A Randomised Controlled Trial to Assess the Immunogenicity, Safety and Reactogenicity of Standard Dose Versus Fractional Doses of COVID-19 Vaccine (Pfizer-BioNTech) Given as a Booster Dose After Priming With Sinopharm, AstraZeneca or Sputnik in Healthy Adults in Mongolia
Phase: PHASE3
Conditions: COVID-19
Sponsor: Murdoch Childrens Research Institute

 
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Study Name: CEPI 
Protocol Number: 81800 
Version & date: version 7.0, dated  20 September 2023 
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PROTOCOL  
 
 
A randomised controlled trial to assess the immunogenicity 
as well as safety and reactogenicity of standard dose versus 
fractional doses of COVID-19 vaccine (Pfizer-BioNTech) given 
as a booster dose after priming with Sinopharm, 
AstraZeneca or Sputnik in healthy adults in Mongolia. 
 
 
Protocol Number: 81800 
Protocol Version 7.0,  
20 September 2023 
 
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, standards of Good Clinical Practice (as defined by the International Conference 
on Harmonisation), ethical principles that have their origin in the Declaration of Helsinki and all applicable 
national and local regulations. 
 
This clinical trial is not sponsored by any pharmaceutical company or other commercial entity 
 
 
 

 
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CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS .............................................................................................................. 10 
INVESTIGATOR AGREEMENT ................................................................................................................. 11 
1. 
ADMINISTRATIVE INFORMATION .............................................................................................. 12 
1.1. 
Trial registration ........................................................................................................................ 12 
1.1.1. Trial registry ............................................................................................................................... 12 
1.2. 
Sponsor ..................................................................................................................................... 12 
1.3. 
Expected duration of study ....................................................................................................... 12 
1.4. 
Contributorship ......................................................................................................................... 12 
1.5. 
Stakeholder involvement........................................................................................................... 13 
2. 
INTRODUCTION AND BACKGROUND ......................................................................................... 13 
2.1. 
Trial rationale and aim ............................................................................................................... 13 
2.2. 
Background ............................................................................................................................... 14 
2.3. 
Risk/Benefit assessment ............................................................................................................ 15 
2.3.1. Known potential risks ................................................................................................................ 15 
2.3.2. Assessment of potential risks and benefits ............................................................................... 16 
2.3.1. Known potential benefits .......................................................................................................... 16 
3. 
TRIAL OBJECTIVES AND OUTCOMES ......................................................................................... 16 
3.1 
Objectives .................................................................................................................................. 16 
3.1.1 Primary objectives ..................................................................................................................... 16 
3.1.2 Secondary objectives ................................................................................................................. 16 
3.2 
Outcomes .................................................................................................................................. 17 
4 
TRIAL DESIGN ............................................................................................................................ 20 
4.1 
Overall 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 
4.7 
Recruitment and identification of potential participants .......................................................... 22 

 
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4.8 
Consent ..................................................................................................................................... 23 
5 
INTERVENTION .......................................................................................................................... 23 
5.1 
Treatment arms ......................................................................................................................... 23 
5.2 
Trial Intervention(s) ................................................................................................................... 23 
5.2.1 Description of trial investigational products.............................................................................. 23 
5.2.1.1 Trial Products ............................................................................................................................ 23 
5.2.2 Dosage ....................................................................................................................................... 24 
5.2.3 Dose modification ..................................................................................................................... 24 
5.2.4 Storage, preparation, dispensing and administration of trial drug ............................................ 24 
5.2.5 Product accountability............................................................................................................... 24 
5.2.6 Excluded medications and treatments ...................................................................................... 25 
5.2.7 Concomitant therapy ................................................................................................................ 25 
5.2.8 Discontinuation from trial intervention ..................................................................................... 25 
6 
RANDOMISATION AND BLINDING ............................................................................................. 25 
6.1 
Concealment mechanism .......................................................................................................... 25 
6.2 
Breaking of the trial blind .......................................................................................................... 26 
6.2.1 On trial ....................................................................................................................................... 26 
7 
TRIAL VISITS AND PROCEDURES ................................................................................................ 26 
7.1 
Schedule of assessments ........................................................................................................... 26 
7.2 
Description of procedures ......................................................................................................... 28 
7.2.1 Visit 2 (Day 1) ............................................................................................................................ 28 
7.2.2 Visit 3 (Day 7) ............................................................................................................................ 28 
7.2.3 Visit 4 (Day 28) .......................................................................................................................... 29 
7.2.4 Visit 5 (3 Months) ...................................................................................................................... 29 
7.2.5 Visit 6 (6 Months) ...................................................................................................................... 29 
7.2.6 Visit 7 (12 Months) .................................................................................................................... 29 
7.2.7 Unscheduled visits ..................................................................................................................... 30 
7.2.8 Withdrawal of consent - participant withdraws from all trial participation .............................. 30 
7.2.9 Losses to follow-up .................................................................................................................... 31 
7.2.10 Replacements ............................................................................................................................ 31 
7.2.11 Trial Closure ............................................................................................................................... 31 
8 
SAFETY MONITORING AND REPORTING .................................................................................... 31 
8.1.1 Definitions for use in trials involving investigational medicinal products .................................. 31 

 
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8.2 
Capturing and eliciting adverse event/reaction information ..................................................... 32 
8.3 
Documentation of AEs ............................................................................................................... 33 
8.4 
Assessing the relatedness (causality) of a participant’s AE ........................................................ 33 
8.6 
Reporting of safety events......................................................................................................... 34 
9 
DATA AND INFORMATION MANAGEMENT ............................................................................... 35 
9.1 
Data management ..................................................................................................................... 35 
9.1.1 Data generation (source data) ................................................................................................... 35 
9.1.2 Data capture methods and data use, storage, access, and disclosure during the trial.............. 36 
9.1.3 Data confidentiality ................................................................................................................... 37 
9.1.4 Quality assurance ...................................................................................................................... 38 
9.1.5 Archiving - Data and document retention ................................................................................. 39 
10 
TRIAL OVERSIGHT ...................................................................................................................... 39 
10.1 
Governance structure................................................................................................................ 39 
10.1.1 Trial Management Group (TMG) ............................................................................................... 39 
10.1.2 Trial Steering Committee (TSC) ................................................................................................. 39 
10.1.3 Safety Monitoring ...................................................................................................................... 40 
10.2 
Site Monitoring .......................................................................................................................... 40 
10.3 
Quality Control and Quality Assurance ...................................................................................... 40 
11 
STATISTICAL METHODS ............................................................................................................. 41 
11.1 
Sample Size Estimation .............................................................................................................. 41 
11.2 
Population to be analysed ......................................................................................................... 41 
11.3 
Methods of analysis ................................................................................................................... 42 
11.4 
Interim Analyses ........................................................................................................................ 43 
12 
ETHICS AND DISSEMINATION .................................................................................................... 43 
12.1 
Research Ethics Approval & Local Governance Authorisation ................................................... 43 
12.2 
Amendments to the protocol .................................................................................................... 43 
12.3 
Protocol Deviations and Serious Breaches ................................................................................ 44 
13 
CONFIDENTIALITY ...................................................................................................................... 44 
14 
PARTICIPANT REIMBURSEMENT ................................................................................................ 44 
15 
FINANCIAL DISCLOSURE AND CONFLICTS OF INTEREST ............................................................ 44 
16 
DISSEMINATION AND TRANSLATION PLAN ............................................................................... 44 
17 
ADDITIONAL CONSIDERATIONS ................................................................................................. 45 
18 
REFERENCES .............................................................................................................................. 46 

 
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19 APPENDICES ..................................................................................................................................... 47 
  
 

 
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PROTOCOL SYNOPSIS 
TITLE 
A randomised controlled trial to assess the immunogenicity as well 
as safety and reactogenicity of standard dose versus fractional 
doses of COVID-19 vaccine (Pfizer-BioNTech) given as a booster 
dose after priming with Sinopharm, AstraZeneca or Sputnik in 
healthy adults in Mongolia. 
TRIAL DESCRIPTION 
This clinical trial will be a single blind*, randomised study to 
determine the safety, reactogenicity and immunogenicity of 
booster doses of SARS-CoV-2 vaccines in adults. Both standard and 
fractional doses will be tested.   
* Subjects and assessors will be blinded to the vaccine dose for one week 
following administration, and laboratory staff will be blinded to vaccine 
dose associated with specimens. 
 
