A Phase 1 Monotherapy Study to Evaluate the Safety, Tolerability & Immunogenicity of Vaccination With Candidate Chimpanzee Adenovirus-vectored HepB Virus Vaccine ChAdOx1 HBV in Healthy Participants & Participants With Chronic HepB Infection
Phase: PHASE1
Conditions: Hepatitis B, Healthy
Sponsor: Barinthus Biotherapeutics

Cover page containing NCT Number for the purpose of ClinicalTrials.gov 
CLINICAL STUDY PROTOCOL 
 
A Phase 1 Monotherapy Study to Evaluate the Safety 
Tolerability and Immunogenicity of Vaccination with 
Candidate Chimpanzee Adenovirus-vectored Hepatitis B 
Virus Vaccine (ChAdOx1-HBV) in Healthy Participants 
and Participants with Chronic Hepatitis B infection  
Study Code: HBV001  
 
EudraCT Number: 2019-003420-20 
 
 
Version: 9.0 
24 Nov 2021 
 
 

 
                                                 CONFIDENTIAL
CLINICAL STUDY PROTOCOL 
A Phase 1 Monotherapy Study to Evaluate the Safety 
Tolerability and Immunogenicity of Vaccination with 
Candidate Chimpanzee Adenovirus-vectored Hepatitis B 
Virus Vaccine (ChAdOx1-HBV) in Healthy Participants 
and Participants with Chronic Hepatitis B infection
Study Code: HBV001
EudraCT Number: 2019-003420-20
Version: 9.0
24 Nov 2021
Sponsor's Authorised Representative:
 
Chief Scientific Officer
Signature
Date
Printed Name 
Information in this protocol is confidential and should not be disclosed, other than to those 
directly involved in the execution or the ethical/regulatory review of the study, without written 
authorisation from 
29-NOV-2021

 
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ADMINISTRATIVE AND CONTACT INFORMATION 
 
Sponsor Medical Oversight 
 
 
 
 
 
 
 
Local Medical Monitor 
 
 
 
 
 
 
 
 
Chief Investigator 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 

 
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Principal Investigator 
 
  
 
  
 
 
 
  
 
 
Immunogenicity Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Manufacturing Facility 
 
 
 
 
 
 
 
Study Vaccine Packaging, 
Labelling & Distribution Centre 
 
 
 
 
 
 
 

 
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Central Laboratory 
(for pgRNA and HBcAg analysis) 
 
 
 
 
 
 
 
Statistics and Data Management 
 
 
 
 
 
 
 
 

 
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INVESTIGATOR AGREEMENT 
I, the undersigned, agree to conduct this study in accordance with this protocol, International 
Council on Harmonisation Good Clinical Practice (ICH GCP), the ethical principles set forth 
in the Declaration of Helsinki, and with local regulatory requirements.   
 
Signature 
 
 
 
 
 
 
Date 
 
 
Printed Name  
 
 
 
 

 
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TABLE OF CONTENTS 
ADMINISTRATIVE AND CONTACT INFORMATION ............................................................................. 2 
INVESTIGATOR AGREEMENT .................................................................................................................. 5 
TABLE OF CONTENTS ................................................................................................................................ 6 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES ......................................................................................................................................... 9 
PROTOCOL AMENDMENT CHANGE HISTORY.................................................................................... 10 
PROTOCOL SYNOPSIS .............................................................................................................................. 16 
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................................... 23 
1 
BACKGROUND ................................................................................................................................ 25 
1.1 
Disease Review ....................................................................................................................... 25 
1.2 
Treatment Review ................................................................................................................... 25 
1.3 
Summary of Non-clinical Studies ........................................................................................... 26 
1.4 
Summary of Clinical Experience ............................................................................................ 27 
1.5 
Study Rationale ....................................................................................................................... 27 
1.5.1 Rationale for Investigation of Dosing Interval With Respect to COVID-19 
Vaccines ....................................................................................................................... 28 
2 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................................... 30 
3 
STUDY OVERVIEW ........................................................................................................................ 31 
3.1 
Overall Study Design and Methodology ................................................................................. 31 
3.1.1 Study Design ................................................................................................................ 31 
3.1.2 Study Methodology ...................................................................................................... 32 
3.1.3 Study Stopping Criteria/Holding Criteria/Dose Escalation Process ............................ 33 
3.1.4 Duration of Study......................................................................................................... 34 
 
Duration for Each Participant ..................................................................... 34 
 
Duration of Study ........................................................................................ 34 
3.2 
Discussion of Study Design .................................................................................................... 34 
3.3 
Benefit Risk Assessment ......................................................................................................... 35 
4 
STUDY POPULATION ..................................................................................................................... 36 
4.1 
Number of Participants ........................................................................................................... 36 
4.2 
Inclusion Criteria ..................................................................................................................... 36 
4.3 
Exclusion Criteria ................................................................................................................... 37 
4.3.1 Removal of Participants from Vaccination or Assessment .......................................... 39 
 
Contraindications to Vaccination ................................................................ 39 
 
Study Discontinuation ................................................................................. 39 
4.3.2 Study Termination ....................................................................................................... 39 
5 
STUDY VACCINE ............................................................................................................................ 41 
5.1 
Study Vaccines Administered ................................................................................................. 41 
5.2 
Identity of Study Vaccine ........................................................................................................ 41 
5.3 
Labelling, Packaging and Shipping ......................................................................................... 42 
5.4 
Storage .................................................................................................................................... 42 
5.5 
Accountability ......................................................................................................................... 42 
5.6 
Destruction or Disposal ........................................................................................................... 42 
5.7 
Method of Assigning Participants to Treatment Groups ......................................................... 43 
5.8 
Selection of Doses, Dosing Schedule and Administration ...................................................... 43 
5.8.1 Selection of Doses in the Study ................................................................................... 43 
5.8.2 Selection and Timing of Dose for each Participant ...................................................... 43 

 
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Dosing Schedule ......................................................................................... 43 
 
Study Vaccine Preparation and Administration .......................................... 44 
 
Dose and Schedule Modifications ............................................................... 44 
5.9 
Prior and Concomitant Vaccines and Medications ................................................................. 44 
5.10 
Treatment Compliance ............................................................................................................ 44 
5.11 
Post-study Vaccine .................................................................................................................. 45 
6 
STUDY PROCEDURES AT EACH VISIT/SCHEDULE OF ASSESSMENTS .............................. 46 
6.1 
Screening and Baseline Pre-Dose Assessments ...................................................................... 49 
6.2 
Treatment Day Assessments (Day 0) ...................................................................................... 49 
6.3 
Follow-up Period Assessments ............................................................................................... 50 
6.3.1 Telephone Call: Day 1 ................................................................................................. 50 
6.3.2 Clinic Visit: 7 ............................................................................................................... 50 
6.3.3 Clinic Visit: Day 14 ..................................................................................................... 50 
6.3.4 Clinic Visit: Days 28, 56 (Cohorts 1-4) and 168 (End of Study Visit Cohorts 1-4)
 ..................................................................................................................................... 51 
6.3.5 Clinic Visit: Day 84 (including End of Study Visit Cohorts 5 and 6) .......................... 51 
6.4 
Assessments at Unscheduled Visits ........................................................................................ 51 
6.5 
Participant Discontinuation ..................................................................................................... 51 
7 
DETAIL OF STUDY ASSESSMENTS ............................................................................................ 52 
7.1 
Demographic and Baseline Assessments ................................................................................ 52 
7.1.1 Demographic Data and Baseline Variables.................................................................. 52 
7.1.2 Medical and Disease History ....................................................................................... 52 
7.1.3 Prior Medications and Therapies ................................................................................. 52 
7.1.4 Laboratory Eligibility Tests ......................................................................................... 52 
 
Haematology ............................................................................................... 52 
 
Biochemistry and Liver Function Tests ...................................................... 52 
 
HIV, HBV, HCV and HDV Diagnostic Testing ......................................... 53 
 
Urinalysis .................................................................................................... 53 
7.1.5 Urine Pregnancy Test ................................................................................................... 53 
7.2 
Immunogenicity Assessments ................................................................................................. 53 
7.2.1 Secondary Outcomes in Blood Samples ...................................................................... 53 
7.2.2 Exploratory Analysis ................................................................................................... 54 
 
Exploratory Analysis in Blood Samples ..................................................... 54 
 
Exploratory Analysis in Liver Fine Needle Aspirates ................................. 54 
7.3 
Safety Assessments ................................................................................................................. 54 
7.3.1 Adverse Events ............................................................................................................ 54 
 
Solicited Adverse Events ............................................................................ 54 
 
Unsolicited Adverse Events ........................................................................ 54 
7.3.2 Laboratory Safety Tests ............................................................................................... 55 
7.3.3 Physical Examination .................................................................................................. 55 
7.3.4 Vital Signs ................................................................................................................... 55 
8 
SAFETY MANAGEMENT ............................................................................................................... 56 
8.1 
Responsibilities for Ensuring the Safety of Study Participants ............................................... 56 
8.1.1 Investigator .................................................................................................................. 56 
8.1.2 Study Sponsor .............................................................................................................. 56 
8.1.3 Local Medical Monitor ................................................................................................ 56 
8.1.4 Safety Monitoring Committee ..................................................................................... 56 

 
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8.1.5 Data Monitoring Committee ........................................................................................ 57 
8.1.6 Research Ethics Committee ......................................................................................... 57 
8.1.7 Competent Authority ................................................................................................... 57 
8.2 
Adverse Events ....................................................................................................................... 57 
8.2.1 Definitions ................................................................................................................... 57 
 
Adverse Event ............................................................................................. 57 
 
Adverse Reaction ........................................................................................ 58 
 
Serious Adverse Event ................................................................................ 58 
 
Suspected Unexpected Serious Adverse Reaction ...................................... 59 
8.2.2 Study Reporting Period for Adverse Events ................................................................ 59 
8.2.3 Recording and Assessment of Adverse Events by the Investigator ............................. 59 
 
Assessment of Severity ............................................................................... 60 
 
Assessment of Relationship ........................................................................ 60 
 
Action Taken with Study Vaccine .............................................................. 61 
 
Assessment of Outcome .............................................................................. 61 
8.2.4 Reporting Requirements and Procedures for Serious Adverse Events ........................ 61 
 
Follow-up Information on an SAE .............................................................. 62 
 
Required Follow-up for SAEs ..................................................................... 62 
 
Medical Review and Reporting by the Sponsor .......................................... 63 
 
Sponsor Responsibility for Expedited Safety Reports ................................ 63 
8.2.5 Follow-up of Participants after Adverse Events .......................................................... 63 
 
Investigator Follow-up ................................................................................ 63 
8.2.6 Post-study Adverse Events .......................................................................................... 64 
8.3 
Other Events of Special Interest .............................................................................................. 64 
8.4 
Overdoses or Incorrect Administration ................................................................................... 64 
8.5 
Management of Pregnancy ...................................................................................................... 64 
8.5.1 Notification and Follow-up .......................................................................................... 64 
8.5.2 Outcome ....................................................................................................................... 65 
9 
DATA QUALITY ASSURANCE AND QUALITY CONTROL ...................................................... 66 
9.1 
Protocol Violations and Deviations ......................................................................................... 66 
9.2 
Monitoring and Source Document Verification ...................................................................... 66 
9.3 
Data Management and Coding ................................................................................................ 66 
10 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ...................................................... 68 
10.1 
Sample Size Determination ..................................................................................................... 68 
10.2 
Statistical and Analytical Plans ............................................................................................... 68 
10.2.1 Analysis Sets ................................................................................................................ 68 
10.2.2 Study Analyses ............................................................................................................ 68 
 General Principles ....................................................................................... 68 
 Disposition .................................................................................................. 69 
 Protocol Deviations ..................................................................................... 69 
 Demographics and Baseline Data ............................................................... 69 
 Immunogenicity Analyses ........................................................................... 69 
 Safety Data .................................................................................................. 69 
10.2.2.6.1 
Adverse Events ..................................................................... 69 
10.2.2.6.2 
Laboratory Safety Tests ........................................................ 70 
10.2.2.6.3 
Vital Signs ............................................................................ 70 

