Randomised Controlled Trials to Assess Approved SARS-CoV-2 Vaccines in Immunocompromised Patients: A Master Protocol for the Set-up of a Swiss Cohorts Based Trial Platform
Phase: PHASE3
Conditions: Immunocompromised Patients
Sponsor: University Hospital, Basel, Switzerland

Clinical Study second sub-protocol 
Randomised controlled trials to assess approved SARS-CoV-2 vaccines in 
immunocompromised patients: Second sub-protocol for an observational trial 
extension comparing additional benefits and potential risks of a third SARS-
CoV-2 vaccination with BNT162b2 or mRNA-1273  
 
 
This is the second sub-protocol linked to the master protocol entitled “Randomised controlled trials 
to assess approved SARS-CoV-2 vaccines in immunocompromised patients: A master protocol 
for the set-up of a Swiss Cohorts Based Trial Platform” and the first sub-protocol entitled 
“Randomised 
controlled 
trials 
to 
assess 
approved 
SARS-CoV-2 
vaccines 
in 
immunocompromised patients: First sub-protocol for a pilot trial comparing  the mRNA vaccines 
Comirnaty® and Covid-19 mRNA Vaccine Moderna®” (submitted to ethical committee: 15.12.2020, 
finally approved: 19.04.2021; ID number 2021-000593). 
 
Short title: Immunocompromised Swiss Cohorts Based Trial Platform 
Acronym: COVERALL (COrona VaccinE tRiAL pLatform) 
 
 
Study Type: 
Extension of a clinical trial with Investigational Medicinal Product 
(IMP) 
Study Categorisation: 
Category A  
Study Registration: 
Clinicaltrials.gov: NCT04805125 
Study Identifier: 
COVERALL 
Sponsor, Sponsor-Investigator or 
Principal Investigator: 
University Hospital Basel 
Prof. Heiner C. Bucher MD MPH  
Basel Institute for Clinical Epidemiology & Biostatistics  
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
Phone: +41 (0)61 328 61 01 
Email: heiner.bucher@usb.ch 
 
Investigational Product: 
BNT162b2 licensed by Pfizer-BioNTech (Comirnaty) and 
mRNA-1273 licensed by Moderna (Spikevax) 
Protocol Version and Date: 
Version 1.0; 12. 11. 2021 
 
 
 
CONFIDENTIAL 
The information contained in this document is explicitly not confidential. We will make all study protocols (including 
master 
protocol, 
sub-protocols, 
as 
well 
as 
amendments) 
publicly 
available 
at 
clinicaltrials.gov 
(https://clinicaltrials.gov/ct2/show/NCT04805125). 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 2 of 39 
 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 3 of 39 
Authors of the study protocol: 
 
Benjamin Speich, PhD 
Prof. Heiner C. Bucher MD MPH 
PD Michael Koller, PhD 
Prof. Nicolas Müller MD 
Prof. Huldyrch Günthard MD PhD 
Prof. Andri Rauch MD PhD 
Prof. Matthias Briel MD, PhD, MSc 
Alexandra Griessbach, MSc 
Dr. Marcel Stoeckle, MD, MIH 
 
Trial statistician: 
Frédérique Chammartin, PhD 
 
Data Management: 
Katharina Kusejko, PhD 
Daniel Smith 
 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 4 of 39 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 5 of 39 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 6 of 39 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 7 of 39 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 8 of 39 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 9 of 39 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 10 of 39 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 11 of 39 
  

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 12 of 39 
 
In the master protocol (submitted to the ethical committee on the 15. December 2020; EC ID 2021-
000593) we described the platform and the outline for our pilot trial which randomised patients from 
the Swiss Transplant Cohort Study (STCS) and the Swiss HIV Cohort Study (SHCS) to the two SARS-
CoV-2 vaccines that were first approved in Switzerland. In the meantime the first two SARS-CoV-2 
vaccines reached market authorisation by Swissmedic. Therefore, we have conducted a first sub-
study (as outlined in the first sub-protocol, submitted to the ethical committee on the 15. December 
2020; EC ID 2021-000593), conducting a head to head comparison of the vaccines by Pfizer/Biontech 
and Moderna.  
 
In the meantinme, severely immunodeficient persons ≥ 12 years of age who have received two doses 
of an mRNA vaccine should receive a third dose of Comirnaty® or Spikevax® as part of the basic 
immunization, regardless of any antibody titer. Among all other immunocompromised patients a 
booster vaccination with an mRNA vaccine is recommended. These vaccines will be administered to 
patients from the SHCS and the STCS in the frame of clinical routine. In this second sub-protocol we 
propose an observational study to collect a blood sample before the third vaccination and 8 weeks 
after vaccination, to assess the additional benefit of a third SARS-CoV-2 vaccine in these 
immunocompromised patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 13 of 39 
Table of Contents 
ABBREVIATIONS ................................................................................................................................. 16 
STUDY SYNOPSIS ............................................................................................................................... 18 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 21 
Sponsor-Investigator ............................................................................................................................. 21 
1.1 LOCAL PRINCIPAL INVESTIGATOR(S) ..................................................................................... 21 
1.2 STATISTICIAN ("BIOSTATISTICIAN") ........................................................................................ 22 
1.3 LABORATORY .............................................................................................................................. 22 
1.4 CO-INVESTIGATORS ................................................................................................................... 22 
1.5 MONITORING INSTITUTION ........................................................................................................ 23 
1.6 DATA SAFETY MONITORING COMMITTEE ............................................................................... 23 
1.7 ANY OTHER RELEVANT COMMITTEE, PERSON, ORGANISATION, INSTITUTION ............... 23 
1.8 AUTHOR CONTRIBUTIONS ......................................................................................................... 23 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 24 
2.1 STUDY REGISTRATION ............................................................................................................... 24 
2.2 CATEGORISATION OF STUDY ................................................................................................... 24 
2.3 COMPETENT ETHICS COMMITTEE (CEC) ................................................................................. 24 
2.4 COMPETENT AUTHORITIES (CA) .............................................................................................. 24 
2.5 ETHICAL CONDUCT OF THE STUDY ......................................................................................... 24 
2.6 DECLARATION OF INTEREST .................................................................................................... 24 
2.7 PATIENT INFORMATION AND INFORMED CONSENT ............................................................. 25 
2.8 PARTICIPANT PRIVACY AND CONFIDENTIALITY ................................................................... 25 
2.9 EARLY TERMINATION OF THE STUDY ..................................................................................... 25 
2.10 PROTOCOL AMENDMENTS ........................................................................................................ 25 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 25 
3.1 BACKGROUND AND RATIONALE .............................................................................................. 25 
4. 
INVESTIGATIONAL PRODUCT (TREATMENT, DEVICE) AND INDICATION ........................... 26 
4.1 PRECLINICAL EVIDENCE ............................................................................................................ 26 
4.2 CLINICAL EVIDENCE TO DATE .................................................................................................. 26 
4.3 RISKS / BENEFITS ....................................................................................................................... 26 
4.4 JUSTIFICATION OF CHOICE OF STUDY POPULATION ........................................................... 26 
5. 
STUDY OBJECTIVES ................................................................................................................... 27 
5.1 OVERALL OBJECTIVE ................................................................................................................. 27 
5.2 OBJECTIVES RELATED TO PLATFORM TRIAL SET-UP AND FEASIBILITY OF COHORT 
BASED PATIENT RECRUIT, TRIAL INCLUSION AND DATA COLLECTION .................................. 27 
5.3 OBJECTIVES RELATED TO A PLATFORM BASED NESTED EXTENSION STUDY TO 
INVESTIGATE THE COMPARATIVE EFFECTIVENESS OF A THIRD DOSE OF A MRNA VACCINE 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 14 of 39 
(BNT162B2 VS MRNA-1273) AGAINST SARS-COV-2 ....................................................................... 27 
5.4 SAFETY OBJECTIVES ................................................................................................................. 27 
5.5 STUDY OUTCOMES ..................................................................................................................... 27 
5.6 IMMUNOLOGICAL OUTCOMES .................................................................................................. 28 
5.7 CLINICAL OUTCOMES ................................................................................................................. 28 
5.8 OTHER OUTCOMES OF INTEREST ............................................................................................ 28 
5.9 SAFETY OUTCOMES ................................................................................................................... 28 
6. 
STUDY DESIGN ............................................................................................................................ 29 
6.1 GENERAL STUDY DESIGN AND JUSTIFICATION OF DESIGN ............................................... 29 
6.2 METHODS OF MINIMISING BIAS ................................................................................................ 29 
6.2.1 Randomisation .................................................................................................................... 29 
6.2.2 Blinding procedures ............................................................................................................ 29 
6.2.3 Other methods of minimising bias ....................................................................................... 29 
6.3 UNBLINDING PROCEDURES (CODE BREAK) .......................................................................... 29 
6.4 STUDY POPULATION .................................................................................................................. 29 
6.5 RECRUITMENT AND SCREENING .............................................................................................. 30 
6.6 ASSIGNMENT TO STUDY GROUPS ........................................................................................... 31 
6.7 CRITERIA FOR WITHDRAWAL / DISCONTINUATION OF PARTICIPANTS ............................. 31 
6.8 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN PARTICIPANTS ........................ 31 
6.9 TRIAL SPECIFIC PREVENTIVE MEASURES.............................................................................. 31 
6.10 CONCOMITANT INTERVENTIONS (TREATMENTS) .................................................................. 31 
7. 
STUDY DRUG / MEDICAL DEVICE ACCOUNTABILITY ............................................................ 32 
8. 
RETURN OR DESTRUCTION OF STUDY DRUG / MEDICAL DEVICE ...................................... 32 
9. 
STUDY ASSESSMENTS ............................................................................................................... 32 
Study flow chart(s) / table of study procedures and assessments ........................................................ 32 
9.1 ASSESSMENTS OF OUTCOMES ................................................................................................ 32 
9.1.1 Assessment of feasibility outcomes .................................................................................... 32 
9.1.2 Assessment of immunological endpoints ............................................................................ 33 
9.1.3 Assessment of clinical endpoints ........................................................................................ 33 
9.1.4 Assessment of safety outcomes ......................................................................................... 34 
9.1.5 Assessments in participants who prematurely stop the study ............................................ 34 
9.1.6 Assessments in participants who prematurely stop the study ............................................ 34 
10. PROCEDURES AT EACH VISIT ................................................................................................... 34 
10.1.1 Eligibility .............................................................................................................................. 34 
10.1.2 Baseline assessment (before third SARS-CoV-2 vaccination) ........................................... 34 
10.1.3 Study specific follow-up ...................................................................................................... 35 
10.1.4 Continuous follow-up in the frame of the cohort ................................................................. 35 
11. SAFETY ......................................................................................................................................... 35 
12. STATISTICAL METHODS ............................................................................................................. 35 
Hypothesis ............................................................................................................................................. 35 
12.1 DETERMINATION OF SAMPLE SIZE .......................................................................................... 35 
12.2 STATISTICAL CRITERIA OF TERMINATION OF TRIAL ............................................................ 35 
12.3 PLANNED ANALYSES ................................................................................................................. 35 
12.3.1 Datasets to be analysed, analysis populations ................................................................... 35 
12.3.2 Analyses of immunological and clinical outcomes .............................................................. 36 
12.3.3 Interim analyses .................................................................................................................. 36 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 15 of 39 
12.3.4 Safety analysis .................................................................................................................... 36 
12.3.5 Deviation(s) from the original statistical plan ...................................................................... 37 
12.4 HANDLING OF MISSING DATA AND DROP-OUTS ................................................................... 37 
12.5 QUALITY ASSURANCE AND CONTROL .................................................................................... 37 
12.6 DATA HANDLING AND RECORD KEEPING / ARCHIVING ....................................................... 37 
13. DATA MANAGEMENT .................................................................................................................. 37 
14. MONITORING ................................................................................................................................ 37 
15. AUDITS AND INSPECTIONS........................................................................................................ 37 
16. CONFIDENTIALITY, DATA PROTECTION .................................................................................. 37 
17. STORAGE OF BIOLOGICAL MATERIAL AND RELATED HEALTH DATA .............................. 37 
18. PUBLICATION AND DISSEMINATION POLICY.......................................................................... 37 
19. FUNDING AND SUPPORT ............................................................................................................ 38 
20. INSURANCE .................................................................................................................................. 38 
21. REFERENCES ............................................................................................................................... 38 
22. APPENDICES ................................................................................................................................ 39 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 16 of 39 
 