Primary vaccine 
Booster vaccines 
Sinopharm (BBIBP-CorV®) 
1 Pfizer-BioNTech (BNT162b2, or 
Comirnaty®) Standard dose (30µg) 
n= 200 
2 Pfizer-BioNTech (BNT162b2, or 
Comirnaty®) Fractional dose 
(15µg) n= 200 
AstraZeneca (ChAdOx1-S, or 
Vaxzevria®) 
3 Pfizer-BioNTech (BNT162b2, or 
Comirnaty®) Standard dose (30µg) 
n= 100 
4 Pfizer-BioNTech (BNT162b2, or 
Comirnaty®) Fractional dose 
(15µg) n= 100 
Sputnik V (Gam-COVID-Vac®) 
3 Pfizer-BioNTech (BNT162b2, or 
Comirnaty®) Standard dose (30µg) 
n= 100 
4 Pfizer-BioNTech (BNT162b2, or 
Comirnaty®) Fractional dose 
(15µg) n= 100 
OBJECTIVES 
Primary objectives –  
• 
To assess and compare the immune response measured as 
binding antibodies (IgG ELISA) following fractional versus 
standard doses of Pfizer vaccine given as single additional dose 
in adults 18 years and older in Mongolia who have been 
primed through previous vaccination with Astra Zeneca, 
Sinopharm or Sputnik vaccines. (Timepoint – 28 days post 
vaccination) 

 
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• 
To assess the rate and severity of the reactogenicity within 
one-week post-booster for each schedule evaluated 
(Timepoint – daily, for seven days post vaccination) 
 
Secondary objectives - (timepoint – 6 ,12, 18, and 24 months for 
all) 
• 
To compare the duration of immunity, both humoral and 
cellular, over 24 months for fractional vs standard booster 
doses of the vaccines listed.  
• 
To evaluate the different priming capacities of Sinopharm, 
AstraZeneca and Sputnik vaccines.  
• 
To assess the impact of prior natural exposure on boosting 
regimens.  
• 
To evaluate the safety of the booster dose regimens 
OUTCOMES AND 
OUTCOME MEASURES 
 
Outcomes 
• 
Reactogenicity will be measured using the accepted 
standardised method for evaluation of systemic and local side 
effects following vaccination using a structured questionnaire 
for seven days post-vaccination.  All moderate or severe 
reactions will be reviewed by study staff. 
• 
All solicited adverse events (AE) will be collected for 7 days, all 
unsolicited AE will be collected for 28 days, and all medically 
attended AE will be collected to 3 months. SAE will be collected 
throughout the follow up period of 24 months.  Adverse events 
of special interest will be categorised as per CEPI  guidelines (1). 
Antibodies (binding and functional) and cellular immune 
responses will be measured (see outcome measures for details) 
 
Outcome measures 
Reactogenicity will be measured by recording the following 
parameters: 
o Local reaction - pain, tenderness, erythema/redness, 
hardness, swelling, warmth, itch 
o 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 on serum collected at 6 
timepoints (baseline, 28 days, 6 months, 12 months, 18 
months and 24 months.  For all subjects, the 28 days post-
vaccination sample will be assayed within four weeks of 
collection in Mongolia. 

 
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Functional antibody – All samples will be assayed using the 
GenScript cPass SARS-CoV-2 Neutralization Antibody detection 
kit, for both the ancestral Wuhan strain and Omicron variant 
RBD antigen. 
Neutralizing antibody - A fraction of samples (20%) will be 
assessed using a SARS-CoV-2 neutralizing antibody assay 
undertaken at the Doherty Institute, Melbourne.  Testing will 
be at 6 timepoints and for the Wuhan strain and 2 variants of 
concern.  
Cellular immunity (on a 40% subset of samples at baseline, 28 
days, 6 months, 12 months, 18 months and 24 months post-
vaccination) as follows:–  
• 
QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) – These 
whole blood tests will be used on site.  
• 
Peripheral blood mononuclear cells (PBMCs) will be 
isolated by density gradient centrifugation within 12 hrs of 
collection and stored in liquid nitrogen at the lab in 
Ulaanbaatar, Mongolia prior to shipment to MCRI, 
Melbourne for testing. Cell mediated immunity assays will 
include IFN-γ Elispot, intracellular cytokine assays (flow 
cytometry) and multiplex cytokine assays. 
TRIAL POPULATION 
Participants will be adults aged 18 years or older who have received 
two doses of either Sinopharm (BBIBP-CorV®), AstraZeneca 
(ChAdOx1-S, or Vaxzevria®), or Sputnik V (Gam-COVID-Vac®) ≥ 6 
months before entering this study. There will be no upper age limit.  
200 participants will be required in the Sinopharm groups and 100 
per group in the Astra Zeneca and Sputnik arms, and therefore 
there will be 800 participants in total.  Procedures will be 
implemented to ensure participants of all ages (aged 18 and above) 
are included and that there is an even age distribution (<50 and 
≥50 years) in each group.  
DESCRIPTION OF SITES 
ENROLLING PARTICIPANTS 
Participants will be enrolled at government health centres or 
hospitals in Ulaanbaatar and provincial sites where Pfizer booster 
vaccinations are currently being offered to all adults. 
DESCRIPTION OF 
INTERVENTIONS  
The interventions being studied are as follows: 
 Pfizer-BioNTech (BNT162b2, or Comirnaty®) Standard Dose (30µg)   
Pfizer-BioNTech (BNT162b2, or Comirnaty®) Fractional Dose (15µg)   
TRIAL DURATION 
The total duration of the trial will be 36 months.  The initial 
recruitment period has been completed  and took  approximately 4 
months. Each participant will have nine visits over a follow-up period 
of 24 months following their immunisation visit.  

 
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To extend the follow-up from 12 months to 24 months after the 
study vaccine, participants will be invited to reconsent to the study 
extension following their 12 month visits.  
PARTICIPANT DURATION 
Participant duration will be 24 months, and there will be nine visits 
(six in-person visits and three phone calls). The DSMB will review 
participant safety regularly during the 24 months of participant 
involvement. Binding ELISA results (Euroimmun) will be reviewed by 
the DSMB for all participants who receive a fractional dose and 
compared with those who received a full dose. They will review all 
cases that do not meet the seroresponse definition (p38-39). The 
DSMB will decide if participants who received a fractional dose will 
be offered a further booster dose.  

 
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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 
GMT 
Geometric mean titres  
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICH  
International Conference on Harmonisation  
IM 
Intramuscular  
MCRI 
Murdoch Children’s Research Institute 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSDS 
Material Safety Data Sheet 
PBMC 
Peripheral blood mononuclear cells 
PDI 
Peter Doherty Research Institute 
PI / CPI 
Principal Investigator / Coordinating or Chief Principal Investigator 
PI 
Product Information (available for an approved drug or device) 
QA 
Quality Assurance 
QC 
Quality Control 
RAT 
Rapid Antigen Test 
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 
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  

 
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INVESTIGATOR AGREEMENT  
 
I have read the protocol entitled “A randomised controlled trial to assess the immunogenicity, safety 
and reactogenicity of standard dose versus fractional doses of COVID-19 vaccines (Pfizer-BioNTech) 
given as an additional dose after priming with Sinopharm, AstraZeneca or Sputnik in healthy adults in 
Mongolia.”. 
 
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 Tsetsegsaikhan Batmunkh 
Co-Principal 
Investigator 
 
 
 
 

 
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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.  
 