 
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10.2.2.6.4 
Physical Examination ........................................................... 70 
10.2.3 Interim Analyses .......................................................................................................... 70 
10.2.4 Handling Missing, Unused or Spurious Data ............................................................... 71 
11 
STUDY DOCUMENTATION, INSPECTIONS AND RECORD KEEPING ................................... 72 
11.1 
Study Documentation .............................................................................................................. 72 
11.2 
Audits and Study Centre Inspections ...................................................................................... 72 
11.3 
Retention of Records ............................................................................................................... 72 
12 
FINANCE AND INSURANCE ......................................................................................................... 74 
13 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................. 75 
13.1 
Local Regulations/Declaration of Helsinki ............................................................................. 75 
13.2 
Competent Authority Approval ............................................................................................... 75 
13.3 
Research Ethics Committee Approval .................................................................................... 75 
13.4 
Informed Consent .................................................................................................................... 75 
13.5 
Protocol Amendments ............................................................................................................. 76 
13.6 
Confidentiality of Study Documents and Participant Records ................................................ 76 
14 
STUDY COMPLETION .................................................................................................................... 78 
15 
PUBLICATION OF DATA ............................................................................................................... 79 
16 
REFERENCES ................................................................................................................................... 80 
APPENDICES ............................................................................................................................................... 83 
Appendix 1 Toxicity Table for Clinical and Laboratory Abnormalities.......................................... 83 
Appendix 2 Details of Changes Made in Protocol Amendments .................................................... 93 
 
LIST OF TABLES 
Table 1 
Study Vaccine Treatment Groups in HBV001 ........................................................................ 41 
Table 2 
Overall Schedule of Assessments at Each Study Visit ............................................................ 47 
Table 3 
Severity Grading of Adverse Events not listed in the Toxicity Table for Clinical and 
Laboratory Abnormalities ....................................................................................................... 60 
LIST OF FIGURES 
Figure 1 
Schematic of Hepatitis B Virus Immunogen ........................................................................... 27 
Figure 2 
Overall Study Design .............................................................................................................. 31 
 
 

 
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PROTOCOL AMENDMENT CHANGE HISTORY 
This is Version 9.0 of the protocol. The original protocol (Version 1.0) was issued on 
30 Sep 2019. All the amendments are listed in the table below - the Summary of Main Changes. 
For detailed protocol amendment changes refer to Appendix 2. 
SUMMARY OF MAIN CHANGES  
Version 8.2, 24 Nov 2021 
Summary and Justification of Change 
Sections Changed 
Inclusion criterion 16 has been updated to 
allow the inclusion of participants who have 
received more than two COVID-19 vaccine 
administrations as the HBV focused T cell 
response is not expected to vary based on the 
number of booster doses received. 
Section 1.5.1 Rationale for Investigation of 
Dosing Interval With Respect to COVID-19 
Vaccines 
Section 3.1.1 Study Design 
Section 3.1.2 Study Methodology 
Section 4.1 Number of participants 
Section 4.2: Inclusion Criteria 
 
 
 
Version 8.0, 22 Sep 2021 
Summary and Justification of Change 
Sections Changed 
Healthy participants who have received the 
Moderna mRNA COVID-19 vaccine will 
now also be eligible to participate in Cohort 
6.As no interference on HBV-focused T cell 
response is expected from either the Pfizer or 
the Moderna vaccine the interval from the 
second COVID-19 vaccine has been adjusted 
to 6 to 30 weeks. 
Section 1.5.1: Rationale for Investigation of 
Dosing Interval With Respect to COVID-19 
Vaccines 
Section 3.1.1: Study Design 
Section 3.1.2: Study Methodology 
Section 4.1: Number of Participants 
Section 4.2: Inclusion Criteria 
Section 
5.7: 
Method 
of 
Assigning 
Participants to Treatment Groups 
 
 
 
Version 7.0, 08 Jul 2021 
Summary and Justification of Change 
Sections Changed 

 
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To evaluate the effect of prior ChAdOx1 
vaccines against COVID-19 on the T cell 
response to ChAdOx1-HBV, and to support 
the proposed interval of 3 months between 
the vaccines, two cohorts of 15 healthy 
participants each have been added (one 
including those who have previously 
received AZD1222 and the other including 
those who have received Pfizer mRNA 
COVID-19 vaccine). 
Section 1.5.1: Rationale for Investigation of 
Dosing Interval With Respect to COVID-19 
Vaccines 
Section 2: Study Objectives 
Section 3.1.1: Study Design 
Section 3.1.2: Study Methodology 
Section 
3.1.4.1: 
Duration 
for 
Each 
Participant 
Section 3.2: Discussion of Study Design 
Section 4.1: Number of Participants 
Section 4.2: Inclusion Criteria 
Section 4.3: Exclusion Criteria 
Section 5.1: Study Vaccines Administered 
Section 
5.7: 
Method 
of 
Assigning 
Participants to Treatment Groups 
Section 6: Study Procedures at each 
Visit/Schedule of Assessments 
Section 6.2: Treatment Day Assessments 
(Day 0) 
Section 6.3.4: Clinic Visit: Days 28, 56 
(Cohorts 1-4) and 168 (End of Study Visit 
Cohorts 1 4) 
Section 6.3.5: Clinic Visit: Day 84 (including 
End of Study Visit Cohorts 5 and 6) 
Section 7.2.1: Secondary Outcomes in Blood 
Samples 
Dr 
Thomas 
Evans 
has 
replaced 
Dr Meg Marshall as Sponsor’s Authorised 
Representative 
Front Page 
Details of a second laboratory for the 
analysis of immunogenetic samples and a 
new central laboratory have been added. 
Administrative and Contact Information 
Abstinence from heterosexual intercourse 
has been added as a method of contraception 
Section 4.2: Inclusion Criteria 
The email address for the Investigator to send 
the SAE form to has been corrected 
Section 8.2.4: Reporting Requirements and 
Procedures for Serious Adverse Events 
 
Version 6.0, 01 Mar 2021 

 
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Summary and Justification of Change 
Sections Changed 
Dr Kingsley Urakpo has left the company 
and Dr Thomas Evans has taken over the 
responsibility of Sponsor Medical Oversight 
for this study. 
Administrative and Contact Information 
The exclusion criterion 8 has been amended 
to include patients who have had adenoviral 
vaccines 3 months prior to screening and 3 
months after receiving ChAdOx1-HBV in 
the study. There is evidence that prior 
adenoviral vectors may interfere with T cell 
responses, when given within the first three 
months of an adenoviral vaccine, especially 
if it’s the same vector encoding the same 
foreign protein.  
Protocol synopsis: Inclusion and Exclusion 
Criteria 
Section 4: Exclusion Criteria 
Benefit Risk Assessment section has been 
updated with the available data 
Section 3.3: Benefit Risk Assessment 
Minimum data required to report an SAE has 
been updated to be in line with the ICH-GCP 
guidelines 
Section 8.2.4: 8.2.4 
Reporting 
Requirements and Procedures for Serious 
Adverse Events 
 
Version 5.0, 29 Oct 2020 
Summary and Justification of Change 
Sections Changed 
The acceptable HBsAg level for the CHB 
patients has been raised from 4000IU/mL to 
10000IU/mL. 
Protocol synopsis: Inclusion and Exclusion 
Criteria 
Section 4.2: Inclusion Criteria 
 
Version 4.0, 24 Feb 2020 
Summary and Justification of Change 
Sections Changed 
Dr Kingsley Urakpo has joined the company 
and will replace Dr Mariem Charafeddine as 
responsible for Sponsor Medical Oversight. 
Administrative and Contact Information 
A new site has been added to the study to 
accelerate the recruitment. 
Administrative and Contact Information 
Clarification given on the HBV disease 
markers assessed in Healthy Volunteers and 
the participant with CHB infection on each 
visit. 
Protocol Synopsis: Study Procedures and 
Frequency 
Section 3.1.2: Study Methodology 
Section 6: Table 2: Overall Schedule of 
Assessments at Each Study Visit 

 
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Section 7.1.4.3:  
HIV, HBV, HCV and 
HDV Diagnostic Testing 
Clarification given on the allocation of 
participant number to state that a single 
participant number will be used per 
participant throughout the study.  
Section 
5.7: 
Method 
of 
Assigning 
Participants to Treatment Groups 
Pharmacy 
Manual 
is 
replaced 
with 
Investigational Product Handling Manual 
Section 5: Study Vaccine 
Section 5.2: Identity of Study Vaccine 
Section 5.3: Labelling, Packaging and 
Shipping 
Section 5.8.2.2: Study Vaccine Preparation 
and Administration 
Clarification given to say that the dressing 
applied on the vaccination site will be kept 
on the vaccination site for at least 10 minutes 
after vaccination 
Section 5.8.2.2: Study Vaccine Preparation 
and Administration 
Clarification given that the HDV antibody 
assessment will be applicable for the 
participants with CHB infection only 
Section 6: Table 2: Overall Schedule of 
Assessments at Each Study Visit  
Section 6.1: Screening and Baseline Pre-
Dose Assessments 
For practical reasons, LFNA test has been 
moved from Day 0 to within the screening 
period.  
Protocol Synopsis: Study Procedures and 
Frequency 
Section 3.1.2: Study Methodology 
Section 6: Table 2: Overall Schedule of 
Assessments at Each Study Visit  
Section 6.1: Screening and Baseline Pre-
Dose Assessments 
The units of following tests were changed in 
line with UK’s standard practice –  
• Total bilirubin: mg/dL to µmol/L 
• Platelet counts:  per mL to x109/L 
Protocol Synopsis: Inclusion and Exclusion 
Criteria: 
Section 4.3: Exclusion Criteria 
Clarification 
given 
to 
state 
that 
hospitalisation for scheduled treatments and 
elective medical/surgical procedures related 
to a pre-existing condition should not be 
considered as an SAE 
Section 8.2.1.3: Serious Adverse Event 
 
Version 3.0, 04Dec2019 

 
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Summary and Justification of Change 
Sections Changed 
In response to MHRA assessment, state that 
the only reason why a participant must be 
discontinued from the study is withdrawal of 
consent. In all other circumstances, the 
participants must be encouraged to continue 
the safety follow-up procedures described in 
the protocol  
Section 4.3.1.2: Study Discontinuation 
In response to MHRA assessment, state that 
it is the investigator’s responsibility to 
determine the causality relationship to the 
study vaccine 
Section 8.1.3: Local Medical Monitor 
Section 8.2.3.2: Assessment of Relationship 
Section 8.2.4.3: Medical Review and 
Reporting by the Sponsor 
In response to MHRA assessment, state the 
following are the only acceptable hormonal 
methods of contraception to be used during 
the study: 
− Combined (estrogen and progestogen 
containing) 
hormonal 
contraception 
associated with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
− Progestogen-only hormonal 
contraception associated with inhibition 
of ovulation: 
− oral 
− injectable 
− implantable 
Section 4.2: Inclusion Criteria 
 

 
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Version 2.0, 13Nov2019 
Summary and Justification of Change 
Sections Changed 
Update collection of HBV disease markers in 
serum 
in 
order 
to 
ensure 
complete 
serological history is obtained prior to 
vaccination and is appropriate to the 
development of the study vaccine and ensure 
alignment with clinical practice in the 
secondary care setting. 
Administrative and Contact Information 
Section 2: Study Objectives and Endpoints 
Section 6: Study Procedures at each 
Visit/Schedule of Assessments 
Section 7.1.4.3: HIV, HBV, HCV and HDV 
Diagnostic Testing 
Section 7.2.1: Secondary Outcomes in Blood 
Samples. 
7.2.2.1: Exploratory Analysis in Blood 
Samples 
Remove transcriptomics at all timepoints as 
this does not contribute significantly to the 
study endpoints. It also saves on blood 
volume contributed by participants and 
reduces the total number of study visits. 
Section 6.3.2: Clinic Visit: 7 
Section 7.2: Immunogenicity Assessments 
Change the Day 1 visit from a ‘face to face’ 
clinic visit to a telephone to ease the burden 
on participants (vital signs and symptom 
directed physical examination were also 
removed appropriately) 
Section 3.1.2: Study Methodology 
Section 6: Study Procedures at each 
Visit/Schedule of Assessments 
Section 6.3.1: Telephone Call: Day 1 
Clarify the function of the DMSC which is 
to review safety and tolerability in HBV001 
only (not efficacy and immunogenicity) 
Section 3.1.1: Study Design 
8.1.5: Data Safety Monitoring Committee 
Provide further clarity and correct 
typographical errors 
Abbreviation Table 
Throughout 
 

 
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PROTOCOL SYNOPSIS 
Title of Study: 
A Phase 1 Monotherapy Study to Evaluate the Safety, Tolerability and 
Immunogenicity of Vaccination with Candidate Chimpanzee Adenovirus-vectored 
Hepatitis B Virus Vaccine (ChAdOx1-HBV) in Healthy Participants and Participants 
with chronic hepatitis B infection 
Short Title: 
First in human study of ChAdOx1-HBV 
Sponsor: 
 
Protocol Number: 
HBV001 
Chief Investigator: 
 
 
 
 
 
