A Randomised Controlled Trial to Assess the Immunogenicity, Safety and Reactogenicity of a Bivalent mRNA Moderna COVID-19 Vaccine or a Protein-based Novavax COVID-19 Vaccine Given as a Fourth Dose in Healthy Adults in Australia
Phase: PHASE3
Conditions: COVID-19
Sponsor: Murdoch Childrens Research Institute

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 1 of 52 
 
 
PROTOCOL  
A randomised controlled trial to assess the immunogenicity, 
safety and reactogenicity of a bivalent mRNA Moderna 
COVID-19 vaccine or a protein-based Novavax COVID-19 
vaccine given as a fourth dose in healthy adults in Australia  
 
Protocol Number: 91108 
Protocol Version 8.0 and date:  
9 January 2025 
Document history: 
Version Number and Date 
Summary of changes 
V8.0 9 January 2025 
Extend follow-up to 30 months 
V7.0 28 June 2024 
Extend follow-up to 24 months 
V6.0 21 February 2024 
Extend follow-up to 18 months 
V5.0 31 May 2023 
Additional recruitment strategies added.  
V4.0 27 April 2023 
Change in recruitment, group numbers and product accountability sections 
V3.0 14 March 2023 
Change in Day 28 visit window and additional details for Moderna BA.4-5 
V2.0 19 January 2023 
Amendments including feedback from sponsorship committee and PATH  
V1.2 23 November 2022 
Revisions based on ethics review 
V1.1, 27 October 2022 
Revisions based on peer review and other minor changes  
V1.0, 24 October 2022 
Incorporated input from investigators  
 
CONFIDENTIAL 
This protocol is confidential and is the property of Murdoch Children’s Research Institute. No part of it may be 
transmitted, reproduced, published, or used without prior written authorisation from the institution. 
Statement of Compliance 
This clinical trial will be conducted in compliance with all stipulations of this protocol, the conditions of the 
ethics committee approval, the NHMRC National Statement on Ethical Conduct in Human Research (2007 and 
all updates), the Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2), dated 9 
November 2016 annotated with TGA comments and the NHMRC guidance Safety monitoring and reporting in 
clinical trials involving therapeutic goods (EH59, 2016). 
This clinical trial is not sponsored by any pharmaceutical company or other commercial entity. 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 2 of 52 
 
CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS .............................................................................................................. 10 
INVESTIGATOR AGREEMENT ................................................................................................................. 11 
1. 
ADMINISTRATIVE INFORMATION .......................................................................................... 11 
1.1. 
Trial registration .................................................................................................................... 11 
1.1.1. 
Trial registry ........................................................................................................................... 11 
1.2. 
Sponsor ................................................................................................................................. 11 
1.3. 
Expected duration of study ................................................................................................... 12 
1.4. 
Contributorship ..................................................................................................................... 12 
1.5. 
Stakeholder involvement....................................................................................................... 12 
2. 
INTRODUCTION AND BACKGROUND ..................................................................................... 13 
2.1. 
Background ........................................................................................................................... 13 
2.2. 
Trial rationale and aim ........................................................................................................... 14 
2.3. 
Risk/Benefit assessment ........................................................................................................ 15 
2.3.1. 
Known potential risks ............................................................................................................ 15 
2.3.2. 
Known potential benefits ...................................................................................................... 16 
2.3.3. 
Assessment of potential risks and benefits ........................................................................... 16 
3. 
TRIAL OBJECTIVES AND OUTCOMES ...................................................................................... 16 
3.1 
Objectives .............................................................................................................................. 16 
3.1.1 
Primary objective .................................................................................................................. 16 
3.1.2 
Secondary objectives ............................................................................................................. 17 
3.1.3 
Exploratory objectives ........................................................................................................... 17 
3.2 
Outcomes .............................................................................................................................. 17 
4 
TRIAL DESIGN ........................................................................................................................ 20 
4.1 
Study design .......................................................................................................................... 20 
4.2 
Justification for dose ............................................................................................................. 21 
4.3 
Trial population ..................................................................................................................... 21 
4.4 
Eligibility criteria .................................................................................................................... 21 
4.4.1 
Inclusion criteria .................................................................................................................... 21 
4.4.2 
Exclusion criteria ................................................................................................................... 22 
4.5 
Lifestyle considerations ......................................................................................................... 22 
4.6 
Screen failures ....................................................................................................................... 22 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 3 of 52 
 
4.7 
Recruitment and identification of potential participants ...................................................... 22 
4.8 
Consent ................................................................................................................................. 23 
5 
INTERVENTION ...................................................................................................................... 24 
5.1 
Treatment arms ..................................................................................................................... 24 
5.2 
Trial Intervention(s) ............................................................................................................... 24 
5.2.1 
Description of trial investigational products.......................................................................... 24 
5.2.1.1 
Trial Products ........................................................................................................................ 24 
5.2.2 
Dosage ................................................................................................................................... 25 
5.2.3 
Dose modification ................................................................................................................. 25 
5.2.4 
Storage, preparation, dispensing and administration of trial drug ........................................ 25 
5.2.5 
Product accountability........................................................................................................... 26 
5.2.6 
Excluded medications and treatments .................................................................................. 27 
5.2.7 
Concomitant therapy ............................................................................................................ 27 
5.2.8 
Discontinuation from trial intervention ................................................................................. 27 
6 
RANDOMISATION AND BLINDING ......................................................................................... 27 
6.1 
Concealment mechanism ...................................................................................................... 28 
6.2 
Breaking of the trial blind ...................................................................................................... 28 
6.2.1 
On trial ................................................................................................................................... 28 
7 
TRIAL VISITS AND PROCEDURES ............................................................................................ 29 
7.1 
Schedule of assessments ....................................................................................................... 29 
7.2 
Description of procedures ..................................................................................................... 30 
7.2.1 
Visit 1 (Day 0) ........................................................................................................................ 30 
7.2.2 
Visit 2 (Day 1) – only vaccine groups (A&B) ........................................................................... 31 
7.2.3 
Visit 3 (Day 7) – only vaccine groups (A&B) ........................................................................... 31 
7.2.4 
Visit 4 (Day 28) ...................................................................................................................... 31 
7.2.5 
Visit 5 (3 Months) – all groups (A,B,C) ................................................................................... 32 
7.2.6 
Visit 6 (6 Months) – all groups (A,B,C) ................................................................................... 32 
7.2.7 
Visit 7 (12 months) – all groups (A,B,C) ................................................................................. 32 
7.2.8. 
Visit 8 (18 months) – all groups (A,B,C) ................................................................................. 32 
7.2.9         Visit 9 (24 months) – all groups (A,B,C) ................................................................................. 33 
7.2.10       Visit 10 (30 months) – all groups (A,B,C) ............................................................................... 33 
7.2.8 
Unscheduled visits ................................................................................................................. 34 
7.2.9 
Withdrawal of consent - participant withdraws from all trial participation .......................... 35 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 4 of 52 
 
7.2.10 
Losses to follow-up ................................................................................................................ 35 
7.2.11 
Replacements ........................................................................................................................ 36 
7.2.12 
Trial Closure ........................................................................................................................... 36 
8 
SAFETY MONITORING AND REPORTING ................................................................................ 36 
8.1.1 
Definitions for use in trials involving investigational medicinal products .............................. 36 
8.2 
Capturing and eliciting adverse event/reaction information ................................................. 37 
8.3 
Documentation of AEs ........................................................................................................... 37 
8.4 
Assessing the relatedness (causality) of a participant’s AE .................................................... 38 
8.6 
Reporting of safety events..................................................................................................... 39 
9 
DATA AND INFORMATION MANAGEMENT ........................................................................... 39 
9.1 
Data management ................................................................................................................. 40 
9.1.1 
Data generation (source data) ............................................................................................... 40 
9.1.2 
Data capture methods and data use, storage, access, and disclosure during the trial.......... 41 
9.1.3 
Data confidentiality ............................................................................................................... 42 
9.1.4 
Quality assurance .................................................................................................................. 43 
9.1.5 
Archiving - Data and document retention ............................................................................. 44 
10 
TRIAL OVERSIGHT .................................................................................................................. 44 
10.1 
Governance structure............................................................................................................ 44 
10.1.1 
Trial Management Group (TMG) ........................................................................................... 44 
10.1.2 
Trial Steering Committee (TSC) ............................................................................................. 44 
10.1.3 
Safety Monitoring .................................................................................................................. 45 
10.2 
Site Monitoring ...................................................................................................................... 45 
10.3 
Quality Control and Quality Assurance .................................................................................. 45 
11 
STATISTICAL METHODS ......................................................................................................... 46 
11.1 
Sample Size Estimation .......................................................................................................... 46 
11.2 
Statistical methods and the Estimand framework ................................................................. 46 
11.3 
Methods of analysis - outcome variables and methods ........................................................ 47 
11.3.1 
Primary outcome ................................................................................................................... 47 
11.3.2. 
Secondary outcomes.............................................................................................................. 47 
11.3.3      Exploratory outcome ............................................................................................................. 48 
12 
ETHICS AND DISSEMINATION ................................................................................................ 48 
12.1 
Research Ethics Approval & Local Governance Authorisation ............................................... 48 
12.2 
Amendments to the protocol ................................................................................................ 49 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 5 of 52 
 
12.3 
Protocol Deviations and Serious Breaches ............................................................................ 49 
13 
CONFIDENTIALITY .................................................................................................................. 49 
14 
PARTICIPANT REIMBURSEMENT ............................................................................................ 49 
15 
FINANCIAL DISCLOSURE AND CONFLICTS OF INTEREST ........................................................ 50 
16 
DISSEMINATION AND TRANSLATION PLAN ........................................................................... 50 
17 
ADDITIONAL CONSIDERATIONS ............................................................................................. 50 
18 
REFERENCES .......................................................................................................................... 50 
19  
APPENDICES .......................................................................................................................... 52 
  
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 6 of 52 
 
PROTOCOL SYNOPSIS 
TITLE 
A randomised controlled trial to assess the immunogenicity, safety and 
reactogenicity of a bivalent mRNA Moderna COVID-19 vaccine or a protein-
based Novavax COVID-19 vaccine given as a fourth dose in healthy adults in 
Australia. 
TRIAL 
DESCRIPTION 
 
 
 
 
 
 
This clinical trial will be a blinded*, two-arm randomised study to determine 
the safety, reactogenicity and immunogenicity of a fourth dose of SARS-CoV-
2 vaccines in Australia in adults 18 years or older who have received their 
third dose of COVID-19 vaccine at least six months previously. A separate 
non-randomised control arm will be enrolled for comparison.  
  Group 
Vaccine given 
Group A – (Moderna) 
225 participants 
Bivalent Moderna (mRNA-1273.214) 
(Ancestral SARS-CoV-2 25μg + Omicron 
Variant (B.1.1.529) 25μg). 
 
Replaced by Bivalent Moderna (mRNA-
1273.222) (Ancestral SARS-CoV-2 25μg + 
Omicron 
Variant 
(BA.4-5) 
25μg) 
when 
introduced. 
Group B – (Novavax) 
225 participants 
Novavax (5μg of SARS-CoV-2 spike protein 
adjuvanted with 50μg of Matrix-M) 
 
**Group C – (Control 
group) 
150 participants 
 
No vaccine given 
*Participants and reactogenicity assessors will be blinded for seven days as vaccine details will be uploaded 
to the Australian Immunisation Register seven days post-vaccination.  
**Control group will not be randomised and will be recruited into proportional predefined age bands (18-
29 years, 30-49 years, 50-59 years).  
JUSTIFICATION 
• 
Investigating a fourth dose will allow us to explore whether 
additional boosters are needed in a setting with high rates of prior 
infection. 
• 
We will include a non-randomised control group aged under 60 
years who will not receive a fourth dose to investigate whether 
three doses are adequate for this age group and what additional 
benefit a fourth dose provides in terms of cellular immunity as a 
proxy for moderate/severe disease.  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 7 of 52 
 
• 
The design will allow comparison of immune responses following 
mRNA and protein-based vaccine boosters, including the breadth of 
immunity against different (emerging) variants. 
• 
We will follow-up participants for 30 months (i.e., at least 36 months 
following the third dose for the control arm) to determine the 
duration of immune responses. 
• 
We will document breakthrough infections to explore potential 
differences between groups with regards to number of infections 
and severity.  
OBJECTIVES 
Primary objectives –  
• 
To assess and compare the immune response in two randomised 
vaccine groups (groups A and B) at 28 days post-vaccination 
measured as binding antibodies (IgG ELISA – Wuhan and/or 
Omicron).  
• 
To assess the rate and severity of reactogenicity within one-week 
post-second booster for the two vaccine groups (groups A and B) 
(Timepoint – daily, for seven days post-vaccination). 
Secondary objectives -  
• 
To assess and compare the immune response in groups A and B at 
28 days post-vaccination measured as functional antibodies (sVNT 
and nAb) and cell-mediated immunity (CMI).  
• 
To assess and compare the immune response in groups A and B at 6, 
12, 18, 24 and 30 months post-vaccination measured as binding 
antibodies (IgG ELISA), functional antibodies (sVNT and nAb), and 
CMI.  
• 
To describe binding and functional antibodies in group C compared 
with groups A and B at baseline, 6, 12, 18, 24 and 30 months. 
• 
To assess whether a fourth COVID-19 vaccine dose provides an 
immunological benefit over a third dose by comparing CMI at 6, 12, 
18, 24 and 30 months in group C with groups A and B. 
• 
To evaluate the safety of fourth booster dose regimens. 
Exploratory objective -  
• 
To describe the number and severity of breakthrough cases in group 
C compared with groups A and B, up until 30 months.  
• 
To correlate virological markers (viral load and viral genome 
characteristics) and immunological markers (humoral antibody, CMI) 
among mild and severe breakthrough cases. 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 8 of 52 
 
