every AE whether a causal relationship with the IMP and/or 
study procedure can be assumed or not. The assessment includes consideration of the nature and 
type of reaction, the temporal relationship with the IMP, the clinical status of the trial subject, 
concomitant medication and other relevant clinical factors. If the event is considered as a symptom 
or sign of an underlying disorder, no causal relationship will be assumed. 
Every AE will be assessed (eCRF/SAE-Report) according to the causality determinations of CIOMS VI-
Group (Council for International Organizations of Medical Sciences) as follows: 
• 
Related: There is a reasonable possibility that the AE may be related to the IMP. 
• 
Not related: There is not a reasonable possibility that the AE may be related to the IMP. 
A report on an event which cannot be judged because information is insufficient or contradictory or 
has not been judged will be regarded as related. 
Specific to this trial: 
The investigator will assess therefore every AE whether a causal relationship with the following IMPs 
and/or study procedure can be assumed or not. 
IMP: 
• 
BTN162b2 (Comirnaty). 
• 
mRNA-1273 (Spikevax). 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 74 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Vaccines can be modified in composition to address emerging VOCs. 
 
Please follow the below clarifications from the master protocol for the assessment of relatedness. 
7.2.3.1. 
Related 
• 
A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory rechallenge procedure if necessary. 
• 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfil this definition. 
• 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, but which could also be explained by concurrent disease or other 
drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
• 
A clinical event, including laboratory test abnormality, reported as an adverse reaction, 
about which more data is essential for a proper assessment or the additional data are under 
examination. 
• 
A report suggesting an adverse reaction which cannot be judged because information is 
insufficient or contradictory, and which cannot be supplemented or verified. 
7.2.3.2. 
Unrelated 
• 
A clinical event, including laboratory test abnormality, with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
7.3. Reporting of serious adverse events, adverse events of special interest, pregnancy and 
changes in risk-benefit assessment 
According to section 7.3. in the accompanying master protocol: 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 75 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
Every SAE that occurs from the time of IMP administration until up to the last visit, also as specified 
in the respective sub-protocol, must be documented in the appropriate part of the CRF and reported 
on an SAE form to the sponsor. 
Instructions in case of pregnancy do not apply in this trial since female participants eligible for this 
trial are post-menopausal. 
7.3.1. 
Reports from the investigator to the sponsor 
According to section 7.3.1 in the accompanying master protocol: 
 
The investigator will inform the sponsor of the occurrence or receipt of knowledge of the occurrence 
of an SAE without delay, at the latest within 24 hours of being made aware of the event. 
The study specific SAE report forms must be completed and submitted by fax or e-mail to the Clinical 
Trials Center Cologne (CTCC, ZKS Köln) to which the sponsor has delegated the SAE management 
procedures: 
SAE Dedicated Fax: 
+49 221 478 7984 
SAE Reporting E-Mail: 
ZKS-Safety@uk-koeln.de  
 
In the interest of participants’ safety, follow-up for up to 30 days after the individual participant’s 
study termination (individual study termination is defined as last visit) is required for SAEs that are 
not sufficiently resolved at the participant’s final trial visit, if applicable. 
7.3.2. 
Assessment of SAEs by the sponsor 
According to section 7.3.2. in the accompanying master protocol: 
All cases of suspected SAEs are assessed by the sponsor with regard to seriousness (see Section 
7.1.3), causality (see Section 7.2.3) and expectedness (see Section 7.1.4), regardless of the 
investigator’s assessments. 
7.3.3. 
Unblinding for SUSAR when treatment is blinded 
In contrast to section 7.3.3. in the accompanying master protocol, no blinding is foreseen in this trial. 
Therefore, unblinding processes do not apply. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 76 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
7.3.4. 
Notification of ethics committee and competent authority 
According to section 7.3.4. in the accompanying master protocol: 
Every SUSAR that becomes known in a clinical trial will be reported by the sponsor to the competent 
authority and the ethics committee. 
All reporting requirements are regulated in the appropriate document (manual or SOP). 
Further, according to the corresponding section in the accompanying master protocol. 