Trial Sponsor 
MCRI 
Contact name 
Fran Justice - fran.justice@mcri.edu.au 
Address 
Flemington Road, Parkville 
Sponsor-Investigator  
Prof Kim Mulholland 
 
 
1.3. 
Expected duration of study 
The expected duration of the study is 36 months which includes preparation and reporting.  The 
recruitment period is anticipated to be 2 months and all participants will be followed up for 24 
months. At or following the 12 month visit, participants will be invited to participate in a study 
extension and those who join will be followed until 24 months after their booster dose. 
 
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 
Dr Nadia Mazarakis 
Investigator - Immunology  
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 Lien Anh Ha Do 
Investigator - Virology 
MCRI 
Dr Cattram Nguyen 
Investigator - Statistics 
MCRI 
Dr Eleanor Neal 
Investigator – Data 
Management/Analysis 
MCRI 
Dr John Hart 
Investigator - Medical 
MCRI 
Ms Fran Justice 
Investigator – Mongolia Project 
Manager 
MCRI 
Dr Kerryn Moore 
Investigator - Statistician 
MCRI 

 
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Name 
Summary of contribution 
Affiliation 
Dr Tsetsegsaikhan Batmunkh 
Principal Investigator (Mongolia) 
MoH, Mongolia 
Dr Unursaikhan Surenjav 
Investigator  
Public Health Centre, 
Mongolia 
Dr Khishigjargal Batsukh 
Investigator – Study Physician 
State First Hospital, 
Mongolia 
Dr Batbayar Ochirbat 
Investigator 
MoH, Mongolia 
Dr Bilegtsaikhan Tsolmon 
Investigator 
NCCD, Mongolia 
Dr. Dashpagam Otgonbayar 
Investigator 
NCCD, Mongolia 
Dr Chinbayar Tserendorj 
Investigator 
NCCD, Mongolia 
Dr Azjargal Enkhsaikhan 
Investigator 
MMRA, Mongolia 
Dr Narantuya Namjil 
Laboratory consultant 
Onoshmed Laboratory, 
Mongolia  
Dr Otgonbold Jamyandorj 
Investigator 
City Health Department, 
Mongolia  
Dr Sarantsetseg Jamyan 
Laboratory consultant 
State First Hospital, 
Mongolia 
Dr Tsegmed Sambuu 
Data manager 
Public Health Centre, 
Mongolia 
Dr Gantuya Dorj 
Data manager 
National Medical Science 
University 
Dr Otgonjargal Amraa 
Investigator – Study Physician 
NCCD, Mongolia 
Ms Khaliunaa Mashbaatar 
Investigator - Laboratory 
NCCD, Mongolia 
 
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.  CEPI 
has reviewed this protocol, and they have been involved in the development of the project.  
 
2. INTRODUCTION AND BACKGROUND 
 
2.1. 
Trial rationale and aim 
Additional or booster doses of Covid-19 vaccines are now used in most countries although data remain 
insufficient regarding optimal timing, target groups, duration of protection and safety. Although vaccine 
distribution is now generally sufficient, there remain a number of critical outstanding questions related 
to the use of booster doses. These include optimal timing, particularly after priming with inactivated 
vaccines that provide shorter duration of protection, and the potential use of fractional dosage. We 
have chosen three sites (Australia, Mongolia, and Indonesia) which together will be suitable to answer 
these questions.   
Due to the rapidly developing field much of the data had been presented in various WHO meetings, 
but is currently unpublished (Appendix 1). Currently the most comprehensive published booster study 

 
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is the UK-based multi-site CovBoost study (2). This study demonstrated the use of fractional doses of 
Pfizer vaccine to be very close to equivalent in patients primed with AstraZeneca or Pfizer vaccines. 
The CovBoost study did not include patients primed with inactivated vaccines. 
This protocol covers the component to be studied in Mongolia and will focus on booster regimens 
relevant to Mongolia and not previously studied elsewhere in the world. 
 
2.2. 
Background 
It is clear that all Covid-19 vaccines are not equal. While all the EUL listed products are effective in the 
short term for preventing severe and fatal Covid-19, prevention of mild or asymptomatic infection is 
variable, and the duration of protection seems limited and highly variable. When this study 
commenced, many low- or middle-income countries were unable to access sufficient Covid-19 vaccines 
for their population. However, other countries were already providing booster doses and it was clear 
that more evidence on boosting immunity was required. Our understanding of boosting immunity with 
different vaccines, particularly following priming with the inactivated vaccines, CoronaVac and BBIBP-
CorV, remains unclear. We are proceeding with this project for the following reasons: 
1. Some countries that have achieved high coverage with inactivated vaccines with little impact 
on overall disease rates have begun programs of heterologous (e.g., UAE, Mongolia) or 
homologous (e.g., Chile) boosting, without a strong scientific basis for the schedules chosen. 
Guidance is needed on how to design optimal booster vaccine strategies.  
2. Countries that began vaccination early with support from COVAX have usually started by 
vaccinating front line health workers (e.g., Indonesia).  With minimal vaccination of the general 
population, health workers have been exposed to large numbers of infected patients and 
increasing numbers of Covid-19 illness and death among health care workers have led to 
informal attempts to boost immunity for this group (3). 
3. The use of fractional doses as boosters has been shown to produce similar boosting to standard 
doses for two vaccines (Johnson & Johnson (4) and Moderna (5)), and an unpublished study 
from Thailand (Appendix 1) and data from UK (2) have shown a similar effect with half dose 
Pfizer vaccine.  The use of fractional doses for booster doses and potentially primary series 
could save large volumes of vaccine, potentially freeing up vaccine for communities that 
currently lack access. Updated guidelines in the US and UK recommend the use of half dose 
(50µg) for Moderna booster doses, while follow-up of earlier studies indicate that a 20µg dose 
is likely to be adequate as a booster (6, 7). 
Vaccine breakthrough infections are made more likely due to host immune factors such as waning 
immunity (e.g. due to low neutralising antibodies) as well as 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 is still being defined.  
 
 

 
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2.3. Study follow-up rationale 
The World Health Organization’s Strategic Advisory Group of Experts on Immunization (WHO SAGE) 
revised the roadmap for prioritizing the use of COVID-19 vaccines in March 2023. The new roadmap 
accounted for the Omicron impact and high population-level immunity due to infection and vaccination. 
The roadmap outlined three priority groups for COVID-19 vaccination based on risk of severe disease 
and death. SAGE recommended an additional booster 6-12 months (e.g second or third booster) after 
the last dose for the high priority group (older adults, younger adults with significant comorbidities, 
people with immunocompromising conditions, pregnant women and frontline health workers). SAGE 
did not routinely recommend boosters for the medium or low risk groups. Extending surveillance to 
investigate the immunogenicity of these groups at additional timepoints would provide longitudinal 
data to support the need for boosters in different risk groups, and document breakthrough infections 
and will help to advise the next steps for an appropriate COVID-19 vaccine schedule.   
 
2.4. Risk/Benefit assessment 
2.4.1. Known potential risks   
 
This study will provide safety data of the booster regimens being studied and will collect safety data for 
fractional doses of the booster vaccines.  
 
The safety profiles of the vaccine being tested are well described (see Appendix 2 - Product information 
sheets).  
 
Possible lower efficacy of fractional booster dose 
Participants who receive a fractional dose are at a small risk of not receiving sufficient vaccine to protect 
against COVID-19. 
 
Risks associated with sample taking  
Participants may experience discomfort and/or localised bruising from venepuncture and there is a 
small risk of fainting. The total volume of blood drawn over a 24-month period will be up to 180mls 
which is safe in otherwise healthy adults.  
 
Allergic reactions 
Allergic reactions may occur to any of the constituents of the booster vaccine. These may range from 
mild to severe but are usually rare. Patients should be questioned regarding allergic reactions to any 
vaccines in the past.  All participants will have previously received two 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, a recent study showed similar 
reactogenicity between homologous and heterologous booster schedules. Those who received 
fractional doses may also be expected to have lower reactogenicity. Superior immunogenicity has been 
reported with heterologous boosting schedules. 
 