ABBREVIATIONS 
 
AE 
Adverse Event  
BAG 
Bundesamt für Gesundheitswesen 
BASEC 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
BOD 
Burden of disease 
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
COVID 
Corona virus diseases 
CRF 
Case Report Form  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin, in Italian: OSRUm) 
CONSORT 
Consolidated Standards of Reporting Trials 
eCRF 
Electronic Case Report Form  
CTCAE 
Common terminology criteria for adverse events 
DSUR 
Development safety update report 
FDA 
Food and drug administration 
GCP 
Good Clinical Practice  
GMT 
Geometric mean titers 
IB 
Investigator’s Brochure 
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
HIV 
Human Immunodeficiency Virus 
HRA 
Federal Act on Research involving Human Beings (in German: HFG, in French: 
LRH, in Italian: LRUm) 
IMP 
Investigational Medicinal Product 
IIT 
Investigator-initiated Trial 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
MD 
Medical Device  
MedDO 
Medical Device Ordinance (in German: MepV, in French: ODim) 
PI 
Principal Investigator  
RBD 
Receptor binding domain 
RECORD 
REporting of studies Conducted using Observational Routinely-collected Data 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SDV 
Source Data Verification  
SHCS 
Swiss HIV Cohort Study 
SOP 
Standard Operating Procedure 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 17 of 39 
SPC 
Summary of product characteristics 
SPIRIT 
Standard Protocol Items: Recommendations for Interventional Trials 
STCS 
Swiss Transplant Cohort Study 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File  
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 18 of 39 
STUDY SYNOPSIS 
Randomised 
controlled 
trials 
to 
assess 
approved 
SARS-CoV-2 
vaccines 
in 
immunocompromised patients: Second sub-protocol for an observational trial extension 
comparing additional benefits and potential risks of a third SARS-CoV-2 vaccination with 
BNT162b2 or mRNA-1273  
 
Brief Title: Immunocompromised Swiss Cohorts Based Trial Platform,  
Acronym: COVERALL (COrona VaccinE tRiAL pLatform) 
 
Rationale: A new highly contagious corona virus SARS-CoV-2 has emerged in late 2019 in Wuhan, 
China, and caused in a two-month period a pandemic with the highest disease burden in elderly and 
people with pre-existing medical conditions. After nearly one year into the epidemic over 0.5 milllion 
infections, over 21’000 hospitalisations, and over 82000 deaths due to Sars-CoV-2 have been recorded 
in Switzerland (January 21, 2021).  
Since January 12, 2021 two mRNA vaccines against Sars-CoV-2 by Pfizer / BioNTech (Comirnaty®) 
and COVID-19 mRNA Vaccine Moderna® by Moderna have been licensed in Switzerland and roll-out 
of vaccines has started.   
We have set up a COrona VaccinE tRiAL pLatform (COVERALL) nested into the existing prospectively 
collected data structure of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study 
(STCS). Within the frame of a first sub-study (see first sub-protocol) we have assessed in a head-to-
head comparison the efficacy of BNT162b2 by Pfizer-BioNTech and mRNA-1273 by Moderna in 
immunocompromised patients form the SHCS and the STCS. In these patients the antibody response 
of mRNA-1273 was non-inferior to BNT162b2. Patients living with HIV had in general an antibody 
response, while a high proportion of transplant recipients had no antibody response. Switzerland has 
already started to give third “booster” vaccines. 
The aim of the proposed observational extension is the collection of blood samples to assess the 
additional benefits and potential risks of a third SARS-CoV-2 vaccination with BNT162b2 or mRNA-
1273 among immunocompromised patients. The third vaccine dose will be administered as 
recommended and as part of the clinical routine. 
   
Objectives and Endpoints:   
To conduct an observational study with a head-to-head comparison of a third BNT162b2 or mRNA-1273 
vaccination dose with respect to the immune response (binary outcome). 
The original randomized trial population will be enlarged to gain precision in assessing the effect of 
individual factors (including vaccine type) on the immunological response (titers) to a third dose of mRNA 
vaccine.  
 