7.3.4.1. 
Fatal and life-threatening SUSARs 
The competent authority and the responsible ethics committee must be informed by the sponsor of 
all fatal or life-threatening SUSARs. This must be done without delay, at the latest 7 calendar days 
after becoming aware of the minimum criteria for reporting. In all cases, attempts will be made to 
obtain further relevant information which will be supplied to the competent authority and the ethics 
committee within a further 8 days. 
7.3.4.2. 
SUSARs that are not fatal or life-threatening 
The competent authority and the responsible ethics committee will be informed without delay by the 
sponsor of all SUSARs, at the latest within 15 calendar days of becoming aware of the minimum 
criteria for reporting. Further relevant details will be passed on as soon as possible. 
If the information at the time of reporting is incomplete, further information to enable adequate 
assessment of the case will be requested from the reporter or other available sources. 
7.3.5. 
Review and reporting of changes in the risk-benefit ratio 
According to section 7.3.5. in the accompanying master protocol: 
The sponsor will inform the competent authority, the responsible ethics committee and the 
competent authorities of all other member states of the EU or EEA where the trial is being 
conducted, of any events or factors that mean that the risk-benefit ratio of the IMP has to be 
reviewed. This will be done without delay, at the latest within 15 days. This includes, but is not 
restricted to: 
• 
Individual reports of expected SARs with an unexpected outcome; 
• 
A clinically relevant increase in the rate of occurrence of expected SARs; 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 77 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
• 
SUSARs in trial subjects who have already completed the follow-up period of the clinical trial 
(”end-of-trial visit”); 
• 
Events in connection with the conduct of the study or the development of the investigational 
medicinal product which may affect the safety of the trial subjects. 
7.3.6. 
Informing the Data Monitoring Committee 
According to section 7.3.6. in the accompanying master protocol: 
The DMC will be informed of all safety-relevant events by the sponsor. 
An independent data monitoring committee (DMC) consisting of independent scientists not 
otherwise involved in the trial will be appointed and will review the data regularly during the study 
for safety and scientific integrity and will make recommendations to the sponsor regarding the 
stopping of an intervention for harm or for futility. The frequency of the committee data review 
meetings and other aspects such as stopping rules will be detailed in a separate charter. There will 
only be one DMC overseeing all trial arms, and this committee will communicate with the DMCs of 
other corresponding platform trials to exchange information. The level of monitoring will depend on 
the safety profile of the intervention. 
7.3.7. 
Informing the investigators 
According to section 7.3.7. in the accompanying master protocol: 
The sponsor will inform investigators of all SUSARs including all relevant further information within 
the periods set by the competent authority. 
The sponsor will inform all investigators on any change of information concerning the scientific 
documents of the trial (SmPC, Investigator’s Brochure, risk-benefit-ratio). 
7.3.8. 
Informing the marketing authorisation holder 
According to section 7.3.8. in the accompanying master protocol: 
The sponsor will also inform the marketing authorisation holder about all SUSARs including 
information reported to the competent authority and ethics committee in accordance with 
contractual agreements, if applicable. 
Specific to this trial: not applicable. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 78 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
7.4. Annual safety report (DSUR) 
According to section 7.4. in the accompanying master protocol: 
The sponsor will supply annually a report on the safety of trial subjects with all available relevant 
information concerning patient safety during the reference period to the competent authorities of all 
concerned member states of the EU or EEA. This report will also be supplied to the responsible ethics 
committee. 
The annual safety report will be compiled according to the corresponding ICH guideline E2F 
„Development Safety Update Report – DSUR“. 
The sponsor will supply the report within 60 days after the reference date (data-lock point) defined 
as one year from the first authorisation to conduct the clinical trial by the sponsor (the 
“Development International Birth Date” (DIBD) of the study drug. The start of the annual period for 
the DSUR is the month and date of the DIBD. The data lock point of the DSUR should be the last day 
of the one-year reporting period. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 79 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
8. Trial results and publication 
8.1. Reports 
8.1.1. 