 
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2.4.2. Assessment of potential risks and benefits  
 
The vaccine being used in this study is a registered product available to the general population for 
booster vaccination. The trial component is to examine administration of fractional doses. The risk of 
fractional doses is the potential for lower effectiveness, while the use of heterologous boosters poses 
the risks of increased reactogenicity and uncertain effectiveness. These factors are balanced against 
the potential benefits of heterologous boosting which include preservation of vaccine through the use 
of fractional doses, and potentially superior immunogenicity, and broader protection. It should be 
noted that the risks and benefits from homologous boosting also remain unclear. 
 
2.4.1. Known potential benefits   
 
Booster doses of Covid-19 vaccines are available to all adults in Mongolia and there may be no direct 
benefits for participants enrolling in this study, apart from the opportunity to learn their antibody 
response following the booster. In addition, the fractional dose booster may be shown to be equally 
effective with less reactogenicity. Participants will receive a heterologous boost which may be shown 
to be superior to a homologous boost. Studies have shown that mRNA boosting potentially offers 
superior immunogenicity for individuals primed with AstraZeneca. 
 
While early reports from Israel and the US confirm the effectiveness of a first booster dose of Covid-19 
vaccine in some heterologous or homologous regimens, there is only limited data on the use of 
fractional dosage in heterologous regimens. This study will provide data crucial to designing optimal 
vaccine strategies in Mongolia and other countries that have used Sinopharm (BBIBP-CorV®), 
AstraZeneca (ChAdOx1-S, or Vaxzevria®) or Sputnik V (Gam-COVID-Vac) as primary two dose regimens. 
 
 
3. TRIAL OBJECTIVES AND OUTCOMES 
3.1 
Objectives 
3.1.1 
Primary objectives 
 
• 
To assess and compare the immune response measured as binding antibodies (IgG ELISA) following 
standard versus fractional doses of Pfizer vaccine given as a single additional dose to adults 18 
years or older in Mongolia who have been primed through previous vaccination with Sinopharm, 
AstraZeneca or Sputnik vaccines. (Timepoint – 28 days post vaccination) 
• 
To assess the rate and severity of reactogenicity within one-week post-booster for each schedule 
evaluated.  
 
3.1.2 
Secondary objectives 
 
The secondary objectives are to:  
• 
To compare the immunogenicity, both humoral and cellular, over 24 months following fractional 
and standard booster doses of the vaccines listed.  
.  

 
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• 
To evaluate the different priming capacities of Sinopharm, AstraZeneca and Sputnik vaccines 
• 
To assess the impact of prior natural exposure on boosting regimens.  
• 
To evaluate the safety of the booster dose regimens  
 
3.2 
Outcomes 
 
3.2.1 Primary outcomes 
Immune response 
Binding antibody – These will be evaluated using the commercial Euroimmun S1 IgG ELISA on all serum 
samples collected at 6 timepoints (baseline, 28 days, 6 months, 12 months, 18 months and 24 months).   
Assays for all subjects will be completed within 4 weeks of sample collection. Assays on the 28 days 
post-vaccination sample, comparing fractional and standard dose, will be reviewed by the DSMB.  
 
Reactogenicity 
Reactogenicity will be measured using the accepted standardised method to evaluate systemic and 
local side effects following vaccination using a structured questionnaire for days post-vaccination as 
outlined in Table 1 below.  
 
Table 1. Grading system for evaluation of systemic and local side effects following vaccination (8).  

 
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Local Reaction to Injectable Product 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 
reliever or 
prevents 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 
reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Warmth (usually 
reported with 
redness) 
Absence   
Presence  
Itch  
Absence   
Presence  
a For all parameters, grade 0 will be recorded 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 

 
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Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
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 h
ours  
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 reliever or 
prevents 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 For all parameters, grade 0 will be recorded if specific symptoms are absent or temperature is <38.0.  
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 at all timepoints will be assayed using the GenScript cPass 
 
 

 
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SARS-CoV-2 Neutralization Antibody detection kit for both the Wuhan strain and Omicron variant 
RBD antigen in Mongolia.  
Neutralizing antibody - A fraction of samples (20%) will be assessed using a SARS-CoV-2 
microneutralisation assay undertaken at the PDI, Melbourne.  Assays will be done at all six 
timepoints to the Wuhan strain (first generation COVID vaccine) and for 2 Variants of Concern. 
Cellular immunity - Cellular immunity will be assessed on a subset of 40% of participants, with 
samples collected at six timepoints: baseline, 28 days, 6 months, 12 months, 18 months and 24 
months post-vaccination as follows:  
• 
QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) will be performed using heparinised whole 
blood 
• 
Peripheral blood mononuclear cells (PBMCs) will also be isolated by density gradient 
centrifugation within 12 hours of collection and stored in liquid nitrogen at MCRI. Assays 
performed will include IFN-γ Elispot, intracellular cytokine assays (flow cytometry) and 
multiplex cytokine assays. 
• 
To assess the impact of prior natural exposure on boosting regimens by comparing antibody 
responses between those who do/don’t report a previous COVID infection.  
 
Safety 
 
4 
TRIAL DESIGN 
4.1 
Overall design  
 
This clinical trial will be a single blind, randomised study to determine the immunogenicity and 
reactogenicity of booster doses of SARS-CoV-2 vaccines in adults. Both fractional and standard doses 
will be tested.  
The groups are described below. The trial intervention will be a single booster dose of vaccine: - 
 
• 
All solicited adverse events (AE) will be collected for 7 days, all unsolicited AE will be collected 
for 28 days, and all medically attended AE will be collected for 3 months. SAE will be collected 
throughout the follow up period of 24 months. 
Primary vaccine 
Booster vaccines 
Sinopharm (BBIBP-CorV®) 
1. Pfizer-BioNTech (BNT162b2, or Comirnaty®) Standard 
dose (30µg) n= 200 
2. Pfizer-BioNTech (BNT162b2, or Comirnaty®) Fractional 
dose (15µg) n= 200 
AstraZeneca (ChAdOx1-S, or 
Vaxzevria®) 
3. Pfizer-BioNTech (BNT162b2, or Comirnaty®) Standard 
dose (30µg) n= 100 
4. Pfizer-BioNTech (BNT162b2, or Comirnaty®) Fractional 
dose (15µg) n= 100 
Sputnik V (Gam-COVID-Vac®) 
5. Pfizer-BioNTech (BNT162b2, or Comirnaty®) Standard 
dose (30µg) n= 100 
6. Pfizer-BioNTech (BNT162b2, or Comirnaty®) Fractional 
dose (15µg) n= 100 

 
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The trial intervention will be given 6 or more months after the primary vaccine schedule. The groups 
size will be either 200 (Sinopharm groups) or 100 (AstraZeneca and Sputnik groups) individuals with an 
even spread of participants above and below 50 years in each group. The Sinopharm vaccinee impact 
is of greater importance to Mongolia as this is the main vaccine used for the primary series in Mongolia. 
In addition, Sinopharm is the least effective of the 3 vaccines used, so we expect to see evidence of 
more breakthrough cases and therefore a wider range of pre-booster immunity levels.  The trial will be 
conducted at multiple sites (health centres, hospital or vaccination clinics) in Ulaanbaatar and provincial 
sites. 
The trial will be single blind. The participants and those evaluating reactogenicity will be blinded to the 
vaccine dose allocation for the first 28 days following vaccination. After that, both the clinical 
investigators and potentially participants will be aware of their investigational product dose allocation. 
Immunologists and laboratory staff will remain blinded to the investigational product dose allocation.  
  