OUTCOMES AND 
OUTCOME 
MEASURES 
 
Reactogenicity 
Reactogenicity will be measured using a structured questionnaire for seven 
days post-vaccination by recording the following parameters: 
• 
Local reaction - pain, tenderness, erythema/redness, hardness, 
swelling, warmth, itch. 
• 
Systemic – Nausea, vomiting, diarrhoea, headache, fatigue/malaise, 
myalgia, arthralgia, fever, enlarged lymph nodes. 
Immunology endpoints   
• 
Binding antibody – These will be evaluated using the commercial 
Euroimmun S1 IgG ELISA (Wuhan and Omicron [once available]) on 
serum collected at seven timepoints (baseline, 28 days, 6, 12, 18, 24 
and 30 months) for the two vaccine groups and six timepoints 
(baseline, 6, 12, 18, 24 and 30 months) for the control group. The 28 
days post-vaccination sample will be assayed within four weeks of 
collection for the two vaccine groups.  
• 
Functional antibody – All samples will be assayed using the GenScript 
cPass SARS-CoV-2 Neutralization Antibody detection kit for WT and 
Omicron variant RBD antigen or other key newly emerging variants. 
Samples will be tested at the same time points as for binding 
antibodies.   
• 
Neutralizing antibody - A fraction of samples (20%) will be assessed 
using a SARS-CoV-2 assay at the Peter Doherty Research Institute (PDI), 
Melbourne up to 12 months. Testing will be at the same time points as 
for binding antibodies for Wuhan strain and two Variants of Concern 
(VoC), including Omicron or other key newly emerging variants.  
• 
Cellular immunity - Cellular immunity will be assessed on 50% of 
participants per group of samples collected as follows:  
o QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) will be 
performed using whole blood (Wuhan), at four timepoints for 
Groups A and B (baseline, 28 days, 6 months, and 12 months) and 
three timepoints for Group C (baseline, 6 months, and 12 months). 
o Assays performed on PBMCs will include IFN-γ Elispot, intracellular 
cytokine assays (flow cytometry) and multiplex cytokine assays 
(Wuhan and Omicron) at seven timepoints for Groups A and B 
(baseline, 28 days, 6 months, 12 months, 18 months, 24 months 
and 30 months) and six timepoints for Group C (baseline, 6 
months, 12 months, 18 months, 24 months, and 30 months).  
Breakthrough infections  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 9 of 52 
 
• 
At baseline, previous infections (RAT or PCR positive or symptomatic 
with close contact) and vaccinations will be recorded.  
• 
Breakthrough infections will be recorded and tested for during the 
study, until 30 months post-enrolment.  
• 
Nasal swabs will be collected from all severe breakthrough cases and 
a subset of mild cases within three days of illness. A representative 
sample of positive samples will be processed for viral load and whole 
genome sequencing of SARS-CoV-2. 
• 
We will explore the differences in viral load and viral genome 
characteristics and immunological markers among mild and severe 
breakthrough cases. 
TRIAL 
POPULATION 
Participants will be adults 18 years or older who have received three doses of 
any COVID-19 vaccine six or more months before the study start for all three 
groups.  There will be no upper age limit for groups A and B. Only those aged 
18 to <60 years will be recruited to group C (controls), as knowledge and the 
benefit of additional boosters for this age group are not well established. 
Participants will be recruited from the Murdoch Children’s Research Institute, 
the Royal Children’s Hospital (RCH), the University of Melbourne, the Peter 
Doherty Research Institute, and, if necessary, the greater Melbourne area. We 
will initially target people working in the medical, science, and healthcare 
fields and then expand to the general population as needed. 
450 participants will be recruited into either the bivalent Moderna, or 
Novavax group. 150 participants will be recruited into the control group. 
There will be a total of 600 participants. Procedures will be implemented to 
ensure participants of all ages (aged 18 years and above) are included and that 
there is an equitable age distribution (<50 and ≥50 years) in each vaccine 
group and for the bivalent Moderna vaccine transition for the randomised 
controlled trial. 
DESCRIPTION OF 
SITES  
This will predominantly be a single-site study with participants enrolled at 
RCH. In select cases participants may be enrolled at GP clinics or community 
centres.   
DESCRIPTION OF 
INTERVENTIONS  
The two interventions to be studied are as follows:  
Bivalent Moderna (mRNA-1273.214) (Ancestral SARS-CoV-2 25μg + Omicron 
Variant (B.1.1.529) 25μg). 
 
Replaced by Bivalent Moderna (mRNA-1273.222) (Ancestral SARS-CoV-2 25μg 
+ Omicron Variant (BA.4-5) 25μg) when introduced. 
Novavax (5μg of SARS-CoV-2 spike protein adjuvanted with 50μg of Matrix-M) 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 10 of 52 
 
 
GLOSSARY OF ABBREVIATIONS  
ABBREVIATION 
TERM 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AR  
Adverse Reaction 
ATAGI 
Australian Technical Advisory Group on Immunisation 
BRF 
Biobank Registration Form (MCRI) 
CEPI 
Coalition for Epidemic Preparedness Innovations  
CMI 
Cell mediated immunity 
CRF / eCRF 
Case Report Form / electronic Case Report Form 
DSMB 
Data Safety Monitoring Board 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GMC 
Geometric mean concentration 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICH  
International Conference on Harmonisation  
IM 
Intramuscular  
MCRI 
Murdoch Children’s Research Institute 
PBMC 
Peripheral blood mononuclear cells 
PDI 
Peter Doherty Research Institute 
PI  
Principal Investigator 
QC 
Quality Control 
RGO 
Research Governance Office 
RCH 
Royal Children’s Hospital (Melbourne) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction  
SoA 
Schedule of Assessments 
TRIAL DURATION 
The recruitment period will be approximately 4-6 months.  Each participant 
in the vaccine groups (A&B) will have ten visits, including their immunisation 
visit, with a follow-up period of 30 months. Group C will have eight visits. 
PARTICIPANT 
DURATION 
Participant duration will be 30 months. The vaccine groups (A & B) will have 
ten visits (three telephone calls and seven in-person). Group C will have eight 
visits (two telephone calls and six in-person). The DSMB will review participant 
safety data.  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 11 of 52 
 
SOP 
Standard Operating Procedure 
SSI 
Significant Safety Issue 
SST 
Serum separator tube 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TGA 
Therapeutic Goods Administration  
UAR 
Unexpected Adverse Reaction  
USM 
Urgent Safety Measure  
VoC 
Variants of concern  
 
INVESTIGATOR AGREEMENT  
I have read the protocol entitled “A randomised controlled trial to assess the immunogenicity, safety 
and reactogenicity of a bivalent mRNA Moderna COVID-19 vaccine or a protein-based Novavax 
COVID-19 vaccine given as a fourth dose in healthy adults in Australia.” 
By signing this protocol, I agree to conduct the clinical trial, after approval by a Human Research 
Ethics Committee or Institutional Review Board (as appropriate), in accordance with the protocol, the 
principles of the Declaration of Helsinki, and the good clinical practice guidelines adopted by the TGA 
[Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2), dated 9 November 
2016 annotated with TGA comments]. 
Changes to the protocol will only be implemented after written approval is received from the Human 
Research Ethics Committee, with the exception of medical emergencies.   
I will ensure that trial staff fully understand and follow the protocol and evidence of their training is 
documented on the trial training log. 
 
Name  
Role 
Signature and date 
Prof Kim Mulholland 
Sponsor-
investigator 
 
Dr Claire von Mollendorf 
Co-Principal 
Investigator 
 
 
1. ADMINISTRATIVE INFORMATION  
1.1. 
Trial registration 
1.1.1.  Trial registry 
The trial will be registered on ClinicalTrials.gov prior to trial commencement. 
 
1.2. 
Sponsor 
On behalf of the Sponsor, MCRI, the Sponsor-Investigator leading the trial, will undertake and oversee 
those Sponsor responsibilities delegated by the Sponsor. The delegated Sponsor responsibilities are 
documented in the study file.  
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 12 of 52 
 
Trial Sponsor 
MCRI 
Contact name 
Kathryn Bright – kathryn.bright@mcri.edu.au 
Address 
Flemington Road, Parkville 
Sponsor-Investigator  
Prof Kim Mulholland 
 
1.3. 
Expected duration of study 
The expected study duration will be two years, including preparation and reporting. The recruitment 
period is anticipated to be 4-6 months and all participants will be followed up for 12 months. 
 
1.4. 
Contributorship  
Name 
Summary of contribution 
Affiliation 
Prof Kim Mulholland 
Sponsor-investigator 
MCRI 
A/Prof Paul Licciardi 
Investigator - Immunology  
MCRI 
Dr Claire von Mollendorf 
Investigator – Medical/Epidemiology 
MCRI 
Prof Nigel Crawford 
Investigator - Advisor/ Chair of ATAGI/ 
Immunization specialist 
MCRI 
Prof Kanta Subbarao  
Investigator - Immunology 
PDI 
A/Prof Siddhartha Mahanty 
Investigator – Infectious Disease Specialist 
PDI 
Dr Nadia Mazarakis 
Investigator - Immunology  
MCRI 
Dr Lien Anh Ha Do 
Investigator - Virology 
MCRI 
Dr Cattram Nguyen 
Investigator - Statistics 
MCRI 
Dr Kerryn Moore  
Investigator - Statistics 
MCRI 
Dr Eleanor Neal 
Investigator – Data Management/Analysis 
MCRI 
Kathryn Bright 
Investigator – Melbourne Project Manager 
MCRI 
Emma Watts 
Investigator – Project Manager (Indonesia) 
MCRI 
Fran Justice  
Investigator – Project Manager (Mongolia) 
MCRI 
Dr John Hart  
Investigator – Study Doctor  
MCRI 
Sonja Elia 
Investigator – Immunisation Nurse Practitioner 
RCH 
Dr Zheng Quan (Ryan) Toh  
Investigator - Immunology  
MCRI 
Prof Andrew Davidson  
Investigator – Medical 
RCH 
 
1.5. 
Stakeholder involvement 
The Coalition for Epidemic Preparedness Innovations (CEPI) is a foundation that takes donations from 
public, private, philanthropic, and civil society organisations to finance independent research projects 
to develop vaccines against emerging infectious diseases. CEPI is providing funding for this study up 
until the 12-month blood sample. CEPI has been involved in discussing and developing the project.  
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 13 of 52 
 
2. INTRODUCTION AND BACKGROUND 
2.1. 
Background 
First and second booster doses of COVID-19 vaccines are now being widely used. Some countries are 
likely to consider regular boosters for certain population groups, raising questions regarding the 
necessity of booster doses and which vaccines may be both effective and acceptable for this role. As 
recommended by the WHO, vaccine booster introduction should be based on evidence and focus on 
reducing severe disease, hospitalisations, and death. There is some evidence that fourth doses are 
effective for this purpose, although with limited follow-up. While all the WHO Emergency Use Listing 
(EUL)-listed products effectively prevent severe and fatal COVID-19 in the short term, with most shown 
to be effective as boosters, the duration of protection is highly variable. 
 
Monovalent ancestral strain boosters are being offered in several countries. Several studies during 
Omicron predominance, including from Israel (1-6) and Canada (7), have reported short-term 
effectiveness of a fourth dose. Five studies were conducted in individuals older than 60 years of age (3-
7), and two included healthcare workers (HCWs) (1, 2). The follow-up in these studies was short and 
ranged from two to ten weeks after the fourth dose. All studies in the elderly showed a reduction in 
severe disease with a fourth dose compared to a third dose (3-7). One study described vaccine 
effectiveness against severe disease compared to unvaccinated individuals and found that vaccine 
effectiveness increased with each additional dose (7). The two HCW studies were conducted in Israel 
and compared third to fourth dose recipients (1, 2). The first study (1) enrolled HCWs who had received 
their third dose of Pfizer BNT162b2 at least four months prior. A total of 154 HCWs received a fourth 
dose of BNT162b2, and 120 received mRNA-1273 with two age-matched controls for each vaccine. Both 
vaccines induced binding antibodies and increased neutralizing antibody titres by 9-10-fold. Vaccine 
efficacy against any SARS-CoV-2 infection was low (30% for BNT162b2 and 11% for mRNA-1273) but 
higher for symptomatic disease (1). Early data from a second study demonstrated that a fourth vaccine 
dose reduced breakthrough infection rates from 20% to 6-12% compared to a third dose (2). In 
combination, these studies showed some potential benefits of using a fourth dose of mRNA vaccines in 
healthcare workers and the elderly or immunocompromised, but a key issue is the limited follow-up 
time. There is a lack of data on healthy individuals to show that an additional booster would reduce 
hospitalisations or deaths. Immunogenicity and reactogenicity data are also limited.  
 
Nucleic acid vaccines, specifically mRNA vaccines, are excellent boosting vaccines, including as dose 
four boosters, at least during the short-term follow-up available. Protein vaccines have been late to the 
field with subsequent limited data but may have characteristics that support their use as repeated 
boosters, perhaps with year-to-year modifications. The protein vaccine developed by Novavax 
(Nuvaxovid) has shown adequate boosting of Pfizer and AstraZeneca-primed individuals in the UK, 
although boosting responses were lower than those following the Pfizer vaccine (8). The clinical 
relevance of this lower response is unknown, as is the comparative duration of immunity. Notably, 
protein vaccine reactogenicity is lower than mRNA vaccines, which may be an important advantage, 
especially for long-term programs, reducing vaccine hesitancy and improving vaccine uptake. In the UK 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 14 of 52 
 
study, 80% efficacy was maintained over six months, and efficacy against the variants circulating was 
superior to other vaccines (8). 
 
With the emergence of new variants of concern, there is a need to improve current vaccine 
formulations to address the evolution of the SARS-CoV-2 virus. New formulations include bivalent 
vaccines containing the ancestral SARS-CoV-2 strain and a variant of concern. The Moderna mRNA-
1273.214 vaccine (25μg ancestral Wuhan-Hu-1 and 25μg omicron B.1.1.529 spike SARS-CoV-2 mRNA) 
demonstrated a superior neutralising antibody response against Omicron and non-inferior neutralising 
antibody response against ancestral SARS-CoV-2 compared to the monovalent Moderna vaccine (9). 
Similar data have been reported for the Pfizer BA.1 adapted bivalent vaccine. BA.4/5 adapted vaccines 
are also available from Moderna and Pfizer and licensed in the USA for individuals aged five years and 
older, and in Europe for individuals from 12 years as booster vaccines. Further adaptations to both the 
mRNA vaccines and protein vaccines, such as Novavax, are expected to be produced as required to 
respond to further mutations in SARS-CoV-2.  
 
