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

COVERALL: third sub-protocol 
Controlled 
trials 
to 
assess 
approved 
SARS-CoV-2 
vaccines 
in 
immunocompromised patients: Third sub-protocol for an observational study 
comparing benefits and potential risks of the newly approved bivalent SARS-
CoV-2 vaccines  
 
This is the third 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”, 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), and the 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” (submitted to ethical committee: 24.11.2021, 
finally approved: 07.12.2021; ID number 2021-000593). 
 
Short title: Immunocompromised Swiss Cohorts Based Trial Platform 
Acronym: COVERALL (COrona VaccinE tRiAL pLatform) bivalent 
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 
Benjamin Speich, PhD 
CLEAR-Methods Center, Division of Clinical Epidemiology, 
Department of Clinical Research 
University Hospital Basel 
Totengässlein 3 
4051 Basel 
Switzerland 
Phone: +41 (0)61 328 38 19 
Email: benjamin.speich@usb.ch 
 
Investigational Product: 
Bivalent booster vaccine m-RNA-1273.214 licensed by 
Moderna and bivalent booster vaccine Comirnaty 
Original/Omicron BA.4-5 licensed by Pfizer-BioNTech (both 
applied in the frame of clinical routine and not within this 
observation study) 
Protocol Version and Date: 
Version 1.0; 28.09.2022 
 
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 3, Version 1.0 (28/09/2022) 
 
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Local Principal Investigator at study site*: 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
COVERALL: third sub-protocol 
Controlled trials to assess approved SARS-CoV-2 vaccines in immunocompromised patients: 
Third sub-protocol for an observational study comparing benefits and potential risks of the 
newly approved bivalent SARS-CoV-2 vaccines 
 
 
 
Site 
Basel HIV Cohort 
Dep. of Infectious Diseases and Hospital Hygiene 
University Hospital Basel 
Petersgraben 4 
Principal investigator 
Dr. Marcel P. Stoeckle 
 
 
 
Place/Date 
 
Signature 
 
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
 
 
 

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Local Principal Investigator at study site*: 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
COVERALL: third sub-protocol 
Controlled trials to assess approved SARS-CoV-2 vaccines in immunocompromised patients: 
Third sub-protocol for an observational study comparing benefits and potential risks of the 
newly approved bivalent SARS-CoV-2 vaccines 
 
 
 
Site 
Bern HIV Cohort 
Universitätsklinik für Infektiologie 
Freiburgstrasse 16p, Haus 5, Stock E 
3010 Bern 
Principal investigator 
Dr. Anna Lena Eichenberger 
 
 
 
Place/Date 
 
Signature 
 
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
 
 
 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
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Local Principal Investigator at study site*: 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
COVERALL: third sub-protocol 
Controlled trials to assess approved SARS-CoV-2 vaccines in immunocompromised patients: 
Third sub-protocol for an observational study comparing benefits and potential risks of the 
newly approved bivalent SARS-CoV-2 vaccines 
 
 
 
Site 
Klinik für Nephrologie  
UniversitätsSpital Zürich 
Rämistrasse 100 
8091 Zürich 
Principal investigator 
Prof Thomas Müller 
 
 
 
 
Place/Date 
 
Signature 
 
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
 
 
 

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Local Principal Investigator at study site*: 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
COVERALL: third sub-protocol 
Controlled trials to assess approved SARS-CoV-2 vaccines in immunocompromised patients: 
Third sub-protocol for an observational study comparing benefits and potential risks of the 
newly approved bivalent SARS-CoV-2 vaccines 
 
 
 
Site 
Klinik für Pneumologie  
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
Principal investigator 
PD Dr. Macé Schuurmans 
 
 
 
Place/Date 
 
Signature 
 
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
 
 

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Local Principal Investigator at study site*: 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
COVERALL: third sub-protocol 
Controlled trials to assess approved SARS-CoV-2 vaccines in immunocompromised patients: 
Third sub-protocol for an observational study comparing benefits and potential risks of the 
newly approved bivalent SARS-CoV-2 vaccines 
 
 
 
Site 
CHUV 
Centre de transplantation d’organes 
Rue du Bugnon 46 
1011 Lausanne 
Principal investigator 
Prof. Oriol Manuel, MD 
 
 
 
Place/Date 
 
Signature 
 
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
 
  
 

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In the master protocol (submitted to the ethics 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. We 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), that compared head to head the vaccines by Pfizer/Biontech and Moderna.  
 
Thereafter, a third dose of a SARS-CoV-2 vaccine was recommended for the entire population, 
priorising severely immunodeficient persons. These vaccines were administered to patients from the 
SHCS and the STCS in the frame of clinical routine. In a second sub-study (as outlined in the second 
sub-protocol, submitted to the ethical committee on the 24. November 2021; EC ID 2021-000593) we 
assessed in an observational study the additional benefit of a third SARS-CoV-2 vaccine in these 
immunocompromised patients 8 weeks after vaccination. 
 
Recently, new adapted bivalent mRNA SARS-CoV-2 vaccines were developed, showing potent 
neutralizing antibody response against Omicron subvariants in the general population. As a third sub-
protocol embedded in our COVERALL trial platform, we propose to conduct an observational study to 
assess the immunologic response and safety of the bivalent SARS-CoV-2 vaccines among 
immunocompromised persons (persons living with HIV or kidney or lung transplant recipients). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
ABBREVIATIONS ................................................................................................................................. 15 
STUDY SYNOPSIS ............................................................................................................................... 17 
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 DATA MANAGEMENT .................................................................................................................. 23 
2. 
COMMITTEES AND INVOLVED INSTITUTIONS:........................................................................ 23 
2.1 MONITORING INSTITUTION ........................................................................................................ 23 
2.2 DATA SAFETY MONITORING COMMITTEE ............................................................................... 23 
2.3 ANY OTHER RELEVANT COMMITTEE, PERSON, ORGANISATION, INSTITUTION ............... 23 
2.4 AUTHOR CONTRIBUTIONS ......................................................................................................... 23 
3. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 24 
3.1 STUDY REGISTRATION ............................................................................................................... 24 
3.2 CATEGORISATION OF STUDY ................................................................................................... 24 
3.3 COMPETENT ETHICS COMMITTEE (CEC) ................................................................................. 24 
3.4 COMPETENT AUTHORITIES (CA) .............................................................................................. 24 
3.5 ETHICAL CONDUCT OF THE STUDY ......................................................................................... 24 
3.6 DECLARATION OF INTEREST .................................................................................................... 24 
3.7 PATIENT INFORMATION AND INFORMED CONSENT ............................................................. 24 
3.8 PARTICIPANT PRIVACY AND CONFIDENTIALITY ................................................................... 24 
3.9 EARLY TERMINATION OF THE STUDY ..................................................................................... 24 
3.10 PROTOCOL AMENDMENTS ........................................................................................................ 25 
4. 
BACKGROUND AND RATIONALE .............................................................................................. 25 
4.1 BACKGROUND AND RATIONALE .............................................................................................. 25 
5. 
INVESTIGATIONAL PRODUCT (TREATMENT, DEVICE) AND INDICATION ........................... 26 
5.1 PRECLINICAL EVIDENCE ............................................................................................................ 26 
5.2 CLINICAL EVIDENCE TO DATE .................................................................................................. 26 
5.3 RISKS / BENEFITS ....................................................................................................................... 26 
5.4 JUSTIFICATION OF CHOICE OF STUDY POPULATION ........................................................... 27 
6. 
STUDY OBJECTIVES ................................................................................................................... 27 
6.1 OVERALL OBJECTIVE ................................................................................................................. 27 
6.2 OBJECTIVES RELATED TO A PLATFORM BASED NESTED EXTENSION STUDY TO 
INVESTIGATE THE IMMUNOLOGIC RESPONSE AND SAFETY OF THE CURRENT BIVALENT 
MRNA VACCINES ................................................................................................................................ 27 
6.3 SAFETY OBJECTIVES ................................................................................................................. 27 
6.4 STUDY OUTCOMES ..................................................................................................................... 28 
6.4.1 Immunological Outcomes ................................................................................................... 28 
6.4.2 Clinical Outcomes ............................................................................................................... 28 
6.4.3 Other Outcomes of Interest ................................................................................................. 28 
6.4.4 Safety Outcomes ................................................................................................................. 28 