Interim reports  
Section 7.4 describes the requirements for annual reports on the safety of trial subjects. Interim 
reports about the clinical trial progress will be provided upon requirements of the public funder of 
this trial. 
8.1.2. 
Final report 
According to section 8.1.2. in the accompanying master protocol: 
The competent authority and ethics committee will be informed within 90 days after the end of the 
trial.  
Within one year after the end of the trial, the competent authority and the ethics committee will be 
supplied with the full final study report (competent authority) or the summary of the final study 
report (ethics committee). 
8.2. Publication 
According to section 8.2. in the accompanying master protocol: 
Trials under the master protocol will be registered in a public register, in which trial results will be 
posted. The results of this study will be published in a suitable publication irrespective of findings. 
Results will also be presented at scientific meetings. 
The sponsor will comply with the requirements for publication of trials results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of multicentre 
studies only in their entirety and not as individual site data. In this case, a coordinating investigator 
will be designated by mutual agreement. 
Authorship for each will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Conflicts of interests will be 
disclosed. The contribution of e.g., CTCC, ECRIN, national partners and others will be fairly described 
in the acknowledgement section or as co-author, depending on the contribution in the trial design, 
planning and publication. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 80 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
In line with the EU data sharing policy, individual patient-level data will be shared with the scientific 
community (either as anonymised or pseudonymised data sets), while maintaining the integrity and 
privacy of the trial participants and in compliance with the EU General Data Protection Regulation 
and national or local rules. 
Data and other trial documents should be made available through an appropriate data repository, 
helping to ensure that the data objects are properly prepared, are available in the longer term, are 
stored securely and are subject to rigorous governance. It is planned to use the COVID-19 repository 
for individual participant data from clinical trials developed within the EU-project EOSC-Life. The 
terms and conditions of data transfers to a repository and the data sharing process shall be subject 
to specific data processing agreements to be established between the concerned parties as well as to 
a specific data sharing plan, where the details are specified. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 81 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
9. Amendments to the trial protocol 
According to section 9. of the accompanying master protocol: 
Changes to the master trial protocol and/or sub-protocols under the master protocol may only be 
implemented if agreed by the sponsor, sponsor’s representative, the PCI and statistician. Any 
changes to the trial procedures must be made in writing and must be documented with reasons and 
signed by the sponsor’s representative (i.e., the PCI) and the statistician. 
Significant changes will be implemented after approval by the competent authority and favourable 
opinion of the ethics committee, only. Exceptions to this are amendments made to avoid immediate 
dangers. 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 82 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
10. References 
1. 
The European Medicines Agency. Guideline for Good Clinical Practice; (ICH Topic E6(R2)) 
(EMA/CHMP/ICH/135/1995). 
2. 
The European Medicines Agency. Note for Guidance on Structure and Content of Clinical Study 
Reports; (ICH Topic E3) (CPMP/ICH/137/95). 
3. 
National Cancer Institute. Protocol Templates, Applications and Guidelines 
http://ctep.cancer.gov/guidelines/templates.html 
4. 
EMEA-Guideline on Data Monitoring Committees: EMEA/CHMP/EWP/5872/03 Corr. 
5. 
The DAMOCLES Study Group. A proposed charter for clinical trial 2005 data monitoring 
committees: helping them do their job well. Lancet 2005; 365: 711-22 
6. 
Clinical trial registration: a statement from the International Committee of Medical Journal 
Editors. Accessed on 22 May 2007 at http://www.icmje.org/clin_trial.pdf.  
7. 
WHO - Standardised case causality assessment. 
http://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessme
nt.pdf  
8. 
Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 
explanation and elaboration: guidance for protocols of clinical trials. Bmj. 2013;346:e7586. 
9. 
 The European Medicines Agency. Note for Guidance on Statistical Principles for Clinical Trials; 
(ICH Topic E9) (CPMP/ICH/363/96) http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/statistical-principles-for-clinical-trials.html. 
10. 
Uniform requirements for manuscripts submitted to biomedical journals (International 
Committee of Medical Journal Editors’ (ICMJE) [JAMA 1997; 277: 927-34]. 