In Australia, national COVID-19 vaccinations were rolled out in February 2021, starting with healthcare 
workers, the elderly and high-risk groups. Very high vaccine coverage for the primary schedule was 
achieved for all age groups due to vaccine mandates. Booster vaccines were introduced in October 
2021, again starting with healthcare workers. The Australian Technical Advisory Group on Immunisation 
(ATAGI) recommended a second COVID-19 vaccine booster dose on 25 March 2022 to increase vaccine 
protection before winter. The recommendation initially focused on high-risk groups to reduce severe 
disease, 
with 
subsequent 
expansion 
to 
all 
adults 
30 
years 
and 
over 
(https://www.health.gov.au/news/atagi-updated-recommendations-for-a-winter-dose-of-covid-19-
vaccine). The booster recommendations were initially for Pfizer and Moderna monovalent vaccines and 
from 9th October 2022 included the Moderna bivalent vaccine. 
 
Vaccine breakthrough infections are made more likely due to host immune factors such as waning 
immunity (e.g., low neutralising antibodies) and virological factors, particularly new variants such as 
Omicron, that evade the immune response. The role that different factors play in breakthrough 
infections and the immune boosting of natural infections against SARS-CoV-2 for different variants are 
still being defined.  
 
2.2. 
Trial rationale and aim 
Omicron subvariants have shown evidence of immune escape (10, 11) with lower neutralising antibody 
titres induced by vaccination and infection, requiring updated vaccines. Omicron-targeting mRNA 
bivalent vaccines have been introduced as boosters in many countries. 
 
Available data show that COVID-19 vaccine effectiveness wanes considerably, although much more 
slowly against severe disease than infection (12). There is strong evidence that a third dose of WHO 
EUL vaccines provides additional protection against severe disease and these are now widely 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 15 of 52 
 
recommended. However, the information is not yet available to determine whether a fourth dose is 
required, particularly in the healthy population. It is also unclear regarding the utility of additional 
boosters in the context of varying natural immunity, especially with high rates of previous infections. 
Lastly, it is not clear if mRNA bivalent vaccines are necessarily the best choice of booster for long-term 
repeat booster programs, particularly given their relatively high reactogenicity and rapid waning 
immunity. This project will compare the long-term immunogenicity of fourth doses of Moderna bivalent 
and Novavax boosters and a control group who do not receive a fourth dose. 
 
The study-specific aims are to:  
• 
Assess and compare the immune response in two randomised vaccine groups (Moderna 
bivalent and Novavax) at 28 days, 6-, 12, 18, 24 and 30-months post-vaccination, measured as 
binding antibodies.  
• 
To assess whether a fourth COVID-19 vaccine dose provides an immunological benefit over a 
third dose by comparing CMI at 6, 12, 18, 24 and 30-months in a control group compared 
with the two vaccine groups. 
• 
Assess the rate and severity of reactogenicity within one-week post-second booster for each 
group. 
• 
Describe the frequency and severity of breakthrough infections in the vaccine and control 
groups up to 30 months post-vaccination. 
 
2.3. 
Risk/Benefit assessment 
2.3.1. Known potential risks   
This study will provide safety data for Omicron-specific bivalent second booster regimens and the 
protein-based vaccines being studied. The safety profiles of both vaccines are described (Appendix 1 - 
Product information sheets).  
 
Risks associated with sample taking  
Participants may experience discomfort and/or localised bruising from venepuncture. There is a small 
risk of fainting. The total volume of blood drawn over 18 months will be up to 150ml, which is safe in 
otherwise healthy adults.  
 
Allergic reactions 
Allergic reactions to any of the constituents of the booster vaccine may occur. Allergic reactions range 
from mild to severe but are rare. Patients should be questioned regarding allergic reactions to any 
vaccines in the past.  All participants will have previously received three doses of a COVID-19 vaccine. 
 
Reactogenicity 
Although it is anticipated that participants might experience more reactogenicity if their booster 
vaccine differs from the vaccine used in their primary two-dose schedule, data from a first booster 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 16 of 52 
 
study showed similar reactogenicity between homologous and heterologous booster schedules (13). 
There is limited data on reactogenicity from second booster dose studies (14). 
 
2.3.2. Known potential benefits   
Second booster doses of COVID-19 vaccines are currently recommended by ATAGI for adults over 30 
years of age in Australia. The bivalent Moderna and Novavax vaccines are approved by the TGA for 
booster doses in adults 18 years and older. There may be no direct benefits for participants enrolling in 
this study apart from the opportunity to learn their antibody response following the second booster. 
Data on the best second booster, in terms of immunogenicity and reactogenicity, and based on the 
previous vaccines received are limited.  
 
Although there are some data on the use of second booster doses and the immunogenicity of the new 
Omicron-specific vaccines, additional data is needed from settings with variable community SARS-CoV-
2 transmission and epidemiology to advise on optimal dosing schedules, vaccine choices and duration 
of protection. There is limited data on protein-based vaccines as second boosters. This study will 
provide additional data for Australia and other countries that are introducing second boosters to design 
optimal vaccine strategies. 
 
2.3.3. Assessment of potential risks and benefits  
Moderna bivalent and Novavax vaccines given as a second booster are available to Australians ≥30 years 
of age and those 16-29 years with complex, chronic, or severe medical conditions that increase their 
risk of severe illness from COVID-19. This trial will examine the second booster doses in all adults 18 
years and older. This study will use vaccines in line with those available in the Australian government 
vaccine program. In some studies, heterologous boosters have been associated with slightly increased 
reactogenicity. Potential benefits include superior immunogenicity, broader protection of heterologous 
boosting, and access to antibody response results. In addition, this study will provide additional data to 
inform future booster strategies. Fourth doses may be unnecessary in healthy young individuals with a 
low risk of severe disease or hospitalisation. However, data for this group are limited, and a reduction 
in breakthrough infections was observed in specific groups such as healthcare workers (2).   
 
3. TRIAL OBJECTIVES AND OUTCOMES 
3.1 
Objectives 
3.1.1 
Primary objective 
The primary objectives of the study are to:  
• 
Assess and compare the immune response in two randomised vaccine groups (bivalent 
Moderna and Novavax) at 28 days post-vaccination measured as binding antibodies (IgG ELISA 
– Wuhan and/or Omicron) who have been boosted at least six months earlier.   
• 
Assess the rate and severity of reactogenicity within one-week post-second booster for the 
Moderna and Novavax groups (Timepoint – daily, for seven days post-vaccination). 
 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 17 of 52 
 
3.1.2 
Secondary objectives 
The secondary objectives are to: 
• 
Assess and compare the immune response in two randomised vaccine groups (bivalent 
Moderna and Novavax) at 28 days post-vaccination measured as functional antibodies 
(sVNT and nAb) and cell-mediated immunity (CMI).  
• 
Assess and compare the immune response in two randomised vaccine groups (bivalent 
Moderna and Novavax) at 6, 12, 18, 24 and 30-months post-vaccination measured as binding 
antibodies (IgG ELISA), functional antibodies (sVNT and nAb), and CMI.  
• 
To describe binding and functional antibodies in the control group compared with the two 
vaccine groups (bivalent Moderna and Novavax) at baseline, 6, 12, 18, 24 and 30-months. 
• 
To assess whether a fourth COVID-19 vaccine dose provides an immunological benefit over a 
third dose by comparing CMI at 6, 12, 18, 24 and 30-months in the control group compared 
with the two vaccine groups (bivalent Moderna and Novavax). 
• 
To evaluate the safety of fourth booster dose regimens. 
 
3.1.3 
Exploratory objectives  
• 
To describe the number and severity of breakthrough cases in the control group compared with 
the two vaccine groups (bivalent Moderna and Novavax) to 30 months post-vaccination. 
• 
To correlate virological markers (viral load and viral genome characteristics) and immunological 
markers (humoral antibody, CMI) among mild and severe breakthrough cases to 30 months 
post-vaccination. 
 
3.2 
Outcomes 
3.2.1 Primary outcomes 
Immune response 
Binding antibodies – These will be evaluated using the commercial Euroimmun S1 IgG ELISA (Wuhan 
and Omicron [once available]) on serum collected at seven timepoints (baseline, 28 days, 6 months, 12 
months, 18 months, 24 months and 30 months) for the two vaccine groups and six timepoints (baseline, 
6 months, 12 months, 18 months, 24 months and 30 months) for the control group. Assays will be 
completed within 4 weeks of sample collection for the day 28 visit.  
 
Reactogenicity 
Reactogenicity for vaccine groups (A&B) will be measured using the accepted standardised method to 
evaluate systemic and local side effects following vaccination using a structured questionnaire for seven 
days post-vaccination, as outlined in Table 1 below.  
 
 
 
.  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 18 of 52 
 
Table 1. Grading system for evaluating systemic and local side effects following vaccination (15, 16).  
Local Reaction to Injectable Products a 
 
Mild 
(Grade 1) 
Moderate (Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of 
nonnarcotic pain 
reliever >24 hours or 
interferes with activity 
Any use of narcotic 
pain relief or 
prevention of daily 
activity 
ER visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/ 
redness b 
2.5 − 5 cm 
5.1 − 10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Swellingc 
2.5 − 5 cm and 
does not interfere 
with activity 
5.1 − 10 cm or 
interferes with activity 
>10 cm or prevents 
daily activity 
Necrosis 
  
Hardnessc  
2.5 − 5 cm and 
does not interfere 
with activity 
5.1 − 10 cm or 
interferes with activity 
>10 cm or prevents 
daily activity 
Necrosis 
 
 
Axillary 
lymphadenopathy  
Does not interfere 
with activity 
Repeated use of 
nonnarcotic pain 
reliever >24 hours or 
interferes with activity 
Any use of narcotic 
pain relief or 
prevention daily 
activity 
ER visit or 
hospitalization 
Warmth (usually 
reported with 
redness) 
Absence   
Presence  
Itch  
Absence   
Presence  
a Grade 0 will be recorded for parameters if specific symptoms are absent.  
b The measurement should be recorded as a continuous variable in addition to grading the measured local 
reaction at the greatest single diameter.  
c Hardness and swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
Systemic (General) a 
 
Mild 
(Grade 1) 
Moderate (Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 19 of 52 
 
Fever (°C): Oral or 
axillary 
temperature 
38.0 − 38.4 
 
38.5 − 38.9 
 
39.0 − 40 
 
>40 
 
Nausea  
No interference 
with activity  
Some interference 
with activity  
Prevents daily 
activity 
ER visit or 
hospitalization  
Vomiting 
No interference 
with activity or 
1 − 2 episodes/24 
hours  
Some interference 
with activity or 
>2 episodes/24 hours  
Prevents daily 
activity, or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
for hypotensive 
shock  
Diarrhoea 
No interference 
with activity 
Some interference 
with activity 
Prevents daily 
activity, or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
for hypotensive 
shock 
Headache  
No interference 
with activity  
Repeated use of 
nonnarcotic pain 
reliever >24 hours or 
some interference 
with activity  
Significant; any use 
of narcotic pain 
relief or prevention 
of daily activity  
ER visit or 
hospitalization 
Fatigue/Malaise 
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
ER visit or 
hospitalization 
Myalgia 
(muscle pain) 
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
ER visit or 
hospitalization 
Arthralgia  
(joint pain) 
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
ER visit or 
hospitalization 
a Grade 0 will be recorded for parameters if specific symptoms are absent, or the temperature is <38° C. In 
addition, appearance of the following potential signs of myocarditis/pericarditis will prompt referral for 
cardiology evaluation: Chest pain, dyspnoea, painful breathing, palpitations, or syncope. 
 
3.2.2 Secondary outcomes 
Immunogenicity 
• 
Functional antibody – All samples will be assayed using the GenScript cPass SARS-CoV-2 
Neutralization Antibody detection kit for WT and Omicron variant RBD antigen or other key 
newly emerging variants. Samples will be tested on serum collected at seven timepoints 
(baseline, 28 days, 6 months, 12 months, 18 months, 24 months and 30 months) for the two 
vaccine groups and six timepoints for the control group.   
 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 20 of 52 
 
• 
Neutralizing antibody - A fraction of samples (20%) will be assessed using a SARS-CoV-2 assay at 
the PDI, Melbourne up to 12 months. Testing will be at the same time points as for binding 
antibodies for Wuhan strain and two Variants of Concern (VoC), including Omicron or other key 
newly emerging variants.  
• 
Cellular immunity - Cellular immunity will be assessed on 50% of participants per group of 
samples collected at seven timepoints for the two vaccine groups and six timepoints for the 
control group as follows:  
o 
QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) will be performed using heparinised whole 
blood (Wuhan), only up to 12 months. 
o 
Peripheral blood mononuclear cells (PBMCs) will be isolated by density gradient 
centrifugation within 12 hours of collection and stored in liquid nitrogen at MCRI for all 
samples up to 30 months. Assays will include IFN-γ Elispot, intracellular cytokine assays (flow 
cytometry) and multiplex cytokine assays (Wuhan and Omicron). 
 
Safety 
All solicited AEs will be collected for 7 days, all unsolicited AEs will be collected for 28 days, and all 
medically attended AEs will be collected for 3 months. SAEs will be collected throughout the 12-month 
follow-up period.  
 
3.2.3  Exploratory outcomes  
• 
At baseline, previous infections (RAT or PCR positive or symptomatic with close contact) and 
vaccinations will be recorded.  
• 
Breakthrough infections will be recorded and tested for during the study.  
• 
Nasal swabs will be collected from all severe breakthrough cases and a subset of mild cases within 
three days of illness. A representative sample of positive samples will be processed for viral load 
and whole genome sequencing of SARS-CoV-2. 
• 
We will explore the differences in viral load and viral genome characteristics and immunological 
markers among mild and severe breakthrough cases. 
 
4 
TRIAL DESIGN 
4.1 
 Study design  
This clinical trial will be a blinded, two-arm randomised study to determine the safety, reactogenicity 
and immunogenicity of a fourth dose of SARS-CoV-2 vaccines in Australia in adults 18 years or older 
who have received their third dose of COVID-19 vaccine, at least six months previously. A separate non-
randomised control arm will be enrolled for comparison. The groups are described below. The trial 
intervention will be a single booster dose of vaccine: - 
 
 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 21 of 52 
 
Group 
Vaccine given  
Group A – (Moderna) 
225 participants 
Bivalent Moderna (mRNA-1273.214) (Ancestral SARS-CoV-2 25μg 
+ Omicron Variant (B.1.1.529) 25μg). 
 