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7. 
STUDY DESIGN ............................................................................................................................ 29 
7.1 GENERAL STUDY DESIGN AND JUSTIFICATION OF DESIGN ............................................... 29 
7.2 METHODS OF MINIMISING BIAS ................................................................................................ 29 
7.2.1 Randomization .................................................................................................................... 29 
7.2.2 Blinding procedures ............................................................................................................ 29 
7.2.3 Other methods of minimising bias ....................................................................................... 29 
7.3 UNBLINDING PROCEDURES (CODE BREAK) .......................................................................... 29 
7.4 STUDY POPULATION .................................................................................................................. 29 
7.5 RECRUITMENT AND SCREENING .............................................................................................. 30 
7.6 ASSIGNMENT TO STUDY GROUPS ........................................................................................... 30 
7.7 CRITERIA FOR WITHDRAWAL / DISCONTINUATION OF PARTICIPANTS ............................. 31 
7.8 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN PARTICIPANTS ........................ 31 
7.9 TRIAL SPECIFIC PREVENTIVE MEASURES.............................................................................. 31 
7.10 CONCOMITANT INTERVENTIONS (TREATMENTS) .................................................................. 31 
8. 
STUDY DRUG / MEDICAL DEVICE ACCOUNTABILITY ............................................................ 31 
9. 
RETURN OR DESTRUCTION OF STUDY DRUG / MEDICAL DEVICE ...................................... 31 
10. STUDY ASSESSMENTS ............................................................................................................... 31 
Study flow chart(s) / table of study procedures and assessments ........................................................ 31 
10.1 ASSESSMENTS OF OUTCOMES ................................................................................................ 32 
10.1.1 Assessment of immunological endpoints ............................................................................ 32 
10.1.2 Assessment of clinical endpoints ........................................................................................ 33 
10.1.3 Assessment of safety outcomes ......................................................................................... 33 
10.1.4 Assessments in participants who prematurely stop the study ............................................ 34 
10.1.5 Assessments in participants who prematurely stop the study ............................................ 34 
10.1.6 Other assessments ............................................................................................................. 34 
11. PROCEDURES AT EACH VISIT ................................................................................................... 34 
11.1.1 Eligibility .............................................................................................................................. 34 
11.1.2 Baseline assessment (before application of bivalent SARS-CoV-2 vaccination) ............... 35 
11.1.3 Study specific follow-up ...................................................................................................... 35 
12. SAFETY ......................................................................................................................................... 35 
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.
 
35 
13. STATISTICAL METHODS ............................................................................................................. 35 
Hypothesis ............................................................................................................................................. 35 
13.1 DETERMINATION OF SAMPLE SIZE .......................................................................................... 35 
13.2 STATISTICAL CRITERIA OF TERMINATION OF TRIAL ............................................................ 35 
13.3 PLANNED ANALYSES ................................................................................................................. 35 
13.3.1 Datasets to be analysed, analysis populations ................................................................... 35 
13.3.2 Analyses of immunological and clinical outcomes .............................................................. 35 
13.3.3 Interim analyses .................................................................................................................. 36 
13.3.4 Safety analysis .................................................................................................................... 36 
13.3.5 Deviation(s) from the original statistical plan ...................................................................... 36 

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13.4 HANDLING OF MISSING DATA AND DROP-OUTS ................................................................... 36 
13.5 QUALITY ASSURANCE AND CONTROL .................................................................................... 36 
13.6 DATA HANDLING AND RECORD KEEPING / ARCHIVING ....................................................... 36 
14. DATA MANAGEMENT .................................................................................................................. 36 
15. MONITORING ................................................................................................................................ 36 
16. AUDITS AND INSPECTIONS........................................................................................................ 36 
17. CONFIDENTIALITY, DATA PROTECTION .................................................................................. 36 
18. STORAGE OF BIOLOGICAL MATERIAL AND RELATED HEALTH DATA .............................. 36 
19. PUBLICATION AND DISSEMINATION POLICY.......................................................................... 37 
20. FUNDING AND SUPPORT ............................................................................................................ 37 
21. INSURANCE .................................................................................................................................. 37 
22. REFERENCES ............................................................................................................................... 37 
23. APPENDICES ................................................................................................................................ 38 
 
 
 

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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 
CI 
Confidence Interval 
COVERALL 
COrona VaccinE tRiAL pLatform 
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 
Elecsys S 
Immunoassay Elecsys Anti-SARS-CoV-2 S Roche Test 
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) 
ICMJE 
International Committee of Medical Journal Editors 
IFN-γ 
Interferon gamma 
Ig 
Immunoglobulin 
IIT 
Investigator-initiated Trial 
IMP 
Investigational Medicinal Product 
IMV 
Institut für Medizinische Virologie in Zürich 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
MD 
Medical Device  
MedDO 
Medical Device Ordinance (in German: MepV, in French: ODim) 

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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 
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  
 
 
 

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STUDY SYNOPSIS 
Controlled trials to assess approved SARS-CoV-2 vaccines in immunocompromised patients: 
Third sub-protocol for an observational study comparing benefits and potential risks of the 
newly approved bivalent SARS-CoV-2 vaccines 
 
Brief Title: Immunocompromised Swiss Cohorts Based Trial Platform,  
Acronym: COVERALL (COrona VaccinE tRiAL pLatform) bivalent 
 
Rationale: Since January 12, 2021 two mRNA based vaccines against SARS-CoV-2 by Pfizer-
BioNTech (Comirnaty®) and by Moderna (COVID-19 mRNA Vaccine 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. The second sub-
study found similar results 8 weeks after the 3rd vaccination (i.e. non-inferiority of moderna vaccine; 
antibody response in patients living with HIV, high proportion of transplant recipients with inadequate 
antibody response).  
Recently smaller phase II-II studies with bivalent SARS-CoV-2 vaccines have shown superior antibody 
response against variants that are being monitored such as alpha (B.1.1.7 and Q lineages), beta 
(B.1.351 and descendent lineages), gamma (P.1 and descendent lineages), delta (B.1.617.2 and AY 
lineages) and the variant of concern omicron (B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4 and BA.5 
lineages) when compared to the approved monovalent vaccine. We therefore aim to conduct an 
observational study assessing the immunologic response and safety of the bivalent SARS-CoV-2 
vaccines. Currently (23. 9. 2022) the bivalent SARS-CoV-2 vaccine from Moderna (i.e. m-RNA-
1273.214) is approved by the Swiss authorities (Swissmedic) and the bivalent SARS-CoV-2 vaccine by 
Pfizer-BioNTech is under evaluation. Since we do not know when the product from Pfizer-BioNTech will 
become available, we describe and pre-specify two scenarios for this study.  
Scenario 1 (Comparison): In this observational study, we will recruit patients who have received m-
RNA-1273.214 by Moderna in the frame of clinical routine. We will start a second arm of our 
observational study as soon as another bivalent mRNA vaccine (from Pfizer-BioNTech) has been 
approved by Swissmedic. This will allow for a non-randomized comparison of the 2 bivalent mRNA 
vaccines.  
Scenario 2 (No comparison): In case there is a delay in the approval of the second bivalent mRNA 
vaccine of more than 3 months after the start of the substudy-3, we will conduct a single arm 
observational study only (Scenario 2 in Figure 1), because the comparability of the two arms will be 
increasingly compromised over time.   
   