Feasibility endpoints: 
We refer to the master protocol 
 
Immunological endpoints  
 
- 
Primary endpoint: The proportion of patients with a positive antibody response to SARS-CoV-2 
spike (S1) protein receptor binding domain in human serum or plasma assessed by the 
commercial immunoassay Elecsys Anti-SARS-CoV-2 S (Elecsys S) from Roche Diagnostics (1). 
An antibody response will be considered as positive using the threshold ≥ 100 units/ml, 
predicting a protective immune response as indicated by Hall et al. (2), and Khoury and 
colleagues (3) 
 
Secondary immunological endpoints: 
- 
The proportion of patients with a positive antibody response using SARS-CoV-2 spike (S1) 
Elecsys S by Roche, using a threshold of ≥0.8 units/ml as defined by the manufacturer. 
- 
The proportion of patients with a positive antibody response using antibody response using 
the Antibody CORonavirus Assay (ABCORA) 2 that assesses seropositivity by measuring 
specific IgG, IgA and IgM responses to SARS-CoV-2 receptor binding domains, S1, S2 and N 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 19 of 39 
16. 
- 
The proportion of patients with neutralizing neutralization activity against the vaccine strain 
Wuhan-Hu-1 in sera, defined as having an ABCORA sum S1 (sum of S1 signal over cut-off 
values of IgG, IgA, IgM) above the threshold of 17. 
- 
Immune response (pan-Ig antibodies against the receptor binding domain (RBD) in the S1 
subunit of the spike protein (pan-Ig anti–S1-RBD) of SARS-CoV-2. 
- 
Mean immune response of IgM, IgA and IgG to the subunit S1 using ABCORA. 
- 
Newly PCR-confirmed asymptomatic SARS-CoV-2 infection. 
Clinical Endpoints: 
- 
Newly PCR-confirmed SARS-CoV-2 infection   
- 
Newly PCR-confirmed asymptomatic SARS-CoV-2 infection   
- 
Newly PCR-confirmed symptomatic SARS-CoV-2 infection   
- 
Severe COVID-19 infection, hospitalization due to COVID-19 or death 
- 
Patient reported asymptomatic or symptomatic infections of household members.  
- 
Follow up on adverse events from vaccines as defined in subprotocol 1  
 
Safety endpoints 
- 
Serious Events 
 
Overall Design:  
Observational study extension of a multicenter randomised controlled, open-label, 2-arm platform trial 
nested in two national cohorts (see master-protocol and first sub-protocol). 
Number of Participants enrolled: 
The 430 participants from the already completed COVERALL study (352 from the SHCS and 78 from 
the STCS) will be included. Since our trial platform is nested within two national cohort studies, we have 
the possibility to supplement the randomized study population by including additional cohort patients 
who already received two doses of a mRNA SARS-CoV-2 vaccine outside of the COVERALL RCT. To 
increase the precision in estimating the effect of patient’s characteristics on the antibody response 
(titers) to a third dose vaccine, we plan to enrol additional cohort participants from the SHCS and the 
STCS, (i.e. who have already received two SARS-CoV-2 vaccinations) reaching a sample size of up to 
700 participants. 
 
Biological Sample and health related data Collection and Duration: 
Participants of the Swiss HIV Cohort and Swiss Transplant Cohort Studies with informed consent and 
no exclusion criteria will be included. At day 0 patients will provide a baseline blood sample and will 
receive the third SARS-CoV-2 vaccine. 8 weeks later (± 2 weeks) participants will have a follow up visit 
in which they provide a blood sample. Clinical outcomes as well as safety outcomes will be assessed. 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 20 of 39 
 
Study schedule  
 
 
Eligibility 
Baseline 
assessment 
(before third vaccination) 
Study specific 
follow-up 
Continuous follow-
up in the frame of 
the cohort 
Time point 
Approximately 
-14 to 0 days 
Day 0 
8 weeks (±2 
weeks) 
 
Eligibility screen 
X 
 
 
 
Informed consent 
Xa 
 
 
 
Baseline blood samples 
 
Xb 
 
 
Assessment of baseline 
characteristics 
 
X 
 
 
cThird SARS-CoV-2 
vaccine in the frame of 
clinical routine (mRNA-
1273 by Moderna or 
BNT162b2 by Pfizer-
BioNTntech) 
 
Xc 
 
 
Immunological 
endpoints 
 
 
X 
 
Clinical endpoints 
 
 
X 
X 
- Adverse events from 
vaccines 
 
 
X 
 
Safety (Serious Events)  
 
 
X 
X 
a Informed consent can also be given at later time point if third vaccine was already administered in the frame of 
clinical routine and consent is only referring to blood samples and use of data. 
b If available it is also possible to use a blood sample that were routinely collected in the frame of the cohort studies. 
c Will be administered in the frame of clinical routine based on recommendation from treating physician (i.e. outside 
of this study). 
 
 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 21 of 39 
1. STUDY ADMINISTRATIVE STRUCTURE  
 
Sponsor-Investigator  
 
University Hospital Basel 
Prof. Heiner C. Bucher MD, MPH 
Basel Institute for Clinical Epidemiology & Biostatistics  
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
Phone: +41 (0)61 328 6101 
Email: heiner.bucher@usb.ch  
1.1 LOCAL PRINCIPAL INVESTIGATOR(S)  
Dr. Marcel P. Stoeckle 
Basel HIV Cohort 
Division of Infectious Diseases and Hospital Epidemiology 
University Hospital Basel 
Petersgraben 4 
4031 Basel 
 
Prof. Huldrych Günthard 
Zürich HIV Cohort 
Division of Infectious Diseases and Hospital Epidemiology 
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Dr. Anna Lena Eichenberger 
Bern HIV Cohort 
Universitätsklinik für Infektiologie 
Freiburgstrasse 16p, Haus 5, Stock E 
3010 Bern 
 
PD Dr. Macé Schuurmans 
STCS Zürich (Lung transplantations) 
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Prof. Thomas Müller 
STCS (Kidney) Zürich 
Klinik für Nephrologie  
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Prof. Michael Tamm 
STCS (Lung) Basel 
Universitätsspital Basel 
Pneumologie 
Petersgraben 4 
4051 Basel 
 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 22 of 39 
Dr. med. Oriol Manuel 
CHUV 
Service des maladies infectieuses 
Rue du Bugnon 46 
1011 Lausanne 
 
Prof. Michael Dickenmann  
STCS (Kidney) Basel 
Universitätsspital Basel 
Transplantationsimmunologie & Nephrologie 
Petersgraben 4 
4051 Basel 
 
1.2 STATISTICIAN ("BIOSTATISTICIAN")  
Dr. Frédérique Chammartin 
Basel Institute for Clinical Epidemiology & Biostatistics  
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
Email: frederique.chammartin@usb.ch 
 
1.3 LABORATORY 
Dr. sc.nat. Dr.med. Irene A. Abela 
Institut für medizinische Virologie 
Universität Zürich 
Winterthurerstrasse 190 
8057 Zürich 
 
1.4 CO-INVESTIGATORS  
Dr. Speich, Benjamin 
Prof. Matthias Briel MD, PhD, MSc  
Alexandra Griessbach, MSc 
Basel Institute for Clinical Epidemiology and Biostatistics 
Departement Klinische Forschung 
University Hospital Basel 
Switzerland 
 
PD Michael Koller, PhD 
Transplantationsimmunologie und Nephrologie, Datenzentrum Swiss Transplant Cohort Study  
Universitätsspital Basel und Universität Basel  
Spitalstrasse 12 
4031 Basel 
Switzerland 
Email: Michael.koller@usb.ch 
 
Prof. Nicolas Müller MD  

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 23 of 39 
Klinik für Infektionskrankheiten und Spitalhygiene 
Universitätsspital Zürich und Universität Zürich 
Rämistrasse 100 
8091 Zürich 
Email: nicolas.mueller@usz.ch 
 
Prof. Huldyrch Günthard MD PhD 
Universitätsspital Zürich und Universität Zürich 
Rämistrasse 100 
8091 Zürich 
Email: huldrych.guenthard@usz.ch 
Spitalstrasse 12 
4056 Basel 
Switzerland 
 
Prof. Andri Rauch MD PhD 
Inselspital, Universitätsspital Bern 
Freiburgstr. 16p 
3010 Bern 
Email: andri.rauch@insel.ch 
 
1.5 MONITORING INSTITUTION 
Central monitoring of data entry into the trial platform and cohort database will be done within the 
routine procedures by the central and local cohort data managers and the biostatistician responsible 
as already implemented in sub-protocol 1.  
 
1.6 DATA SAFETY MONITORING COMMITTEE  
Due to the observational nature of this study extension, no data safety moniroring committee will be 
used.  
1.7 ANY OTHER RELEVANT COMMITTEE, PERSON, ORGANISATION, 
INSTITUTION  
Not applicable. 
1.8 AUTHOR CONTRIBUTIONS 
Benjamin Speich (BS); Heiner C. Bucher (HCB); Michael Koller (MK); Matthias Briel (MB); Frédérique 
Chammartin (FC); Irene A. Abela (IAA); and Huldyrch Günthard (HG) designed the study. Nicolas Müller 
(NM); Andri Rauch (AR); and Katharina Kusejko (KK) gave scientific input. BS wrote the first draft of the 
sub-protocol. All authors critically revised and approved the final version of the study protocol. BS and 
HB acquired funding for the trial.  
 