Replaced by Bivalent Moderna (mRNA-1273.222) (Ancestral SARS-
CoV-2 25μg + Omicron Variant (BA.4-5) 25μg) when introduced. 
Group B – (Novavax) 
225 participants 
Novavax (5μg of SARS-CoV-2 spike protein adjuvanted with 50μg 
of Matrix-M) 
Group C – (Control group) 
150 participants 
No vaccine given 
 
We will aim to enrol approximately 225 individuals in each vaccine group and 150 individuals in the 
control group. This will ensure sufficient representation of participants aged < 50 and >50 years 
receiving the newer Moderna BA.4-5 vaccine.    
The participants and those evaluating reactogenicity will be blinded to the vaccine allocation for the 
first seven days following vaccination until details are entered in the Australian Immunisation Register 
(AIR). After that, participants will be aware of their investigational product allocation. Immunologists 
and laboratory staff will remain blinded to the investigational product allocation.  
  
4.2 
Justification for dose  
The trial will use standard doses of the bivalent Omicron-specific Moderna and Novavax vaccines in line 
with current TGA recommendations. The trial will transition to newer Omicron-specific vaccines 
according to availability in Australia.  
 
4.3 
Trial population  
The trial population will be adults 18 years and older who have been boosted at least six months earlier 
with a third COVID-19 vaccine dose. There will be no upper age limit for groups A and B.  Only those 
aged > 18 - 60 years will be recruited to group C (controls), as this is the target age group for which the 
need for additional boosters is not well established. Additional booster doses are strongly 
recommended for individuals 60 years and over. Procedures will be implemented to ensure an even 
age distribution for Moderna product transition in each vaccine group. 
 
4.4 
Eligibility criteria  
If informed consent is granted, study staff will ensure all the eligibility criteria are met. Potential 
participants must meet all the inclusion criteria and none of the exclusion criteria to be eligible. 
 
4.4.1 
Inclusion criteria  
Each participant must meet all the following criteria to be enrolled in this trial: 
1. Have received a third COVID-19 vaccine dose at least six months before the start of the study. 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 22 of 52 
 
2. No confirmed SARS-CoV-2 infection by PCR or RAT within the last three months.   
3. Willing and able to give written informed consent.  
4. Aged 18 years or above. 
5. Willing to complete the follow-up requirements of the study. 
Note that subjects with comorbidities other than those listed below as contraindications will be 
included. Pregnant women or women who may become pregnant will be included. 
 
4.4.2 
Exclusion criteria  
Potential participant meeting any of the criteria below will be excluded from this trial: 
1. Currently receiving immunosuppressive medication or anti-cancer chemotherapy. 
2. Known HIV infection. 
3. Congenital immune deficiency syndrome. 
4. Received immunoglobulin or other blood products in the three months prior to potential study 
booster vaccination. 
5. Study staff and their relatives. 
6. Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical 
exemption to receiving further COVID-19 vaccines.   
7. Cannot read or understand English. 
 
4.5 
Lifestyle considerations 
Not Applicable.  
 
4.6 
Screen failures   
Screen failures are defined as participants who consent to participate in the trial but are found during 
screening procedures to be ineligible. They, therefore, do not receive the intervention and are not 
randomised. We anticipate that there will be very few screen failures due to the nature of the 
inclusion/exclusion criteria. 
 
4.7 
Recruitment and identification of potential participants   
Prior to starting the study a comprehensive recruitment plan will be developed. The study will be 
advertised across the Melbourne Children’s Campus (MCRI, Royal Children’s Hospital, University of 
Melbourne), Royal Melbourne Hospital, the Doherty Research Institute, the Parkville precinct and, the 
broader Melbourne community. We will initially target people working in the medical, science, and 
healthcare fields and expand recruitment to the general public as needed. We will target specific study 
or age groups as needed as the study proceeds. Study information (via email, healthcare facilities notice 
board and/or website/social media, patient/participant registries and recruitment services etc.) will 
include an information sheet about the study and a link to the study website where they can evaluate 
their eligibility and obtain additional study details, such as the participant information sheet and 
consent form (PICF). The potential participant can register their interest and will be given the 
opportunity to talk with a research team member by phone or zoom if they have any further questions. 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 23 of 52 
 
All potential participants will be recorded on a recruitment/enrolment log. No identifying information 
will be retained if the potential participant decides not to participate.  
In addition, participants will also be recruited directly from interested general practices. Potentially 
eligible participants will be sent an email or SMS with the study details from their GP practice and be 
given the option to contact the COVID-19 booster study team if they want more information or wish to 
join the study. The COVID-19 booster study team will not have access to GP patient records. In select 
cases satellite clinics may be conducted at GP clinics with facilities to conduct vaccinations. Similarly at 
community clinics with access to medical facilities.  
Participants from other relevant MCRI studies (for example the BRACE trial), who consented to be 
contacted for future research, will be contacted by the original study teams. The original study team 
will send the participants an email with the study details and give them the option to contact the COVID-
19 booster study team if they want more information or wish to join the study. The COVID-19 booster 
study team will not have access to the participant details. 
 
4.8 
Consent  
Informed consent is a process initiated prior to the agreement to participate in the trial and continues 
throughout study participation. Before obtaining informed consent, the vaccination’s possible risks and 
benefits will be discussed with potential participants. Trial staff will go through the Informed Consent 
Form (ICF), which describes in plain language the trial interventions, the study procedures, and the risks 
and benefits of participation. The ICF will be HREC-approved, and the potential participant will be asked 
to read and review the ICF. The trial staff will explain the research study further and answer any 
questions.  
Written documentation of informed consent is required prior to enrolment into the trial. The potential 
participant will sign and date the final page of the ICF. The trial staff will witness the consent, confirming 
that the trial has been fully explained and that the participant understands the rationale and processes 
for the trial. The potential participant will be informed that they are free to withdraw from the trial at 
any time. A copy of the ICF will be given to the potential participant.  
 
4.9 
Additional Consent 
4.9.1 Extended Follow-Up Period: At or after the 12-month study visit, participants will be 
approached to provide consent for the continued collection of breakthrough infection information.  
This will involve monitoring any instances of breakthrough infections beyond the initial 12-month study 
period. The continuation of study procedures beyond the 18 month visit, including potential extensions 
up to 30 months, will be contingent upon the availability of future funding. Should additional funding 
be secured, the study intends to extend its duration to 30 months, incorporating blood collections at 
the 18, 24 and 30-month intervals. Participants will be asked to provide separate consent for these 
study procedures. 
Extended Follow-up Period 2: Additional funding is available to collect a blood sample at 18 months 
and conduct some testing. The funding will cover the collection and biobanking of serum and PBMC 
samples (from CMI subset) and IgG testing. Further funding will be needed to complete the additional 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 24 of 52 
 
immunological assays, including CMI assays. Funding applications for an NHMRC Ideas grant has been 
submitted. Participants will be asked to provide additional consent for the 18-month blood sample and 
for the continued collection of breakthrough information until 24 months. Participants will be informed 
prior to the 24-month visit whether this will occur in-person or via phone call. SMS messages will be 
sent to participants every 3 months to remind them to report any breakthrough infections. 
Extended Follow-Up Period 3: We intend to extend the study to 30 months.  The funding will cover the 
24-month collection, biobanking of serum and PBMC samples (from CMI subset) and IgG testing. 
Further funding will be needed to complete the additional immunological assays, including CMI assays.  
A funding application for NIH has been submitted.  Furthermore, funding for the additional 30-month 
visit is pending confirmation.  If funding isn’t secured participants will be informed and the scheduled 
30-month appointments cancelled. We will ask participants to sign one consent form at the 24-month 
visit which includes the 30-month visit to avoid them having to sign another consent at 30-months 
again.  
 
5 
INTERVENTION   
5.1 
Treatment arms  
Treatment Arms 
Route 
Dose 
Group A: Bivalent Moderna (mRNA-
1273.214)  
or Bivalent Moderna (mRNA-1273.222) 
IM 
Ancestral SARS-CoV-2 25μg + Omicron 
Variant (B.1.1.529) 25μg. 
Replaced by (Ancestral SARS-CoV-2 25μg 
+ Omicron Variant (BA.4-5) 25μg) when 
introduced. 
Group B:  Novavax  
IM 
Novavax (5μg of SARS-CoV-2 spike protein 
adjuvanted with 50μg of Matrix-M) 
Group C  
- 
No vaccine  
 
5.2 
Trial Intervention(s) 
The bivalent Moderna (mRNA-1273.214 or mRNA-1273.222) COVID-19 Vaccine contains equal amounts 
of mRNAs (25μg of each mRNA sequence) that encode the prefusion stabilized spike glycoproteins of 
the ancestral SARS-CoV-2 (Wuhan-Hu-1) and the Omicron variant (B.1.1.529 [BA.1] or BA.4-5) with 
mRNAs encapsulated in lipid nanoparticles. 
Novavax contains 5μg of SARS-CoV-2 spike protein and is adjuvanted with Matrix-M. Adjuvant Matrix-
M contains, per 0.5 mL dose: Quillaja saponaria saponins fraction A (42.5 micrograms) and Quillaja 
saponaria saponins fraction C (7.5 micrograms). 
 
5.2.1 
Description of trial investigational products  
5.2.1.1 Trial Products 
Active substance 
25μg of each mRNA sequence that encodes the prefusion stabilized spike 
glycoproteins of the ancestral SARS-CoV-2 (Wuhan-Hu-1) and the 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 25 of 52 
 
Omicron variant (B.1.1.529 [BA.1]). mRNAs are encapsulated in lipid 
nanoparticles. 
Trade or Generic name 
Moderna (mRNA-1273.214) or Spikevax bivalent original/omicron® 
(elasomeran/imelasomeran). 
Dosage form 
Liquid for injection – standard dose for boosting is 0.5ml containing 25μg 
of elasomeran (Wuhan-Hu-1) and 25μg of imelasomeran (Omicron variant, 
B.1.1.529 [BA.1]).  
Route of administration Intramuscular injection 
 
 
Active substance 
25μg of each mRNA sequence that encodes the prefusion stabilized spike 
glycoproteins of the ancestral SARS-CoV-2 (Wuhan-Hu-1) and the Omicron 
variant (BA.4-5). mRNAs are encapsulated in lipid nanoparticles. 
Trade or Generic name 
Moderna (mRNA-1273.222) or Spikevax bivalent original/omicron BA.4-5 
(elasomeran/davesomeran). 
Dosage form 
Liquid for injection – standard dose for boosting is 0.5ml containing 25μg 
of elasomeran (Wuhan-Hu-1) and 25μg of davesomeran (Omicron variant, 
BA.4-5).  
Route of administration Intramuscular injection 
 
 
Active substance 
SARS-CoV-2 rS (NVX-CoV2373) adjuvanted with Matrix-M 
Trade or Generic name 
Nuvaxovid® 
Dosage form 
Liquid for injection – standard dose for boosting is 0.5ml containing 5μg of 
SARS-CoV-2 spike protein and is adjuvanted with Matrix-M. 
Route of administration Intramuscular injection 
 
5.2.2 
Dosage  
Bivalent Omicron-specific Moderna COVID-19 vaccine contains 25μg of ancestral SARS-CoV-2 (Wuhan-
Hu-1) and 25μg of Omicron variant B.1.1.529 [BA.1] in 0.5ml or 25μg of ancestral SARS-CoV-2 (Wuhan-
Hu-1) and 25μg of Omicron variant BA.4-5 in 0.5ml.  
Novavax contains 5μg of SARS-CoV-2 spike protein in 0.5ml. 
 
5.2.3 
Dose modification  
Dose modification is not permitted and must be given as per randomisation. 
 
5.2.4 
Storage, preparation, dispensing and administration of trial drug  
All study vaccines will be stored in the pharmacy at RCH and will be stored in accordance with the 
manufacturers’ recommendations. Vaccine accountability, storage, shipment, and handling will be in 
accordance with relevant SOPs and forms. 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 26 of 52 
 
Storage  
• 
The Moderna vaccine can be stored at -50ºC to -15ºC. It should not be stored or transported 
on dry ice or below -50ºC. Once thawed, it should not be re-frozen and may be stored 
refrigerated at 2 °C to 8 °C, protected from light for up to 30 days if not used (needle 
punctured). After removal from refrigerated conditions, an unopened vial's chemical and 
physical stability has been demonstrated for up to 24 hours at 8° to 25°C. Chemical and physical 
stability has been demonstrated for 19 hours at 2 to 25 ºC after first puncture (within the 
allowed use period of 30 days at 2°C to 8°C and 24 hours at 8°C to 25°C).  
Single use unopened pre-filled BA.4-5 syringes may be stored at 8°C to 25°C up to 24 hours 
after removal from refrigerated conditions. The prefilled syringe is for single use in one patient 
only. Any residue should be discarded. 
• 
The unopened Novavax vaccine is stored refrigerated at 2°C to 8°C, protected from light. Do 
not freeze. It has been shown to be stable for up to 12 hours at 25°C when unopened. Storage 
at 25°C is not the recommended storage or shipping condition. Chemical and physical in-use 
stability has been demonstrated from the time of the first needle puncture to administration 
for 6 hours when opened at 2°C to 25°C. 
 
Preparation 
All study vaccines will be prepared in accordance with the manufacturers’ recommendations.  
 
Administration 
The unblinded vaccine administrator will inject the allocated vaccine intramuscularly into the left 
deltoid region or the right deltoid region if there is a reason to prefer this side, such as left-handedness. 
The vaccine administrator should ensure that an appropriate needle length is used, taking the 
participant’s BMI into account. 
 