Study Centres: 
This study will be performed in at least 2 study centres 
Objectives: 
Primary Objective 
Determine the safety and tolerability of different doses 
of a single vaccination of ChAdOx1-HBV in healthy 
participants and 
in participants with 
chronic 
hepatitis B virus (CHB) infection and virally 
suppressed with oral antiviral medication. 
Endpoints: 
Primary Endpoints 
Incidence of safety and reactogenicity events: 
• 
Adverse events and/or adverse events leading to 
study discontinuation 
• 
Serious adverse events 
• 
Grade ≥3 local and systemic reactions  
Secondary Objectives 
• 
Determine 
the 
immunogenicity 
of 
ChAdOx1-HBV in (A) healthy participants and 
in (B) participants with CHB, virally suppressed 
with oral antiviral medication 
Determine the effect of ChAdOx1-HBV on the 
level of hepatitis B surface antigen (HBsAg) in 
participants 
with 
CHB 
infection, 
virally 
suppressed with oral antiviral medication 
 
 
• 
Cohorts 5 and 6 only: Assess whether the receipt 
of 
prior 
ChAdOx1-SARS-CoV-2 
vaccine 
(AZD1222) results in decreased T cell responses 
to 
ChAdOx1-HBV, 
when 
administered 
10-18 weeks prior to ChAdOx1-HBV 
Secondary Endpoints 
• 
A multi-parameter index made of CD4+ 
magnitude, CD4+ avidity, and CD8+ magnitude 
• 
Mean reduction in HBsAg titre at Day 84 and 
Day 168 post-vaccination (last visit) 
• 
Proportion of CHB participants with hepatitis B 
e-antigen (HBeAg) and HBsAg loss 
• 
Proportion of CHB participants with HBeAg 
and HBsAg seroconversion 
• 
Reduction of hepatitis B deoxyribonucleic acid 
(DNA) levels 
• 
Total T cell response to the antigens encoded by 
ChAdOX1-HBV as measured in a peptide 

 
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Exploratory objective 
Determine the effect of ChAdOx1-HBV on virological 
and immunological systemic and intrahepatic changes 
in participants with CHB infection and virally 
suppressed with oral antiviral medication 
Exploratory Endpoints 
• 
Effect on serum hepatitis B core-related antigen 
(HBcAg) 
• 
Effect on serum hepatitis B circulating 
pre-genomic ribonucleic acid (pgRNA)  
• 
Liver fine needle aspirate (LFNA) assays will be 
used to quantify and characterise intrahepatic 
immune 
and 
parenchymal 
cells 
and/or 
hepatitis B virus (HBV) DNA and ribonucleic 
acid (RNA) transcripts 
• 
Effect of prior AZD1222 on the CD4+ and 
CD8+ T cell magnitude and phenotype as 
measured by multiparameter flow cytometry 
Study Design: 
This is a Phase 1, first in human study of ChAdOx1-HBV. The study will be 
conducted in 40 healthy participants and 12 participants with CHB and virally 
suppressed with oral antiviral medication. This will be an open-label, 
non-randomised dose escalation study comparing the safety, tolerability and 
immunogenicity of 2 different doses of ChAdOx1-HBV vaccine.  T cell responses in 
healthy participants who have received a prior two-dose series of AZD1222 will be 
compared with those who have received at least two doses of the Pfizer mRNA 
COVID 19 vaccine or the Moderna COVID 19 vaccine. The study design is shown 
in Figure S1. 
Participants will be screened in the period Day -42 to Day -1. Informed consent will 
be obtained before any study specific procedures are performed. Eligible participants 
will then attend the clinic to receive study vaccine on Day 0. Participants will be 
enrolled sequentially.  
The study will investigate the study vaccine as shown in Table S1. On Day 0, an 
electronic diary (eDiary), tape measure and thermometer will be provided to perform 
self assessment of local and systemic reactogenicity. All participants will then have 
a follow-up telephone call on Day 1 and return to the clinic for study assessments on 
Days 7, 14, 28, 84. Participants in cohorts 1-4 only, will also have follow up visits 
on Day 56 and Day 168. End of study visit procedures will be performed at the final 
visit. 
Five healthy participants will be administered the low dose first (cohort 1). Dose 
escalation will only be initiated in the next 5 healthy participants (cohort 2) following 
Safety Monitoring Committee (SMC) review. 
Six CHB participants will be administered the low dose (cohort 3) before the dose 
escalation is initiated in the remaining 6 CHB participants (cohort 4). 
Thirty healthy participants (15 who have received two doses of AZD1222 [cohort 5] 
and 15 who have received at least two doses of either the Pfizer or Moderna mRNA 
COVID-19 vaccine [cohort 6]) will be dosed in parallel with the high dose used in 
cohorts 2 and 4. 
The first participant in each of cohorts 1-4 will be assessed for 1 hour in the clinic 
post-vaccination in case of immediate adverse events (timed after the end of study 
vaccine administration). All other participants will be assessed for 30 minutes. 
Five reviews of the safety, tolerability and available immunogenicity data will be 
performed by a SMC: 
• 
First review: at least 48 hours after the first healthy participant has received the 
first low dose of ChAdOx1-HBV vaccine. This review will occur before 
dosing the remaining participants in cohort 1 
• 
Second review: at least 48 hours after the last healthy participant has received 
the last low dose of ChAdOx1-HBV vaccine. This review will occur before 
dosing high dose healthy participants in cohort 2 

 
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• 
Third review: at least 48 hours after the last healthy participant has received 
the last high dose of ChAdOx1-HBV vaccine. This review will occur before 
dosing low dose CHB participants in cohort 3 
• 
Fourth review: at least 48 hours after the first CHB participant has received the 
first low dose of ChAdOx1-HBV vaccine. This review will occur before 
dosing the remaining low dose CHB participants in cohort 3 
• 
Fifth review: at least 48 hours after the last participant with CHB has received 
the low dose of ChAdOx1-HBV vaccine cohort 3 before dosing high dose CHB 
participants in cohort 4 
A Data Monitoring Committee (DMC) will be appointed to perform unscheduled 
reviews of the available safety and tolerability study data and make recommendations 
concerning the continuation, modification or termination of the study if one of the 
study stopping or holding rules is met. 
Figure S1 Overall Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ChAdOx1-HBV=chimpanzee adenovirus-vectored hepatitis B virus vaccine; CHB=chronic hepatitis B virus; HD=high 
dose; LD=low dose; N=number of participants; vp=viral particles 
Duration of Study: 
Duration for each participant: 
Cohorts 1-4: Up to 8 months (up to 1.5 months for screening and 6.5 months on the 
study with study vaccine given on Day 0). 
Cohorts 5 and 6: Up to 4.5 months (up to 1.5 months for screening and 3 months on 
the study with study vaccine given on Day 0). 
Duration of whole study: It is planned that the study will take 16 months to 
implement, enrol and read out.  
Participant Numbers: 
52 participants: Forty healthy participants and 12 participants with CHB infection 
and virally suppressed with oral antiviral medication.  
A total of 10 healthy participants and 12 participants with CHB infection is 
considered sufficient to confirm the safety, tolerability and immunogenicity of 
ChAdOx1-HBV and to answer the objectives of the study before progressing to 
larger studies. An additional 30 healthy participants (15 who have received two doses 
of AZD1222 and 15 who have received at least two doses of either the Pfizer or 
Moderna mRNA COVID-19 vaccine) will be recruited to assess whether prior receipt 
of AZD1222 results in decreased T cell responses to ChAdOx1-HBV. 
Cohort 1 (N=5) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Cohort 2 (N=5) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 3 (N=6) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Healthy Participants 
CHB Participants 
Cohort 4 (N=6) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Healthy Participants 
Cohort 5 AZD1222 
(N=15) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 6 
Pfizer/Moderna mRNA
(N=15) HD 
ChAdOx1-HBV 
10

 
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Inclusion and 
Exclusion Criteria: 
Inclusion Criteria 
1. 
Adult males or females aged ≥18 to ≤65 years at screening 
2. 
Body Mass Index ≤30 kg/m2 
3. 
Able to provide informed consent indicating they understand the purpose of, 
and procedures required, for the study and are willing to participate  
4. 
If female, willing not to become pregnant up to 8 weeks after last dose of study 
vaccine, not breast feeding  
5. 
If female: Not pregnant, and one of the following: 
• 
Of non-childbearing potential (i.e. women who have had a hysterectomy 
or tubal ligation or are post-menopausal, as defined by no menses in 
≥1 year) 
• 
Sexual abstinence, only if the participant refrains from heterosexual 
intercourse during the entire study period and it is the usual lifestyle of the 
participant 
• 
Of childbearing potential but agrees to practice highly effective 
contraception for 4 weeks prior to study vaccine and 8 weeks after study 
vaccine. Highly effective methods of contraception include one or more 
of the following:  
− 
Male partner who is sterile (medically effective vasectomy) prior to 
the female participant’s entry into the study and is the sole sexual 
partner for the female participant 
− 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
− 
Progestogen-only hormonal contraception associated with inhibition 
of ovulation: 
− oral 
− injectable 
− implantable 
− 
An intrauterine device 
− 
Bilateral tubal occlusion 
Healthy participants (cohorts 1 and 2) 
6. 
Considered to be healthy with no current conditions that may significantly 
impair participant safety or influence study results, in the opinion of the 
Investigator 
Participants with well controlled CHB (cohorts 3 and 4): 
7. 
Documented evidence of chronic HBV infection (e.g. HBsAg positive 
≥6 months with detectable HBsAg levels at screening) 
8. 
Receipt of only either entecavir or tenofovir for at least 12 months before 
screening 
9. 
Virally suppressed (HBV DNA <40 IU/mL for ≥6 months) 
10. HBsAg <10000 IU/mL 
Healthy participants (cohort 5): 
11. Considered to be healthy with no current conditions that may significantly 
impair participant safety or influence study results, in the opinion of the 
Investigator 
12. Adult males or females aged ≥40 to ≤60 years at screening 

 
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13. Completed second dose of COVID-19 AZD1222 vaccine 10 to 18 weeks before 
enrolment 
Healthy participants (cohort 6): 
14. Considered to be healthy with no current conditions that may significantly 
impair participant safety or influence study results, in the opinion of the 
Investigator 
15. Adult males or females aged ≥40 to ≤60 years at screening 
16. Received the latest dose of Pfizer (Comirnaty®) or Moderna (Spikevax®) 
mRNA COVID 19 vaccine  6 to 30 weeks before enrolment 
Exclusion Criteria 
1. 
Presence of any significant acute or chronic, uncontrolled medical/ psychiatric 
illness 
2. 
Hepatitis C virus antibody positive.  
3. 
Human immunodeficiency virus antibody positive 
4. 
History or evidence of autoimmune disease or known immunodeficiency of any 
cause  
5. 
Prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics 
(e.g. monoclonal antibodies, interferon) within 3 months of screening 
6. 
Receipt of immunoglobulin or other blood products within 3 months prior to 
screening 
7. 
Receipt of any investigational drug or vaccine within 3 months prior to 
screening  
8. 
Cohorts 1-4: Receipt of any adenoviral vaccine within 3 months prior to 
administration of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-
based vaccine within 3 months after Day 0 
Cohorts 5 and 6: Receipt of any adenoviral vaccine (other than AZD1222 per 
inclusion criterion 13) within 3 months prior to administration of ChAdOx1-
HBV on Day 0, or plan to receive an adenoviral-based vaccine within 3 months 
after Day 0 
9. 
Receipt of any live vaccines within 30 days prior to screening 
10. Receipt of any inactivated vaccines within 14 days prior to screening 
11. History of allergic disease or reactions likely to be exacerbated by any 
component of the vaccine 
12. Any history of anaphylaxis in reaction to vaccination 
13. Malignancy within 5 years prior to screening with the exception of specific 
cancers that are cured by surgical resection (e.g. except basal cell skin 
carcinoma of the skin and cervical carcinoma). Participants under evaluation for 
possible malignancy are not eligible 
14. Current alcohol or substance abuse judged by the Investigator to potentially 
interfere with participant safety and compliance  
15. Significant cardiac disease or unstable uncontrolled cardiac disease 
16. Any laboratory test at screening which is abnormal and which is deemed by the 
Investigator to be clinically significant 
17. Any other finding that, in the opinion of the Investigator, deems the participant 
unsuitable for the study 
Additionally, for healthy participants (cohorts 1, 2, 5 and 6) 
18. HBsAg positive 
Additionally, for participants with well controlled CHB (cohorts 3 and 4) 
19. Co-infection with hepatitis delta 
20. Documented cirrhosis or advanced fibrosis indicated by a liver biopsy within 
6 months prior to screening.  