&29(5$//VXESURWRFRO9HUVLRQ

3DJHRI
 (7+,&$/$1'5(*8/$725<$63(&76
:HUHIHUWRWKHPDVWHUSURWRFRO
 678'<5(*,675$7,21
7KH SLORW WULDO LV UHJLVWHUHG ZLWK WKH 86 1DWLRQDO ,QVWLWXWHV RI +HDOWK ZZZFOLQLFDOWULDOVJRY XQGHU
1&77KHFXUUHQWUHJLVWUDWLRQZLOOEHDGDSWHGWRLPSOHPHQWWKHSURSRVHGWULDOH[WHQVLRQ$OO
VXESURWRFROVDUHIUHHO\DYDLODEOHRQKWWSVFOLQLFDOWULDOVJRYFWVKRZ1&77KHSLORWWULDOZLOO
DOVREHUHJLVWHUHGZLWKWKH.RRUGLQDWLRQVVWHOOH)RUVFKXQJDP0HQVFKNRIDP
 &$7(*25,6$7,212)678'<
7KLV VXEVWXG\ LV DQ REVHUYDWLRQDO H[WHQWLRQ +)9 LQ WKH &DWHJRU\ $ 7KLV VXEVWXG\ ZLOO DVVHVV
SDWLHQWVEORRGVDPSOHDIWHUURXWLQHYDFFLQDWLRQIRULPPXQHUHVSRQVHDJDLQVW6$56&R9

)LJXUH0DVWHUSURWRFROVXESURWRFRODQGFDWHJRULVDWLRQRIREVHUYDWLRQDOVWXG\+)9



 &203(7(17(7+,&6&200,77((&(& 
:HUHIHUWRWKHPDVWHUSURWRFRO
 &203(7(17$87+25,7,(6&$
:HUHIHUWRWKHPDVWHUSURWRFRO
 (7+,&$/&21'8&72)7+(678'<
:HUHIHUWRWKHPDVWHUSURWRFRO
 '(&/$5$7,212),17(5(67
:HUHIHUWRWKHPDVWHUSURWRFRO

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 25 of 39 
2.7 PATIENT INFORMATION AND INFORMED CONSENT 
 
We refer to the master protocol. 
2.8 PARTICIPANT PRIVACY AND CONFIDENTIALITY 
We refer to the master protocol. 
2.9 EARLY TERMINATION OF THE STUDY 
 
The Sponsor-Investigator may terminate the sub-study 2 prematurely according to certain 
circumstances, for example: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, 
 
alterations in accepted clinical practice that make the continuation of this extension study 
unwise,  
2.10 PROTOCOL AMENDMENTS 
We refer to the master protocol. 
3. BACKGROUND AND RATIONALE 
3.1 BACKGROUND AND RATIONALE 
A new highly contagious corona virus SARS-CoV-2 has emerged in late 2019 in Wuhan, China, and 
caused in a two month period a pandemic with the highest disease burden in elderly and people with 
pre-existing medical conditions (4-6). After nearly one year into the epidemic over 0.5 million infections, 
over 21’000 hospitalisations, and over 8`200 deaths due to SARS-CoV-2 have been recorded in 
Switzerland (January 21, 2021). The highest burden of severe Covid-19 infections and deaths is in the 
elderly and in individuals with comorbidities known to present risk factors for a severe infection. Since 
January 12, 2021 two mRNA vaccines against Sars-CoV-2 by Pfizer / BioNTech (Comirnaty®) and 
COVID-19 mRNA Vaccine Moderna® by Moderna have been licensed in Switzerland and role-out of 
vaccines has started (7, 8).  
In phase III licensing trials of both vaccines which were both submitted as emergency use authorisation 
(EUA) to FDA with parallel submission to Swissmedic, vaccine efficacy of 95% and 94% were found 
and both vaccines appeared to be safe. However, estimates of vaccine efficacy were imprecise and with 
large confidence intervals in the subgroups of individuals most at risk of complications from SARS-CoV-
2 infection like the elderly and persons with comorbidities. Likewise, data on immune response overall 
and in subgroups was not available when the vaccines (i.e. first two doses) were approved (9, 10). In 
particular very few individuals in both trials with HIV infection were included (and no solid organ 
recipients were allowed in the trials). In the first COVERALL sub-study (see sub-protocol 1) we could 
show that HIV patients had an immune response 8 weeks after the second SARS-CoV-2 vaccine, while 
a large proportionof solid organ transplant recipients had no immune response (Speich et al., currently 
under review). Studies have shown, that a third SARS-CoV-2 vaccine in transplant patients increases 
the proportion of individuals with an immune response (2). Hence, on strongly immune suppressed 
indivudials, the thirs SARS-CoV-2 vaccine is highly recommended(11). In the frame of clinical routine a 
third SARS-CoV-2 vaccine will be offered to all patients from the STCS and the SHCS in the near future. 
Data from a head-to-head conparison on vaccine efficacy of the third SARS-CoV-2 vaccine, induced 
immune response and safety in immunosuppressed individuals with chronic HIV infection or solid organ 
transplantation is missing. We intend to close this information gap with a trial extension which represents 
the second sub-study trial of the established trial platform that is linked and nested into the existing 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 26 of 39 
prospectively collected data structure of the two most prominent cohort studies in Switzerland, the Swiss 
HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) (12, 13).   
4. INVESTIGATIONAL PRODUCT (TREATMENT, DEVICE) AND INDICATION 
4.1 PRECLINICAL EVIDENCE 
We refer to the first sub-protocol for preclinical evidence on the SARS-CoV-2 vaccine by Pfizer-
BioNTech (BNT162b2; Comirnaty) and Moderna (mRNA-1273; Spikevax). 
4.2 CLINICAL EVIDENCE TO DATE  
(ICH/E6 6.2.2; SPIRIT #6a) 
ICH: A summary of findings from Phase III clinical trials submitted to regulators. 
 
For clinical evidence information on the first two SARS-CoV-2 vaccines of BNT162b2 and mRNA-1273 
we refer to the master-protocol and the first sub-protocol. Here we summarise the clinical evidence of 
the third SARS-CoV-2 vaccine.  
 
Our results from the first COVERALL sub-study 1 were in line with the findings from a published 
observational study reporting that immune response in solid organ transplant recipients was 
detectable in 54% of patients (357/658) (14). An RCT conducted by Hall et al. has shown that solid 
organ transplant recipients have a higher immune response after a third SARS-CoV-2 vaccination, 
hence a booster should be considered in this population (2). Two recently published case reports in 14 
and 12 virologically suppressed patients living with HIV found high antibody titers after the second 
vaccination with mRNA-1273 (15, 16). In an observational study conducted in Israel in more than 4 
million individuals, SARS-CoV-2 infection rates were ten times lower in individuals who received a 
third SARS-CoV-2 vaccine compared to the population who did not receive the third “booster” vaccine 
(17). Due to this high evidence all patients from the STCS and also from the SHCS will be invited in 
the frame of the clinical routine to receive the third SARS-CoV-2 vaccine. 
 
4.3 RISKS / BENEFITS  
 
Patients gain information on there immune status following booster vacination. There are only minimal 
risks associated with the sampling of blood (18). The study population frequently requires drawing of 
blood and the study samples can be drawn in the context of other routine blood examinations avoiding 
any additional risk. Results such as immune response of the patients obtained by the analysis of the 
blood samples will be communicated to the participant. By taking part in this study the participant will 
help benefit future patients by adding to the knowledge base for this particular population and 
potentially improving vaccination strategies.    
4.4 JUSTIFICATION OF CHOICE OF STUDY POPULATION 
 
According to the Swiss Federal Office of Public Health immunocompromised patients are of high priority 
of vaccinations (19). Whereas for the general population a third vaccine is not recommended before six 
months after the second vaccine, people with a compromised immunesystem can receive the third 
vaccine already 28 days after the second vaccination (11). The rationale behind this is that in 
immunocompromised 
patients 
the 
third 
vaccine 
is 
classified 
as 
a 
primo-vaccination 
(“Grundimmunisierung”) while for the general population it is regarded as a booster vaccination 
(“Auffrischimpfung”). According to the treating physicians from the STCS and the SHCS administering 
third vaccination doses within the clinical routine has already started to some extent (STCS) or will start 
within the near future. More information on the choice of study population is included within the first sub-

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 27 of 39 
protocol. 
5. STUDY OBJECTIVES 
5.1 OVERALL OBJECTIVE 
To examine the blood samples through which the  impact of a third vaccination with BNT162b2 or 
mRNA-1273 SARS-CoV-2 vaccine on a wide range of immunological response parameters and safety 
in immunocompromised patients (HIV patients and transplant recipients) can be assessed.  
5.2 OBJECTIVES 
RELATED 
TO 
PLATFORM 
TRIAL 
SET-UP 
AND 
FEASIBILITY 
OF 
COHORT 
BASED 
PATIENT 
RECRUIT, 
TRIAL 
INCLUSION AND DATA COLLECTION 
We refer to the master protocol.  
5.3 OBJECTIVES RELATED TO A PLATFORM BASED NESTED EXTENSION 
STUDY TO INVESTIGATE THE COMPARATIVE EFFECTIVENESS OF A 
THIRD DOSE OF A MRNA VACCINE (BNT162B2 VS MRNA-1273) 
AGAINST SARS-COV-2 
The study seeks to determine the following SARS-CoV-2 related objectives (for detailed definitions see 
under 5.6 immunological endpoints and 5.7 study endpoints): 
 
Immune response (pan-Ig antibodies against the receptor-binding domain (RBD) in the S1 
subunit of the spike protein (pan-Ig anti–S1-RBD) of SARS-CoV-2. 
 