Objectives and Endpoints:   
Aim Scenario 1: To compare immunologic response and safety of the bivalent mRNA-1273.214 vaccine 
from Moderna among immunocompromised persons (persons living with HIV or kidney or lung 
transplant recipients) to the immunologic response of immunocompromised persons who received the 
bivalent mRNA vaccine from Pfizer-BioNTech. 
Aim Scenario 2: To assess immunologic response and safety of the bivalent mRNA-1273.214 vaccine 
among immunocompromised persons (persons living with HIV or kidney or lung transplant recipients). 
 
Objectives: 
All objectives and endpoints apply to both scenarios. However, Scenario 1 allows for a comparison of 
the endpoints between the two vaccines. 
 
1) To assess the efficacy of the bivalent mRNA-1273.214 booster vaccine  

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2) To evaluate the durability of the bivalent mRNA-1273.214 booster vaccine response: Proportion 
of participants that show waning of antibody response at 8 weeks and 6 months, respectively, 
measured by pan-Immunoglobulin (Ig) antibodies 
3) To describe the longitudinal T-cell immune response of the bivalent mRNA-1273.214 booster 
vaccine in a sub-sample of participants: cellular immune response build up and waning 
4) To assess the safety of the bivalent mRNA-1273.214 booster vaccine 
 
Endpoints:  
Immunological endpoints:  
 
The proportion of patients with a positive antibody response to SARS-CoV-2 spike (S1) protein 
receptor binding domain (RBD) in human plasma assessed by the commercial immunoassay 
Elecsys Anti-SARS-CoV-2 S (Elecsys S) from Roche (1) 4 weeks, 8 weeks, and 6 months after 
vaccination. An antibody response will be considered to be still sufficient, using the threshold 
≥100 units/ml, predicting a protective immune response as indicated by Hall et al. (2), and 
Khoury and colleagues.(3)  
 
Geometric mean of quantitative antibodies against RBD at 4 weeks, 8 weeks, and 6 months 
using Elecsys S test from Roche. 
 
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 at 4 
weeks, 8 weeks, and 6 months. 
 
T-Cell response, using a commercially available Interferon gamma (IFN-γ) release assays 
(Quant-T-Cell SARS-CoV-2 by Euroimmun and Elecsys® IGRA SARS-CoV-2 by Roche) in a 
subsample of 60 patients (40 receiving bivalent (Wuhan/BA.1) SARS-CoV-2 mRNA-1273.214 
vaccine by Moderna; 20 receiving bivalent (Wuhan/BA.1) SARS-CoV-2 mRNA vaccine by 
Pfizer-BioNTech) 4 weeks and 6 months after vaccination (sub-sample will be decreased to 40 
patients in Scenario 2). 
Clinical Endpoints: 
 
Newly confirmed SARS-CoV-2 infections 4 weeks, 8 weeks, and 6 months after vaccination. 
 
Newly confirmed symptomatic SARS-COV-2 infection 4 weeks, 8 weeks, and 6 months after 
vaccination 
 
Severe COVID-19 infections (requiring hospitalization or leading to death) 4 weeks, 8 weeks, 
and 6 months after vaccination 
Safety endpoints 
 
Vaccine-related adverse events 4 weeks after vaccination 
 
Serious adverse events 4 weeks, 8 weeks, and 6 months after vaccination 
 
Overall Design:  
Observational study extension conducted within our trial-platform (COVERALL) nested in two national 
cohorts. 
Number of Participants enrolled: 
Since our trial platform is nested within two national cohort studies (SHCS and STCS), we have the 
possibility to identify and invite cohort patients who will receive the new bivalent mRNA Sars-CoV-2 
vaccine in the frame of clinical routine. We plan to enrol the following number of individuals: 
 
Scenario 1: 
160 patients receiving bivalent (Wuhan/BA.1) SARS-CoV-2 mRNA-1273.214 vaccine by Moderna 
 
kidney transplant recipients (n=30) 
 
lung transplant recipients (n=30) 
 
people living with HIV with CD4 cell counts below 350 cells/µL (n=50) 
 
people living with HIV with CD4 cell counts of ≥ 350 cells/µL (n=50) 

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AND  
80 patients receiving bivalent (Wuhan/BA.1) SARS-CoV-2 mRNA vaccine by Pfizer-BioNTech 
 
kidney transplant recipients (n=10) 
 
lung transplant recipients (n=10) 
 
people living with HIV with CD4 cell counts below 350 cells/µL (n=30) 
 
people living with HIV with CD4 cell counts of ≥ 350 cells/µL (n=30) 
Sub-sample: A sub-sample of 60 patients will be selected (n=40 bivalent mRNA-1273.214 vaccine by 
Moderna; n=20 bivalent SARS-CoV-2 mRNA vaccine by Pfizer-BioNTech) for whom we will assess the 
T-Cell response, measured using the Quant-T-Cell SARS-CoV-2 by Euroimmun and Elecsys® IGRA 
SARS-CoV-2 by Roche. For this sub-sample we aim to prioritize patients which are at higher risk for a 
low immune response (i.e. solid organ transplant recipients and people living with HIV wit CD4 counts 
below 350 cells/µL so that we can include from each of the above groups 10 patients  who received 
bivalent mRNA-1273.214 and 5 who received bivalent SARS-CoV-2 mRNA vaccine by Pfizer-
BioNTech).  
 
Scenario 2:  
160 patients receiving bivalent (Wuhan/BA.1) SARS-CoV-2 mRNA-1273.214 vaccine by Moderna 
 
kidney transplant recipients (n=30) 
 
lung transplant recipients (n=30) 
 
people living with HIV with CD4 cell counts below 350 cells/µL (n=50) 
 
people living with HIV with CD4 cell counts of ≥ 350 cells/µL (n=50) 
 
Sub-sample: A sub-sample of 40 patients will be selected for whom we will assess the T-Cell response 
(10 from each of the groups listed above). 
  
 
Biological Sample and health related data Collection and Duration: 
Participants of the Swiss HIV Cohort Study (SHCS) and Swiss Transplant Cohort Study (STCS) 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 in the frame of clinical routine. At 4 weeks 
(± 1 week), 8 weeks (± 2 weeks), and 6 months (± 4 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. 
 