 
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In the absence of an appropriate liver biopsy, either 1 of the following:  
• 
Screening Fibroscan with a result >9 kPa within ≤6 months of screening 
or 
• 
Screening FibroTest >0.48 and aspartate aminotransferase (AST) to platelet 
ratio index of >1  
In the event of discordant results between non-invasive methods, the Fibroscan 
result will take precedence. 
21. Alanine transaminase (ALT) >3 × upper limit of normal, international 
normalised ratio (INR) >1.5 unless the participant was stable on an 
anticoagulant regimen affecting INR, albumin <35 g/L, total bilirubin >34.2 
µmol/L, platelet count < 100 x 109/L 
22. A history of liver decompensation (e.g. ascites, encephalopathy or variceal 
haemorrhage) 
23. Prior or current hepatocellular carcinoma 
24. Chronic liver disease of a non-HBV aetiology 
25. Any herbal supplements and or other medicines with potential liver toxicity 
within the previous 3 months prior to enrolment into this study 
Study Vaccines: 
ChAdOx1-HBV is a non-replicating viral vector encoding HBV consensus 
sequences from a group C genotype. It will be given by intramuscular injection into 
the deltoid muscle in the non-dominant arm. 
The study vaccines to be given in each treatment group are shown in Table S1. 
All study vaccine will be administered sequentially. Participants will receive study 
vaccine on Day 0 only. 
Table S1 Study Vaccine Treatment Groups in HBV001 
Treatment Cohort 
Vaccine Single Dose 
N 
Cohort 1 LD 
Healthy Participants 
ChAdOx1-HBV  
2.5 x 109 vp 
5 
Cohort 2 HD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 1010 vp 
5 
Cohort 3 LD 
Participants with CHB 
ChAdOx1-HBV 
2.5 x 109 vp 
6 
Cohort 4 HD 
Participants with CHB 
ChAdOx1-HBV 
2.5 x 1010 vp 
6 
Cohorts 5 and 6 HD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 1010 vp 
30 
Abbreviations: ChAdOx1-HBV=chimpanzee adenovirus-vectored hepatitis B virus 
vaccine; CHB=chronic hepatitis B virus; HD=high dose; LD=low dose; vp=viral 
particles 
Study Procedures and 
Frequency: 
The safety, tolerability and immunologic assessments to be performed in cohorts 1-4 
are: 
• 
Haematology (full blood count, haemoglobin, haematocrit, erythrocytes, mean 
cell volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin 
concentration, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, fibrinogen, prothrombin time and INR, activated partial 
thromboplastin time and platelets) will be analysed at screening, pre-vaccination 
on Day 0 and on Days 7, 14, 28, 56, 84 and 168 
• 
Biochemistry (sodium, potassium, urea, creatinine and albumin) will be analysed 
at screening, pre-vaccination on Day 0 and on Days 7, 14, 28, 56, 84 and 168 
• 
Liver function tests (alkaline phosphatase, gamma-glutamyl transpeptidase, 
ALT, AST and total bilirubin) will be analysed at screening, pre-vaccination on 
Day 0 and on Days 7, 14, 28, 56, 84 and 168 

 
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• 
HBV disease markers in serum: 
o Healthy participants: qualitative HBsAg will be tested at screening, 
HBsAb and HBcAb will be tested at Day 0 and repeated at the end of the 
trial if negative at baseline, or at the discretion of the investigator  
o CHB participants: HBV DNA and quantitative HBsAg will be tested at 
screening and repeated on Days 0, 28, 56, 84 and 168. The following 
parameters will also be analysed on Days 0, 28, 56, 84 and 168: HBeAg, 
HBcAg, anti-HBs, anti-HBe, anti-HBc, pgRNA  
• 
A full physical examination will be performed at screening and pre-vaccination 
on Day 0. A symptom-directed physical examination will be performed on 
Days 7, 14, 28, 56, 84 and 168 
• 
Vital signs will be performed at screening, pre-vaccination and post-vaccination 
on Day 0 and on Days 7, 14, 28, 56, 84 and 168 
• 
Local and systemic reactogenicity (pain, induration, warmth, erythema at the 
vaccination site plus feverishness, chills, myalgia, fatigue, headache, nausea, 
arthralgia, malaise) will be captured pre-vaccination and post-vaccination on 
Day 0 and by eDiary for 3 days post-vaccination 
• 
Unsolicited adverse events will be recorded in the eCRF from the date the 
informed consent is signed, at all clinic visits to cover the period since the 
previous visit and during the visit and up to 28 days post-vaccination  
• 
Serious adverse events and adverse events of special interest will be recorded 
from the date the informed consent is signed until the end of the study and or 
resolved or until participant contact discontinues 
• 
Cellular immune responses will be measured in peripheral blood mononuclear 
cells samples taken on pre-vaccination on Day 0 and on Days 14, 28, 56, 84, 168. 
Samples will be analysed by intracellular cytokine staining 
For healthy participants in cohorts 5 and 6, all assessments on Days 0, 7, 14, 28 and 
84 above will be performed. In addition, neutralising antibodies to ChadOx1 will be 
assessed on Days 0 and 84. 
In CHB participants who consent to LFNAs, these will be taken pre-vaccination 
within screening period and at the clinic visit on Day 84. Liver fine needle aspirate 
assays may be used to quantify and characterise intrahepatic immune and 
parenchymal cells and/or HBV DNA and RNA transcripts. These aspirates and 
subsequent LFNA assessments are optional. 
Statistical Methods 
and Analysis: 
All data will be summarised using descriptive statistics. Immunogenicity and 
efficacy data may be subjected to additional statistical analysis. 
 
 

 
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ABBREVIATIONS AND DEFINITIONS OF TERMS  
ABBREVIATION 
DEFINITION 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
anti-HBe 
Hepatitis B e-Antibody 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
cccDNA 
Closed Circular DNA 
ChAdOx1 
Chimpanzee Adenovirus Oxford 1 
ChAdOx1-HBV 
Chimpanzee Adenovirus-vectored Hepatitis B Virus Vaccine 
CHB 
Chronic Hepatitis B Virus 
DNA 
Deoxyribonucleic Acid 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
EDTA 
Ethylenediaminetetraacetic Acid 
ELISpot 
Enzyme-linked Immunospot 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transpeptidase 
GMO 
Genetically Modified Organism 
HBcAb/anti-HBc 
Hepatitis B Core Antibody 
HBcAg 
Hepatitis B Core-related Antigen 
HBeAg 
Hepatitis B e-Antigen 
HBsAb/anti-HBs 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HDV Ab 
Hepatitis D Virus antibody 
HIV 
Human Immunodeficiency Virus 
HRA 
Health Research Authority 
ICH 
International Council on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ICS 
Intracellular Cytokine Staining 
IFN 
Interferon 
IFN-γ 
Interferon-gamma 
INR 
International Normalised Ratio 
IP 
Investigational Product 
ISF 
Investigator’s Site File 
LFNA 
Liver Fine Needle Aspirate 
LFTs 
Liver Function Tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome 
MVA 
Modified Vaccinia Ankara 
NA 
Nucleotide Analogue 

 
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ABBREVIATION 
DEFINITION 
PBMC 
Peripheral Blood Mononuclear Cell 
PD-1 
Programmed Cell Death Protein 1 
pgRNA 
Pre-genomic RNA 
PT 
Prothrombin time 
REC 
Research Ethics Committee 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SI 
International System of Units 
SIi 
Shark Class-II invariant Chain 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
vp 
Viral Particles 
 

 
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1 
BACKGROUND 
1.1 
Disease Review 
Hepatitis B virus (HBV) is a complex, small deoxyribonucleic acid (DNA) virus that goes 
through a ribonucleic acid (RNA) intermediate life cycle requiring reverse transcription. After 
transmission through infected blood, contaminated body fluids or through perinatal transfer, 
the virus infects the liver and can then either integrate into the hepatocyte genome or can exist 
as a stable chromosomal closed circular DNA. Once infection takes place, HBV infection 
results in chronic liver disease in 5-10% of infected adults, whereas the rate for perinatal 
transmission is the opposite, with greater than 90% of infected neonates progressing to chronic 
disease [1]. After a chronic HBV (CHB) infection is established, the rate of natural clearance 
is minimal. Such CHB infection frequently progresses to necrotic inflammation and ongoing 
liver damage, which may lead to cirrhosis and hepatocellular carcinoma (HCC) [1]. 
1.2 
Treatment Review 
Highly effective prophylactic vaccines were implemented in the early 1980's; however, these 
vaccines are ineffective once infection is established [2]. Despite the wide use of prophylactic 
vaccines, there are an estimated 240 million CHB carriers and over 686,000 related deaths per 
year worldwide [3].  
Two classes of antiviral therapies have been approved and recommended for treatment of 
hepatitis B: interferons (IFNs) and nucleotide analogues (NAs). The use of IFN results in higher 
rates of hepatitis B e-antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss compared 
to NAs. 
Pegylated IFN administered for up to 52 weeks results in HBsAg loss in 3-7% of patients 
compared to 0-3% HBsAg loss after the same duration of NA therapy. Response to IFN is also 
more durable, and HBsAg loss may occur after cessation of treatment, while virological relapse 
is frequent after cessation of NA. However, IFN is less effective at suppressing viral replication 
compared to NAs, requires parenteral administration, is associated with significant side effects, 
and is contraindicated in patients with decompensated cirrhosis or severe exacerbations of 
hepatitis and those with autoimmune or psychiatric illnesses.  
Nucleotide analogues are administered orally and have negligible adverse effects. The 
recommended first-line NAs, entecavir and tenofovir, have low risk of drug resistance; but the 
requirement for indefinite therapy increases the cost and the risk of non-adherence.[4] 
Various combinations of IFN and NA have been evaluated, but most studies have not shown 
an added benefit compared to monotherapy [5,6,7]. A recent study showed that combination of 
pegylated IFN and tenofovir increased the rate of HBsAg loss to 9.1% at Week 72, but the 
benefit was mainly observed with those infected with HBV genotype A [8].  
Many research programs are ongoing to develop new treatment concepts that focus on the 
clearance of HBsAg in a significant proportion of patients, with the principle aims of: 
1) stopping treatment with no risk of virological relapse and no risk of liver disease progression 
and, 2) to further decrease the risk of HCC. Several potential target mechanisms for immune 
modulation to restore HBV specific immune responses in conjunction with profound inhibition 
of HBV replication and HBsAg production to attain immunological control are being evaluated 
[3]. 
The immune clearance of CHB is likely to depend on the use of modalities that induce effective 
CD8+ T cells [9,10]. For over two decades vaccination strategies to induce these CD8+ T cells 

 
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to counter such infections as tuberculosis (TB), human immunodeficiency virus (HIV) and 
malaria have been investigated [11,12,13]. One platform approach that has induced remarkably 
high levels of T cells in man has been to use a non-replicating adenovirus "prime" followed by 
a heterologous viral vector "boost" utilising a non-replicating pox virus (modified vaccinia 
Ankara [MVA]) [14,15,16]. Non-replicating chimpanzee adenoviruses are often used rather 
than human adenoviruses, as there is minimal prior immunity to the vector itself. [17,18] The 
combination of chimpanzee adenoviruses (used in thousands of participants) plus MVA 
(administered to over 130,000 people) has been shown to induce large immune responses in 
man in malaria, TB, HIV, influenza and respiratory syncytial virus [13,16,19-22]. The 
chimpanzee adenovirus vector proposed in this study (chimpanzee adenovirus Oxford 1; 
ChAdOx1), a serogroup E adenovirus, has been administered to over 200 people in trials of 
Middle East Respiratory Syndrome (MERS), influenza, TB, chikungunya, and prostate cancer, 
and has been safe and immunogenic. It has also been modified to enhance immunogenicity 
through the addition of a short shark invariant chain (SIi) sequence and use of the tissue 
plasminogen promoter.  
Hepatitis B virus circulates in the world as a number of genotypes (A-I), of which the most 
prevalent (especially in Asia) is genotype C [23]. The proteins expressed by ChAdOx1 in this 
study include most of the HBV genome from a genotype C consensus, including HBsAg, 
polymerase and core. In vitro experiments have demonstrated that the HBV polymerase was 
successfully inactivated through the insertion of point mutations at critical sites. In order to 
stop aggregation of surface antigen, the protein was split into two separate coding regions in 
the viral vectors.  
The genetic HBV insert was then cloned into both the ChAdOx1 vector (chimpanzee 
adenovirus vectored hepatitis B virus vaccine; ChAdOx1-HBV), and also into an MVA vector 
(MVA-HBV) that will be used as a boost in a subsequent study after the evaluation of the 
ChAdOx1-HBV given alone is completed. 
This study is designed to assess the safety and immunogenicity of ChAdOx1-HBV and to 
assess the breadth of responses to the proteins encoded by the vaccine vector. The cross 
reactivity to other genotypes will also be assessed. Doses of ChAdOx1 vaccines in previous 
studies have varied from 108 to over 1011 viral particles (vp) per dose and the middle two doses 
will be evaluated in this study to prepare for a further heterologous prime-boost regimen. 
1.3 
Summary of Non-clinical Studies 
Immunogen design: 1,447 HBV genotype C nucleotide sequences (HBV database) were 
aligned, and an HBV genotype C consensus sequence was generated. Then, a patient’s HBV 
genotype C sequence (accession number: KP017269.1 HBV isolate JP-02) that had maximum 
similarity to the consensus was chosen for use in the HBV immunogen design. The HBV 
immunogen encompasses three full length HBV-antigens (pre-core/core, polymerase and 
preS1/preS2/surface) along with truncated SIi and tissue plasminogen activator genetic 
adjuvants and it is encoded in the chimpanzee adenoviral vector. Point mutations were 
introduced within the polymerase protein encoded in the immunogen in order to abolish its 
function and to ensure no replication-competent HBV genome could arise from the immunogen 
sequences. An HBV-polymerase assay performed by the laboratory of Prof. Michael Nassal at 
University Hospital Freiburg, Germany, confirmed the absence of polymerase activity of the 
polymerase contained in the HBV immunogen. A schematic of the HBV immunogen is shown 
in Figure 1. 