Newly PCR-confirmed asymptomatic SARS-CoV-2 infection,  
 
Newly PCR-confirmed symptomatic SARS-CoV-2 infection   
 
Severe COVID-19 infection,  
 
Patient reported asymptomatic or symptomatic infections of household members.  
 
Adverse events 
 
Safety parameters 
o 
Serious events  
5.4 SAFETY OBJECTIVES 
If a serious event occurs, the research project will be interrupted and the Ethics Committee notified on 
the circumstances via BASEC within 7 days according to HRO Art. 211. 
5.5 STUDY OUTCOMES 
For the feasibility outcomes we refer to the master protocol.  
 
                                                     
1 A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the 
sampling 
of 
biological 
material 
or 
the 
collection 
of 
health-related 
personal 
data, 
and 
which: 
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 28 of 39 
5.6 IMMUNOLOGICAL OUTCOMES 
Immunological endpoints  
 
- 
Primary endpoint: The proportion of patients with a positive antibody response to SARS-CoV-2 
spike (S1) protein receptor binding domain in human serum or plasma assessed by the 
commercial immunoassay Elecsys Anti-SARS-CoV-2 S (Elecsys S) from Roche Diagnostics (1). 
An antibody response will be considered as positive using the threshold ≥ 100 units/ml, 
predicting a protective immune response as indicated by Hall et al. (2), and Khoury and 
colleagues (3) 
 
Secondary immunological endpoints: 
- 
The proportion of patients with a positive antibody response using SARS-CoV-2 spike (S1) 
Elecsys S by Roche, using a threshold of ≥0.8 units/ml as defined by the manufacturer. 
- 
The proportion of patients with a positive antibody response using antibody response using 
the Antibody CORonavirus Assay (ABCORA) 2 that assesses seropositivity by measuring 
specific IgG, IgA and IgM responses to SARS-CoV-2 receptor binding domains, S1, S2 and N 
16. 
- 
The proportion of patients with neutralizing neutralization activity against the vaccine strain 
Wuhan-Hu-1 in sera, defined as having an ABCORA sum S1 (sum of S1 signal over cut-off 
values of IgG, IgA, IgM) above the threshold of 17. 
- 
Immune response (pan-Ig antibodies against the receptor binding domain (RBD) in the S1 
subunit of the spike protein (pan-Ig anti–S1-RBD) of SARS-CoV-2. 
- 
Mean immune response of IgM, IgA and IgG to the subunit S1 using ABCORA. 
- 
Newly PCR-confirmed asymptomatic SARS-CoV-2 infection. 
5.7 CLINICAL OUTCOMES 
- 
Newly PCR-confirmed SARS-CoV-2 infection   
- 
Newly PCR-confirmed asymptomatic SARS-CoV-2 infection   
- 
Newly PCR-confirmed symptomatic SARS-CoV-2 infection   
- 
Severe COVID-19 infection, hospitalization due to COVID-19 or death 
- 
Patient reported asymptomatic or symptomatic infections of household members.  
- 
any local symptom (redness or swelling or prolonged pain at injection side) limiting 
continuation of normal daily activities during the first 7 days after vaccination  
- 
any systemic symptom (fever, generalized muscle or joint pain) limiting continuation of normal 
daily activities during the first 7 days after vaccination  
- 
any vaccine related symptom leading to contacting a physician during the first 7 days after 
vaccination 
 
 
All clinical outcomes will be measured in the trial database at a follow up 8 weeks (±2 weeks) after the 
third SARS-CoV-2 vaccine was administered. 
 
5.8 OTHER OUTCOMES OF INTEREST 
None. 
5.9 SAFETY OUTCOMES 
 
If a serious event occurs, the research project will be interrupted and the Ethics Committee notified on 
the circumstances via BASEC within 7 days according to HRO Art. 212. 
                                                     
2 A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the 
sampling 
of 
biological 
material 
or 
the 
collection 
of 
health-related 
personal 
data, 
and 
which: 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 29 of 39 
6. 
 STUDY DESIGN 
6.1 GENERAL STUDY DESIGN AND JUSTIFICATION OF DESIGN  
Nested within the Swiss HIV Cohort study (SHCS)(13) and the Swiss Transplant Cohort Study 
(STCS)(12) we have set-up the COrona VaccinE tRiAL pLatform (COVERALL; see also master-protocol 
and first sub-protocol). This trial platform allowed for rapid patient recruitment, efficient and cost-saving 
data collection, as well as high flexibility in adapting the study design, which is key given the rapid 
changing circumstances during the COVID-19 pandemic. The platform set-up and a first pilot trial were 
supported by a competitive grant from the Swiss National Science Foundation (20).  
Within the established trial platform we conducted a first multicentre randomised controlled, open-label, 
2-arm randomised controlled trial (first sub-protocol) in immunocompromised patients to assess the 
efficacy of the two mRNA SARS-CoV-2 vaccines (i.e. BNT162b2 by Pfizer / BioNTech and mRNA-1273 
by Moderna) that reached market authorisation in Switzerland. The primary clinical outcome was change 
in pan-lg antibody response (pan-Ig anti-S1-RBD; baseline vs. 12 weeks after first vaccination; 8 weeks 
after second vaccination, respectively). We randomised a total of 430 patients (352 from SHCS and 78 
from STCS). 
 
In the proposed extension, we plan to 1) assess non-inferiority of a third mRNA-1273 vaccination 
compared to a third BNT162b2 vaccination with respect to immune response (binary outcome), and 2) 
assess the effect of patients’ characteristics on the antibody titer after a third SARS-CoV-2 vaccine in 
immunocompromised individuals who received vaccination within routine practice, following current 
guidelines. Patients from the first sub-study will receive a third dose of SARS-CoV-2 vaccine according 
to their randomisation group. In addition, we will include up to 300 additional patients from both cohorts 
(at least 100 additional from the STCS) who have already received two doses of SARS-CoV-2 vaccine 
in an observational extension of the COVERALL study to further explore the main drivers of immune 
response to a third dose in immunocompromised patients, and to examine the benefits and potential 
risks of a third vaccination with BNT162b2 or mRNA-1273. 
 
6.2 METHODS OF MINIMISING BIAS 
6.2.1 
Randomisation 
Not applicable in observational study  
6.2.2 
Blinding procedures 
All personnel and patients will know which vaccine was given in clinical routine. Outcome assessors 
conducting laboratory analyses will not be aware which vaccine patients received. 
6.2.3 
Other methods of minimising bias 
6.3 UNBLINDING PROCEDURES (CODE BREAK) 
Not applicable. 
6.4 STUDY POPULATION 
This is a multi-centre study recruiting patients from 3 of the 7 study centres of the SHCS and 2 of the 6 
                                                     
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 30 of 39 
study centres of the STCS (i.e. University Hospital Basel, University Hospital Zürich, University Hospital 
Bern [only SHCS]). Both cohorts are representative for individuals living with HIV and solid organ 
transplants: 
 
SHCS study centres:  
 
Department of Infectious Diseases, Bern University Hospital, University of Bern 
 
Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel 
 
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University 
of Zurich 
STCS study centres: 
 
Klinik für Pneumologie, Universitätsspital Zürich  
 
Klinik für Nephrologie, Universitätsspital Zürich 
 
Universitätsspital Basel, Pneumologie 
 
Universitätsspital Basel, Transplantationsimmunologie & Nephrologie,  
 
The cohorts are described in more detail elsewhere (12, 13, 21, 22). The study will be explained to 
eligible patients during their visit at the cohort centre. Cohort patients will be contacted by phone or letter 
to inform them about the study.  
 