 

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Study schedule  
 
 
a Informed consent can also be given at later time point if bivalent vaccine was already administered in the frame 
of clinical routine and consent is only referring to blood samples and use of data. 
b Will be administered in the frame of clinical routine based on recommendation from treating physician 
 
 
 
Assessment 
Baseline 
4 weeks  
(± 1 week) 
8 weeks  
(± 2 weeks) 
6 months  
(± 4 weeks) 
Eligibility and consenta 
X 
 
 
 
Baseline assessment 
X 
 
 
 
Assessment 
of 
monoclonal 
antibody 
treatment 
and 
flu 
vaccination 
X 
X 
X 
X 
Vaccination (mRNA-1273.214 or 
product by Pfizer-BioNtech) in 
the frame of clinical routineb 
X 
 
 
 
Anti-SARS-CoV-2 
S 
and 
N 
antibody tests (Elecsys® Roche) 
X 
X 
X 
X 
T-cell test (IFN-γ release assay): 
Quant-T-Cell SARS-CoV-2 by 
Euroimmun and Elecsys® IGRA 
SARS-CoV-2 by Roche 
Only 
in 
sub-sample 
of 
60 
patients (Scenario 1) or 40 
patients (Scenario 2) 
X 
X 
 
X 
Clinical outcomes 
 
X 
X 
X 
Vaccine specific adverse events 
 
X 
 
 
Serious adverse events 
 
X 
X 
X 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
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1. STUDY ADMINISTRATIVE STRUCTURE  
Sponsor-Investigator  
University Hospital Basel 
Benjamin Speich, PhD 
CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research 
University Hospital Basel 
Totengässlein 3 
4051 Basel 
Switzerland 
Phone: +41 (0)61 328 38 19 
Email: benjamin.speich@usb.ch 
1.1 LOCAL PRINCIPAL INVESTIGATOR(S)  
Dr. Marcel P. Stoeckle 
Basel HIV Cohort 
Division of Infectious Diseases and Hospital Epidemiology 
Universitätsspital 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, Inselspital Bern 
Freiburgstrasse 16p 
3010 Bern 
 
PD Dr. Macé Schuurmans 
STCS Zürich (Lung transplantations) 
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Prof. Thomas Müller 
STCS Zürich (Kidney transplantations) 
Klinik für Nephrologie  
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Prof. Michael Tamm 
STCS Basel (Lung transplantations) 
Universitätsspital Basel 
Pneumologie 
Petersgraben 4 
4051 Basel 
 
PD Dr. med. Patrizia Amico 
STCS Basel (Kidney transplantations) 

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Universitätsspital Basel 
Transplantationsimmunologie & Nephrologie 
Petersgraben 4 
4051 Basel 
 
Prof, Oriol Manuel, MD 
STCS Lausanne  
CHUV  
Centre de transplantation d’organes 
Rue du Bugnon 46 
1011 Lausanne 
1.2 STATISTICIAN ("BIOSTATISTICIAN")  
Dr. Frédérique Chammartin, PhD 
Division Klinische Epidemiologie 
Departement Klinische Forschung 
Universitätsspital Basel und Universität Basel  
Totengässlein 3, 4051 Basel 
1.3 LABORATORY 
Dr. Irene A. Abela, MD PhD 
Annette Audigé, PhD 
Prof. Alexandra Trkola 
Institut für Medizinische Virologie 
Universität Zürich 
Winterthurerstrasse 190, 8057 Zürich 
1.4 CO-INVESTIGATORS  
Prof. Heiner C. Bucher, MD, MPH 
Prof. Matthias Briel, MD, PhD 
Christof Schönenberger, MSc 
Alexandra Griessbach, MSc 
Alain Amstutz, MD, PhD 
Prof. Niklaus Labhardt, MD, MSc 
Division Klinische Epidemiologie 
Departement Klinische Forschung 
Universitätsspital Basel und Universität Basel  
 
PD Michael Koller, MD, MSc 
Transplantationsimmunologie und Nephrologie, Datenzentrum Swiss Transplant Cohort Study  
Universitätsspital Basel und Universität Basel  
 
Prof. Barbara Hasse, MD 
Dominique L. Braun, MD PhD 
Prof. Nicolas J. Müller, MD 
Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 
Zurich, Switzerland 
 
Papadimitriou-Olivgeris, MD 
Infectious Diseases Service and Transplantation Center, Lausanne University Hospital, 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
Page 23 of 38 
Lausanne, Switzerland 
 
Prof. Andri Rauch, MD 
Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, 
Bern, Switzerland 
 
1.5 DATA MANAGEMENT 
Katharina Kusejko, PhD 
Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 
Zurich, Switzerland 
 
2. COMMITTEES AND INVOLVED INSTITUTIONS: 
2.1 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 and 2.  
 
2.2 DATA SAFETY MONITORING COMMITTEE  
Due to the observational nature of this study extension, no data safety moniroring committee will be 
used.  
2.3 ANY OTHER RELEVANT COMMITTEE, PERSON, ORGANISATION, 
INSTITUTION  
Scientific protocol writing committee: Members of the scientific protocol writing committee, consisting of 
Alain Amstutz, Benjamin Speich, Heiner C. Bucher, Alexandra Griessbach, Niklaus Labhardt, Irene 
Abela, Katharina Kusejko, and Matthias Briel, were responsible for designing the study, receiving 
funding and writing the study protocol. 
2.4 AUTHOR CONTRIBUTIONS 
Alain Amstutz (AA); Benjamin Speich (BS); Heiner C. Bucher (HCB); Michael Koller (MK); Matthias Briel 
(MB); Niklaus Labhardt (NL); Frédérique Chammartin (FC); and Irene A. Abela (IAA) designed the study. 
Katharina Kusejko (KK) gave scientific input. AA and BS wrote the first draft of the sub-protocol 3. All 
authors critically revised and approved the final version of the study protocol. AA, BS, FC, IAA, MB, NL 
and HCB acquired funding for the trial.  
 

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Page 24 of 38 
3. ETHICAL AND REGULATORY ASPECTS  
We refer to the master protocol. 
3.1 STUDY REGISTRATION 
COVERALL is registered with the U.S. National Institutes of Health (www.clinicaltrials.gov) under 
NCT04805125. The current registration will be adapted to implement the proposed trial extension. All 
sub-protocols are freely available on https://clinicaltrials.gov/ct2/show/NCT04805125. This extension 
will also be registered with the Koordinationsstelle Forschung am Mensch (kofam).  
3.2 CATEGORISATION OF STUDY 
This substudy is an observational extension (HFV2) in the Category A. This sub-study will assess 
patients blood sample after routine vaccination for immune response against SARS-CoV-2. Of note, the 
first study within out trial platform (sub-protocol 1) was an interentional study (klinV), while also substudy-
2 (sub-protocol 2) was an observational study (HFV2). 
3.3 COMPETENT ETHICS COMMITTEE (CEC)  
We refer to the master protocol. 
3.4 COMPETENT AUTHORITIES (CA) 
We refer to the master protocol. 
3.5 ETHICAL CONDUCT OF THE STUDY 
We refer to the master protocol. 
3.6 DECLARATION OF INTEREST 
We refer to the master protocol. 
3.7 PATIENT INFORMATION AND INFORMED CONSENT 
 
We refer to the master protocol. 
3.8 PARTICIPANT PRIVACY AND CONFIDENTIALITY 
We refer to the master protocol. 
3.9 EARLY TERMINATION OF THE STUDY 
 