 
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Figure 1 
Schematic of Hepatitis B Virus Immunogen 
 
The HBV immunogen was cloned and recovered into the ChAdOx1 vector genome to generate 
ChAdOx1-HBV. Research stocks of the ChAdOx1-HBV vector were generated at the viral 
vector core facility of the Jenner Institute, University of Oxford. 
Preclinical immunogenicity testing: ChAdOx1-HBV was found to be highly immunogenic 
when tested in mouse immunogenicity experiments in both inbred (BALB/c, C57BL/6) and 
outbred (CD-1) mice, measured using interferon-gamma (IFN-γ) enzyme-linked immunospot 
(ELISpot) and intracellular cytokine staining (ICS) assays. 
A Good Laboratory Practice toxicology study is ongoing (see Investigator’s Brochure for 
further study details and results). 
1.4 
Summary of Clinical Experience 
ChAdOx1 has been administered to over 200 participants (MERS, malaria, influenza and 
prostate cancer) and as the prime for an MVA boost in the malaria, influenza and prostate 
cancer studies (NCT03399578, NCT03203421, NCT01818362, NCT01623518 and 
NCT03815942). In all of those studies, extremely high levels of transgene-specific CD4+ and 
CD8+ T cells have been induced and there have been no vaccine-associated serious adverse 
events (SAEs). This is the first clinical study for the HBV ChAdOx1 vaccine.  
Further information on ChAdOx1-HBV is contained in the Investigator’s Brochure; this 
information should be reviewed prior to study initiation. 
1.5 
Study Rationale 
Chronic hepatitis B virus infection is a global public health challenge on the same scale as TB, 
HIV and malaria. The current prophylactic vaccine has no effect on established chronic 
infection. Available treatments suppress viral replication, but they are not curative, largely due 
to the persistence of the viral covalently closed circular DNA (cccDNA) transcriptional 
template in infected hepatocytes and the failure of chronically infected patients to mount an 
immune response that is sufficiently robust, functional, and sustained to clear the infection. 
Thus, in most cases, treatment must continue for life. However, even successfully virally 
suppressed patients may still develop liver cancer. 
Many research programs are ongoing to develop new treatment concepts that focus on the 
clearance of HBsAg in a significant proportion of patients, with the principle aims of: 
1) stopping treatment with no risk of relapse and no risk of liver disease progression and 2) to 
further decrease the risk of HCC. 
Pre-clinical models still have considerable limitations in this indication, and important gaps in 
our understanding of the HBV replication cycle and the host immune response must be 
addressed to expand the exploitable vulnerabilities in the replication cycle that can be targeted 
therapeutically to cure the infection. 
A major effort has been made to compare the efficient integrated response resulting in HBV 
clearance of acute infection to the dysregulated response observed in patients with chronic 
hepatitis B. A complex interplay of innate and adaptive immune responses is essential for viral 
clearance and a failure of these responses can result in liver pathogenesis. CD8+ T cells are the 
main effector cells that eliminate the virus by cytolytic and non-cytolytic effector functions 

 
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[24,25]. Sufficient CD4 T cell activity and the production of neutralising anti-HBV envelope 
antibodies are required for protective immunity [26].  
The combination of chimpanzee adenoviruses (used in thousands of participants) plus MVA 
(administered to over 130,000 people) has been shown to induce large immune responses in 
man in malaria, TB, HIV, influenza and respiratory syncytial virus [13,16,19-22]. 
Doses of ChAdOx1 vaccines in previous studies have varied from 108 to over 1011 vp per dose 
and the middle two doses will be evaluated in this study to prepare for a further heterologous 
prime-boost regimen. The safety of ChAdOx1-HBV and the breadth of systemic and 
liver-specific immune responses will be explored. A prime-boost strategy using ChAdOx1 
vector (ChAdOx1-HBV) and an MVA vector (MVA-HBV), with and without anti-
programmed cell death protein 1 (PD-1) will be evaluated in a subsequent study. 
1.5.1 
Rationale for Investigation of Dosing Interval With Respect to COVID-19 
Vaccines 
There are concerns that the prior use of a vectored vaccine may result in anti-vector responses, 
which would decrease the response to a subsequent use of the same vector. Specifically, there 
have been concerns raised that the use of the AstraZeneca ChAdOx1-SARS-CoV-2 vaccine 
(AZD1222 or Vaxzevria®) might reduce either the antibody or T cell response to a subsequent 
vaccine using the same vector. This potential decrease has been attributed to the induction of a 
neutralising cross-reactive T cell response to the viral vector.  
For adenoviral vectors, prior infection with a replicating adenovirus of the same strain (e.g., 
human adenoviral 5) does appear to have an effect on the subsequent T cell and antibody 
response. However, this neutralisation is primarily directed against the fibre protein. This 
interference was a primary motivating factor in the development of replication-incompetent 
adenoviral vectors based on simian strains (chimpanzee, bonobo, and gorilla). In contrast, the 
neutralisation resulting from the use of the replication incompetent adenoviral vectors 
themselves is directed primarily to the abundant hexon capsid protein, and this response may 
have only minor effect on cell entry and immunogenicity, mainly mediated by the fibre.  
In studies of AZD1222, there was no statistical relation between the level of neutralisation 
response following the first immunisation, and the resultant antibody or T cell response (as 
measured by IFN-γ ELISpot) following a second immunisation [27]. Likewise prior receipt of 
a ChAdOx1 vaccine (either ChAdOx1-MERs or ChAdOx1-mening) had no effect on the 
response to AZD1222.  
However, the improvement of antigen-specific immunogenicity of a delayed interval is 
supported by reports in the literature of clinical trials assessing homologous or heterologous 
prime-boost regimes with adenoviral vectors [28-33]. In summary, the longer the interval 
between first and second dose of the adenoviral vector, the better the antigen-specific boosting 
capacity of the second dose. This has been mostly studied with antibody responses to the same 
adenoviral vector encoding the same antigen. This has been in part attributed to declining titres 
of vector-neutralising and vector-binding antibodies with time. Specifically, antigen-specific 
antibodies were boosted 3-fold when the boosting interval was 4 weeks, but this increased to 
10-fold when the interval between the two vaccines was 24 weeks [29]. In another study, 
antibody titres were boosted 10-fold after a prime-boost interval of 12 weeks, and T cells were 
also boosted [28]. Nonetheless, it is well-known that increasing interval may boost responses, 
and the association of the increase in titres with increasing intervals has not been clearly shown 
in any of the cited studies to be attributed to the level of anti-vector neutralizing antibodies.  

 
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It is important to note that all previous clinical experience with second administration of the 
same adenoviral vector has been in the context of a single antigen, for example, Ad26-gag 
prime followed by Ad26-gag boost. This is in contrast to the scenario discussed here, where a 
possible administration of the ChAdOx1-nCoV-19 vaccine is followed by administration of a 
ChAdOx1 vector encoding HBV antigens. This is not a prime-boost scenario per se but rather 
the re-use of the same vector platform in a different indication.  
Given this uncertainty and the improved responses seen three months after initial immunization 
compared to one month in studies of homologous prime-boost of the same antigen, and lacking 
clear data, the Sponsor has advised that participants not receive the ChAdOx1 vaccine in this 
and other 
-sponsored trials until at least three months after receiving the AZD1222 
or J&J hAd26, and that a three-month interval should also be advised if the COVID-19 vaccine 
follow entry into our study. However, this is not based on firm data, and either a shorter or 
longer interval may indeed be warranted. 
To support this interval, this study aims to produce data of the response in healthy volunteers 
to our ChAdOx-1 HBV vaccine following the use of the AZD1222 vaccine. T cell responses 
(the critical immunological factor in chronic HBV infection) will be compared in participants 
who have received either a prior two-dose series of AZD1222 with those who have received at 
least two prior doses of either the Pfizer mRNA COVID 19 vaccine (Comirnaty) or the 
Moderna COVID-19 vaccine (Spikevax). Due to the recommendation to use the AZD1222 in 
those over the age of 40 years, we will confine our study to 40-60 years of age and keep the 
interval from the latest COVID-19 vaccine to a narrow window of 10-18 weeks. No 
interference on HBV -focused T cell responses is expected from either the Pfizer vaccine or 
the Moderna vaccine, so the interval from the latest COVID-19 vaccine will be between 6 to 
30 weeks 

 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Determine the safety and tolerability of 
different doses of a single vaccination of 
ChAdOx1-HBV in healthy participants and in 
participants with CHB infection and virally 
suppressed with oral antiviral medication. 
Primary 
Incidence of safety and reactogenicity events: 
• 
Adverse events and/or adverse events 
leading to study discontinuation 
• 
Serious adverse events 
• 
Grade ≥3 local and systemic reactions 
Secondary 
• 
Determine 
the 
immunogenicity 
of 
ChAdOx1-HBV in (A) healthy participants 
and in (B) participants with CHB, virally 
suppressed with oral antiviral medication 
Determine the effect of ChAdOx1-HBV on 
the level of HBsAg in participants with 
CHB infection, virally suppressed with oral 
antiviral medication 
 
 
 
• 
Cohorts 5 and 6 only: Assess whether the 
receipt of prior ChAdOx1-SARS-CoV-2 
vaccine (AZD1222) results in decreased 
T cell responses to ChAdOx1-HBV, when 
administered 
10-18 weeks 
prior 
to 
ChAdOx1-HBV 
Secondary 
• 
A multi-parameter index made of CD4+ 
magnitude, CD4+ avidity, and CD8+ 
magnitude 
• 
Mean reduction in HbsAg titre at 
Day 84 and Day 168 post-vaccination 
(last visit) 
• 
Proportion of CHB participants with 
HbeAg and HbsAg loss 
• 
Proportion of CHB participants with 
HbeAg and HbsAg seroconversion 
• 
Reduction of hepatitis B DNA levels 
• 
Total T cell response to the antigens 
encoded 
by 
ChAdOx1-HBV 
as 
measured 
in 
a 
peptide-stimulated 
ELISpot assay 
Exploratory 
Determine the effect of ChAdOx1-HBV on 
virological and immunological systemic and 
intrahepatic changes in participants with CHB 
infection and virally suppressed with oral 
antiviral medication. 
Exploratory 
• 
Effect on serum hepatitis B core-related 
antigen (HBcAg) 
• 
Effect on serum hepatitis B circulating 
pre-genomic ribonucleic acid (pgRNA)  
• 
Liver fine needle aspirate (LFNA) 
assays will be used to quantify and 
characterise intrahepatic immune and 
parenchymal cells and/or HBV DNA 
and RNA transcripts 
• 
Effect of prior AZD1222 on the CD4+ 
and CD8+ T cell magnitude and 
phenotype 
as 
measured 
by 
multiparameter flow cytometry 
 

 
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3 
STUDY OVERVIEW 
3.1 
Overall Study Design and Methodology 
3.1.1 
Study Design 
This is a Phase 1, first in human study of ChAdOx1-HBV. The study will be conducted in 
40 healthy participants and 12 participants with CHB and virally suppressed with oral antiviral 
medication. This will be an open-label, non-randomised dose escalation study comparing the 
safety, tolerability and immunogenicity of 2 different doses of ChAdOx1-HBV vaccine. T cell 
responses in healthy participants who have received a prior two-dose series of AZD1222 or at 
least two doses of the Pfizer or Moderna mRNA COVID-19 vaccines will also be analysed. 
The study design is shown in Figure 2. 
Figure 2 
Overall Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ChAdOx1-HBV=chimpanzee adenovirus-vectored hepatitis B virus vaccine; CHB=chronic 
hepatitis B virus; HD=high dose; LD=low dose; N=number of participants; vp=viral particles 
Five reviews of the safety, tolerability and available immunogenicity data will be performed 
by a Safety Monitoring Committee (SMC): 
• 
First review: at least 48 hours after the first healthy participant has received the first 
low dose of ChAdOx1-HBV vaccine. This review will occur before dosing the 
remaining participants in cohort 1 
• 
Second review: at least 48 hours after the last healthy participant has received the last 
low dose of ChAdOx1-HBV vaccine. This review will occur before dosing high dose 
healthy participants in cohort 2 
• 
Third review: at least 48 hours after the last healthy participant has received the last 
high dose of ChAdOx1-HBV vaccine. This review will occur before dosing low dose 
CHB participants in cohort 3 
Cohort 4 (N=6) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 1 (N=5) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Cohort 2 (N=5) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Healthy Participants 
CHB Participants 
Cohort 3 (N=6) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Healthy Participants 
Cohort 5 AZD1222 
(N=15) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 6 
Pfizer/Moderna mRNA
(N=15) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 