4.2 
Justification for dose  
 
This project is designed to evaluate the potential use of fractional dose and heterologous booster 
regimens for individuals who have previously received two doses of Covid-19 vaccine. The fractional 
dose has advantages for the individual and the broad community. At an individual level, the likelihood 
of moderate adverse reactions is reduced by the use of a fractional dose.  Existing data suggests that 
immunogenicity and effectiveness will be maintained, but this will be evaluated early in the project and 
if immunogenicity proves to be inadequate this will be addressed according to the recommendations 
of the DSMB. At a national and global level, the approach carries the potential to greatly expand the 
availability of Covid-19 vaccine, helping to correct the inequity that currently characterises the global 
Covid-19 situation. 
 
4.3 
Trial population  
The trial population will be adults 18 years and older who have received two doses of Covid-19 vaccines, 
either Sinopharm (BBIBP-CorV®) AstraZeneca (ChAdOx1-S, Vaxzevria®) or Sputnik V (Gam-COVID-Vac®) 
at least 6 months prior. There will be no upper age limit. 
Procedures will be implemented to ensure participants of all ages (aged 18 and above) are included 
and that there is an even age distribution (<50 and ≥50 years) in each group. 
 
4.4 
Eligibility criteria  
If informed consent is granted, study staff will ensure that 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 completed two doses of Sinopharm, AstraZeneca or Sputnik vaccines with the 
recommended schedule at least 6 months prior to the date of enrolment 
2. Willing and able to give written informed consent  
3. Aged 18 years or above 

 
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4. 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. Received 3 doses of COVID-19 vaccine 
2. Received 2 doses of COVID-19 less than 6 months prior to the start of the trial 
3. Currently on immunosuppressive medication or anti-cancer chemotherapy 
4. Known HIV infection 
5. Congenital immune deficiency syndrome 
6. Has received immunoglobulin or other blood products in the 3 months prior to vaccination 
7. Study staff and their relatives 
8. Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical 
exception to receiving further COVID-19 vaccines   
Symptomatic potential participants (cough, sore throat, fever or other symptoms) or those who have 
tested positive (on PCR or RAT) or are waiting for a SARS-CoV-2 test result will not be enrolled. Such 
potential participants will be asked to return once their symptoms have resolved and their SARS-CoV-2 
test is negative if they were tested. 
 
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 minimal 
inclusion/exclusion criteria. 
 
4.7 
Recruitment and identification of potential participants   
 
The study will be offered to attendees at District Health centres and hospitals to those who previously 
attended the clinics for their priming vaccinations. Those interested will be provided with the 
participant information sheet and consent form (PICF) and a member of the research team will be 
available to answer their questions. If recruitment is slow, the study may be promoted by the Ministry 
of Health through their daily media briefings. A record of all potential participants will be recorded on 
a recruitment log.  If the potential participant decides not to participate no identifying information will 
be retained.   
 

 
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4.8 
Consent  
 
Informed consent is a process that is initiated prior to the agreement to participate in the trial and 
continues throughout study participation. Discussion of risks and possible benefits of this vaccination 
will be provided to the potential participants prior to obtaining informed consent. 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 then explain the 
research study further and answer any questions that may arise.  
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 for the trial 
and the trial processes. 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.  
Following or at the 12 month visit, participants will be invited to participate in an extension study with 
follow-up visits at 18 months and 24 months. They will be asked to sign a new consent form for the 
extension. 
 
5 
INTERVENTION   
5.1 
Treatment arms  
Treatment Arms 
Route 
Dose    
1) Pfizer-BioNTech (BNT162b2, or Comirnaty®)  IM 
Standard Dose - (30µg) 
2) Pfizer-BioNTech (BNT162b2, or Comirnaty®)  IM 
Fractional Dose - (15µg) 
 
5.2 
Trial Intervention(s) 
 
Pfizer BioNTech (BNT162b2) BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified mRNA 
vaccine that encodes trimerised SARS-CoV-2 spike glycoprotein. BNT162b2 encodes the SARS-CoV-2 
full-length spike, modified by two proline mutations to lock it in the prefusion conformation and more 
closely mimic the intact virus with which the elicited virus-neutralizing antibodies must interact. mRNA 
vaccines use the pathogen’s genetic code as the vaccine; this then exploits the host cells to translate 
the code and then make the target spike protein. The protein then acts as an intracellular antigen to 
stimulate the immune response. The mRNA is then degraded within days. The vaccine RNA is 
formulated in lipid nanoparticles (LNPs) for more efficient delivery into cells after intramuscular 
injection.  
5.2.1 
Description of trial investigational products  
 
5.2.1.1 Trial Products 
  
Active substance 
The Pfizer-BioNTech COVID-19 vaccine, BNT162b2, encodes 
a P2 mutant spike protein and is formulated as an RNA-lipid 
nanoparticle (LNP) of nucleoside-modified mRNA (modRNA). 

 
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Trade or Generic name 
Pfizer-BioNTech (BNT162b2, or Comirnaty®) 
Dosage form 
Liquid for injection – standard dose is 0.3ml containing 30µg; 
fractional dose is 0.15ml containing 15ug.  
Route of administration 
Intramuscular injection 
 
5.2.2 
Dosage  
 
The standard dose of Pfizer BioNTech COVID-19 vaccine is 30µg contained in 0.3ml of the diluted 
vaccine and is currently the standard dose that is used for a booster. A half dose is 15 µg contained in 
0.15ml of the diluted vaccine. Each pack of the Pfizer BioNTech vaccine contains 195 vials with 5 
standard doses per vial (975 doses per pack). It is supplied with 0.9% sodium chloride diluent for 
injection plastic ampoules.  
 
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 at the central vaccine storage building at the National Center for 
Communicable Diseases (NCCD) and will be stored in accordance with the manufacturers’ 
recommendations. See below: 
• 
The Pfizer BioNTech vaccine should be stored at -70°C +/- 10°C and has shelf life of 6 months. 
Once thawed, the vaccine may be stored for 31 days at 2-8°C. 
Vaccine accountability, storage, shipment, and handling will be in accordance with relevant SOPs and 
forms. 
5.2.5 
Product accountability  
 
The trial vaccines will be provided by the Ministry of Health at District Health centres and hospitals.  
Study nurses will collect supplies each day and return any unused vaccines at the end of the day.  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 kept 
blinded during the first week post-vaccination. 
The unblinded vaccinators 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. Any discrepancies will be investigated, resolved, 
and documented by the trial team. Unused trial vaccines will be destroyed in compliance with 
applicable regulations. 
 
Detailed information regarding product accountability will be provided in an SOP. 
 

 
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5.2.6 
Excluded medications and treatments 
 
There are no excluded medications or treatments apart from those associated with exclusions listed in 
section 4.4.2.   
 
5.2.7 
Concomitant therapy  
 
Concomitant medications taken by participants during the study will be documented, as outlined 
below, as part of the safety review procedures.  
From the study start until 24 months, only the following medications of interest will be recorded:  
• Any vaccine.  
• Any investigational products.  
• Immunosuppressive therapies. 
• Therapies taken for suspected or confirmed COVID-19 
Concomitant medications records will include the drug name, total daily dose, route of 
administration, start and stop date of administration, and indication for use. 
  
5.2.8 
Discontinuation from trial intervention 
 
See Section 7.2.8.  
 
6 
RANDOMISATION AND BLINDING  
 
Once consent has been obtained, and following eligibility assessment, eligible participants will be 
recruited and randomised. Participants will be randomised 1:1 to one of the 2 intervention groups 
(Comirnaty® standard dose, Comirnaty® fractional dose) stratified by the primary vaccine received 
(BBIBP-CorV®, Comirnaty® or Gam-COVID-Vac®) and age (<50 and ≥50 years).  A secure, password-
protected web-based randomisation schedule will be provided by an independent statistician from the 
Melbourne Children’s Trial Centre at the Murdoch Children’s Research Institute.  Blocked 
randomisation will be used with random blocks of permuted length. To ensure there are even numbers 
by primary vaccine and age group, participants will be recruited until the number required in each 
stratum has been reached.   
40% of participants from each group will be included in the CMI subgroup analysis. The strata that will 
be used for CMI analysis will be identified at this time, and measures will be taken to ensure that the 
age strata (<50 and ≥50 years) are equally represented in this group with a separate randomisation list. 
Only 10-20 CMI samples can be processed per day. We will therefore recruit the first 10-20 participants 
to participate in this sub study per day. Daily recruitment for the sub study will be stopped once the 
maximum number is reached. 
 