The Sponsor-Investigator may terminate the sub-study 3 prematurely according to certain 
circumstances, for example: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
Page 25 of 38 
 
alterations in accepted clinical practice that make the continuation of this extension study 
unwise 
3.10 PROTOCOL AMENDMENTS 
We refer to the master protocol. 
4. BACKGROUND AND RATIONALE 
4.1 BACKGROUND AND RATIONALE 
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), according to an adaptive trial master protocol (4). Within the frame of a first sub-study 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 (5). 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. 
The second sub-study found similar results 8 weeks after the 3rd vaccination (i.e. non-inferiority of 
moderna vaccine; antibody response in patients living with HIV, high proportion of transplant recipients 
with inadequate antibody response; manuscript in preparation).  
The currently used SARS-CoV-2 vaccines were developed targeting the SARS-CoV-2 wild type and 
show limited efficacy against newer SARS-CoV-2 variants of concern. Hence, Moderna has developed 
a new bivalent booster vaccine based on variant spike sequences (Wuhan/Omicron BA.1). In a recent 
study this newly developed bivalent mRNA-1273.214 vaccine showed also a potent neutralizing 
antibody response against Omicron subvariants and a superior antibody response against alpha, beta, 
gamma, delta and omicron variants when compared to the approved monovalent vaccine mRNA-1273 
Spikevax (6). Similarly, Pfizer-BioNTech has developed a bivalent mRNA vaccine (Wuhan/Omicron 
BA.1) with promising results (7, 8). Currently, evidence on the efficacy and safety of bivalent mRNA- 
vaccines in immunocompromised persons is very limited.  
Hence, we propose a third sub-study of our COVERALL study assessing the humoral and cellular 
immune response, clinical and safety outcomes of the bivalent mRNA-vaccines (Wuhan/Omicron BA.1) 
in patients from the SHCS and STCS who have received at least three monovalent m-RNA SARS-CoV-
2 vaccinations by either Moderna or Pfizer-BioNTech. Little is known about the cellular (T-cell mediated) 
immune response for these bivalent vaccines. Evidence from previous mRNA vaccine studies has 
shown inconsistent patterns between humoral and cellular response, especially among solid organ 
transplant recipients (9-11). 
We propose to conduct an observational study, with two possible scenarios, dependent on how soon 
the second bivalent mRNA SARS-CoV-2 vaccine from Pfizer-BioNTEch will become available. 
Independently, we will start the study with the bivalent mRNA vaccine from Moderna which has already 
been approved by Swissmedic, being the first bivalent mRNA vaccine available in Switzerland. We will 
start a second observational arm with the bivalent mRNA vaccine from Pfizer-BioNTech, as soon as it 
has been approved by Swissmedic. This will allow a non-randomized comparison of the 2 bivalent 
mRNA vaccines (Scenario 1 in Figure 1). In case the approval of Pfizer-BioNTech’s bivalent mRNA 
vaccine comes later than than 3 months after study start, we will not open this second observational 
arm because the non-randomized comparability of the two arms will be too compromised due to time 
difference (Scenario 2 in Figure 1). 
 

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Page 26 of 38 
5. INVESTIGATIONAL PRODUCT (TREATMENT, DEVICE) AND INDICATION 
5.1 PRECLINICAL EVIDENCE 
Moderna’s bivalent mRNA-1273.214 vaccine showed a potent neutralizing antibody response against 
variants that are being monitored such as alpha, beta, gamma, delta and the variant of concern omicron 
when compared to their approved monovalent vaccine mRNA-1273 Spikevax (6). Similarly, Pfizer-
BioNTech has developed a bivalent mRNA vaccine (Wuhan/Omicron BA.1) with promising results (7). 
5.2 CLINICAL EVIDENCE TO DATE  
 
In a phase 2–3 study, Moderna compared the 50-μg bivalent vaccine mRNA-1273.214 (25 μg each of 
ancestral Wuhan-Hu-1 and omicron B.1.1.529 [BA.1] spike messenger RNAs) with their previously 
authorized 50-μg mRNA-1273 booster among adults who received a two-dose (100-μg) primary series 
and first booster (50-μg) dose of mRNA-1273 (≥3 months earlier) (6). “In participants with no previous 
SARS-CoV-2 infection, the geometric mean titers (GMT) of neutralizing antibodies against the omicron 
BA.1 variant were 2372.4 (95% confidence interval [CI], 2070.6 to 2718.2) after receipt of the mRNA-
1273.214 booster and 1473.5 (95% CI, 1270.8 to 1708.4) after receipt of the mRNA-1273 booster. In 
addition, 50-μg mRNA-1273.214 and 50-μg mRNA-1273 elicited GMT of 727.4 (95% CI, 632.8 to 836.1) 
and 492.1 (95% CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5 (BA.4/5), and the 
mRNA-1273.214 booster also elicited higher binding antibody responses against multiple other variants 
(alpha, beta, gamma, and delta) than the mRNA-1273 booster. Safety and reactogenicity were similar 
with the two booster vaccines.” (6).  
  
No peer-reviewed publication is currently available for the bivalent SARS-CoV-2 vaccine from Pfizer-
BiNTech (19. September 2022) . Hence we cite from the available press releases (7, 8). 
“Pfizer/BioNTech’s bivalent vaccine contains 15-µg of mRNA encoding the wild-type spike protein of 
SARS-CoV-2, which is present in the Original Pfizer-BioNTech COVID-19 Vaccine, and 15-µg of mRNA 
encoding the spike protein of the Omicron BA.4/BA.5 subvariants.” (8). Pfizers’ Omicron-adapted 
vaccine candidates (30 µg and 60 µg) studied in the Phase 2/3 trial in 1,234 participants 56 years of 
age and older elicited substantially higher neutralizing antibody responses against Omicron BA.1 when 
compared to the companies’ current COVID-19 vaccine (7). “The pre-specified criterion for superiority 
was measured by the ratio of neutralizing geometric mean titers (GMR) with the lower bound of the 95% 
confidence interval >1. The geometric mean ratio for the bivalent 30 µg and 60 µg vaccines compared 
to the current COVID-19 vaccine were 1.56 (95% CI: 1.17, 2.08) and 1.97 (95% CI: 1.45, 2.68), 
respectively” (7). One month after administration, a booster dose of the Omicron-adapted bivalent 
candidates (30 µg and 60 µg) conferred a 9.1 and 10.9-fold increase in neutralizing GMTs against 
Omicron BA.1. The vaccine candidates were well-tolerated in participants who received one or the other 
Omicron-adapted vaccine. In addition, “a SARS-CoV-2 live virus neutralization assay tested on sera 
from participants over 56 years of age and older, sera efficiently neutralized BA.4/BA.5 with titers 
approximately 3-fold lower than BA.1” (7). 
 
There is no evidence on the efficacy and safety of these bivalent mRNA vaccines in 
immunocompromised people. 
 
5.3 RISKS / BENEFITS  
Participants gain information on their immune status following booster vaccination over time (at 4 
weeks, 8 weeks, and 6 months). This knowledge can be important to participants and treating 
physicians when new boosters might be considered. There are only minimal risks associated with the 
sampling of blood (12). 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 for this particular population and potentially improving vaccination 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
Page 27 of 38 
strategies.    
5.4 JUSTIFICATION OF CHOICE OF STUDY POPULATION 
According to the Swiss Federal Office of Public Health immunocompromised patients are of high priority 
of vaccinations and further research is needed to understand their response to vaccines appropriately. 
The treating physicians of the STCS and the SHCS will administer the vaccines according to the latest 
vaccine recommendations (13). 
6. STUDY OBJECTIVES 
6.1 OVERALL OBJECTIVE 
Overall Objective Scenario 1: To compare immunologic response and safety of the bivalent mRNA-
1273.214 vaccine from Moderna among immunocompromised persons (persons living with HIV or 
kidney or lung transplant recipients) to the immunologic response of immunocompromised persons who 
received the bivalent mRNA vaccine from Pfizer-BioNTech. 
Overall Objective Scenario 2: To assess immunologic response and safety of the bivalent mRNA-
1273.214 vaccine among immunocompromised persons (persons living with HIV or kidney or lung 
transplant recipients). 
 