 
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• 
Fourth review: at least 48 hours after the first CHB participant has received the first 
low dose of ChAdOx1-HBV vaccine. This review will occur before dosing the 
remaining participants in cohort 3 
• 
Fifth review: at least 48 hours after the last participant with CHB has received the low 
dose of ChAdOx1 HBV vaccine cohort 3 before dosing high dose CHB participants in 
cohort 4 
No SMC review is required for cohorts 5 and 6 as the dose administered has been assessed in 
the previous cohorts of healthy participants. 
A Data Monitoring Committee (DMC) will be appointed to perform unscheduled reviews of 
the available data including safety and tolerability study data and make recommendations 
concerning the continuation, modification or termination of the study if one of the study 
stopping or holding rules defined in Section 3.1.3 is met. 
3.1.2 
Study Methodology 
Participants will be screened in the period Day -42 to Day -1. Informed consent will be 
obtained before any study specific procedures are performed. Eligible participants will then 
attend the clinic to receive study vaccine on Day 0. Participants will be enrolled sequentially.  
The study will investigate response to study vaccine as shown in Table 2. On Day 0, an 
electronic diary (eDiary), tape measure and thermometer will be provided to perform 
self-assessment of local and systemic reactogenicity. All participants will then have a follow-up 
telephone call on Day 1 and return to the clinic for study assessments on Days 7, 14, 28, 84. 
Participants in cohorts 1-4 only, will also have follow up visits on Day 56 and Day 168.  End 
of study visit procedures will be performed at the final visit. 
Five healthy participants will be administered the low dose first (cohort 1). Dose escalation 
will only be initiated in the next 5 healthy participants (cohort 2) following SMC review. 
Six CHB participants will be administered the low dose (cohort 3) before the dose escalation 
is initiated in the remaining 6 CHB participants (cohort 4). 
Thirty healthy participants (15 who have received two doses of AZD1222 [cohort 5] and 
15 who have received at least two doses of either Pfizer or Moderna mRNA COVID-19 vaccine 
[cohort 6]) will be dosed in parallel with the high dose used in cohorts 2 and 4. 
The first participant in each of cohorts 1-4 will be assessed for 1 hour in the clinic 
post-vaccination in case of immediate adverse events (timed after the end of study vaccine 
administration). All other participants will be assessed for 30 minutes. 
The safety and immunogenicity assessments to be performed in cohorts 1-4 are: 
• 
Haematology (full blood count, haemoglobin, haematocrit, erythrocytes, mean cell 
volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, 
leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, fibrinogen, 
prothrombin time [PT] and international normalised ratio [INR], activated partial 
thromboplastin time [aPTT] and platelets) will be analysed at screening, 
pre-vaccination on Day 0 and on Days 7, 14, 28, 56, 84 and 168 
• 
Biochemistry (sodium, potassium, urea, creatinine and albumin) will be analysed at 
screening, pre-vaccination on Day 0 and on Days 7, 14, 28, 56, 84 and 168 
• 
Liver function tests (LFTs; alkaline phosphatase [ALP], gamma-glutamyl 
transpeptidase [GGT], alanine transaminase [ALT], aspartate transaminase [AST] and 

 
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total bilirubin) will be analysed at screening, pre-vaccination on Day 0 and on Days 7, 
14, 28, 56, 84 and 168 
• 
HBV disease markers in serum: 
o  Healthy participants: qualitative HBsAg will be tested at screening, hepatitis B 
surface antibody (HBsAb) and HBcAb will be tested at Day 0, and repeated at 
the end of the trial if negative at baseline, or at discretion of the Investigator 
o CHB participants: HBV DNA and quantitative HBsAg will be tested at 
screening and repeated on Days 0, 28, 56, 84 and 168. The following parameters 
will also be analysed on days 0, 28, 56, 84 and 168: HBeAg, HBcAg, anti-HBs, 
anti-HBe, anti-HBc, pgRNA  
• 
A full physical examination will be performed at screening and pre-vaccination on 
Day 0. A symptom-directed physical examination will be performed on Days 7, 14, 28, 
56, 84 and 168 
• 
Vital signs will be performed at screening, pre-vaccination and post-vaccination at the 
on Day 0 and on Days 7, 14, 28, 56, 84 and 168 
• 
Local and systemic reactogenicity (pain, induration, warmth, erythema at the 
vaccination site plus feverishness, chills, myalgia, fatigue, headache, nausea, arthralgia, 
malaise) will be captured pre-vaccination and post-vaccination on Day 0 and by eDiary 
for 3 days post-vaccination 
• 
Unsolicited adverse events will be recorded in the eCRF from the date the informed 
consent is signed, at all clinic visits to cover the period since the previous visit and 
during the visit and up to 28 days post-vaccination 
• 
Serious adverse events (SAEs) and adverse events of special interest (AESIs) will be 
recorded from the date the informed consent is signed until the end of the study and or 
resolved or until participant contact discontinues 
• 
Cellular immune responses will be measured in peripheral blood mononuclear cells 
(PBMCs) samples taken on pre-vaccination on Day 0 and on Days 14, 28, 56, 84 and 
168. Samples will be analysed by ICS 
For participants in cohorts 5 and 6, all assessments on Days 0, 7, 14, 28 and 84 above will be 
performed. In addition, neutralising antibodies to ChadOx1 will be assessed on Days 0 and 84. 
In CHB participants who consent to LFNAs, these will be taken pre-vaccination within the 
screening period and at the clinic visit on Day 84. Liver fine needle aspirate assays may be 
used to quantify and characterise intrahepatic immune and parenchymal cells and/or HBV 
DNA and RNA transcripts. These aspirates and subsequent LFNA assessments are optional. 
3.1.3 
Study Stopping Criteria/Holding Criteria/Dose Escalation Process 
There will be a review of the study data by the DMC when there is a reasonable possibility that 
the investigational vaccine caused any of the listed following adverse events based on the 
assessment of the Investigator in one or more participants at any dose. Vaccinations will be 
held pending this review: 
• 
Death  
• 
Life-threatening adverse event or life-threatening suspected reaction 
• 
Serious suspected adverse reaction 

 
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• 
Suspected, unexpected, serious adverse reaction (SUSAR)  
• 
Acute allergic reaction or anaphylactic shock following the administration of vaccine 
investigational product  
• 
Anaphylaxis or bronchospasm, indicative of an immediate hypersensitivity reaction to 
study vaccine 
• 
If any participant has any of the following: 
− 
ALT or AST >8 x upper limit of normal (ULN) 
− 
ALT or AST >5 x ULN for more than 2 weeks  
− 
ALT or AST >3 x ULN and (total bilirubin >2 x ULN or INR >1.5) 
− 
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
The competent authority and Research Ethics Committee (REC) will be notified of a temporary 
halt within 15 days according to the local requirements. If, following the review of data, a 
recommendation is made by the DMC to resume study enrolment and vaccine administration, 
the DMC will record their judgment in a memorandum to the study file and notify the Sponsor. 
The DMC memorandum will be forwarded to the local Medical Monitor and Investigators. 
3.1.4 
Duration of Study 
 
Duration for Each Participant 
Cohorts 1-4: Up to 8 months (up to 1.5 months for screening and 6.5 months on the study with 
study vaccine given on Day 0). 
Cohorts 5 and 6: Up to 4.5 months (up to 1.5 months for screening and 3 months on the study 
with study vaccine given on Day 0). 
 
Duration of Study 
It is planned that the study will take 16 months to implement, enrol and read out. 
The end of the study is defined as the date of database lock. 
3.2 
Discussion of Study Design 
This is a first in human study of the ChAdOx1 vaccine and is designed to assess the safety in 
both healthy adults, as well as in the target CHB population. As T cell responses to natural 
infection are blunted or exhausted in participants with CHB, it will be important to determine 
how responses in CHB compare to healthy participants. Given the uncertainty around prior use 
of a vectored vaccine resulting in anti-vector responses, this study will also assess the response 
of healthy participants who have previously received AZD1222 to ChAdOx1-HBV. 
In CHB participants, low dose of the vector (selected based on doses given in a large number 
of other studies (NCT03399578, NCT03203421, NCT01818362, NCT01623518 and 
NCT03815942), will first be evaluated to minimise the risk that immune responses generated 
by vaccination do not results in liver toxicity. To further minimise this likelihood, only those 
participants whose DNA levels are well controlled on antivirals will be included in the study, 
and those with advanced liver fibrosis or cirrhosis will be excluded. After safety review, a 
higher dose, but one shown to be safely used in many other ChAdOx1 studies (HIV, malaria, 
influenza, MERS), will then be given. Dose selection for future studies will be based on safety 

 
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and the induction of T cell activity, as measured by both magnitude of response as well as 
functionality.  
Hepatitis B biomarkers will be evaluated as the basis for future comparison and to assess 
potential efficacy.  
The study will be used as a first step prior to the evaluation of a combination vaccine approach 
using ChAdOx1-HBV combined with both a MVA encoding the same genetic insert, with or 
without a low dose PD-1 inhibitor.  
3.3 
Benefit Risk Assessment 
There are potential known and unknown risks associated with vaccination. With any vaccine, 
including those that are licensed, there is a rare risk of anaphylaxis which can be fatal. All 
participants will be observed in the clinic for at least 30 minutes post-vaccination.  
Intramuscular injection of vaccines frequently causes the local and systemic signs and 
symptoms that are being collected as adverse events. These will be solicited from the 
participant to ensure they are not occurring more frequently or are more severe than expected 
based on previous experience with the same or similar viral vectors.  
With any new treatment there is always a possibility of an unexpected adverse events. 
The administration of ChAdOx1-HBV in this study may interfere with the effectiveness of 
other vaccines subsequently administered to the participant. The ChAdOx1 vector induces 
anti-vector immunity in addition to an antigen-specific immune response. Of particular concern 
are neutralising antibodies directed against the capsid structure of the vector, which may have 
a negative effect on subsequent immunisations with the same or related adenoviral vector by 
neutralising the vector before it has a chance to transduce target cells.  This effect decreases 
with longer interval between the vaccines [28,29].  In particular, there is a concern that the 
ChAdOx1-HBV administered in this study could decrease the response to the AstraZeneca 
COVID-19 vaccine, which has the same viral vector, especially if it is administered within 
3 months of ChAdOx1-HBV. The Janssen (Johnson & Johnson) COVID-19 vaccine is also 
made with an adenovirus, and some interference cannot be ruled out. Therefore, it is 
recommended that participants in this study receive an alternative type of COVID-19 vaccine, 
such as an mRNA or protein vaccine, at least 2 weeks before and after ChAdOx1-HBV in this 
study. 
There are also routinely scheduled reviews of safety and efficacy data throughout the study by 
the SMC. Stopping and holding rules have been defined for the study (see Section 3.1.3) and a 
DMC will perform a review of safety data if one of these is met.  
Although this is the first time ChAdOx1-HBV has been administered to humans, the ChAdOx1 
vector has been widely administered for many pathologies without significant safety concerns 
(see Section 1.4). Further detail is provided in the Investigator’s Brochure. 
As this is a first in human study without prior clinical data there may be no benefit to study 
participants. The participants in the CHB groups will however receive additional monitoring 
of their HBV status compared to the standard of care. 