5.2.5 
Product accountability  
The trial vaccines will be stored in the pharmacy at RCH. The RCH immunisation clinic pharmacist or 
designated vaccination nurse trained in administrating COVID-19 vaccines, will draw up the study 
vaccines each day based on confirmed study bookings. The study nurses will ensure that storage 
requirements are maintained. Study vaccines will be administered by unblinded vaccinators, who will 
maintain blinding such that those evaluating reactogenicity are blinded during the first-week post-
vaccination when assessing symptoms. 
The study clinic will maintain accurate records of the receipt of all trial vaccines, including dates of 
receipt. In addition, study nurses will keep accurate records regarding when and how much trial vaccine 
is dispensed and used for each participant in the trial. Reasons for departure from the expected 
dispensing regimen will be recorded. At the end of the trial, there will be final reconciliation of trial 
vaccine received, dispensed, consumed, and returned. The trial team will investigate, resolve, and 
document any discrepancies. Unused trial vaccines will be destroyed in compliance with applicable 
regulations. Detailed information regarding product accountability will be provided in an SOP. 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 27 of 52 
 
 
5.2.6 
Excluded medications and treatments 
There are no excluded medications or treatments for enrolled participants.  
Study participants will be asked to inform us of any non-study COVID-19 vaccine doses that they receive 
before their 30 month visit. 
 
5.2.7 
Concomitant therapy  
Concomitant medications and vaccines taken by participants during the study will be documented as 
part of the safety review procedures. 
From day 0 to 28, all concomitant medication will be recorded.  
From 28 days until 30 months, only the following medications of interest will be recorded:  
• 
Any vaccine.  
• 
Any investigational products other than those given for this protocol.  
• 
Immunosuppressive therapies. 
• 
Therapies taken for suspected, or laboratory confirmed SARS-CoV-2 infection or COVID-
19 
The following information will be recorded on the CRF for all applicable medications: 
• 
Trade name 
• 
Indication 
• 
Start and stop date 
• 
Dosage 
• 
Route of administration 
Dietary supplements will not be recorded on the CRF. 
 
5.2.8 
Discontinuation from trial intervention 
See Section 7.2.9.  
 
6 
RANDOMISATION AND BLINDING  
The two vaccine groups will be randomised 1:1 to one of two interventions (bivalent Omicron-specific 
Moderna and Novavax) stratified by age (<50 and ≥50 years). An independent statistician from the 
Melbourne Children’s Trial Centre at the Murdoch Children’s Research Institute will provide a secure, 
password-protected web-based randomisation schedule. Blocked randomisation will be used with 
random blocks of permuted length.  
 
50% of participants from each vaccine group will be included in the cell-mediated immunity (CMI) 
subgroup analysis. We will ensure that the age strata (<50 and ≥50 years) are equally represented in 
the CMI vaccine groups. As only 10-20 CMI samples can be processed per day, we will recruit the first 
10-20 participants per day to participate in this substudy.  
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 28 of 52 
 
The control group will not be randomised and will be recruited from participants <60 years of age who 
indicate that they are not planning to receive a fourth vaccine dose at the time of recruitment. Controls 
will be recruited into proportional predefined age bands (18-29 years, 30-49 years, 50-59 years).  
 
6.1 
Concealment mechanism 
Randomisation will be stratified according to age (<50 and ≥50 years). Fourth dose vaccine participants 
will be randomised in a 1:1 ratio for each of the two booster schedules using randomisation lists in 
REDCap (see table below).  
 
Study staff involved in administering the vaccine will use REDCap to receive the information on the 
participant’s randomisation (study ID) number and vaccine. Study staff will upload vaccination 
information to the AIR after one week. Participants will remain blinded to their vaccine type until day 
seven post-vaccination, when their vaccination history is uploaded to the AIR. Study staff involved in 
assessing reactogenicity and immunogenicity will be blinded to each participant’s vaccine allocation, 
which will be hidden in REDCap for blinded study staff. Statisticians and analysts will remain blinded 
during the development of the SAP and will develop and finalise all codes using a dummy variable for 
treatment allocation. 
 
The booster vaccines for all groups will be prepared daily by the RCH immunisation clinic pharmacist or 
designated vaccination nurse, delivered to the vaccination room, and stored in the vaccine fridge.   
 
Group 
Number  
Age 
Booster vaccine 
Dose given 
Group A 
75 
<50 years  
Bivalent Moderna BA.1 
50µg 
75 
<50 years  
Bivalent Moderna 
BA.4-5 
50µg 
75 
≥50 years 
Bivalent Moderna 
BA.4-5 
50µg 
Group B 
150 
<50 years  
Novavax 
50µg 
75 
≥50 years 
Novavax 
50µg 
Group C 
150 
<60 years 
No vaccine  
- 
 
6.2 
Breaking of the trial blind 
6.2.1 
On trial 
The study will only be blinded for the first seven days as vaccine details will be entered in the AIR after 
one week. In the unlikely event that it becomes necessary to unblind during this period, the PI will take 
that decision, and the subject and physicians caring for the subject will be made aware of the allocation. 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 29 of 52 
 
7 
TRIAL VISITS AND PROCEDURES  
7.1 
Schedule of assessments 
Assessments/ 
activities* 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Visit 7 
 
Visit 8 
Visit 9 
Visit 10 
Timing  
Day 0 
Day 1 
Day 7 
Day 28 
3 
months 
6 
months 
12 
months 
18 
months 
24 
months  
30 
months 
Visit window 
 
 
+ 3 
days 
- 3 days 
+ 7 days 
+/- 
14 days 
+/- 
14 days 
+/- 
30 days 
+/- 
30 days 
+/- 
30 days 
+/- 
30 days 
Group  
A,B,C 
A,B 
A,B 
A,B,C 
A,B,C 
A,B,C 
A,B,C 
A,B,C 
A,B,C 
A,B,C 
Location of 
visits 
At 
RCH 
Phone 
call 
Phone 
call 
At RCH 
(A,B) 
Phone 
call (C) 
Phone 
call 
At RCH 
At RCH 
At RCH  
At RCH  
At RCH 
Informed 
consent 
X 
 
 
 
 
 
X 
X 
X 
 
Eligibility 
confirmation 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
X 
(A,B) 
 
 
 
 
 
 
 
 
 
Blood sampling 
X 
 
 
X (A,B) 
 
X 
X 
X 
X 
X 
Vaccination 
X 
(A,B) 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
(A,B) 
 
 
 
 
 
 
 
 
 
Issue diary card, 
ruler, and 
thermometer 
X 
(A,B) 
 
 
 
 
 
 
 
 
 
Collect diary 
card 
X (daily) for vaccine 
groups (A&B) 
 
 
 
 
 
 
 
Documentation 
of Solicited AE  
X 
X 
X 
 
 
 
 
 
 
 
Documentation 
of unsolicited 
AE 
X 
X 
X 
X 
 
 
 
 
 
 
Documentation 
of medically 
attended AE 
X 
X 
X 
X 
X 
 
 
 
 
 
Documentation 
of SAE 
Throughout study period 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 30 of 52 
 
Documentation 
of confirmed 
breakthrough 
SARS-COV-2 
infection/ 
COVID-19 
Throughout study period 
*Unless otherwise indicated, assessments/activities are valid for Groups A, B and C. 
  
7.2 
Description of procedures 
7.2.1 
Visit 1 (Day 0) 
Vaccine groups (A&B) 
Informed consent must be signed by both participant and the study doctor or nurse. Participant 
eligibility must be confirmed prior to randomisation and on the same date as the administration of the 
investigational product.  
 
Eligibility must be confirmed by a study doctor or study nurse. Randomisation for vaccine groups must 
be completed by the vaccinator, who will document the participant’s randomisation number on the 
recruitment/enrolment log.  
 
Study staff will administer a Visit 1 questionnaire documenting demographic information, height and 
weight, history of previous breakthrough infections, dates and types of previous COVID-19 vaccines 
received any comorbidities and concomitant medication. A study doctor or nurse will record vital signs 
(temperature, pulse, and respiratory rate) before vaccination.  
 
Before vaccination, 5mL of blood will be collected from all participants and processed according to the 
SOP. CMI participants will have an additional 25ml collected and processed for Quantiferon analysis 
and PBMC separation and storage.  
 
Following randomisation, the unblinded vaccinator will administer the applicable vaccine to the 
participant. Study staff will give the participant a hard copy reactogenicity diary card or email them a 
REDCap survey form. Study staff will instruct the participant on completing the diary card for the day 
of vaccination and seven days following vaccination.  Patients who complete a hard copy diary card will 
be asked to bring it to their next in-person visit.  
 
Study staff will provide the participant with a thermometer and ruler and detailed instructions on how 
to use these for measuring temperature and potential erythema and induration. The study staff will 
provide the participant with a schedule of visit appointments and instruct the participant on how to 
contact the study staff in case of any SAE or symptoms suggestive of COVID-19. Study staff will inform 
participants that they can choose to have additional COVID-19 vaccine doses before their 30-month 
visit and should just inform the team if they have received a vaccine.  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 31 of 52 
 
 
Study staff will keep the participant under observation for a minimum of 15 minutes post-vaccination 
and document any immediate adverse events. Participants with a history of anaphylaxis due to any 
cause should be observed for 30 minutes. 
 
Control group (C) 
Informed consent must be signed by both participant and the study doctor or nurse. Participant 
eligibility must be confirmed prior to enrolment by a study doctor or study nurse. Controls will be 
enrolled in three pre-defined proportional age bands (18-29 years, 30-49 years, and 50-59 years).  
 
Study staff will conduct a Visit 1 questionnaire documenting demographic information, height and 
weight, history of previous breakthrough infections, dates and types of previous COVID-19 vaccines 
received any comorbidities and concomitant medication.  
 
Following consent, 5mL of blood will be collected from all controls and processed according to the SOP. 
CMI participants will have an additional 25ml collected and processed for Quantiferon analysis and 
PBMC separation and storage.  
 
The study staff will provide the participant with a schedule of visit appointments and instruct the 
participant on how to contact the study staff in case of any SAE or symptoms suggestive of COVID-19. 
Study staff will inform participants that if they change their mind and choose to have a fourth dose of 
vaccine before their 30 month visit, they should inform the study staff. They will still be able to continue 
in the study after they receive this additional dose.  
 
7.2.2 
Visit 2 (Day 1) – only vaccine groups (A&B) 
Study staff will contact the participant by phone approximately 24 hours after vaccination to review 
and document adverse events. 
 
7.2.3 
Visit 3 (Day 7) – only vaccine groups (A&B) 
Study staff will contact the participant by phone one week after vaccination. If participants have a hard 
copy diary card, study staff will ask participants to read the details over the phone or send a picture of 
their hard copy diary card (with the name obscured) for review. If the participant completes the REDCap 
diary card, the study staff will review it with the participant to confirm that all symptoms are captured. 
Study staff will also document any significant, unexpected, serious, or unusual adverse events on the 
AE CRF. Participants will be informed regarding their vaccine type if they wish to know, and vaccination 
information will be entered in the AIR.  
 
7.2.4 
Visit 4 (Day 28) 
Vaccine groups (A&B) 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 32 of 52 
 
An in-person visit will be conducted 28 days following vaccination. Participants with hard copy diary 
cards will be asked to bring the card to this visit for collection. All unsolicited adverse events will be 
documented. Study staff will document any new information regarding solicited adverse events with 
onset up to 7 days following vaccination, such as resolution. Information regarding unreported 
breakthrough infections following vaccination will be collected.  
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for the Quantiferon test will be collected in a heparinised tube, and 20mL of blood for 
PBMC will be collected in a heparinised tube. Blood samples will be kept at room temperature and 
transferred to the laboratory within 3 hours of collection. 
 
Control group (C) 
Study staff will contact the participant by phone 28 days following enrolment and document any 
adverse events. Information regarding unreported breakthrough infections following enrolment will be 
collected.  No blood will be taken from the control group at the 28-day visit. 
 
7.2.5 
Visit 5 (3 Months) – all groups (A,B,C) 
Study staff will contact the participant by phone and document any medically attended AE or SAE. 
Study staff will also document any new information regarding unsolicited adverse events with onset up 
to 28 days following vaccination, such as resolution. Information regarding unreported breakthrough 
infections since visit 4 will be collected.   
 
7.2.6 
Visit 6 (6 Months) – all groups (A,B,C) 
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for the Quantiferon test will be collected in a heparinised tube, and 20mL of blood for 
PBMC will be collected in a heparinised tube. Blood samples will be kept at room temperature and 
transferred to the laboratory within 3 hours of collection.  
 
7.2.7 
Visit 7 (12 months) – all groups (A,B,C) 
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for the Quantiferon test will be collected in a heparinised tube, and 20mL of blood for 
PBMC will be collected in a heparinised tube. Blood samples will be kept at room temperature and 
transferred to the laboratory within 3 hours of collection.  
Control group participants will be able to receive a vaccine dose before visit 7 and continue in the 
study. Participants will receive a gift voucher and parking/public transport reimbursement at each in-
person study visit. Available individual test results will be shared and discussed with interested 
participants by a study team member during their study visits. 
 
7.2.8. Visit 8 (18 months) – all groups (A,B,C) 
Prior to the 18 month visit, participants will be asked to attend the 18 month visit in-person for a blood 
draw. Further consent will be obtained prior to any additional blood sampling at 18 months.  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 33 of 52 
 
All participants will have 5mL of blood collected in an SST tube. For participants in the CMI subset, 
20mL of blood will be collected in a heparinised tube for PBMCs. Blood samples will be kept at room 
temperature and transferred to the laboratory within 3 hours of collection.  
 
7.2.9 Visit 9 (24 months) – all groups (A,B,C) 
All participants will be asked to consent and report on breakthrough infections up to 24 months post-
vaccination. Prior to the 24 month visit, participants will be contacted to attend the 24 month visit in-
person for a blood draw. Further consent will be obtained prior to any additional blood sampling at 24 
months.  
All participants will have 5mL of blood collected in an SST tube. For participants in the CMI subset, 
20mL of blood will be collected in a heparinised tube for PBMCs. Blood samples will be kept at room 
temperature and transferred to the laboratory within 3 hours of collection.  
 