 
6.2 OBJECTIVES RELATED TO A PLATFORM BASED NESTED EXTENSION 
STUDY TO INVESTIGATE THE IMMUNOLOGIC RESPONSE AND SAFETY 
OF THE CURRENT BIVALENT MRNA VACCINES 
 
To assess the efficacy of the bivalent mRNA vaccines 
 
To evaluate the durability of the bivalent mRNA vaccine response: Proportion of participants 
that show waning of antibody response at 8 weeks and 6 months, respectively, measured 
by pan-IgG antibodies 
 
To describe the longitudinal T-cell immune response of the bivalent mRNA vaccines in a 
sub-sample of participants: cellular immune response build up and waning 
 
To assess the safety of the bivalent mRNA vaccines 
6.3 SAFETY OBJECTIVES 
 
We aim to systematically assess vaccine-related adverse events until 4 weeks after vaccination and 
serious adverse events over the entire study period.  
If a serious event occurs, defined as a serious complication during a blood draw, the research project 
will be interrupted and the Ethics Committee notified on the circumstances via BASEC within 7 days 
according to HRO Art. 211. 
                                                     
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 

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Page 28 of 38 
 
We aim to systematically assess vaccine-related adverse events until 4 weeks after vaccination and 
serious adverse events over the entire study period 
6.4 STUDY OUTCOMES 
 
6.4.1 
Immunological Outcomes 
Immunological endpoints:  
 
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(1) 4 weeks, 8 weeks, and 6 months after 
vaccination. An antibody response will be considered to be still sufficient, using the threshold 
≥100 units/ml, predicting a protective immune response as indicated by Hall et al.(2), and 
Khoury and colleagues.(3)  
 
Geometric mean of quantitative antibodies against RBD at 4 weeks, 8 weeks, and 6 months 
using Elecsys S test from Roche. 
 
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 at 4 
weeks, 8 weeks, and 6 months. 
 
T-Cell response, using a commercially available IFN-γ release assay (Quant-T-Cell SARS-CoV-
2 by Euroimmun and Elecsys® IGRA SARS-CoV-2 by Roche) in a subsample of 60 patients 
(40 receiving bivalent (Wuhan/BA.1) SARS-CoV-2 mRNA-1273.214 vaccine by Moderna; 20 
receiving bivalent (Wuhan/BA.1) SARS-CoV-2 mRNA vaccine by Pfizer-BioNTech) 4 weeks and 
6 months after vaccination (sub-sample will be decreased to 40 patients in Scenario 2). 
6.4.2 
Clinical Outcomes 
Clinical Endpoints: 
 
Newly confirmed SARS-CoV-2 infections 4 weeks, 8 weeks, and 6 months after vaccination. 
 
Newly confirmed symptomatic SARS-CoV-2 infection 4 weeks, 8 weeks, and 6 months after 
vaccination 
 
Severe COVID-19 infections (requiring hospitalization or leading to death) 4 weeks, 8 weeks, 
and 6 months after vaccination 
6.4.3 
Other Outcomes of Interest 
None. 
6.4.4 
Safety Outcomes 
Safety Endpoints: 
 
Vaccine-related adverse events 4 weeks after vaccination 
 
Serious adverse events 4 weeks, 8 weeks, and 6 months after vaccination 
 
                                                     
c. is life-threatening or results in death. 

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7. 
 STUDY DESIGN 
7.1 GENERAL STUDY DESIGN AND JUSTIFICATION OF DESIGN  
Nested within the Swiss HIV Cohort study (SHCS) (14) and the Swiss Transplant Cohort Study 
(STCS)(15) 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 (first 
sub-protocol) were supported by a competitive grant from the Swiss National Science Foundation (4).  
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 a recently conducted observational extension (i.e. second sub-protocol), we assessed 
the non-inferiority of a third mRNA-1273 vaccination compared to a third BNT162b2 vaccination with 
respect to immune response (manuscript in preparation). 
Within the here proposed substudy-3 (third sub-protocol) we aim to conduct an observational study to 
assess the antibody response in immunocompromised patients from the SHCS or the STCS after having 
received the new bivalent SARS-CoV-2 vaccine either from Moderna or Pfizer-BioNtech. We plan to 
assess the antibody response over time (i.e. at 4 weeks, 8 weeks and 6 months) to be able to assess 
the durability of the bivalent mRNAbooster vaccine response (16) in immunocompromised patients. 
 
7.2 METHODS OF MINIMISING BIAS 
7.2.1 
Randomization 
Not applicable in observational study  
7.2.2 
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. 
7.2.3 
Other methods of minimising bias 
7.3 UNBLINDING PROCEDURES (CODE BREAK) 
Not applicable. 
7.4 STUDY POPULATION 
This is a multi-centre study recruiting patients from 3 of the 7 study centres of the SHCS and 3 of the 6 
study centres of the STCS (i.e. University Hospital Basel, University Hospital Zürich, Inselspital 
University Hospital Bern [only SHCS], and University Hospital Lausanne [CHUV; only STCS]). Both 
cohorts are representative for individuals living with HIV and solid organ transplants: 
 
SHCS study centres:  
 
Department of Infectious Diseases, Inselspital University Hospital Bern, 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 

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STCS study centres: 
 
Klinik für Pneumologie, Universitätsspital Zürich  
 
Klinik für Nephrologie, Universitätsspital Zürich 
 
Klinik für Pneumologie, Universitätsspital Basel 
 
Klinik für Transplantationsimmunologie & Nephrologie, Universitätsspital Basel 
 
Service de pneumologoie, Universitätsspital Lausanne (CHUV) 
 
Centre de transplantation d’organes, Universitätsspital Lausanne (CHUV) 
 
The cohorts are described in more detail elsewhere (14, 15, 17, 18). 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: 
- 
Patients with either a HIV infection or recipients of solid organs registered in the SHCS and STCS 
cohorts and signed informed consent form 
- 
Patients aged ≥18 years 
- 
Patients receiving a new bivalent (Wuhan/Omicron BA.1) mRNA SARS-CoV-2 vaccine in the frame 
of clinical routine, according to the treating physician 
- 
Provide consent for the COVERALL observational bivalent booster extension study (third sub-
protocol) 
 
Exclusion criteria: 
- 
Acute symptomatic SARS-CoV-2 infection, influenza or other acute respiratory tract infection 
- 
Any emergency condition requiring immediate hospitalization for any condition 
- 
Known allergy or contra-indications for vaccines or any vaccine components or any other 
contraindication to receive the vaccine according to the treating physician 
- 
Patients who did not receiv the “baseic immunization” SARS-CoV-2 vaccination (e.g. two shots of 
Spikevax from Moderna, two shots of Comirnaty from Pfizer-BioNtech). 
7.5 RECRUITMENT AND SCREENING 
Patients recruitment 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. 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 either by letter, phone call, or during routine cohort study 
visits to inform and invite them in this study. Of note: only relatively few people living with HIV have CD4 
cell counts below 350 cells/µL (<5%). Therefore local investigator will receive a list, highlighting these 
patients so that they can priories this patient group at the beginning of the study to ensure that we can 
reach the required sample size. 
 
7.6 ASSIGNMENT TO STUDY GROUPS 
Since this is an observational study extension, we will not do any active assignment. Participants will 
receive the bivalent vaccine which they are given during routine practice. We will implement monitoring 
reports so capture how many patients from which sub-group are already participating. When the 
required sample size is reached for a specific sub-group investigators will be informed to stop 
recruitment for this sub-group of patients. 