Inclusion and exclusion criteria:  
Inclusion criteria: 
 
- All patients with either a chronic HIV infection or recipients of solid organs registered with informed 
consent from the SHCS and STCS cohorts aged ≥18 years 
- Patients with solid organ transplantation of lungs or kidneys at least one month post-transplantation 
with a prednisone dose of 20mg or less. 
- Additional consent for participation in trial extension 
- Third covid-19 vaccination recommended by treating physician and administered in the frame of clinical 
routine 
 
Exclusion criteria: 
- Pregnancy 
- Acute symptomatic SARS-CoV-2 infection, influenza or other acute respiratory tract infection 
- Known allergy or contra-indications for vaccines or any vaccine components 
- Any emergency condition requiring immediate hospitalization for any condition 
- Patients with solid organ transplantation (lung or kidney) with the following conditions: 
- Solid organ transplant recipients less than one month post-transplantation  
- Solid organ transplant recipients with the use of T-cell depleting agents in the last 3 months (i. e 
induction treatment in standard risk or high-risk immunological situation or rejection treatment).  
- Solid organ transplant recipients with the need of pulse corticosteroids (>100mg prednisone or 
equivalent) in the last 1 month or rituximab in the last 6 months 
- Solid organ transplant recipients with the need of any kind of chemotherapy treatment for cancer 
 
6.5 RECRUITMENT AND SCREENING 
Patients who participated in the COVERALL-study (first sub-protocol): Patient who should receive a 
third SARS-CoV-2 vaccine in the frame of clinical routine (based on judgment of the treating physician) 
will be contacted by the treating physician or a representative. Patients will be invited to participate to 
the COVERALL-observational extension study (sub-protocol 2) . 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 31 of 39 
 
Newly recruited patients from the SHCS or the STCS: Specific eligibility criteria can be defined and 
implemented by the trial platform data base which is based on all clinical and laboratory cohort data and 
managed by the cohort data centres (figure 2 and separately submitted electronic Case Report Form). 
Both cohorts have developed a clinical information system that summarizes all relevant clinical and 
laboratory information for patients and widely serves as a clinical management and decision support 
system. Eligible patients can be flagged within this system. Treating cohort physicians will contact 
flagged patients to inform and invite them in this study. 
6.6 ASSIGNMENT TO STUDY GROUPS 
Since this is an observational study extension, we will not do any active assignement. Participants will 
receive the third vaccine which they are given during routine practice.  
6.7 CRITERIA FOR WITHDRAWAL / DISCONTINUATION OF PARTICIPANTS 
We refer to the master protocol.  
6.8 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN 
PARTICIPANTS 
Patients have the right to withdraw the planned follow-up visits. Clinical outcomes for those patients will 
be assessed from routinely collected cohort data.  
6.9 TRIAL SPECIFIC PREVENTIVE MEASURES 
(ICH/E6 6.6.2; SPIRIT #11d) 
ICH: Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or 
during the trial. 
All patients included into the trial-extension will continue all medication taken for the treatment of their 
chronic conditions. No drugs are prohibited that would exempt participation from the trial except use of 
ATG or rituximab within 6 months and pulse corticosteroids within 1 months prior to first vaccination for 
solid organ transplant patients. For transplanted patients with recent organ transplant receipt and / or 
more severe immune-suppressant treatment, decision to vaccinate patients and for trial participation is 
taken by the treating physicians by considering all benefit and potential harms for vaccination against 
Sars-CoV-2 in a particular patient.  
Use of any drugs for the treatment of local or systemic adverse effects of vaccines is according to clinical 
judgement by clinicians.  
6.10 CONCOMITANT INTERVENTIONS (TREATMENTS)  
ICH/E6 6.6.2; SPIRIT #11d) 
ICH: Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or 
during the trial. 
All concomitant drugs for patients included into the trial-extension are recorded within the routine cohort 
based data collection structure (see master protocol). Physicians are free in the choice of any 
concomitant drugs for the treatment of HIV, immunosuppressants for transplanted patients or any other 
drugs used for the treatment of additional chronic conditions and take decisions for their use according 
to best clinical judgement and treatment guidelines. There are no particular drugs that are not permitted 
for their use during vaccination and follow-up.  
 
Use of any drugs for the treatment of local or systemic adverse effects of vaccines is according to clinical 
judgement by clinicians.   

&29(5$//VXESURWRFRO9HUVLRQ

3DJHRI

 678'<'58*0(',&$/'(9,&($&&2817$%,/,7<

7KHYDFFLQHVZLOOEHDGPLQLVWHUHGLQWKHIUDPHRIFOLQLFDOURXWLQHDWRIILFLDOYDFFLQDWLRQFHQWUHV7KHVH
FDQEHORFDWHGGLUHFWO\DW8QLYHUVLW\+RVSLWDOVRUDWRWKHUORFDWLRQVHJ0HVVHKDOOHLQ%DVHO:HZLOO
FROOHFWEORRGDWWKHEDVHOLQHYLVLWDQGZHHNVDIWHUYDFFLQDWLRQ

 5(785125'(6758&7,212)678'<'58*0(',&$/'(9,&(
'RHVQRWDSSO\VLQFHWKHYDFFLQHVZLOOQRWEHJLYHQLQWKHIUDPHRIWKHH[WHQVLRQVWXG\
 678'<$66(660(176
6WXG\IORZFKDUWVWDEOHRIVWXG\SURFHGXUHVDQGDVVHVVPHQWV

)LJXUH6WXG\IORZFKDUW2EVHUYDWLRQDO6WXG\([WHQVLRQ



 $66(660(1762)287&20(6

$VVHVVPHQWRIIHDVLELOLW\RXWFRPHV
:HUHIHUWRWKHPDVWHUSURWRFRO

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 33 of 39 
9.1.2 
Assessment of immunological endpoints 
We will assess pan-IgG anti S (RBD) (quantitative) and anti- N antibodies (qualitative) with the 
commercial Elecsys® Anti-SARS-CoV-2 tests at baseline and at 8 weeks following randomisation and 
vaccination (primary immunological endpoint). We assume that some patients may have received 
already the third SARS-CoV-2 vaccine, hence we will not have a baseline blood sample from those 
patients. 
We will assess SARS-CoV-2-binding antibody responses of the participants by analyzing the IgM, IgA 
and IgG responses to a wider range of SARS-CoV-2 proteins (S1, S2, RBD and N using an in-house 
method (ABCORA 2.0) established at the Institute of Medical Virology (IMV), UZH (secondary 
immunological endpoint). The ABCORA 2.0 test allows for a parallel assessment of IgG, IgM and IgA 
reactivity to multiple antigens enabling a high-dimensional temporal resolution of antibody responses 
and a dissection between humoral responses to an infection and vaccination. We expect that the 
ABCORA2.0 antibody test will be more sensitive than the Elecsys® Anti-SARS-CoV-2 S antibody test. 
 
Patients will be invited to see their treating physician or a representative 8 weeks after the third vaccine 
(see Study schedule). A blood sample will be taken (EDTA blood (2 x  7.5 ml)) at baseline and 8 week 
follow-up visit and assessed for the above listed antibodies: 
 
1ml for Elecsys® Anti-SARS-CoV-2  N and S tests (performed locally at each laboratory) 
 
2ml EDTA Plasma for ABCORA 2.0 test (performed at IMV, UZH) 
EDTA blood should be processed within 24h and EDTA plasma should be stored at -20°C. For ABCORA 
2.0  antibody measurements plasma samples will be collected at each center and a collective shipment 
will be sent after baseline and at 12 weeks after randomisation and vaccination to the IMV, UZH. One 
sample will be stored according to SHCS and STCS protocols for later eventual analyses at the centers 
of University Hospital Zurich.  
9.1.3 
Assessment of clinical endpoints 
Patients are informed to contact center physicians in case an asymptomatic or symptomatic SARS-Cov-
2 infections was diagnosed outside the settings of participating cohort centers. Clinical endpoints will be 
assessed at 8 weeks (±2 weeks), and in addition during future cohort visits,.  
 
Newly PCR-confirmed asymptomatic Covid-19 infection (identified by the presence of anti–
SARS-CoV-2 nucleocapsid antibodies ,or PCR or rapid antigen test) and no related symptoms 
[(i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body 
aches, headache, new loss of taste or smell, sore throat, congestion or runny nose nausea or 
vomiting, and diarrhea]) at any time during the 48 weeks of follow-up   
During all visits at the trial centres (study specific at 8 weeks, as well as cohort visits) a PCR SARS-
COV-2 test will only be conducted if the treating physician would also conduct such a test during clinical 
routine (e.g. exposure to infected individual). PCR tests done in between independently will be recorded 
with dates and results.  In case of a positive test result, physicians will check for symptoms and patients 
will be followed-up according to clinical routine and physicians’ judgement. 
 
 
Newly PCR-confirmed symptomatic Covid-19 infection with at least one of the following 
symptoms (i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny 
nose nausea or vomiting, and diarrhea) at any time during the 48 weeks of follow-up 
During all visits at the trial centres (study specific at 8 weeks, as well as cohort visits) a PCR SARS-
COV-2 test will only be conducted if the treating physician would also conduct such a test during clinical 
routine (e.g. COVID-19 related symptoms; exposure to infected individual).  In case of a positive test 
result, physicians will check for symptoms and patients will be followed-up according to clinical routine 
and physicians’ judgement. 
 
 
 
Severe COVID-19 infection with respiratory failure, evidence of shock (as diagnosed by a 
treating physician), clinically significant acute renal, hepatic, or neurologic dysfunction; 
admission to an intensive care unit; or  death at any time during the 48 weeks of follow-up. 
 