7.2.10 Visit 10 (30 months) – all groups (A,B,C) 
All participants will be asked to report on breakthrough infections up to 30 months post-vaccination. 
At the 24 month visit, participants will be asked to attend the 30 month visit in-person for a blood draw.   
Participants will be informed that the study continuation is dependent on funding being secured.  
All participants will have 5mL of blood collected in an SST tube. For participants in the CMI subset, 
20mL of blood will be collected in a heparinised tube for PBMCs. Blood samples will be kept at room 
temperature and transferred to the laboratory within 3 hours of collection.  
Vaccine and control group participants will be able to receive a vaccine dose before visit 10 and 
continue in the study. Participants will receive a gift voucher and parking/public transport 
reimbursement at each in-person study visit. Available individual test results will be shared and 
discussed with interested participants by a study team member during their study visits. 
 
 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 34 of 52 
 
Summary of blood schedule  
Group 
Day 0  
Day 28  
6 months  12 
months  
18 months 
24 
months 
30 
months 
A (Moderna 
bivalent 
group) 
225 
participants 
(150 
participants 
<50 and 75 
participants 
≥50 years)  
Blood 
taken  
– IgG and 
CMI 
(75 for 
<50 and 
37 for 
≥50 years 
for CMI 
group) 
Blood 
taken  
– IgG 
and CMI 
 
Blood 
taken  
– IgG and 
CMI 
 
Blood 
taken  
– IgG and 
CMI 
 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
 
B (Novavax 
group) 
225 
participants 
(150 
participants 
<50 and 75 
participants 
≥50 years) 
Blood 
taken  
– IgG and 
CMI 
(75 for 
<50 and 
37 for 
≥50 years 
for CMI 
group) 
Blood 
taken  
– IgG 
and CMI 
 
Blood 
taken  
– IgG and 
CMI 
 
Blood 
taken  
– IgG and 
CMI 
 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
 
C (Control 
group) 
150 
participants  
(All below 60 
years)  
Blood 
taken  
– IgG and 
CMI 
(75 in 
CMI 
group) 
No 
blood 
taken 
Blood 
taken  
– IgG and 
CMI 
 
Blood 
taken  
– IgG and 
CMI 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
Blood 
taken  
– IgG and 
CMI  
(CMI 
pending 
additional 
funding) 
 
7.2.8 
Unscheduled visits 
To document breakthrough infections, enrolled participants will be requested to contact the Study 
Team if they develop symptoms of COVID-19. They will all be asked to take a RAT test and, if they test 
positive, may be asked to take a second nasal swab. The second swab will be stored for sequencing. To 
enrol those with severe disease and those with higher viral load, the second swab will be requested for 
the first 5-10 cases per month who present within three days of symptom onset, plus any severe cases. 
A representative sample of positive nasal swabs will be chosen for whole genome sequencing following 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 35 of 52 
 
the completion of the 12 month visit and at the end of the study. All positive RAT tests and details 
regarding symptoms will be documented for all participants. 
 
An optional blood sample (10ml, i.e., 5ml sodium heparin + 5 ml SST tube) will be collected if the 
participant consents 28 days after a positive RAT test (convalescent blood). The convalescent blood 
sample will determine whether breakthrough infections boost SARS-CoV-2 specific immune responses 
in previously vaccinated or control group individuals by comparing them to immune responses from 
previous blood samples. CMI will also be accessed. We will explore the association between immune 
protection and viral variants and identify potential viral signatures associated with severe breakthrough 
infections and/or immune escape. The participant will otherwise continue with scheduled study visits. 
The study team will maintain telephone contact with all participants who test positive for the course of 
their illness and fully document all telephone calls. With the participant’s permission, the study team 
will seek clinical data from the health care providers or hospital(s) if the subject becomes clinically ill.   
 
In-between study visits, participants will be sent 3 monthly SMS messages to remind them to report all 
breakthrough infections.  
 
7.2.9 
Withdrawal of consent - participant withdraws from all trial participation  
A participant has the right to withdraw from the trial at any time and for any reason and is not obliged 
to give his or her reasons for doing so. The Investigator may withdraw the participant at any time in the 
interests of the participant’s health and well-being. In addition, the participant may withdraw/be 
withdrawn for any of the following reasons:  
•  Administrative decision by the Investigator  
•  Ineligibility (either arising during the trial or retrospectively, having been overlooked at screening).  
•  Significant protocol deviation  
•  Participant non-compliance with study requirements   
 
The reason for withdrawal will be recorded in the eCRF. If the participant has an AE at the time of 
withdrawal, appropriate follow-up visits or medical care will be arranged, with the agreement of the 
participant, until the AE has resolved, stabilised, or a non-trial-related causality has been assigned.  
If a participant withdraws from the study, storage of samples and data collected before their withdrawal 
will still be used in the analysis unless the participant specifically requests otherwise.  
 
7.2.10 
Losses to follow-up  
A participant will be considered lost to follow-up if he/she fails to return for two consecutive visits and 
is unable to be contacted by the trial staff.   The following action must be taken if a participant fails to 
return to the clinic for a required trial visit: 
• 
Trial staff will attempt to contact the participant within one week of the missed visit and 
reschedule the visit.   

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 36 of 52 
 
• 
Before a participant is deemed lost to follow-up, trial staff will make every effort to regain 
contact.  Three telephone calls will be made, and two emails will be sent.  All contact attempts 
will be documented in the participant’s eCRF. 
• 
If the participant continues to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of loss to follow-up. 
 
7.2.11 Replacements 
Participants who have been randomised and enrolled may NOT be replaced. 
 
7.2.12 Trial Closure 
The end of the trial is the date of the last assay for primary and secondary outcomes conducted on the 
last sample collected. 
 
8 
SAFETY MONITORING AND REPORTING 
8.1.1 
Definitions for use in trials involving investigational medicinal products  
Participant-specific adverse events 
Adverse events must be assessed to determine each of the following: 
1. Seriousness 
2. Relatedness (i.e., causal relationship) 
3. Expectedness  
 
Adverse Event (AE): Any untoward medical occurrence in a patient or clinical trial participant 
administered a medicinal product and does not necessarily have a causal relationship with this 
treatment.  
Adverse Reaction (AR): Any untoward and unintended response to an investigational medicinal product 
related to any dose administered.  
Comment: All adverse events judged by the reporting investigator or the sponsor as having a reasonable 
possibility of a causal relationship to an investigational medicinal product would qualify as adverse 
reactions. The expression ‘reasonable causal relationship’ means to convey, in general, that there is 
evidence or argument to suggest a causal relationship. 
Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR): Any adverse event/adverse reaction that 
results in death, is life threatening, requires hospitalisation or prolongs existing hospitalisation, results 
in persistent or significant disability or incapacity or is a congenital anomaly or birth defect. 
Note: Life-threatening refers to an event in which the participant was at risk of death at the time of the 
event. It does not refer to an event that hypothetically might have caused death if it were more severe.  
Medical and scientific judgement should be exercised in deciding whether an adverse event/reaction 
should be classified as serious in other situations. Important medical events that are not immediately 
life-threatening or do not result in death or hospitalisation but may jeopardise the participant or require 
intervention to prevent one of the other outcomes listed in this definition should also be considered 
serious.  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 37 of 52 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both serious and 
unexpected.  
 
Safety issues (requiring expedited reporting)  
The following definitions describe additional safety events that require expedited reporting to 
stakeholders, including the Sponsor, Investigators, HREC, local governance office and TGA:   
Significant Safety Issue (SSI): A safety issue that could adversely affect the safety of participants or 
materially impact the trial's continued ethical acceptability or conduct.  
Comment: An SSI is a new safety issue or validated signal considered by the Sponsor in relation to the 
investigational medicinal product that requires urgent attention of stakeholders.  This may be because 
of the seriousness and potential impact on the benefit-risk balance of the investigational medicinal 
product, which could prompt regulatory action and/or changes to the overall conduct of the clinical 
trial, including monitoring safety and/or the administration of the investigational medicinal product.   
Urgent Safety Measure (USM): A measure required to eliminate an immediate hazard to a participant’s 
health or safety. Note: This type of SSI can be instigated by either the investigator or sponsor and can 
be implemented before seeking approval from HRECs or institutions. 
 
8.2 
Capturing and eliciting adverse event/reaction information  
Participants will be asked to record local and systemic AEs for 7 days (and longer if symptoms persist at 
day seven, until resolution or stabilisation) following vaccination in the electronic or paper diary card 
(solicited AEs). Unsolicited AEs - all local and systemic AEs occurring in the 28 days following vaccination 
observed by the Investigator or reported by the participant, whether attributed to study medication, 
will be recorded in the AE section of the eCRF.   
Serious adverse events (SAEs) will be followed up for the duration of the trial.  Adverse events of special 
interest will be categorised as per CEPI guidelines (17).  
Any unexpected, serious, or unusual AE following immunisation will be reported to SAEFVIC (vaccine 
safety surveillance service) through SAFEVAC: Integrated Vaccine Safety website that automatically 
forwards reports to the TGA (https://www.safevac.org.au/Home/Info/VIC). Adults who experience a 
significant adverse event reported to SAEFVIC (https://mvec.mcri.edu.au/saefvic/) should be referred 
to the Victorian Specialist Immunisation Services (VicSIS) for review and management of future COVID-
19 vaccination.  
 
8.3 
Documentation of AEs  
The AE will be described in the source documents (e.g., electronic or paper diary card) and captured on 
the eCRF and will include:  
• 
A description of the AE  
• 
The onset date, duration, date of resolution  
• 
Severity (mild, moderate, or severe – how does the event impact the participant’s daily life?)  
• 
Seriousness (i.e., is it an SAE?)  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 38 of 52 
 
• 
Any action taken (e.g., treatment, follow-up tests)  
• 
The outcome (recovery, death, continuing, worsening)  
• 
The likelihood of the relationship of the AE to the trial treatment (Unrelated, Possible, Probable, 
Definite)  
Changes in the severity of an AE will be reported. AEs characterised as intermittent will be documented 
for each episode. All AEs will be followed to adequate resolution, where possible. 
 
8.4 
Assessing the relatedness (causality) of a participant’s AE 
The relationship of the event to the trial intervention will be graded/ assessed as follows:  
Unrelated 
Unlikely temporal relationship to study product. Alternate aetiology likely (clinical 
state, environmental or other interventions) and does not follow known typical or 
plausible pattern of response to study product 
Possible 
Reasonable temporal relationship to study product; or event not readily produced 
by clinical state, environmental or other interventions; or similar pattern of 
response to that seen with other vaccines 
Probable 
Reasonable temporal relationship to study product; and event not readily 
produced by clinical state, environment, or other interventions or known pattern 
of response seen with other vaccines 
Definite 
Reasonable temporal relationship to study product; and event not readily 
produced by clinical state, environment, or other interventions; and known pattern 
of response seen with other vaccines 
 
8.5 
Assessing the expectedness and severity of a participant’s AE 
An AE must be assessed to determine whether the event is or expected or unexpected in terms of the 
current known safety profile of the investigational medicinal product. The investigator will be 
responsible for determining whether an AE is expected or unexpected.  An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the trial intervention. 
 
The severity of an Adverse Event will be graded/ assessed as follows: 
Grade 0 
None 
Grade 1 
Mild: Transient or mild discomfort (< 48 hours); No interference with activity; No 
medical intervention/therapy required 
Grade 2 
Moderate: Mild to moderate limitation in activity – some assistance may be 
needed; no or minimal medical intervention/therapy required 
Grade 3 
Severe: Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required. 
Grade 4 
Potentially Life-threatening: Requires assessment in A&E or hospitalisation 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 39 of 52 
 
8.6 
Reporting of safety events 
Sponsor-Investigator Reporting Procedures 
The Sponsor-Investigator must assess and categorise the Expedited Safety Reports received from 
Investigators and report these to all Site Principal Investigators, the approving HREC and TGA in 
accordance with the NHMRC’s ‘Safety monitoring and reporting in clinical trials involving therapeutic 
goods’ (November 2016) and any additional requirements of the approving HREC.  All safety reports 
must clarify the impact of the safety event on participant safety, trial conduct and trial documentation. 
The Sponsor-Investigator is responsible for the following reporting to PIs, the HREC(s), the DSMB and 
TGA: 
1. All SSIs that meet the definition of a USM within 72 hours of becoming aware of the issue. 
2. All other SSIs within 15 calendar days of instigating or becoming aware of the issue 
3. For SSIs leading to an amendment of trial documentation: 
a. Submit details of the SSI without undue delay and no later than 15 calendar days after 
becoming aware of the issue. 
b. Submit amendment to the HREC without undue delay. 
4. For SSIs leading to a temporary halt or early termination of a trial for safety reasons: 
a. Communicate reasons, scope of halt, measures taken, and further actions planned 
without undue delay and no later than 15 calendar days of the decision to halt. 
b. For a temporary halt, notify the PIs, HREC and TGA when the trial restarts, including 
evidence that it is safe to do so. 
 
The Sponsor will report SUSARs to the TGA through the SAFEVAC website as follows: 
1. Fatal or life-threatening SUSARs immediately, but no later than 7 calendar days after being 
made aware of the issue (follow-up info within a further 8 calendar days) 
2. All other SUSARs no later than 15 calendar days after being made aware of the issue  
 
The Sponsor is responsible for providing the additional safety information to the approving HREC: 
1. Provide an annual safety report, including a summary of the evolving safety profile of the trial 
The Sponsor is also responsible for providing updated Product Information/Investigator’s Brochure to 
Investigators.  
 
9 
DATA AND INFORMATION MANAGEMENT  
The Principal Investigator is responsible for storing essential study documents relevant to data 
management and maintaining a site-specific record of the location(s) of the site’s data management-
related Essential Documents.  
 
The Principal Investigator is responsible for maintaining adequate and accurate source documents 
that include all key observations on all participants at their site. Source data will be attributable, 
legible (including any changes or corrections), contemporaneous, original, accurate, complete, 
consistent, enduring, and available. Changes to source data collected by MCRI must be traceable 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 40 of 52 
 
and explained in a note at relevant variables on the electronic case report form (eCRF).  A site-
specific Source Document Plan will be maintained to indicate the location(s) of source documents.  
 
The Principal Investigator will maintain accurate data collection forms (known as case report forms 
- CRFs) and ensure that the collected and reported data is accurate, legible, complete, entered 
promptly, and enduring.   
 
Any person delegated to collect data, perform data entry, or sign for data completeness will be 
recorded on the delegation log and trained to perform these study-related duties and functions.  
 