11. 
Dagan et al, 2021, DOI: 10.1056/NEJMoa2101765 
12. 
Yelin et al, 2021, DOI: 10.1101/2021.03.16.21253686 
13. 
Mizrahi et al, 2021, DOI: 10.1101/2021.07.29.21261317;  
14. 
Khoury et al, 2021, DOI: 0.1038/s41591-021-01377-8 
15. 
EMA/117973/2021 Reflection paper, 2021-02-23: https://www.ema.europa.eu/en/regulatory-
requirements-vaccines-intended-provide-protection-against-variant-strains-sars-cov-2 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 83 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
16. 
 Lopez Bernal et al, 2021, DOI: 10.1056/NEJMoa2108891 
17. 
 Müller et al, 2021, DOI: 10.1093/cid/ciab381 
18. 
 Choi et al. 2021, DOI: 10.1128/jvi.01313-21 
19. 
Gruell et al, 2021, DOI: 10.1101/2021.12.14.21267769 
20. 
Teo, 2021, DOI: 10.4235/agmr.21.0011 
21. 
Mahase, 2021, DOI: 10.1136/bmj.n3079 
22. 
FDA. Fact sheet for healthcare providers administering vaccine (vaccine providers) emergency 
use authorization (EUA) of the MODERNA COVID-19 vaccine to prevent coronavirus disease 
2019 (COVID-19). https://www.fda.gov/media/144637/download 
23. 
EMA. Spikevax (previously COVID-19 Vaccine Moderna). Summary of Product Characteristics. 
https://www.ema.europa.eu/en/documents/product-information/spikevax-previously-covid-
19-vaccine-moderna-epar-product-information_en.pdf 
24. 
FDA. Vaccines and Related Biological Products Advisory Committee. October 14, 2021 Meeting 
Presentation - Safety and Immunogenicity of a 50 μg Booster Dose of mRNA-1273 (Moderna 
COVID-19 Vaccine).  https://www.fda.gov/media/153089/download 
25. 
FDA.  Addendum to CBER’s review memorandum dated November 18, 2021 entitled, “CBER 
Assessment of a booster dose of Moderna COVID-19 Vaccine (0.25 mL) administered following 
a primary COVID-19 immunization series in individuals 18 years of age and older”. 
https://www.fda.gov/media/154406/download 
26. 
Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 Vaccine After Reports of 
Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization 
Practices — United States, June 2021. MMWR Morb Mortal Wkly Rep 2021;70:977–982. DOI: 
10.15585/mmwr.mm7027e2 
27. 
FDA. CBER Assessment of a booster dose of Moderna COVID-19 Vaccine (0.25 mL) 
administered following a primary COVID-19 immunization series in individuals 18 years of age 
and older. https://www.fda.gov/media/154405/download 
28. 
EMA. Comirnaty / Tozinameran / COVID-19 mRNA Vaccine (nucleoside modified). Summary of 
Product Characteristics. https://www.ema.europa.eu/en/documents/product-
information/comirnaty-epar-product-information_en.pdf 

EudraCT no.: 2021-004526-29 
Protocol code: uni-koeln-4602 
Page 84 of 84 
EU-COVAT-1_AGED_Sub-PROTOCOL_V06_0 
University of Cologne 
29. 
Müller L., Marcel A., Moskorz W. et al. Age-dependent Immune Response to the 
Biontech/Pfizer BNT162b2 Coronavirus Disease 2019 Vaccination. Clin Infect Dis. 2021 Dec 
6;73(11):2065-2072. doi: 10.1093/cid/ciab381 
30. 
Moderna, Inc., Cambridge, MA, USA. Moderna Announces Preliminary Booster Data and 
Updates Strategy to Address Omicron Variant. Press release dated December 20, 2021 
31. 
Munro A., Janani L., Cornelius V. et al. Safety and immunogenicity of seven COVID-19 vaccines 
as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK 
(COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet. 2021 Dec 
18;398(10318):2258-2276. doi: 10.1016/S0140-6736(21)02717-3.