 
 
Patient reported asymptomatic or symptomatic infections of household members.  

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 34 of 39 
Patients will be asked at the 8-week visit if a household member was diagnosed with COVID-19. 
 
9.1.4 
Assessment of safety outcomes 
9.1.4.1 
Serious Events (SEs) 
 
If a serious event occurs, the research project will be interrupted and the Ethics Committee 
notified on the circumstances via BASEC within 7 days according to HRO Art. 21 . 
 
The project is promptly notified (within 24 hours) if immediate safety and protective measures 
have to be taken during the conduct of the research project. The Ethics Committee will be 
notified via BASEC of these measures and of the circumstances necessitating them within 7 
days. 
 
A serious event is defined as any adverse event where it cannot be excluded, that the event 
is attributable to the sampling of biological material or the collection of health-related personal 
data, and which: 
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital 
stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 
9.1.4.2 
Laboratory parameters 
Laboratory parameters besides immune response parameters will be assessed at bi-annually cohort 
visits according to the cohort protocols.  
9.1.4.3 
Vital signs 
Not relevant for purpose of this trial.  
9.1.5 
Assessments in participants who prematurely stop the study 
All clinical outcomes will be assessed from routinely collected cohort data which will also be available if 
patients decide to prematurely stop participating in the clinical trial.  
9.1.6 
Assessments in participants who prematurely stop the study 
We refer to the master protocol 
10. PROCEDURES AT EACH VISIT 
10.1.1 Eligibility  
All patients who participated already in the first sub-study from COVERALL will prospectively be 
assessed for eligibility based on the cohort study based trial platform. Eligible patients will be either 
contacted ahead by cohort centres and informed about the trial-extension and availability of vaccines or 
directly informed during in between visits or cohort study visits. Eligibility of newly enrolled patients from 
STCS and SHCS will be will prospectively be assessed for eligibility based on the cohort study based 
trial platform. Treating physicians from the cohort centres will contact patients and inform them about 
the study. It will be mentioned that the third vaccine will be administered in the frame of clinical routine 
and is not part of this study. In case they wish to to receive the third vaccine outside of this study, they 
have the option to particate in this observational study which only consists of additional blood samples 
being drawn and analysed to assess the immune response of the patient. It will be assessed which 
SARS-CoV-2 vaccines they received (i.e. first and second vaccination) to make sure that the same 
compound can be used for the third vaccination. In case there are any reasons that justify to change to 
the other vaccine (e.g. first and second vaccination with BNT162b2, third vaccination with mRNA-1273) 
this will be allowed following the judgment of the treating physician. 
10.1.2 Baseline assessment (before third SARS-CoV-2 vaccination) 
Patient will return the signed consent form which will also be signed by the treating physician. Patients 
will provide a blood sample at the local study centre. After this they will go to the vaccination centre and 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 35 of 39 
receive the third SARS-CoV-2 vaccine in the frame of clinical routine. 
10.1.3 Study specific follow-up 
Patients will be asked about SARS-CoV-2 infections, adverse events. Further, patients will provide a 
blood sample (8 weekes) to assess the immunological outcomes.  
10.1.4 Continuous follow-up in the frame of the cohort 
Clinical endpoints (i.e. SARS-CoV-2 infections) and serious adverse events will be assessed in the 
frame of the routine cohort visits. 
 
11. SAFETY  
The PI (and if applicable the sponsor) is promptly notified (within 24 hours) if immediate safety and 
protective measures have to be taken during the conduct of the research project. The Ethics Committee 
will be notified via BASEC of these measures and of the circumstances necessitating them within 7 days. 
12. STATISTICAL METHODS  
Hypothesis 
To compare the effectiveness in term of serological immune response of approved SARS-CoV-2 
vaccines in immunocompromised patients, we aim to demonstrate that the second vaccine available in 
the market is no worse than the comparator by more than 10%. Therefore, we formulate the null 
hypothesis H0: π1 ≥ π2 + 10 versus the alternative hypothesis H1: π1 -10 < π2. The choice of a non-
inferiority margin of 10% relies on expert opinion/clinical judgment. 
12.1 DETERMINATION OF SAMPLE SIZE  
Within our previous RCT (first sub-protocol) assessing antibody response in immunocompromised 
patients after the administration of SARS-CoV-2 vaccines, we found that the proportion of patients with 
an immune response 12 weeks after the first SARS-CoV-2 vaccination and 8 weeks after the second 
vaccination was 86.67% (95% confidence interval (CI): 82.07%-91.26%) in the BNT162b2 arm and 
86.14% (95% CI: 81.37-90.90) in the mRNA-1273 arm (positive immune response according to the 
Roche Elecsys anti SARS-CoV-2 S with a cut-off at 100 Unit/ml). After a third dose vaccine, we expect 
a positive antibody response for 50% of transplanted patients (2) and nearly 100% of HIV patients, 
respectively. Thus, we assume vaccine reactivity of 90% in both vaccine groups and power our non-
inferiority trial such that a 95% two-sided confidence interval excludes a difference in favour of the 
reference group of more than 10%. A sample size of 380 (190 in each treatment arm) is required for a 
statistical power of 90% and a type I error of 0.025. We believe that a target sample of 380 patients 
participants is feasible, since we have 412 randomized patients from our first RCT that achieved 
complete follow-up and drop-out rate from our previous RCT was 4%. Sample size was calculated using 
the “ssc_propcomp” function of the R statistical software package “SampleSize4ClinicalTrials’ (23). 
12.2 STATISTICAL CRITERIA OF TERMINATION OF TRIAL  
Not applicable. No interim analysis is planned during the trial extension and termination will not be based 
on any statistical criteria. 
12.3 PLANNED ANALYSES 
12.3.1 Datasets to be analysed, analysis populations 
We refer to the master protocol 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 36 of 39 
12.3.2 Analyses of immunological and clinical outcomes 
 
We will report frequency and percentage of positive serological immune response for both vaccine arms 
among different pre-specified subgroups of patients most prone to complicated infections with SARS-
CoV-2. These are for HIV positive individuals with less and more than 200 CD4 cells/μl, with a 
suppressed and unsuppressed HIV viral load (i.e. >50 copies/ml), for transplanted patients under 
intense (triple or quadruple immunosuppressive regimen) or less intense immunosuppressive therapy 
(dual immunosuppressive regimen) and for allstudy participants according to sex (male/female), age 
group (below 60, 60 to 69, 70 older) and history of cardiovascular diseases or metabolic syndrome. 
Clinical outcomes related to COVID-19 infection and patient reported COVID-19 infection of household 
members will be reported as frequency with percentage for the different treatment arms.  
 
Randomised comparison from COVERALL (only including patients from randomised COVERALL trial): 
Immunological outcomes at baseline and 8-week follow-up will be reported as frequency and percentage 
of positive serologic immune response for both vaccine arms. The primary objective is to assess the 
non-inferiority of the second licensed vaccine versus the first licensed vaccine in regards to the presence 
of pan-IgG antibody, as measured by the Elecsys® Anti-SARS-CoV-2 S immunoassay. Difference in 
primary outcome among the two vaccine arms will be assessed by a two-sided 95% confidence interval, 
showing a credible range for the true difference between the second licensed vaccine and the first 
licensed vaccine. Non-inferiority will be established at the α significance level, if the lower limit of a 95% 
two-sided Wald confidence interval for the difference in antibody response proportion between 
participants receiving mRNA-1273 and BNT162bs vaccines is above –10%, where 10% is the pre-
defined non-inferiority margin.  
 
Randomised comparison from COVERALL (only including patients from randomised COVERALL trial): 
Patients will be primarily analysed according to their allocated randomization group (intention ot treat 
(ITT)). We will also perform analyses according to a per-protocol principle that is defined as restricting 
the analysis to participants who receive the three vaccine doses they were allocated to and an additional 
“strict” per-protocol analysis that is further restricted to individuals who provide available outcome data 
at week 8 ± 2 week after the 3rd vaccine. We will address sensitivity to previous natural infection with a 
sensitivity analyses that excludes participants with positive antibody response to the nucleocapsid 
protein at baseline as indicated by the Elecsys Anti‑SARS‑CoV‑2 test Elecsys N test. 
 