Data generated for this study will be handled according to the relevant standard operating 
procedures (SOPs) and Data Management Plan (DMP). Full details of all processes are provided in a 
separate study-level DMP.  
 
9.1 
Data management 
9.1.1 
Data generation (source data)  
Source documents are all documents used by the investigator that relate to the participant’s medical 
history, verify the existence of the participant, the inclusion and exclusion criteria, and all records 
covering the participant’s participation in the study.  They include but are not limited to laboratory 
reports, memoranda, vaccination records, hospital records, and participant files.  The site principal 
investigator is responsible for maintaining source documents.   
 
An electronic CRF (eCRF) will be completed for all recruited participants. 
 
In this study, the following types of data will be collected: 
• 
Identifying personal information (contact details, dates of birth, home address and 
telephone contact and gender) 
• 
Sensitive information, including health data (dates of COVID-19 vaccinations, medical 
history, previous COVID-19 vaccines, intervention vaccines).  
• 
Reactogenicity information (pain, tenderness, erythema/redness, hardness, swelling, 
warmth, itch, fever, nausea/vomiting, diarrhoea, headache, fatigue/malaise, myalgia, 
arthralgia  
• 
Adverse events and serious adverse events 
• 
SARS-CoV-2 infections prior to enrolment and breakthrough infections  
• 
Biological information (blood sample, immunologic assay results, including binding 
antibodies, functional antibodies, neutralizing antibodies, cellular immunity) 
 
Source Document Plan 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 41 of 52 
 
The source documents for this study include COVID-19 vaccination details, date of birth, and sex; 
questionnaires completed by the participant and researcher (MCRI’s eCRF). 
 
A Source Document Plan will be maintained to document the source (i.e., original recording) for each 
data discrete item/category of items collected for the study. This Source Document Plan, signed and 
dated by the Principal Investigator, will be prepared before the recruitment of the first participant and 
filed in the site’s Investigator Site File on eFlorence. 
 
9.1.2 
Data capture methods and data use, storage, access, and disclosure during the trial 
Data collection methods 
Data capture and entry will be electronic. Data for this study will be collected and entered using 
electronic data collection forms, completed by authorised study staff and participants where 
applicable. 
 
The following licensed research data collection tools will be used: 
• 
Study data will be collected and managed using REDCap electronic data capture tools 
hosted at MCRI. REDCap (Research Electronic Data Capture) is a secure, web-based 
software platform designed to support capture for research studies, providing 1) an 
intuitive interface for validated data capture; 2) audit trails for tracking data manipulation 
and export procedures; 3) automated export procedures for data downloads to common 
statistical packages; and 4) procedures for data integration and interoperability with 
external sources. (18, 19) 
• 
Data recorded will be linked by unique participant identifiers 
 
Further details on the data variables are in the study DMP. 
 
Use of the data  
The data will be used for the analyses specified in the protocol and Statistical Analysis Plan (SAP). 
 
Following the completion and analysis of the study, the data will be retained long-term following 
the mandatory archive period for use in future research projects.  
 
Storage and access 
Electronic data will be securely stored in MCRI's REDCap database system and in files stored in 
MCRI's network file servers, which are backed up nightly. Files containing private or confidential data 
will be stored only in locations accessible by appropriate designated research team members. 
 
REDCap is hosted on MCRI infrastructure and is subject to the same security and backup regimen as 
other systems (e.g., the network file servers). Data is backed up nightly to a local backup server, with 
a monthly backup taken to tape and stored offsite. REDCap maintains an audit trail of data creation, 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 42 of 52 
 
update, and deletion events accessible to project users who are granted permission to view it. 
Access to REDCap will be provided via a REDCap user account created by the MCRI system 
administrator. The permissions granted to each user within each REDCap project will be controlled 
by and will be the responsibility of the study team delegated this task by the Principal Investigator. 
REDCap has functionality that makes adding and removing users and managing user permissions 
straightforward. All data transmissions between users and the REDCap server are encrypted. The 
instructions for data entry to REDCap must be read and the training log signed before personnel 
commence data entry on REDCap. 
 
Authorised representatives of the sponsoring institution and representatives from the HREC, 
Research Governance Office, and regulatory agencies may inspect all documents and records 
required to be maintained by the Investigator for the participants in this study. The study site will 
permit access to such records. 
 
Disclosure  
The study protocol, documentation, data, and all other information generated will be confidential. No 
information concerning the study, or the data will be released to any unauthorised third party without 
the prior written approval of the sponsoring institution. Clinical information will not be released without 
the participant's written permission except as necessary for monitoring by the HREC, Research 
Governance Office, or regulatory agencies. 
 
9.1.3 
Data confidentiality 
Participant confidentiality is strictly held in trust by the Principal Investigator, participating 
investigators, research staff, and the sponsoring institution and their agents. This confidentiality is 
extended to cover the testing of biological samples, genetic tests and clinical information relating to 
participating participants.  
 
To preserve confidentiality and reduce the risk of identification during the collection, analysis, and 
storage of data and information, the following will be undertaken: 
(1) The number of private/confidential variables collected for individual study participants has 
been minimised. The data collected will be limited to that required to address the primary and 
secondary objectives. 
 
(2) Participant identifiers will be stored separately from the data collected, and documents with 
identifiers will be stored separately from participant data. Participant data and samples will be 
identified using a unique study number assigned to the participant (“re-identifiable”). The Principal 
Investigator is responsible for storing a master file of names and other identifiable data with the 
participant ID; access to this document will be restricted to the site study team. The master file will 
be stored securely and separately from study data in locked/ password-protected databases, with 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 43 of 52 
 
passwords kept separately. Age and sex will be included in the data; however, it is unlikely to make 
specific participants or families identifiable as identifiers will be stored separately. 
 
Separation of the roles responsible for the management of identifiers and those responsible for 
content analysis. The Principal Investigator will ensure access to the data is restricted, using REDCap’s 
permission control functionality (“REDCap Users and Permissions”). 
 
9.1.4 
Quality assurance  
Data validity and quality assurance will be ensured by the following: 
(1) Data collection and entry into the eCRF will be completed by authorised staff designated by the 
investigator. Appropriate training on eCRF completion will be conducted with the relevant 
investigator and all authorised staff before the study starts and any data is entered. 
 
(2) All data will be entered in English.  eCRFs are to be completed as soon as possible after each 
participant’s visit.  For information collected specifically for the study, data may be entered directly 
into the eCRF without duplicating the information across separate source documentation and eCRF. 
If data are unavailable or missing, this will be indicated on the eCRF. Changes or corrections made 
on eCRF will be tracked via an audit trail. 
 
(3) Once the eCRFs have been entered, edit and consistency checks will be performed as outlined 
in the DMP.  Data queries generated for logic and legality will be reviewed by authorised study staff 
for clarification. After resolving the queries, the responsible Data Manager will make the necessary 
updates to the database.  An audit trail of all changes to the database will be maintained.  Once all 
queries have been resolved, the database will be locked. 
 
(4) The Principal Investigator must sign off on the eCRF data before the final database lock. 
 
(5) An audit is a systematic and independent examination of trial-related activities and documents 
to determine whether the evaluated related activities were conducted. The data were recorded, 
analysed, and accurately reported according to the protocol, study SOPs, GCP, and the applicable 
regulatory requirement(s). 
 
Authorised representatives of MCRI, its designee, a regulatory authority, or the IEC may visit the centre 
to perform audits or inspections.  The investigator should contact MCRI or the designee immediately if 
a regulatory agency contacts them about an inspection at their centre.  If an audit or inspection occurs, 
the site PI agrees to allow the auditor/inspector direct access to all relevant documents and allocate 
their staff's time to the auditor/inspector to discuss findings and relevant issues. 
The statistician will be provided anonymised data, with participants identifiable only by unique 
participant study numbers/codes. The statistician will analyse the de-identified data. 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 44 of 52 
 
9.1.5 
Archiving - Data and document retention  
Archiving 
The Investigator will take measures to prevent accidental or premature destruction of these 
documents. For this study, essential documents, and data (including biological samples) will be 
retained for a minimum of 15 years post-study.  
 
The central study site and laboratory for this study are: 
New Vaccines Research Group, Infection & Immunity, Murdoch Children’s Research Institute 
Records will not be destroyed without the written consent of the Principal Investigator. 
 
Destruction 
After the archival period of 15 years, The Principal Investigator will take measures to ensure the 
secure destruction of hard copies of study data. Any hardcopy data will be disposed of via a 
confidential shredding process. Noting that simply deleting files does not destroy the information, 
electronic CRFs will be destroyed under guidance from MCRI IT to ensure the files are permanently 
deleted. 
The electronic, anonymised database will not be destroyed. 
At the end of the archival period, eCRFs will be disposed of via secure destruction methods. Electronic 
databases will be retained by MCRI and stored on the secure server.  
 
9.1.6 Sample management: collection and storage 
The biobanking team will manage, process, and store the samples as per section 3 of the protocol.  
 
10 TRIAL OVERSIGHT  
10.1 
Governance structure  
The Governance structure is outlined below. 
 
10.1.1 Trial Management Group (TMG) 
 The Site Principal Investigator is responsible for supervising any individual or party to whom they have 
delegated tasks at the trial site. They must provide continuous supervision and documentation of their 
oversight. To meet this GCP requirement, a small group will be responsible for the day-to-day 
management of the trial and will include, at a minimum, the Site PI, project manager, data manager 
and an Immunology team representative. The group will review all aspects of the trial's conduct and 
progress closely, ensuring a forum for identifying and addressing issues. Meetings must have minutes 
with attendees listed, pertinent emails retained, and phone calls documented.  
 
10.1.2 Trial Steering Committee (TSC) 
A TSC will be established to provide expert advice and overall supervision and ensure that the trial 
meets the required standards. The TSC will meet at least annually, with more frequent meetings as 
needed, and will work to a Terms of Reference.   

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 45 of 52 
 
 
10.1.3 Safety Monitoring  
Monitoring will be performed according to Good Clinical Practice (GCP) guidelines. Following written 
SOPs, the monitors will verify that the clinical trial is conducted, and that data are generated, 
documented, and reported in compliance with the protocol, GCP and the applicable regulatory 
requirements. The investigator will provide direct access to all trial-related source data/documents and 
reports for monitoring purposes.  
 
Independent Data Safety Monitoring Board (DSMB) 
Safety oversight will be under the direction of a DSMB. The DSMB will meet at least 6 monthly to review 
SAEs or AEs deemed possibly, probably, or definitively related to study interventions.  The DSMB will 
make recommendations concerning the conduct, continuation, or modification of the study for safety 
reasons. The DSMB will meet virtually prior to the commencement of the trial and then again on at 
least two occasions to review the safety data.  The DMSB will operate under the rules of an approved 
charter that will be written and reviewed at the organisational meeting of the DSMB.  The DSMB will 
be chaired by an experienced vaccine trial specialist and will include a statistician and an adult physician 
as members. Members of the DSMB will be independent of trial conduct. 
 
10.2 
Site Monitoring  
Trial site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol and amendment(s), good clinical 
practice, and applicable regulatory requirements.  
Full details of trial site monitoring are documented in the Clinical Monitoring Plan (CMP). The CMP 
describes who will conduct the monitoring, at what frequency monitoring will be done, at what level of 
detail monitoring will be performed, and the distribution of monitoring reports.  
Monitoring for this trial will be performed by one of the two external trial managers who are not the 
project manager for this study.  The monitoring will take place on-site.  The monitors will review 100% 
of original signed consent forms, trial eligibility data and data related to the primary outcome, safety 
and other key data variables, all withdrawals from the trial, and targeted review of other data, including 
investigational vaccine administration and accountability.  
The investigational site will provide direct access to all trial-related sites, source data/documents, and 
reports for monitoring and auditing by the sponsor and inspection by local and regulatory authorities. 
 
10.3 
Quality Control and Quality Assurance 
Both the Sponsor-Investigator and Site Investigator have responsibilities in relation to quality 
management.   
The Sponsor-Investigator will develop SOPs that identify, evaluate and control risk for all aspects of the 
trial, e.g., data management, training, eligibility, informed consent, and adverse event reporting.  The 
Sponsor-Investigator will implement quality control (QC) procedures, including the data entry system 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 46 of 52 
 
and QC checks. Any missing data or data anomalies will be communicated to the study staff for 
clarification/resolution. 
As outlined in the previous section (Site Monitoring), the trial monitors will verify that the clinical trial 
is conducted and data are generated, and biological specimens are collected, documented (recorded), 
and reported in compliance with the protocol, good clinical practice, and applicable regulatory 
requirements.  
In the event of non-compliance that significantly affects human participant protection or the reliability 
of results, the Sponsor-Investigator will perform a root cause analysis and corrective and preventative 
action plan (CAPA). 
In addition, the clinical site will perform internal quality management of trial conduct, data, and 
biological specimen collection, documentation, and completion.     
The study trial master file, investigator site file documents and all other filing will be done on eFlorence. 
 
11 STATISTICAL METHODS  
11.1 
Sample Size Estimation 
Sample size calculations were performed using nQuery 8 software and methods described by Van Belle, 
et al. 1993 (20). Precision-based sample size calculations were performed based on the reactogenicity 
outcomes. Assuming the percentage of participants reporting local or systemic reactions is 50%, 100 
participants will produce a confidence interval that is 9.8 percentage points from the observed 
percentage. For immunogenicity, sample size calculations were based on comparing day 28 post-
booster geometric mean concentrations of IgG antibodies between vaccine arms. We assumed the 
coefficient of variation (standard deviation/mean) of the post-booster antibody concentrations would 
be 1.15 (based on data from Munro, et al. 2021 (8), but increased to be conservative). Even though 
previous studies demonstrated a geometric mean ratio (GMR) of up to 4 between the study vaccine 
groups, we considered a clinically important difference between groups to be a GMR of >1.4. Based on 
these assumptions the study will need to recruit 160 participants in each vaccine group overall to 
achieve 90% of power at two-sided 0.05 significance level. Allowing for ~20% loss to follow-up the 
sample size in each arm was expanded to 200. To ensure age representation (<50 and ≥50) in the 
second Moderna bivalent group (BA.4-5) numbers were increased in the younger age group.  
We are confident that the sample size is sufficient as it is likely that the GMR difference will be higher 
than expected and the loss to follow-up lower than anticipated.  
 