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7.7 CRITERIA FOR WITHDRAWAL / DISCONTINUATION OF PARTICIPANTS 
We refer to the master protocol.  
7.8 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.  
7.9 TRIAL SPECIFIC PREVENTIVE MEASURES 
All patients included into the trial-extension will continue all medication taken for the treatment of their 
chronic conditions. 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.  
7.10 CONCOMITANT INTERVENTIONS (TREATMENTS)  
Concomitant drugs for patients included into the trial-extension are recorded within the routine cohort 
based data collection structure (see master protocol). Within substudy-3 we will systematically assess 
during all study visits the use of monoclonal antibodies and the flu vaccination (see case report form). 
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.   
 
8. STUDY DRUG / MEDICAL DEVICE ACCOUNTABILITY  
 
The vaccines will be administered in the frame of clinical routine at official vaccination centres. These 
can be located directly at University Hospitals or at other locations (e.g. Messehalle in Basel). We will 
collect blood at the baseline visit, at 4 weeks, 8 weeks and 6 months after vaccination.  
 
9. RETURN OR DESTRUCTION OF STUDY DRUG / MEDICAL DEVICE 
Does not apply, since the vaccines will not be given in the frame of the substudy-3. 
10. STUDY ASSESSMENTS 
Study flow chart(s) / table of study procedures and assessments 
 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
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Study schedule  
 
 
a Informed consent can also be given at later time point if bivalent vaccine was already administered in the frame 
of clinical routine and consent is only referring to blood samples and use of data. 
b Will be administered in the frame of clinical routine based on recommendation from treating physician 
 
10.1 ASSESSMENTS OF OUTCOMES 
10.1.1 Assessment of immunological endpoints 
 
We will assess 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 (1) 4 weeks, 8 weeks, and 6 months after 
vaccination. An antibody response will be considered to be still sufficient, using the threshold ≥100 
units/ml, predicting a protective immune response as indicated by Hall et al. (2), and Khoury and 
colleagues (3). We will also assess antibody response at baseline (i.e. before vaccination with bivalent 
SARS-CoV-2 vaccine). However, we assume that some patients may have received already the bivalent 
SARS-CoV-2 vaccine before the start of this study, hence we will not have a baseline blood sample 
from those patients. Furthermore we will measure the geometric mean of quantitative antibodies against 
RBD at 4 weeks, 8 weeks, and 6 months using Elecsys S test from Roche and 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 at 4 weeks, 8 weeks, and 6 months. 
Therefore, a blood sample will be taken during each study visit  (EDTA blood sample (1 x 3 ml)): 
Assessment 
Baseline 
4 weeks  
(± 1 week) 
8 weeks  
(± 2 weeks) 
6 months  
(± 4 weeks) 
Eligibility and consenta 
X 
 
 
 
Baseline assessment 
X 
 
 
 
Assessment 
of 
monoclonal 
antibody 
treatment 
and 
flu 
vaccination 
X 
X 
X 
X 
Vaccination (mRNA-1273.214 or 
product by Pfizer-BioNtech) in 
the frame of clinical routineb 
X 
 
 
 
Anti-SARS-CoV-2 
S 
and 
N 
antibody tests (Elecsys® Roche) 
X 
X 
X 
X 
T-cell test (IFN-γ release assay): 
Quant-T-Cell SARS-CoV-2 by 
Euroimmun and Elecsys® IGRA 
SARS-CoV-2 by Roche 
Only 
in 
sub-sample 
of 
60 
patients (Scenario 1) or 40 
patients (Scenario 2) 
X 
X 
 
X 
Clinical outcomes 
 
X 
X 
X 
Vaccine specific adverse events 
 
X 
 
 
Serious adverse events 
 
X 
X 
X 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
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Participating centres can decide if they want to conduct Elecsys® Anti-SARS-CoV-2 N and S tests 
locally at their own routine laboratory, or if they want to send the blood samples in large batches for the 
analyses to the Institut für Medizinische Virologie (IMV), in Zürich 
 
In a sub-sample of 40 patients who receive the bivalent mRNA SARS-CoV-2 vaccine from Moderna and 
20 who receive bivalent vaccine from Pfizer-BioNTech, we will assess the T-Cell response using a 
commercially available IFN-γ release assay (Quant-T-Cell test by Euroimmun (19)) at baseline, 4 weeks 
and 6 months. We will use the same blood sample to conduct an additional T-Cell test by Roche 
(Elecsys® IGRA SARS-CoV-2 (20)) to compare the performance of the two diagnostic tests. 
For this purpose we will collect 1 heparin blood sample (8 ml) from patients selected for this sub-sample. 
As these blood samples have to be processed within the same day we will only select patients from the 
study center Zürich and Basel for this blood sample. Heparin blood sample collected in Basel will be 
sent on the same day by bike carrier to the IMV in Zürich to assure that they are processed within the 
same day as they were collected. 
 
10.1.2 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 4 weeks (±1 week), 8 weeks (±2 weeks) and 6 months (±4 weeks).  
 
Newly PCR-confirmed Covid-19 infection (identified by the presence of anti–SARS-CoV-2 
nucleocapsid antibodies, or PCR or rapid antigen test)  
During all visits at the trial centres (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 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 requiring hospitalization or leading to death 
 
 
10.1.3 Assessment of safety outcomes 
10.1.3.1 Vaccine specific adverse events 
Patients will be asked at the 4 week study visit about the following specific vaccine related adverse 
events: 
 
Any symptoms at injection site (redness, swelling or pain) limiting continuation of normal daily 
activities during the first 7 days following the booster vaccination? 
 
Any systemic symptoms (fever, muscle pain, joint pain) limiting continuation of normal daily 
activities during the first 7 days following the booster vaccination? 
 
Any vaccine related symptoms leading to physician contact during the first 7 days following 
the booster vaccination? 
10.1.3.2 Serious adverse events 
Eventhough this is an observational study, we will systematically assess any serious adverse events 
that lead to hospitalization or death at 4 weeks, 8 weeks and 6 months follow up. Patients will be asked 
at these study visits about hospitalisations after having received the bivalent SARS-CoV-2 vaccines. In 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
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addition, the information system from the hospital will be checked for information about hospitalisations 
or death of the patient.  
10.1.3.3 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. 
10.1.3.4 Laboratory parameters 
Laboratory parameters besides immune response parameters will be assessed at bi-annually cohort 
visits according to the cohort protocols.  
10.1.3.5 Vital signs 
Not relevant for purpose of this trial.  
 
10.1.4 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.  
10.1.5 Assessments in participants who prematurely stop the study 
We refer to the master protocol 
 
10.1.6 Other assessments  
In case a new SARS-CoV-2 vaccine shot will be recommended before the last 6 months follow-up visit 
is conducted we will add a case report form to assess the additional SARS-CoV-2 vaccines applied after 
the first bivalent mRNA vaccine shot. 
11. PROCEDURES AT EACH VISIT 
11.1.1 Eligibility  
Potentially eligible patients will be either contacted ahead by cohort centres and informed about the 
substudy-3 and availability of bivalent vaccines or directly informed during cohort study visits. Eligibility 
of newly enrolled patients from STCS and SHCS will be prospectively assessed for eligibility based on 
the cohort stud- based trial platform. Treating physicians from the cohort centres will contact patients 
and inform them about the study. It will be mentioned that the new bivalent vaccines will be administered 
in the frame of clinical routine (as soon as the guidelines are adapted) and is not part of this study. In 
case they wish to receive the bivalent SARS-CoV-2 mRNA vaccine outside of this study, they have the 
option to participate 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 previously (i.e. first, second, and third vaccination). In case there are any 
reasons that justify to change to vaccine from different producers during their vaccination history this 
will be allowed following the judgment of the treating physician. 