 
Observational analysis of all COVERALL extension participants: 
Linear regression models will be used to identify the most important patient’s characeristics associated 
to the neutralization titers (ABCORA sum of S1 signal over cut-off values of IgG, IgA, IgM). Patients’ 
characteristics not recorded within the trial will be retrieved from the routine cohorts’ follow-up visits. 
Factors considered for analysis of HIV patients will include the type of vaccine, age, sex, CD4 cell count 
at vaccination, CD4/CD8 cell count at vaccination as a proxy of immunosenescence, viral load at 
vaccination, CD4 nadir, history of chronic infection (tuberculosis, chronic hepatitis C), history of immune 
reconstitution inflammatory syndrome, presence of co-morbidities (cardiovascular disease or metabolic 
syndrome, autoimmune disease and cancer), smoking, immunosuppressive co-medication at 
vaccination, and specific antiretroviral regimen (protease inhibitor-based regimen, integrase strand 
transfer inhibitor (INSTI)-based regimen and tenofovir-based regimen). For transplanted patients, 
factors considered will be the type of vaccine, the type of transplant (kidney or lung), age, sex, 
cardiovascular history or metabolic syndrome, smoking status at vaccination, immunosuppression 
therapy (intense versus less intense), co-medication (induction therapy, glucocorticoids, mycophenolate 
mofetil (MMF), azathioprine (AZA), cyclosporine (CSA) and tacrolimus (FK)). Linear regression will be 
performed according to a per-protocol analysis and robustness to temporal titer variation will be 
addressed within a “strict” per-protocol analysis.  
12.3.3 Interim analyses 
No interim analysis will be done 
12.3.4 Safety analysis 
We expect safety issue to be small and do not believe that we will have enough power to demonstrate 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 37 of 39 
any statistical difference between the treatment arms. 
12.3.5 Deviation(s) from the original statistical plan 
We refer to the master protocol. 
 
12.4 HANDLING OF MISSING DATA AND DROP-OUTS 
We refer to the master protocol.  
12.5 QUALITY ASSURANCE AND CONTROL 
12.6 DATA HANDLING AND RECORD KEEPING / ARCHIVING 
We refer to the master protocol.  
13. DATA MANAGEMENT 
We refer to the master protocol. 
14. MONITORING  
We refer to the master protocol. 
15. AUDITS AND INSPECTIONS 
We refer to the master protocol.  
16. CONFIDENTIALITY, DATA PROTECTION 
We refer to the master protocol.  
17. STORAGE OF BIOLOGICAL MATERIAL AND RELATED HEALTH DATA 
Samples used for diagnostic will be stored for 5 years. 
Samples for the ABCORA2.0 and Elecsys® Anti-SARS-CoV-2 S and N tests will be locally stored at the 
University Hospital virology laboratories and will be shipped by two shipments for all samples collected 
at baseline after completion of recruitment and after completion of the 3 months follow-up in all patient 
for all samples collected at three-month follow-up. Samples will be sent to the Institute of Medical 
Virology, University of Zurich and will be evaluated centrally. No samples will be shared with the funder 
of the trial (i.e. Moderna). 
18. PUBLICATION AND DISSEMINATION POLICY 
All trials that are set-up within the trial platform and results from sub-studies will be published (also 
negative results or if a trial has to be discontinued) in peer-reviewed journal publications. We intend to 
make this sub-protocol available on clinicaltrials.gov. Authorship to publications will be granted 
according to the rules of the International Committee of Medical Journal Editors (ICMJE).  

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 38 of 39 
19. FUNDING AND SUPPORT 
This trial extension is funded by Moderna. The set-up of the trial platform was funded by the Swiss 
National Science Foundation (grant # 31CA30_196245). The Swiss HIV Cohort Study (SHCS) and the 
Swiss Transplant Cohort Study (STCS) are funded by the Swiss National Science Foundation (SHCS: 
grant # 177499 and # 201369, STCS: grant # 33CS30_177522). Moderna had the possibility to read 
and approve the study protocol before the study was started. Otherwise, the funders will have no role 
in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 
20. INSURANCE 
We refer to the master protocol.  
21. REFERENCES 
1. 
Roche. 
Elecsys®Covid-19 
Solutions. 
https://diagnostics.roche.com/global/en/products/params/elecsys-anti-sars-cov-2-s.html [accessed: 25 
August 2021]. 
2. 
Hall VG, Ferreira VH, Ku T, Ierullo M, Majchrzak-Kita B, Chaparro C, et al. Randomized Trial of 
a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. N Engl J Med. 2021;385(13):1244-6. 
3. 
Khoury DS, Cromer D, Reynaldi A, Schlub TE, Wheatley AK, Juno JA, et al. Neutralizing 
antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat 
Med. 2021;27(7):1205-11. 
4. 
WHO: Pneumonia of unknown cause – China. WHO. https://www.who.int/csr/don/05-january-
2020-pneumonia-of-unkown-cause-china/en/ [accessed: 23 August 2020]. 
5. 
Zhu RF, Gao YL, Robert SH, Gao JP, Yang SG, Zhu CT. Systematic review of the registered 
clinical trials for coronavirus disease 2019 (COVID-19). J Transl Med. 2020;18(1):274. 
6. 
Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health 
concern. Lancet. 2020;395(10223):470-3. 
7. 
Swissmedic. Swissmedic erteilt die Zulassung für den Covid-19 Impfstoff von Moderna. 
https://www.swissmedic.ch/swissmedic/de/home/news/coronavirus-covid-19/zulassung-covid-19-
impfstoff-moderna.html [accessed: 26 January 2021]. 
8. 
Swissmedic. Swissmedic erteilt Zulassung für den ersten Covid-19-Impfstoff in der Schweiz. 
https://www.swissmedic.ch/swissmedic/de/home/news/coronavirus-covid-19/covid-19-
impfstoff_erstzulassung.html [accessed: 26 January 2021]. 
9. 
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and Efficacy 
of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383(27):2603-15. 
10. 
Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, et al. An mRNA 
Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med. 2020;383(20):1920-31. 
11. 
Bundesamt für Gesundheit. Covid-19: Auffrischimpfung soll ältere Menschen noch besser vor 
schwerer 
Erkrankung 
schützen. 
https://www.bag.admin.ch/bag/de/home/das-
bag/aktuell/medienmitteilungen.msg-id-85583.html [accessed: 15. November 2021]. 
12. 
Swiss Transplant Cohort Study (STCS). https://www.stcs.ch/about/study-description [accessed: 
20 August 2021. 
13. 
Swiss HIV Cohrot Study (SHCS). http://www.shcs.ch/ [accessed: 20 August 2021]. 
14. 
Boyarsky BJ, Werbel WA, Avery RK, Tobian AAR, Massie AB, Segev DL, et al. Antibody 
Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA. 
2021. 
15. 
Ruddy JA, Boyarsky BJ, Bailey JR, Karaba AH, Garonzik-Wang JM, Segev DL, et al. Safety 
and antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in persons with HIV. 
AIDS. 2021. 
16. 
Woldemeskel BA, Karaba AH, Garliss CC, Beck EJ, Wang KH, Laeyendecker O, et al. The 
BNT162b2 mRNA Vaccine Elicits Robust Humoral and Cellular Immune Responses in People Living 
with HIV. Clin Infect Dis. 2021. 

COVERALL, sub-protocol 2, Version 1.0 (24/11/2021) 
 
Page 39 of 39 
17. 
Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Alroy-Preis S, et al. 
Protection Across Age Groups of BNT162b2 Vaccine Booster against Covid-19. medRxiv. 
2021:2021.10.07.21264626. 
18. 
Schweizerische Eidgenossenschaft. Verordnung über klinische Versuche mit Ausnahme 
klinischer 
Versuche 
mit 
Medizinprodukten 
(Verordnung 
über 
klinische 
Versuche; 
KlinV). 
https://www.fedlex.admin.ch/eli/cc/2013/643/de [accessed: 23 November 2021]. 
19. 
Federal 
Office 
of 
Public 
Health. 
Coronavirus: 
Vaccination. 
https://www.bag.admin.ch/bag/en/home/krankheiten/ausbrueche-epidemien-pandemien/aktuelle-
ausbrueche-epidemien/novel-cov/impfen.html#-739379966 [accessed: 26 January 2021]. 
20. 
Speich B, Chammartin F, Smith D, Stoeckle MP, Amico P, Eichenberger AL, et al. A trial 
platform to assess approved SARS-CoV-2 vaccines in immunocompromised patients: first sub-protocol 
for a pilot trial comparing the mRNA vaccines Comirnaty(R) and COVID-19 mRNA Vaccine Moderna(R). 
Trials. 2021;22(1):724. 
21. 
Koller MT, van Delden C, Muller NJ, Baumann P, Lovis C, Marti HP, et al. Design and 
methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide 
long-term follow-up cohort. Eur J Epidemiol. 2013;28(4):347-55. 
22. 
Swiss HIVCS, Schoeni-Affolter F, Ledergerber B, Rickenbach M, Rudin C, Gunthard HF, et al. 
Cohort profile: the Swiss HIV Cohort study. Int J Epidemiol. 2010;39(5):1179-89. 
23. 
Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 2nd Ed. 
Chapman & Hall/CRC Biostatistics Series. 
 
22. APPENDICES 
Not applicable