6.1 
Concealment mechanism 
 

 
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Randomisation will be stratified according to age (<50 and ≥50 years) and primary vaccine (BBIBP-CorV® 
or Comirnaty®). Using REDCap the participants will be randomised to one of two groups in a 1:1 dose 
allocation ratio. (see table below).  
 
Primary vaccines 
Age  
Booster vaccine  
Dose given 
Sinopharm,  
AstraZeneca, or 
Sputnik V  
<50 
 
Pfizer-BioNTech 
30µg 
Pfizer-BioNTech 
15µg 
>=50 
 
Pfizer-BioNTech 
30µg 
Pfizer-BioNTech 
15µg 
 
Study staff (unblinded vaccinator) involved in administering the vaccine will use REDCap to receive the 
information on the participant’s randomisation number and vaccine dose so they will be aware of which 
vaccine the participant is receiving. The participants themselves will remain blinded to their vaccine 
dose (until day 28 post vaccination). Study staff involved in assessing reactogenicity will be blinded to 
each participant’s vaccine dose until 28 days post vaccination, as this variable will be hidden in REDCap 
for blinded study staff. Study staff involved in assessing immunogenicity outcomes will remain blinded 
during the analysis of specimens.  
Vaccines will be prepared out of sight of the participant and the blind will be maintained by applying 
masking tape over the vaccine syringe, so the study participant can’t see the volume. 
Only the study nurse (unblinded vaccinator) administering the vaccine will be aware of which vaccine 
is given to the study participant.   
 
6.2 
Breaking of the trial blind 
6.2.1 
On trial 
 
The study will be blinded for the first 28 days only.  In the unlikely event that it becomes necessary to 
unblind during this period that decision will be taken by the PI, and the subject and physicians who may 
be caring for the subject will be made aware of the dose allocation. 
 
7 
TRIAL VISITS AND PROCEDURES  
7.1 
Schedule of assessments 
 
 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Visit 7 
 
 
Visit 8 
 
 
Visit 9 
 
Location 
At 
health 
centre 
Phone 
call 
Phone 
call 
At 
health 
centre 
Phone 
call 
At 
health 
centre 
At 
health 
centre 
At health 
centre 
At health 
centre 
Timing 
Day 0 
Day 1 
Day 7 
Day 28 
3 
months 
6 
months 
12 
months 
18 
months 
24 
months 
Visit 
window 
 
 
+ 3 
days 
+ 7 
days 
+/- 
14 days 
+/- 
14 days 
+/- 
30 days 
+/- 
30 days 
+/- 
30 days 

 
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Informed 
consent 
X 
 
 
 
 
 
 
 
 
Eligibility 
confirmatio
n 
X 
 
 
 
 
 
 
 
 
Randomisat
ion 
X 
 
 
 
 
 
 
 
 
Blood 
sampling 
X 
 
 
X 
 
X 
X 
X 
X 
Vaccination 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
 
 
Issue diary 
card, ruler 
and 
thermomet
er 
X 
 
 
 
 
 
 
 
 
Collect 
diary card 
X 
(daily) 
 
 
 
 
 
 
 
 
Documenta
tion of 
Solicited AE 
X 
X 
X 
 
 
 
 
 
 
Documenta
tion of 
unsolicited 
AE 
X 
X 
X 
X 
 
 
 
 
 
Documenta
tion of 
medically 
attended 
AE 
X 
X 
X 
X 
X 
 
 
 
 
Documenta
tion of SAE 
Throughout study period 
 
 
 
Documenta
tion of 
confirmed 
breakthrou
gh COVID-
19 
infection 
Throughout study period 
 
 
 
 

 
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7.2 
Description of procedures 
                  7.2.1 Visit 1 (Day 0) 
Informed consent must be signed by both participant and study doctor or nurse.  
Participant eligibility must be confirmed prior to randomisation and on the same date as administration 
of the investigational product.  
 
Eligibility must be confirmed by a study doctor or study nurse. Randomisation must be completed by 
the unblinded vaccinator who will document the participant’s randomisation number on the enrolment 
log. 
 
Study staff will administer a Visit 1 questionnaire documenting demographic information, height and 
weight, dates and type of primary COVID-19 vaccine, prior confirmed SARs-Cov-2 infection(s) 
documented in medical records, any comorbidities and concomitant medication. 
 
The following vital signs will be recorded by a study doctor or study nurse prior to vaccination: 
temperature, pulse rate, respiratory rate, and blood pressure. 
Prior to vaccination, for all participants, 5mL of blood will be collected 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 provide the participant with a hard copy reactogenicity diary card or email them a 
REDCap survey form. Study staff will instruct the participant on how to complete 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 day 28 visit so that the information can be entered in the REDCap 
database.  
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. 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 keep the participant under observation for minimum 15 minutes and document any 
immediate adverse events. 
 
7.2.1 
Visit 2 (Day 1) 
Study staff will contact the participant by phone approximately 24 hours after vaccination to review 
and document adverse events. 
 
7.2.2 
Visit 3 (Day 7) 
Study staff will contact the participant by phone one week after vaccination. If participants have a hard 
copy 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 completed the REDCap 

 
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diary card, study staff will review it with them to confirm that all symptoms are captured. Study staff 
will also document any significant, unexpected, serious or unusual adverse events on the AE CRF. 
 
7.2.3 
Visit 4 (Day 28) 
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 also document any new information regarding solicited adverse events 
with onset up to 7 days following vaccination, such as resolution.  The participant will be informed 
which vaccine dosage they received based on entry into the CRF by the unblinded staff member. 
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for 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. SST tubes should be kept cold (around 4 degrees) if not 
transferred within 3 hours. 
 
7.2.4 
Visit 5 (3 Months) 
Study staff will contact the participant by phone and document information on 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.  
 
7.2.5 
Visit 6 (6 Months) 
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for 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. SST tubes should be kept cold (around 4 degrees) if not 
transferred within 3 hours. An SMS will be sent to participants monthly between Visit 6 and Visit 7 to 
check for any breakthrough infections and AE/SAEs. 
 
7.2.6 
Visit 7 (12 Months) 
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for 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. SST tubes should be kept cold (around 4 degrees) if not 
transferred within 3 hours. Participants will be invited to participate for a further 12 months and will be 
re-consented for Visit 8 and 9. (For those participants who have already attended their 12 month visit, 
a phone call will be made and consent signed at Visit 8). All participants will receive a gift card for 50.000 
Mongolian Tugrik (~14 USD) at 12 months as some visits will be completed at time of extension. An SMS 
will be sent to participants monthly between Visit 7 and Visit 8 to check for any breakthrough infections 
and SAEs. 
 