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11.1.2 Baseline assessment (before application of bivalent 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 of EDTA blood at the local study centre. After this they will go to the 
vaccination centre and receive the bivalent mRNA SARS-CoV-2 vaccine (either by Moderna or Pfizer-
BioNTech) in the frame of clinical routine. Patients will also be asked about their previous vaccine history 
(i.e. which vaccines they received and when [months and year]) and if they have received monoclonal 
antibodies. 
11.1.3 Study specific follow-up 
4 weeks, 8 weeks and 6 months: Patients will be asked about SARS-CoV-2 infections and about adverse 
events. Further, patients will provide a blood sample of EDTA blood to assess the immunological 
outcomes. During all study visits patients will be asked if they received monoclonal antibodies. 
 
Sub sample of patients for T-Cell tests (baseline, 4 weeks and 6 months): Patients will provide at least 
8ml heparin blood which is immediately transferred to the IMV in Zürich for processing on the same day.  
 
12. 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. 
13. STATISTICAL METHODS  
Hypothesis 
All analysese conducted will be of exploratory nature. For scenario 1, we expect to observe similar 
immunological outcomes for the two bivalent vaccines in our study popuation.  
 
13.1 DETERMINATION OF SAMPLE SIZE  
Not applicable. The present study does not aim to test an hypothesis and a convenience sample of 
240 participants for scenario 1 and 160 for scenario 2 has been chosen to better understand 
immunological response to bivalent vaccines in an immunocompromised population. 
 
13.2 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. 
13.3 PLANNED ANALYSES 
13.3.1 Datasets to be analysed, analysis populations 
We refer to the master protocol 
13.3.2 Analyses of immunological and clinical outcomes 
 
Descriptive statistics will be used to present immunological and safety outcomes. We will report 
frequency and percentage with 95% Wald confidene interval (CI) of positive immune response and 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
Page 36 of 38 
geometric mean titer (GMT) with 95% CI. GMT are defiened as the anit-logs of the means and 
addressed anticipated right-skewness of the data. Safety outcomes will be reported as frequency and 
percentage with 95% CI. For scenario 1, we will additionally report mean difference in positive response 
and ratio of GMT between the two bivalent vaccines with 95%CI  .  
Baseline and demographic characteristics will be summarised overall and -for scenario 1 – by vaccine 
received. 
13.3.3 Interim analyses 
No interim analysis will be done 
13.3.4 Safety analysis 
Safety issue is expected to be small and will be describe using number, frequency and 95% CI. 
13.3.5 Deviation(s) from the original statistical plan 
We refer to the master protocol. 
 
13.4 HANDLING OF MISSING DATA AND DROP-OUTS 
We refer to the master protocol.  
13.5 QUALITY ASSURANCE AND CONTROL 
13.6 DATA HANDLING AND RECORD KEEPING / ARCHIVING 
We refer to the master protocol.  
14. DATA MANAGEMENT 
We refer to the master protocol. 
15. MONITORING  
We refer to the master protocol. 
16. AUDITS AND INSPECTIONS 
We refer to the master protocol.  
17. CONFIDENTIALITY, DATA PROTECTION 
We refer to the master protocol.  
18. STORAGE OF BIOLOGICAL MATERIAL AND RELATED HEALTH DATA 
Samples used for diagnostic at the IMV in Zürich will be stored for 5 years. 

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19. 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).  
20. FUNDING AND SUPPORT 
This COVERALL substudy-3 is funded by Moderna (European/Swiss headquarters: Peter Merian-Weg 
10, 4052 Basel, Switzerland). 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. Futhermore Moderna will have the right to review the results 
manuscript before it will be submitted for publication. Otherwise, the funders will have no role in study 
design, data collection and analysis, decision to publish, or preparation of the manuscript. 
21. INSURANCE 
We refer to the master protocol.  
22. REFERENCES 
1. 
Roche. 
Elecsys®Covid-19 
Solutions. 
https://diagnostics.roche.com/global/en/products/params/elecsys-anti-sars-cov-2-s.html [accessed: 08 
July 2022]. 
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. 
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. 
5. 
Speich B, Chammartin F, Abela IA, Amico P, Stoeckle MP, Eichenberger AL, et al. Antibody 
response in immunocompromised patients after the administration of SARS-CoV-2 vaccine BNT162b2 
or mRNA-1273: A randomised controlled trial. Clin Infect Dis. 2022. 
6. 
Chalkias S, Harper C, Vrbicky K, Walsh SR, Essink B, Brosz A, et al. A Bivalent Omicron-
containing Booster Vaccine Against Covid-19. medRxiv. 2022:2022.06.24.22276703. 
7. 
Pfizer-BioNTech. Pfizer and BioNTech Announce Omicron-Adapted COVID-19 Vaccine 
Candidates 
Demonstrate 
High 
Immune 
Response 
Against 
Omicron. 
https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-
omicron-adapted-covid-19 [accessed 5. August 2022]. 
8. 
Pfizer-BioNTech. Pfizer and BioNTech Granted FDA Emergency Use Authorization of Omicron 
BA.4/BA.5-Adapted Bivalent COVID-19 Vaccine Booster for Ages 12 Years and Older. 
https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-granted-fda-
emergency-use-authorization [accessed: 22. September 2022]. 
9. 
Cucchiari D, Egri N, Bodro M, Herrera S, Del Risco-Zevallos J, Casals-Urquiza J, et al. Cellular 
and humoral response after MRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients. Am J 
Transplant. 2021;21(8):2727-39. 
10. 
Deborska-Materkowska D, Kaminska D. The Immunology of SARS-CoV-2 Infection and 
Vaccines in Solid Organ Transplant Recipients. Viruses. 2021;13(9). 

COVERALL, sub-protocol 3, Version 1.0 (28/09/2022) 
 
Page 38 of 38 
11. 
Nimmo A, Gardiner D, Ushiro-Lumb I, Ravanan R, Forsythe JLR. The Global Impact of COVID-
19 on Solid Organ Transplantation: Two Years Into a Pandemic. Transplantation. 2022;106(7):1312-29. 
12. 
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]. 
13. 
Federal Office of Public Health.  Impfempfehlung für die Covid-19-Impfung im Herbst 2022 
(gültig 
ab 
10.10.2022). 
https://www.newsd.admin.ch/newsd/message/attachments/73048.pdf 
[accessed: 22. September 2022]. 
14. 
Swiss HIV Cohort Study (SHCS). http://www.shcs.ch/ [accessed: 28 September 2022]. 
15. 
Swiss Transplant Cohort Study (STCS). https://www.stcs.ch/about/study-description [accessed: 
28 September 2022]. 
16. 
Gilboa M, Regev-Yochay G, Mandelboim M, Indenbaum V, Asraf K, Fluss R, et al. Durability of 
Immune Response After COVID-19 Booster Vaccination and Association With COVID-19 Omicron 
Infection. JAMA Netw Open. 2022;5(9):e2231778. 
17. 
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. 
18. 
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. 
19. 
EUROIMMUN. Quan-T-Cell SARS-CoV-2 & Quan-T-Cell ELISA. https://www.coronavirus-
diagnostics.com/documents/Indications/Infections/Coronavirus/ET_2606_D_UK_A.pdf [accessed: 22 
September 2022]. 
20. 
Roche. Roche launches new diagnostic test for the better understanding of immune response 
to 
SARS-CoV-2. 
https://www.roche.com/media/releases/med-cor-2022-08-15 
[accessed: 
22 
September 2022]. 
 
23. APPENDICES 
Not applicable