11.2 
Statistical methods and the Estimand framework 
Analysis for this trial will be planned using the estimand framework (21). Trial objectives will be 
translated into suitable estimands, with consideration of strategies for handling intercurrent events. 
Analysis methods (estimators) that align with the estimands will be selected. Comparisons will be made 
under the superiority framework. 
Analyses will be performed using Stata software version 17 (22). Detailed methodology will be outlined 
in a separate Statistical Analysis Plan. 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 47 of 52 
 
11.3 
Methods of analysis - outcome variables and methods  
11.3.1  Primary outcome  
Reactogenicity following immunisations will be presented as the number and percentage of participants 
self-reporting local reactions (pain, tenderness, redness, hardness, swelling, warmth, itch at or near the 
injection site) and systemic reactions (fever, nausea, vomiting, diarrhoea, headache, fatigue/malaise, 
myalgia), and the severity of these reactions (mild, moderate, severe, life-threatening, or fatal). 
Reactogenicity data will be presented separately by group and time point. For reactogenicity 
proportions will be estimated with 95% Clopper-Pearson binomial confidence intervals. 
 
For immunogenicity, antibody levels will be presented as geometric mean concentrations (GMC) with 
95% confidence intervals. Changes from baseline will be expressed as geometric mean fold ratios 
(GMFR), calculated as the ratio of the post-booster GMC to the baseline GMC. GMCs will be compared 
between the two vaccine groups at 28 days. We will account for baseline levels, age, primary series and 
first booster vaccine in the analysis. We will use the Treatment Policy strategy for the analysis, meaning 
that each intercurrent event (i.e., breakthrough SARS-CoV-2 infection) is considered to be part of the 
treatment effect. 
 
The binding IgG data using the Euroimmun S1 IgG ELISA kits will be reported as relative units/ml (RU/ml) 
per the manufacturer’s instructions. A result of <8 RU/ml: negative (IgG Antibodies for SARS-CoV-2 are 
not detected), ≥8 to <11 RU/ml: borderline (IgG antibodies are indeterminate/equivocal with this 
sample, ≥11 RU/ml: positive (IgG antibodies for SARS-CoV-2 are detected). Conversion to binding 
antibody units (BAU/ml) will also be done using the WHO reference serum from NIBSC, UK. Data will be 
presented as geometric mean concentrations and 95% confidence intervals. The primary endpoint will 
be the GMR at Day 28 for binding antibody. Linear regression will be used to estimate the differences 
in log antibody concentrations, adjusted for stratifying variables (age group), duration between 
different doses, study day of blood-draw, and baseline levels. The GMR will be calculated as the 
antilogarithms of the mean difference (beta1) and it’s 95% CI. 
 
In addition to the group level assessments described above, for individual patients in the vaccine 
groups, seroresponse will be defined as: 
• ≥4-fold rise in binding antibody concentrations at 28 days post-study vaccine from baseline among 
subjects with no pre-dose (<200 BAU/ml) detectable titres  
•≥ 2-fold rise in binding antibody concentrations at 28 days post-study vaccine among subjects with 
baseline titre of ≥200 BAU/ml pre-booster  
 
11.3.2. Secondary outcomes 
Binding antibodies - changes from baseline will be expressed as geometric mean fold ratios (GMFR), 
calculated as the ratio of the post-booster GMC to the baseline GMC. GMCs will be compared between 
the two vaccine groups and between the vaccine and control groups at 6, 12, 18, 24 and 30 months. 
We will account for age in the analysis.  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 48 of 52 
 
 
Functional antibodies seven time points for vaccine groups [baseline, 1, 6, 12, 18, 24and 30 months] and 
six time points for controls [baseline, 6, 12, 18, 24 and 30 months]) – for the C-PASS assay (sVNT), data 
are reported as percentage (%) inhibition by neutralising antibodies using the manufacturer’s 
instructions. A <30% inhibition is considered negative, while ≥30% inhibition is considered positive. Data 
will be presented as mean and standard deviation.  
 
Neutralizing assay (20% subset of samples at all time points) up to 12 months – Data will be reported 
as endpoint titre calculated using the Reed/Muench method (23). A titre of 10 reflects undetectable 
neutralizing activity.  
 
Cellular immunity: (on a 50% subset at seven time points for vaccine groups and six time points for 
controls) 
Quantiferon COVID IFNγ release assay up to 12 months – Levels of IFNγ will be reported in IU/ml 
according to the manufacturer’s instructions. Data will be reported as GMT and 95% confidence 
intervals. 
 
IFNγ Elispot – The number of IFNγ-producing cells/million PBMCs will be reported using means and 95% 
confidence intervals.  
 
Intracellular cytokine staining – The data will be reported as the frequency (%) of cytokine-expressing T 
cells (e.g., total T cells, CD4 T cells, CD8 T cells). Cytokines such as IFNγ (Th1) and IL-5 (Th2) will be 
measured as a minimum. This will be presented as means and 95% confidence intervals. 
 
Multiplex cytokine assays – A 10-plex panel of cytokines will be measured in supernatants from the 
Elispot studies. Cytokine concentrations will be reported in pg/ml, and data will be presented as GMT 
and 95% confidence intervals. 
 
11.3.3 Exploratory outcome 
We will describe the number of confirmed mild, moderate, and severe breakthrough cases in each of 
the three groups. 
Explore the association between immune protection and viral variants and identify potential viral 
signatures associated with severe breakthrough infections. 
 
12 ETHICS AND DISSEMINATION   
12.1 
Research Ethics Approval & Local Governance Authorisation 
This protocol, the informed consent document, and any subsequent amendments will be reviewed and 
approved by the human research ethics committee (HREC) before the research. A letter of protocol 
approval by HREC will be obtained before the commencement of the trial and approval for other trial 
documents requiring HREC review. 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 49 of 52 
 
 
12.2 
Amendments to the protocol  
This trial will be conducted in compliance with the current version of the protocol. Any change to the 
protocol document or Informed Consent Form that affects the scientific intent, trial design, participant 
safety, or may affect a participant’s willingness to continue participation in the trial is considered an 
amendment and, therefore, will be written and filed as an amendment to this protocol and/or informed 
consent form. All such amendments will be submitted to the HREC for approval before implementation. 
 
12.3 
Protocol Deviations and Serious Breaches  
All protocol deviations will be recorded in the participant record (source document) and on the CRF and 
must be reported to the Site Principal Investigator, who will assess for seriousness.  
Those deviations deemed to affect to a significant degree the rights of a trial participant or the reliability 
and robustness of the data generated in the clinical trial will be reported as serious breaches. Reporting 
will be done promptly (Site Principal Investigator is to report to the Sponsor-Investigator within 72 
hours and to the Site RGO within seven days; Sponsor-Investigator is to review and submit to the 
approving HREC within seven days).  
Where non-compliance significantly affects human participant protection or the reliability of results, a 
root cause analysis will be undertaken, and a corrective and preventative action plan will be prepared.   
Where protocol deviations or serious breaches identify protocol-related issues, the protocol will be 
reviewed and, where indicated, amended.  
 
13 CONFIDENTIALITY 
Participant confidentiality is strictly held in trust by the participating investigators, research staff, the 
sponsoring institution, and their agents. This confidentiality is extended to cover the testing of biological 
samples, genetic tests, and clinical information relating to participating participants.  
The trial protocol, documentation, data, and all other information generated will be strictly confidential. 
No information concerning the trial, or the data will be released to any unauthorised third party without 
the prior written approval of the sponsoring institution. Authorised representatives of the sponsoring 
institution may inspect all documents and records required to be maintained by the Investigator, 
including but not limited to medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this trial. The clinical trial site will permit access to such records.  
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified only by the Participant Identification Number (SID) to maintain participant confidentiality.  
Clinical information will not be released without the participant's written permission except as 
necessary for monitoring by HREC or regulatory agencies. 
Data will be shared with relevant government bodies.  
 
14 PARTICIPANT REIMBURSEMENT  
Study participants will be compensated for their time, the inconvenience of blood tests and procedures, 
and travel expenses (parking or public transport reimbursement).  

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 50 of 52 
 
 
15 FINANCIAL DISCLOSURE AND CONFLICTS OF INTEREST 
No conflict of interests. 
 
16 DISSEMINATION AND TRANSLATION PLAN 
Participants will be given access to their personal antibody levels and the analysed data at each time 
point once it becomes available.  The former will be on request at follow-up visits, while the latter and 
the overall study results will be provided by group email as the analysed antibody data becomes 
available. 
 
After study completion, a major publication will be prepared for an international journal.  The data will 
also be presented at appropriate international conferences and meetings.  
 
17 ADDITIONAL CONSIDERATIONS 
Not applicable.  
 
18 REFERENCES 
1. 
Regev-Yochay G, Gonen T, Gilboa M, Mandelboim M, Indenbaum V, Amit S, et al. Efficacy of a 
Fourth Dose of Covid-19 mRNA Vaccine against Omicron. New England Journal of Medicine. 
2022;386(14):1377-80. 
2. 
Cohen MJ, Oster Y, Moses AE, Spitzer A, Benenson S, Group tI-htvW. Effectiveness of the BNT162b 
vaccine fourth dose in reducing SARS-CoV-2 infection among healthcare workers in Israel, a multi-
center cohort study. medRxiv. 2022:2022.04.11.22273327. 
3. 
Arbel R, Sergienko R, Friger M, Peretz A, Beckenstein T, Yaron S, et al. Effectiveness of a second 
BNT162b2 booster vaccine against hospitalization and death from COVID-19 in adults aged over 60 
years. Nat Med. 2022. 
4. 
Gazit S, Saciuk Y, Perez G, Peretz A, Pitzer VE, Patalon T. Relative Effectiveness of Four Doses 
Compared to Three Dose of the BNT162b2 Vaccine in Israel. medRxiv. 2022:2022.03.24.22272835. 
5. 
Magen O, Waxman JG, Makov-Assif M, Vered R, Dicker D, Hernán MA, et al. Fourth Dose of 
BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. N Engl J Med. 2022;386(17):1603-14. 
6. 
Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Amir O, Freedman L, et al. Protection by a 
Fourth Dose of BNT162b2 against Omicron in Israel. N Engl J Med. 2022;386(18):1712-20. 
7. 
Grewal R, Kitchen SA, Nguyen L, Buchan SA, Wilson SE, Costa AP, et al. Effectiveness of a Fourth 
Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada. medRxiv. 
2022:2022.04.15.22273846. 
8. 
Munro APS, Janani L, Cornelius V, Aley PK, Babbage G, Baxter D, et al. Safety and immunogenicity 
of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or 
BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet. 
2021;398(10318):2258-76. 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 51 of 52 
 
9. 
Chalkias S, Harper C, Vrbicky K, Walsh SR, Essink B, Brosz A, et al. A Bivalent Omicron-Containing 
Booster Vaccine against Covid-19. N Engl J Med. 2022;387(14):1279-91. 
10. Yu J, Collier A-rY, Rowe M, Mardas F, Ventura JD, Wan H, et al. Neutralization of the SARS-CoV-2 
Omicron BA.1 and BA.2 Variants. New England Journal of Medicine. 2022;386(16):1579-80. 
11. Hachmann NP, Miller J, Collier A-rY, Ventura JD, Yu J, Rowe M, et al. Neutralization Escape by SARS-
CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5. New England Journal of Medicine. 
2022;387(1):86-8. 
12. UK Health Security Agency. COVID-19 vaccine weekly surveillance reports. 2022 [Available from: 
https://www.gov.uk/government/publications/covid-19-vaccine-weekly-surveillance-reports  
13. Atmar RL, Lyke KE, Deming ME, Jackson LA, Branche AR, El Sahly HM, et al. Homologous and 
Heterologous Covid-19 Booster Vaccinations. N Engl J Med. 2022. 
14. Munro APS, Feng S, Janani L, Cornelius V, Aley PK, Babbage G, et al. Safety, immunogenicity, and 
reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters 
following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a 
multicentre, blinded, phase 2, randomised trial. Lancet Infect Dis. 2022. 
15. US Food and Drug Administration (FDA). Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers 
Enrolled 
in 
Preventive 
Vaccine 
Clinical 
Trials 
2007 
[Available 
from: 
https://www.fda.gov/media/73679/download. 
16. Munro APS, Janani L, Cornelius V, Aley PK, Babbage G, Baxter D, et al. Safety and immunogenicity 
of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or 
BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet. 
2021. 
17. Coalition for Epidemic Preparedness Innovations (CEPI). Priority List of Adverse Events of Special 
Interest: COVID-19 2020 [Available from: https://brightoncollaboration.us/priority-list-aesi-covid/. 
18. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, et al. The REDCap consortium: 
Building an international community of software platform partners. J Biomed Inform. 2019;95:103208. 
19. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture 
(REDCap)--a metadata-driven methodology and workflow process for providing translational research 
informatics support. J Biomed Inform. 2009;42(2):377-81. 
20. van Belle G, Martin DC. Sample Size as a Function of Coefficient of Variation and Ratio of Means. 
The American Statistician. 1993;47(3):165-7. 
21. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use. Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical 
Principles for Clinical Trials 2019 [Available from: https://database.ich.org/sites/default/files/E9-
R1_Step4_Guideline_2019_1203.pdf (Accessed 22 July 2022). 
22. StataCorp. Stata Statistical Software: Release 17. . College Station, TX: StataCorp LLC.; 2021. 
23. Juno JA, Tan HX, Lee WS, Reynaldi A, Kelly HG, Wragg K, et al. Humoral and circulating follicular 
helper T cell responses in recovered patients with COVID-19. Nat Med. 2020;26(9):1428-34. 
 

 
 Confidential 
 
Study Name: CEPI fourth dose Australia  
Protocol Number: 91108 
Version & date: version 8.0 dated 4 December 2024 
Page 52 of 52 
 
19  
APPENDICES 
APPENDIX 1 – Product information sheets 
Moderna bivalent 
PI.pdf
 
Nuvaxovid_PIL.pdf
 
ModernaBA4_5_PI.p
df