 
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4 
STUDY POPULATION 
4.1 
Number of Participants 
It is planned that 40 healthy participants and 12 participants with CHB infection and virally 
suppressed with oral antiviral medication will be enrolled in the study. Chronic HBV 
participants will be recruited/deemed eligible by hepatologists, infectious disease specialists or 
physicians experienced in treating CHB participants. Centres not meeting the enrolment 
expectations will be considered for replacement with or addition of a new site. If participants 
leave the study before all follow-up visits are completed (for any reason), then these may be 
replaced at the discretion of the study team. A log of all participants enrolled into the study (i.e. 
having given informed consent) will be maintained in the Investigator’s Site File (ISF) at the 
study centre irrespective of whether they have treated with vaccine or not. 
A total of 10 healthy participants and 12 participants with CHB infection is considered 
sufficient to confirm the safety, tolerability and immunogenicity of ChAdOx1-HBV and to 
answer the objectives of the study before progressing to larger studies. An additional 30 healthy 
participants (15 who have received two doses of AZD1222 and 15 who have received at least 
two doses of either Pfizer or Moderna mRNA COVID-19 vaccine) will be recruited to assess 
whether prior receipt of AZD1222 results in decreased T cell responses to ChAdOx1-HBV. 
The statistical considerations used to determine the number of participants planned and 
evaluable are presented in Section 10.1. 
4.2 
Inclusion Criteria 
Participants must meet all the following criteria to be eligible for the study: 
1. Adult males or females aged ≥18 to ≤65 years at screening 
2. Body Mass Index ≤30 kg/m2 
3. Able to provide informed consent indicating they understand the purpose of, and 
procedures required, for the study and are willing to participate  
4. If female, willing not to become pregnant up to 8 weeks after last dose of study vaccine, 
not breast feeding 
5. If female: Not pregnant and one of the following: 
• 
Of non-childbearing potential (i.e. women who have had a hysterectomy or tubal 
ligation or are post-menopausal, as defined by no menses in ≥1 year) 
• 
Sexual abstinence, only if the participant refrains from heterosexual intercourse 
during the entire study period and it is the usual lifestyle of the participant 
• 
Of childbearing potential but agrees to practice highly effective contraception for 
4 weeks prior to study vaccine and 8 weeks after study vaccine. Highly effective 
methods of contraception include one or more of the following:  
− Male partner who is sterile (medically effective vasectomy) prior to the female 
participant’s entry into the study and is the sole sexual partner for the female 
participant 
− Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− oral 
− intravaginal 

 
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− transdermal 
− Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
− oral 
− injectable 
− implantable 
− An intrauterine device  
− Bilateral tubal occlusion 
Healthy participants (cohorts 1 and 2): 
6. Considered to be healthy with no current conditions that may significantly impair 
participant safety or influence study results, in the opinion of the Investigator 
Participants with well controlled CHB (cohorts 3 and 4): 
7. Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with 
detectable HBsAg levels at screening) 
8. Receipt of only either entecavir or tenofovir for at least 12 months before screening 
9. Virally suppressed (HBV DNA <40 IU/mL for ≥6 months) 
10. HBsAg <10000 IU/mL 
Healthy participants (cohort 5): 
11. Considered to be healthy with no current conditions that may significantly impair 
participant safety or influence study results, in the opinion of the Investigator 
12. Adult males or females aged ≥40 to ≤60 years at screening 
13. Completed second dose of COVID-19 AZD1222 vaccine 10 to 18 weeks before 
enrolment 
Healthy participants (cohort 6): 
14. Considered to be healthy with no current conditions that may significantly impair 
participant safety or influence study results, in the opinion of the Investigator 
15. Adult males or females aged ≥40 to ≤60 years at screening 
16. Received the latest dose of either Pfizer (Comirnaty®) or Moderna (Spikevax) mRNA 
COVID-19 vaccine 6 to 30 weeks before enrolment 
4.3 
Exclusion Criteria 
1. 
Presence of any significant acute or chronic, uncontrolled medical/psychiatric illness 
2. 
Hepatitis C virus (HCV) antibody positive.  
3. 
HIV antibody positive 
4. 
History or evidence of autoimmune disease or known immunodeficiency of any cause  
5. 
Prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics 
(e.g. monoclonal antibodies, IFN) within 3 months of screening 
6. 
Receipt of immunoglobulin or other blood products within 3 months prior to screening 
7. 
Receipt of any investigational drug or vaccine within 3 months prior to screening  
8. 
Cohorts 1-4: Receipt of any adenoviral vaccine within 3 months prior to administration 
of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-based vaccine within 
3 months after Day 0 

 
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Cohorts 5 and 6: Receipt of any adenoviral vaccine (other than AZD1222 per inclusion 
criterion 13) within 3 months prior to administration of ChAdOx1-HBV on Day 0, or 
plan to receive an adenoviral-based vaccine within 3 months after Day 0 
9. 
Receipt of any live vaccines within 30 days prior to screening 
10. 
Receipt of any inactivated vaccines within 14 days prior to screening 
11. 
History of allergic disease or reactions likely to be exacerbated by any component of the 
vaccine 
12. 
Any history of anaphylaxis in reaction to vaccination 
13. 
Malignancy within 5 years prior to screening with the exception of specific cancers that 
are cured by surgical resection (e.g. except basal cell skin carcinoma of the skin and 
cervical carcinoma). Participants under evaluation for possible malignancy are not 
eligible 
14. 
Current alcohol or substance abuse judged by the Investigator to potentially interfere with 
participant safety and compliance  
15. 
Significant cardiac disease or unstable uncontrolled cardiac disease 
16. 
Any laboratory test at screening which is abnormal and which is deemed by the 
Investigator to be clinically significant 
17. 
Any other finding that, in the opinion of the Investigator, deems the participant unsuitable 
for the study 
Additionally, for healthy participants (cohorts 1, 2, 5 and 6) 
18. 
HBsAg positive 
Additionally, for participants with well controlled CHB (cohorts 3 and 4) 
19. 
Co-infection with hepatitis delta  
20. 
Documented cirrhosis or advanced fibrosis indicated by a liver biopsy within 6 months 
prior to screening.  
In the absence of an appropriate liver biopsy, either 1 of the following:  
• 
Screening Fibroscan with a result >9 kPa within ≤6 months of screening 
or 
• 
Screening FibroTest >0.48 and AST to platelet ratio index of >1 
In the event of discordant results between non-invasive methods, the Fibroscan result 
will take precedence. 
21. 
ALT >3 × ULN, INR >1.5 unless the participant was stable on an anticoagulant regimen 
affecting INR, albumin <35 g/L, total bilirubin >34.2 µmol/L, platelet count <100 x 109/L 
22. 
A history of liver decompensation (e.g. ascites, encephalopathy or variceal haemorrhage) 
23. 
Prior or current hepatocellular carcinoma 
24. 
Chronic liver disease of a non-HBV aetiology 
25. 
Any herbal supplements and or other medicines with potential liver toxicity within the 
previous 3 months prior to enrolment into this study 

 
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4.3.1 
Removal of Participants from Vaccination or Assessment 
 
Contraindications to Vaccination 
The following events constitute contraindications to administration of study vaccine at that 
point in time; if any one of these events occurs at the time scheduled for vaccination, the 
participant may be vaccinated at a later date, or withdrawn from the study at the discretion of 
the Investigator.  
• 
Acute disease at the time of vaccination. Acute disease is defined as the presence of a 
moderate or severe illness with or without fever. All study vaccines can be administered 
to participants with a minor illness such as diarrhoea, mild upper respiratory infection 
with or without low-grade febrile illness 
• 
Temperature of >38°C (100.4°F) at the time of vaccination 
 
Study Discontinuation 
Participants may choose to discontinue study assessments by withdrawal of consent. If the 
participant discontinues from taking the study vaccine but does not withdraw consent, the 
Investigator or research worker should attempt to continue safety follow-up assessments.  
Participants may be withdrawn from the study vaccine, but followed up for safety, in the event 
of: 
• 
A severe adverse event or SAE 
• 
Difficulties in obtaining blood or other samples 
• 
Failure of the participant to comply with the protocol requirements or to cooperate with 
the Investigator 
• 
For safety reasons, it being in the best interest of the participant that he/she be 
withdrawn, in the Investigator’s opinion 
• 
A positive pregnancy test or if the participant is non-compliant with the contraception 
requirements (see Section 4.2) 
• 
Development of a medical condition that requires concomitant treatment with a 
potentially toxic therapy 
Participants must be withdrawn from the study in the event of: 
• 
Withdrawal of consent 
4.3.2 
Study Termination 
The study may be terminated, either at one centre or all centres for the following reasons: 
• 
The discovery of an unexpected, serious or unacceptable risk to participants enrolled in 
the study 
• 
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation or 
development of ChAdOx1-HBV. In the event of the Sponsor’s decision to no longer 
supply study vaccine, ample notification will be provided so that appropriate 
adjustments to treatment can be made 

 
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• 
Serious failure of the Investigator to comply with International Council on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) Good Clinical Practice (GCP) [34] or local regulations 
• 
Submission of knowingly false information from the study centre to the Sponsor, the 
Health Research Authority (HRA)/ REC or Competent Authorities 
• 
Major and repeated, non-adherence to the protocol 
The Sponsor must be informed immediately in the event of any major protocol deviation or 
serious breach of ICH GCP. 

 
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5 
STUDY VACCINE 
The Investigator must ensure that study vaccine is handled only by study team members who 
have been appropriately trained for the conduct of this clinical study and that dosing is only 
performed by study team members who fully understand the procedures outlined in this section, 
the Investigator's Brochure and the Investigational Product (IP) Handling Manual. A 
Delegation of Authority Log will be maintained by the study centre and will identify the 
individual(s) authorised to prepare and administer the study vaccine. 
5.1 
Study Vaccines Administered 
ChAdOx1-HBV is a non-replicating viral vector encoding HBV consensus sequences from a 
group C genotype. It will be given by intramuscular injection into the deltoid muscle in the 
non-dominant arm. 
The study vaccine to be given in each treatment group are shown in Table 1. 
Table 1 
Study Vaccine Treatment Groups in HBV001 
Treatment Cohort 
Vaccine Single Dose 
N 
Cohort 1 LD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 109 vp 
5 
Cohort 2 HD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 1010 vp 
5 
Cohort 3 LD 
Participants with CHB 
ChAdOx1-HBV 
2.5 x 109 vp 
6 
Cohort 4 HD 
Participants with CHB 
ChAdOx1-HBV 
2.5 x 1010 vp 
6 
Cohorts 5 and 6 HD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 1010 vp 
30 
Abbreviations: ChAdOx1-HBV=chimpanzee adenovirus-vectored hepatitis B virus vaccine; CHB=chronic 
hepatitis B virus; HD=high dose; LD=low dose; vp=viral particles 
All study vaccine will be administered in a sequential manner. Participants will receive study 
vaccine on Day 0 only. 
5.2 
Identity of Study Vaccine 
ChAdOx1-HBV will be manufactured to Good Manufacturing Practice, labelled according to 
local regulations, including Annex 13 of the Good Manufacturing Practice Directive [35] as 
detailed in the IP Handling Manual.  
ChAdOx1-HBV is formulated in an A438 buffer comprising of 10 mM histidine, 35 mM NaCl, 
7.5% sucrose (w/v), 1 mM MgCl2, 0.1% (w/v) PS-80, 0.1 mM ethylenediaminetetraacetic acid 
(EDTA), 0.5% ethanol (v/v), pH 6.6 to a target concentration of 1 x 1011 vp/mL. 
ChAdOx1-HBV will be supplied at a target sterile volume of 0.65 mL in 3 mL Type 1 
borosilicate glass vials allowing 0.5mL to be drawn by syringe for dilution into high dose HBV 
vaccine and low dose HBV vaccine. Dilution to both low and high doses will be detailed in the 
IP Handling Manual. The vials are stoppered with sterilised European Pharmacopoeia/United 

 
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States 
Pharmacopoeia 
Type 1 
chlorobutyl, 
rubber 
stopper 
and 
sealed 
with 
aluminium/copolymer caps. The vaccine is clear to slightly opaque in appearance 
The study vaccines will be released by a qualified person.  
5.3 
Labelling, Packaging and Shipping 
Study vaccine will be shipped by Catalent Pharma Solutions to the study centres on dry ice 
with a continuous temperature monitoring device.  
Upon receipt, the pharmacist or designee must immediately inspect all vials for damage. Any 
damage or discrepancies from the packing list must be documented and promptly discussed 
with the Sponsor and the Study Monitor to determine the appropriate action. The temperature 
monitors should be downloaded according to the accompanying instructions in the shipment. 
Temperature records must be sent to the Sponsor and the centre will receive written 
confirmation that the vials are clinically released before they are used. If the temperature 
monitor has been out of range, then the shipment should be placed into quarantine and the 
Sponsor and Study Monitor contacted immediately to determine whether the study vaccine 
may be used. 
At the start of the study, a sufficient number of study vaccine vials will be shipped to each 
study centre based on projected recruitment at each centre with approximately 20% overage in 
case of spillage or breakage. Further study vaccine supplies may be requested following the 
re-supply process in the IP Handling Manual. 
5.4 
Storage 
Vials of study vaccine in the outer carton (to protect from light) must be stored in a 
continuously monitored freezer at ≤-65°C.  
All study vaccine must be kept in a secured location with no access for unauthorised personnel. 
5.5 
Accountability 
The pharmacist or designee is required to maintain accurate accountability records for the study 
vaccine. Instructions and forms to be completed and kept for accountability will be provided 
to the pharmacist or designee. If the pharmacist or designee wishes to use study centre-specific 
accountability forms, these must be reviewed and approved in advance by the Sponsor. Upon 
completion of the study, all accountability records will be copied and the copies returned to the 
Sponsor or designee. The originals must be maintained at the study centre with the rest of the 
study records. 
The number of vials of study vaccine received and dispensed must be recorded on a participant 
by participant basis, including the applicable batch number.  
5.6 
Destruction or Disposal 
The Sponsor will provide instructions for the return of unused ChAdOx1-HBV. Genetically 
modified organism (GMO) waste, including empty vials after full study vaccine accountability 
has been conducted, will be destroyed by appropriately licensed vendors. This destruction will 
be recorded with an original copy kept at site and a copy sent to the Trial Master File. 