 
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7.2.7 
Visit 8 (18 Months) 
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for 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. SST tubes should be kept cold (around 4 
degrees) if not transferred within 3 hours. An SMS will be sent to participants monthly between Visit 8 
and Visit 9 to check for any breakthrough infections and SAEs. Participants will be asked if they have 
received another covid vaccine since their last visit. 
7.2.8 
Visit 9 (24 Months) 
For all participants, 5mL of blood will be collected in an SST tube. For participants in the CMI subset, 
5mL of blood for 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. SST tubes should be kept cold (around 4 
degrees) if not transferred within 3 hours. 
Participants who complete the 24-month study period will receive a gift card for 50.000 Mongolian 
Tugrik (~14 USD). If they request, results of their tests will be shared and discussed with them by a 
member of the study team at any visit if available. Participants will be asked if they have received 
another Covid-19 vaccine since their last visit.  
7.2.9 
Unscheduled visits 
If any participant develops symptoms of Covid-19 or tests positive on a rapid antigen test (RAT), they 
will be instructed to contact the Study Team and to get a PCR test at the nearest facility.  If the test 
(RAT or PCR) is positive the Study Team will seek to obtain a specimen for virology, either residual 
from the specimen that tested positive, or an additional swab once the positive result is known. One 
month after the positive test a 5ml blood sample will be collected and serum stored for future 
serological analysis if the participant consents. Participants will be reimbursed for unscheduled visits. 
The participant will otherwise continue with scheduled study visits. The virology sample will be tested 
at the National Centre for Communicable Diseases in Mongolia. If there are a large number of 
breakthrough infections, all severe cases and a proportion of mild cases will be prioritised for 
sequencing.   The study team will maintain telephone contact daily with the participant for the course 
of his/her illness and fully document all telephone calls. With the subject’s permission the Team will 
seek clinical data from the health care providers or hospital in the event that the subject becomes 
clinically ill.  If breakthrough infections are not being captured using RAT or PCR testing, an additional 
detection method to measure IgG antibodies specific for SARS-CoV-2 nucleocapsid (N) protein in 
serum (in-house ELISA) may be used to identify if an infection has occurred.  Any confirmed 
breakthrough infections will be documented until the end of the study (Visit 9- 24 months). 
 
7.2.10 
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 

 
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interests of the participants’ 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 CRF. 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.  
 
7.2.11 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.   
• 
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 sent.  All contact attempts will be 
documented in the participants CRF 
• 
If the participant continues to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of lost to follow-up. 
 
7.2.12 Replacements 
Participants who have been randomised and enrolled may NOT be replaced. 
 
7.2.13 Trial Closure 
The end of the trial is the date of the last assay 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  
 

 
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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 either 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 prolongation of 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 may 
require intervention to prevent one of the other outcomes listed in this definition should also be 
considered serious.  
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 continued ethical acceptability or conduct of the trial.  
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 the monitoring of safety and/or the administration of the investigational medicinal 
product.   
Urgent Safety Measure (USM): A measure required to be taken in order to eliminate an immediate 
hazard to a participant’s health or safety. Note: This is a type of SSI that 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 

 
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observed by the Investigator or reported by the participant, whether or not attributed to study 
medication, will also be recorded in participant diary and CRF.   
Serious adverse events (SAE’s) will be followed up for the duration of the trial.  Adverse events of special 
interest will be categorised as per CEPI guidelines (1).  
 
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 CRF and will include:  
• 
A description of the AE  
• 
The onset date, duration, date of resolution  
• 
Severity (mild, moderate, or severe– what is the impact on the participant’s daily life?)  
• 
Seriousness (i.e., is it an SAE?)  
• 
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 and 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 severity of a participant’s AE 
The severity of an Adverse Events will be graded/ assessed as follows: 
Grade 0 
None 

 
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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 
 
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 Medicine and 
Medical Devices Regulatory Agency of Mongolia 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 
Medicine and Medical Devices Regulatory Agency of Mongolia: 
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 of 
becoming aware of the issue. 
b. Submit amendment to the HREC without undue delay. 
4. For SSIs leading to temporary halt or early termination of a trial for safety reasons: 
a. Communicate reasons, scope of halt, measures taken, further actions planned without 
undue delay and no later than 15 calendar days of 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 also report SUSARs to the Medicine and Medical Devices Regulatory Agency of 
Mongolia 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 of 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 any updated Product Information/Investigator’s Brochure 
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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 the Mongolian study team 
must be traceable 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, that 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, primary COVID vaccine (Sinopharm (BBIBP-CorV®), AstraZeneca (ChAdOx1-S, or 
Vaxzevria®) or Sputnik V (Gam-COVID-Vac®)); intervention vaccine (Pfizer-BioNTech 
(NT162b2, or Comirnaty®) 

 
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• 
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 
• 
Biological information (blood sample, immunologic assay results, including binding 
antibodies, functional antibodies, neutralizing antibodies, cellular immunity) 
 
Source Document Plan 
The source documents for this study include: COVID-19 vaccination details, date of birth, and sex); 
questionnaires completed by the participant and researcher (Mongolian study team’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 recruitment of the first participant and filed 
in the site’s Investigator Site File. 
 
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. (10, 11) 
• 
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 

 
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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 members of the research team. 
 
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, 
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 
commencing 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 held in strict 
confidence. 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 and genetic tests in addition to the clinical 
information relating to participating participants.  
 
To preserve confidentiality and reduce the risk of identification during 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 participant study number assigned to the study participant (“re-

 
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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 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 
analysis of content. 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) 
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 to 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 will be required to 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 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 any relevant issues. 
The statistician will be provided with anonymised data, with participants identifiable only by unique 
participant study number/code. The statistician will analyse the de-identified data. 

 
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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 (fifteen) 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 (fifteen) years, The Principal Investigator will take measures to ensure 
secure destruction of hardcopies 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, stored on the secure server. 
 
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 
a representative from the Immunology team. The group will closely review all aspects of the conduct 
and progress of the trial, ensuring that there is 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 is 
conducted to the required standards. The TSC will meet at least annually, with more frequent meetings 
as needed, and will work to a Terms of Reference.   
 

 
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10.1.3 Safety Monitoring  
Monitoring will be performed according to Good Clinical Practice (GCP) guidelines by monitors. 
Following written SOPs, the monitors will verify that the clinical trial is conducted, and 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 the purpose of monitoring.  
 
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 then again on at least 2 
occasions to review the one-month immunogenicity data for the standard and fractional-dose 
recipients, and to review the 6 months data. The DSMB will decide whether a fourth dose is required, 
based on up-to-date safety data, for participants who received a fractional dose and did not mount an 
adequate antibody response. 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 contain one statistician, one adult physician and 
representatives from Indonesia and Mongolia. 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 in detail 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 the MCRI trial manager in conjunction with a Mongolian 
study monitor who will be trained and mentored in their role by the trial manager.  The monitoring will 
take place on-site.  The monitors will review 100% of original signed consent forms, trial eligibility data 
and data related to primary outcome, safety and other key data variables; review of all withdrawals 
from trial; 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 the purpose of 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 
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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 also implement quality control (QC) procedures, which will include the data 
entry system and data 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 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.     
 
11 STATISTICAL METHODS  
11.1 
Sample Size Estimation 
 
Sample size calculations were performed using nQuery 8 software. Sample sizes per group will vary 
between 100 (for the AstraZeneca and Sputnik-primed groups) and 200 (for the Sinopharm-primed 
groups). The Sinopharm vaccinee impact is of greater importance to Mongolia as this is the main 
vaccine used for the primary series in Mongolia. In addition, Sinopharm is the least effective of the 3 
vaccines used, so we expect to see evidence of more breakthrough cases and therefore a wider range 
of pre-booster immunity levels.  Precision-based sample size calculations were performed based on 
the reactogenicity outcomes. Assuming the percentage of participants reporting local or systemic 
reactions is 50%, a sample size of 200 participants will produce a 95% confidence interval that 
extends 6.9 percentage points from the observed percentage. With a sample size of 100, the 95% 
confidence interval will extend 9.8 percentage points from the observed percentage. For 
immunogenicity, sample size calculations were based on the comparison of seroresponse rates 
between the standard and fractional dose groups within the non-inferiority framework. Assuming a -
10% non-inferiority margin and a seroresponse rate of 95% in both arms, the study will have >99% 
power for the non-inferiority comparison using 200 participants per group. Under the same 
assumptions, the study will have 90% power with 100 participants per group for the non-inferiority 
comparisons.  
 
11.2 
Population to be analysed  
Analysis of this trial is planned on both the intention-to-treat population (ITT), with all participants to 
be analysed in the group they were randomised to, as well as on the per-protocol (PP) population, 
consisting of participants who adhered to the study protocol. However, it is expected that withdrawn 
participants may not have data to contribute at all time points as blood samples may not be collected 
after the time of their withdrawal. 
 

 
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11.3 
Methods of analysis  
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 immunogenicity, antibody levels will be presented as geometric mean titres (GMT) with 95% 
confidence intervals. Changes from baseline will be expressed as geometric mean fold ratios (GMFR), 
calculated as the ratio of the post-booster GMT to the baseline GMT. Seroresponse will be defined as 
a 4-fold rise in post-booster antibody levels compared to baseline (or >2-fold rise if the baseline (pre-
booster) antibody level was >=200 BAU/ml). To assess the non-inferiority of the fractional dose 
compared with the standard dose, comparisons will be based on the difference in percentage of 
participants with seroresponse. Using a non-inferiority margin of -10% (fractional-dose minus standard 
dose), non-inferiority will be declared if the lower limit of the 95% confidence interval around the 
difference in percentages is greater than -10%, where confidence intervals are calculated using Score-
based methods (12). 
Analyses will be performed using Stata software (13). Detailed methodology will be outlined in a 
separate Statistical Analysis Plan. 
We will also do a sub-analysis to explore the difference between participants who have/haven’t had 
previous natural infection.  
 
Primary outcome (All samples at all timepoints) 
 
The binding IgG data using the Euroimmun S1 IgG ELISA kits will be reported as relative units/ml (RU/ml) 
as per 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 is 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 titres and 95% confidence intervals.  
 
Analysis comparing fractional and standard dose groups will be based on seroresponse rate (SRR) at 28 
days post study vaccine, defined as: 
• ≥4-fold rise in GMTs at 28 days post study vaccine from baseline among subjects with no pre-dose 
detectable titres  
• ≥2-fold rise in GMTs at 28 days post study vaccine among subjects with detectable titers of >200 
BAU/ml  pre-booster  
 
Secondary outcomes 
 
Functional antibody (all samples at all timepoints) – for the C-PASS assay (sVNT), data is 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.  

 
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Neutralizing assay (20% subset of samples at all timepoints) – Data will be reported as endpoint titre 
calculated using the Reed/Muench method (14). A titre of 10 reflects undetectable neutralizing activity.  
 
Cellular immunity: (on a 40% subset at six timepoints – baseline, 1 month, 6 months, 12 months, 18 
months and 24 months) 
Quantiferon COVID IFNγ release assay – Levels of IFNγ will be reported in IU/ml according to 
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 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 presented as GMC and 95% 
confidence intervals. 
 
11.4 
Interim Analyses  
We will conduct an interim analysis of the antibody responses from the 28 days visits to ensure that the 
responses in the fractional dose groups are adequate. This will be assessed on both individual and group 
levels by the DSMB. If fractional dose responses are considered inadequate an appropriate rescue 
strategy will be developed, probably involving a single dose of the vaccine in question at 3 months or 
as soon as the DSMB has reviewed and made a decision on the results.  If the fractional dose is 
considered inadequate this information will be made public and shared specifically with WHO and other 
groups working in the field.  In addition, an analysis will be undertaken once all data are collected for 
the 6 months analysis to review the potential need for policy changes. All such analyses will be 
undertaken by the trial statistician in Melbourne. 
 
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 committees (HREC) in Ulaanbaatar and Melbourne before the 
research. Letters of protocol approval by HREC will be obtained before the commencement of the trial 
and approval for other trial documents requiring HREC review. 
 
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 

 
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consent form. All such amendments will be submitted to the HREC for approval before being 
implemented. 
 
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 to report to the Sponsor-Investigator within 72 hours 
and to the Site RGO within seven days; Sponsor-Investigator to review and submit to the approving 
HREC within seven days).  
Where non-compliance significantly affects human participant protection or reliability of results, a root 
cause analysis will be undertaken, and a corrective and preventative action plan 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, and 
the sponsoring institution and their agents. This confidentiality is extended to cover the testing of 
biological samples and genetic tests in addition to the clinical information relating to participating 
participants.  
The trial protocol, documentation, data, and all other information generated will be held in strict 
confidence. 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. 
 
14 PARTICIPANT REIMBURSEMENT  
Study participants will be compensated for their time, the inconvenience of having blood tests and 
procedures, and their travel expenses at each in-person visit. At the final visit (12 month or 24 month) 
the participant will be given a gift card for 50.000 Mongolian Tugrik (~14 USD).  
 
15 FINANCIAL DISCLOSURE AND CONFLICTS OF INTEREST 
No conflict of interests. 
 
16 DISSEMINATION AND TRANSLATION PLAN 
Information generated by the trial will be shared at 3 levels.  Participants will be given access to their 
personal antibody levels and to the analysed data at each of the time points once it becomes available.  

 
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The former will be on special request only, while the latter will be provided by group email as the 
analysed antibody data becomes available. 
 
Interim analysis will be prepared from reactogenicity and 28-day immunogenicity data. These analyses 
will be presented to CEPI and WHO and shared with the authorities in Mongolia as soon as available.  
This will represent the first publication. 
 
At the completion of the study 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.  
 
 

 
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18 REFERENCES 
 
 
 
 
 
1. 
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/. 
2. 
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. 
3. 
Indonesia reports record number of doctor deaths from COVID-19 in July  [Available from: 
https://www.reuters.com/business/healthcare-pharmaceuticals/indonesia-reports-record-number-
doctor-deaths-covid-19-july-2021-07-18/. 
4. 
Sadoff J, Le Gars M, Cardenas V, Shukarev G, Vaissiere N, Heerwegh D, et al. Durability of 
antibody responses elicited by a single dose of Ad26.COV2.S and substantial increase following late 
boosting. medRxiv. 2021:2021.08.25.21262569. 
5. 
Chu L, McPhee R, Huang W, Bennett H, Pajon R, Nestorova B, et al. A preliminary report of a 
randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 
vaccine. Vaccine. 2021;39(20):2791-9. 
6. 
Dolgin E. Quarter-dose of Moderna COVID vaccine still rouses a big immune response 2021 
[Available from: https://www.nature.com/articles/d41586-021-01893-0. 
7. 
US Food and Drug Administration (FDA). Moderna COVID-19 Vaccine 2021 [Available from: 
https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-
19/moderna-covid-19-vaccine#additional. 
8. 
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. 
9. 
Australian Technical Advisory Group on Immunisation (ATAGI). ATAGI recommendations on the 
use 
of 
a 
booster 
dose 
of 
COVID-19 
vaccine 
2021 
[Available 
from: 
https://www.health.gov.au/resources/publications/atagi-recommendations-on-the-use-of-a-booster-
dose-of-covid-19-vaccine. 
10. 
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. 
11. 
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. 
12. 
Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Stat Med. 1998;17(8):873-90. 
13. 
StataCorp. Stata Statistical Software: Release 17. . College Station, TX: StataCorp LLC.; 2021. 
14. 
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. 

 
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19 APPENDICES 
APPENDIX 1 – Pfizer half dose booster data from Thailand, courtesy of Dr Kulkanya Chokephaibulkit, 
MD, Professor of Pediatrics, Director, Siriraj Institute of Clinical Research (SICRES), Faculty of Medicine 
Siriraj Hospital, Mahidol University, Bangkok, Thailand. 
 
 
 
The Preliminary Report: Safety and Immunological Response of Heterologous Booster 
COVID-19 Vaccination following the Primary Series of CoronaVac and ChAdOx1 (3 rd Dose Booster)
-Among subjects who 
received 2-dose 
CoronaVac (inacƟvated 
vaccine), a boosƟng 
with ChAdOx1 or 
BNT162b2 provided 
high GM levels
-Among subjects who 
received 2-dose 
ChAdOx1, a boosƟng 
with BNT162b2 
provided high GM 
levels
-Half dose of BNT162b2 
induced high Ɵters not 
diﬀerent from full dose
InacƟvated vaccine 
or homologous 
plaƞorm is not an 
eﬀecƟve booster

 
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APPENDIX 2 – Product information sheets 
 
Product information 
sheet - Pfizer.pdf