 
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5.7 
Method of Assigning Participants to Treatment Groups 
At the screening visit, participants will be sequentially allocated a participant number once 
written, informed consent has been obtained. They will be identified by this number throughout 
the study. 
In cohorts 1-4, the healthy and CHB participants will be allocated to low dose or high dose 
treatment depending on the treatment schedule prepared by statistician. 
As cohorts 5 and 6 were introduced following completion of enrolment of the healthy 
participants in cohorts 1 and 2, all further healthy participants enrolled under protocol 
version 7.0 and 8.0 will receive high dose treatment. 
Participants fulfilling entry criteria will be allocated to treatment based on a treatment schedule.  
Once participant numbers have been assigned, no attempt will be made to use those numbers 
again. If a participant number is allocated incorrectly, no attempt will be made to remedy the 
error once the study vaccine has been dispensed. Any participants that are withdrawn prior to 
vaccination will be replaced on a case by case basis following discussion with the Sponsor. 
Discontinued participants following vaccination who do not complete all follow-up visits will 
be replaced at the determination of the Sponsor. 
Any replacement participants will be given the next sequential participant number. 
The treatment schedule list will be held by the statistician during the study. 
5.8 
Selection of Doses, Dosing Schedule and Administration  
5.8.1 
Selection of Doses in the Study 
The doses of adenoviruses have been taken from historical context of innumerable previous 
adenovirus vaccine studies. A review of the adenoviral pre-clinical and clinical literature 
reveals that the overall T cell response may vary for CD4 and CD8+ T cells, and a number of 
studies have shown that the highest dose of T cell inducing vaccines is not necessarily the most 
protective dose [36,37]. It is hypothesised that the most therapeutic vaccines will need to induce 
both CD4+ and CD8+ T cells, as well as highly functional T cell responses. A scoring system 
will be used to choose the dose to move to further development, which is a combined score for 
CD4+ magnitude of a pooled cytokine response, CD4+ functionality (as measured by CD4+ 
IFN-γ mean fluorescence intensity from ICS flow cytometry) and CD8+ magnitude.  
5.8.2 
Selection and Timing of Dose for each Participant 
 
Dosing Schedule 
The healthy and CHB participants will be allocated to low dose or high dose treatment 
depending on the assignment. Vaccination will be performed on Day 0 after eligibility has been 
re-confirmed. 
There are no restrictions in the time of day that the vaccination should be administered or in 
timing of vaccination in relation to meals. 

 
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Study Vaccine Preparation and Administration 
ChAdOx1-HBV vials will be allowed to reach room temperature before use.  
Doses of ChAdOx1-HBV will be prepared by serial dilution according to the procedure in the 
Investigational Product (IP) Handling Manual. Dilution kits of commercially available 
equipment will be provided by the Sponsor. 
All vaccinations will be made by a suitably qualified health professional. A second study team 
member will be present to account for each vaccination given. 
The suitably qualified healthcare professional will wear gloves, eye protection and an apron or 
laboratory coat/gown during the procedure. The vaccination site will be covered with a sterile 
dressing to minimise dissemination of the recombinant virus into the environment. This should 
absorb any virus that may leak out through the needle track. The sterile dressing will be kept 
at least 10 minutes after vaccination. The dressing will be discarded as GMO waste.  
Allergic reactions to vaccination are possible, therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available and a medically 
qualified study team member trained to recognise and treat anaphylaxis must be present in the 
clinic during the entire vaccination procedure and post-vaccination observation period. 
 
Dose and Schedule Modifications 
Every effort will be made to administer the planned doses of study vaccine. 
5.9 
Prior and Concomitant Vaccines and Medications 
Prior (within the previous 28 days) and concomitant medications include prescription and 
non-prescription drugs or other treatments, and any vaccines other than the study vaccine.  
Recently used and ongoing medications will be reviewed and recorded during screening. 
Concomitant medications used by participants post-vaccination will coincide with the 
collection period of adverse events. All medications taken will be recorded in the eDiary and 
will be discussed with the participant at the scheduled clinic visits during the study. All 
medications taken in the first 28 days will be recorded in the electronic Case Report Form 
(eCRF). Thereafter, only medications taken to treat SAEs will be recorded. 
The name of the medication, treatment start and stop dates (or ‘ongoing’), and indication must 
be recorded on the concomitant medication eCRF. The indication recorded on the concomitant 
medication eCRF must correspond to a medical term/diagnosis recorded on the adverse event 
eCRF, or to a pre-existing condition noted in the participant’s medical history, or be noted as 
prophylaxis, e.g. dietary supplement. 
5.10 
Treatment Compliance 
Vaccine administration will take place at the study centre and will be performed by a suitably 
qualified healthcare professional. The precise date and time of vaccination shall be documented 
in the source documents and eCRF. The study will be monitored by a Study Monitor approved 
by the Sponsor. During monitoring visits, all procedures will be monitored for compliance with 
the protocol. Source documents will be reviewed and compared with the data entries in the 
eCRF to ensure consistency. 

 
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5.11 
Post-study Vaccine 
The Sponsor does not intend to provide ChAdOx1-HBV after the end of the study or after any 
early participant withdrawal, as there is currently no clinical data supporting their efficacy. 
These participants will remain under the care of their healthcare professionals and treated 
according to standard care. 

 
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6 
STUDY PROCEDURES AT EACH VISIT/SCHEDULE OF ASSESSMENTS 
The study consists of the following: 
• 
A 42-day screening period before the start of the study period 
• 
A study period of 168 days, consisting of a vaccination day on Day 0, a follow-up 
telephone call on Day 1 and follow-up visits on Days 7, 14, 28, 56. Participants in 
cohorts 1-4 only, will also have follow up visits on Day 56 and Day 168. End of study 
visit procedures will be performed at the final visit. 
The schedule of assessments at each visit is shown in Table 2 and listed in Section 6.1 to 
Section 6.4. The study assessments are described in Section 7. 
Note: any additional visits or assessments performed during the study e.g. to assess 
adverse events must also be recorded on the unscheduled procedures or unscheduled 
visits in the eCRF. 

 
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Table 2 
Overall Schedule of Assessments at Each Study Visit 
Visit/Call 
Screen 
Vaccination 
Follow-up 
End of Study 
Timepoint 
Day-42 to -1 
Day 0 
Day 1 
Day 7±1 
Day 14±1 
Day 28±2 
Day 56±3 
(cohorts 1-4) 
Day 84±7[a] 
Day 168±7 
(cohorts 1-4) 
 
Pre- 
0 
Post- 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Baseline/eligibility variables 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
X 
X 
 
 
 
 
 
 
 
 
 
HIV Ab, HCV Ab, HBsAg, HDV Ab[b]   
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (β-hCG) [c] 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Laboratory eligibility and safety tests 
 
 
 
 
 
 
 
 
 
 
 
Haematology [d] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Biochemistry[d] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Liver function tests[e] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Study vaccination 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
 
X 
 
 
 
 
 
 
 
 
Post-vaccination observation[f] 
 
 
 
X 
 
 
 
 
 
 
 
Other Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
Directed physical examination if required 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signs[g] 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Local/systemic reactogenicity [h] 
 
X 
 
X 
X 
 
 
 
 
 
 
Unsolicited adverse events [i] 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serious adverse events and adverse events 
of special interest  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for HBV disease markers  
 
 
 
 
 
 
 
 
 
 
 
Healthy participants (HBsAb, HBcAb) 
 
X 
 
 
 
 
 
 
 
 
X[j] 
CHB (HBV DNA, HBsAg quantitative)  
X 
X 
 
 
 
 
 
X 
X 
X 
X 

 
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Visit/Call 
Screen 
Vaccination 
Follow-up 
End of Study 
Timepoint 
Day-42 to -1 
Day 0 
Day 1 
Day 7±1 
Day 14±1 
Day 28±2 
Day 56±3 
(cohorts 1-4) 
Day 84±7[a] 
Day 168±7 
(cohorts 1-4) 
 
Pre- 
0 
Post- 
CHB (HBeAg, anti-HBe, anti-HBs, 
pgRNA, HBcAg, anti-HBc) 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Immunogenicity assessments 
 
 
 
 
 
 
 
 
 
 
 
Blood for cellular immunogenicity [k] 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Blood for neutralising antibodies 
(cohorts 5 and 6 only) 
 
 
X 
 
 
 
 
 
 
X 
 
Liver fine needle aspirates[l]† 
X 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine transaminase; aPTT=activated partial thromboplastin time; AST=aspartate transaminase; CHB=chronic hepatitis B virus; 
DNA=desoxyribonucleic acid; GGT=gamma-glutamyl transpeptidase; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; β-hCG=beta human chorionic 
gonadotrophin; HBcAg=hepatitis B core-related antigen; HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HBsAg=hepatitis B surface antigen; HCV=Hepatitis C virus; 
HDV=Hepatitis D virus; HIV=human immunodeficiency virus; ICS=intracellular cytokine staining; INR= international normalised ratio; LFNA=liver fine needle aspirate; pgRNA=pre-
genomic RNA; PBMCs=peripheral blood mononuclear cells; PT=prothrombin time 
†Optional assessments 
 
[a] 
End of Study Visit for cohorts 5 and 6 
[b] 
HDV Ab serology and HBsAg quantitative test will be done in CHB participants only; HBsAg qualitative test will be done in healthy participants; all participants will be tested for 
HIV and HCV serology 
[c] 
Female participants only 
[d] 
Full haematology (including PT/INR and aPTT) and biochemistry panel  
[e] 
Measurement of ALP, GGT, ALT, AST and total bilirubin 
[f] 
The first participant in each cohort will be assessed for 1 hour in case of immediate adverse events (timed after the end of study vaccine administration). All other participants will be 
assessed for 30 minutes 
[g] 
Pulse, blood pressure and temperature 
[h] 
Captured during clinic visits and then via eDiary for 3 days post-vaccination 
[i] 
Recorded in the eCRF from the date the informed consent is signed, at all clinic visits to cover the period since the previous visit and during the visit and up to 28 days post-vaccination 
[j] 
If negative at baseline, at discretion of the investigator  
[k] 
To be processed into PBMCs for analysis by ICS 
[l] 
Only in CHB participants who consent to LFNAs after confirming eligibility. Coagulation profile must be assessed prior to repeat LFNA on Day 84. For those consenting to LFNAs, 
blood for PT/INR and aPTT testing must be collected 

 
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6.1 
Screening and Baseline Pre-Dose Assessments 
Written informed consent for participation in the study must be obtained before performing 
any study specific screening tests or evaluations according to the process in Section 13.4.  
Unsolicited adverse events will be recorded from the date the informed consent is signed and 
at all clinic visits up to 28 days post-vaccination, by questioning the participant at each visit 
whether they had any adverse events since the previous visit and by observing the participant 
during clinic visits. 
Serious adverse events and AESIs will be recorded from the date the informed consent is signed 
until the end of the study and/or resolved or until participant contact discontinues. 
The following will be performed at screening: 
• 
Demographic data will be collected 
• 
Height and weight will be measured 
• 
A medical and disease history will be recorded, including any medications being taken 
• 
A blood sample will be taken for HIV, HCV, HBV, and in CHB participants only, hepatitis 
D Virus (HDV) diagnostic testing  
• 
Blood samples will be taken for haematology (including PT/INR and aPTT), 
biochemistry and LFTs 
• 
A urinalysis dipstick test will be performed 
• 
A urine pregnancy test will be performed, childbearing status recorded and if of 
childbearing potential, assessment of contraceptive measures performed 
• 
A full physical examination will be performed 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
All screening evaluations must be completed and reviewed to confirm that participants meet 
all eligibility criteria before the first dose of study vaccine. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
Concomitant medications will be recorded throughout the study by questioning the participant 
at each visit whether they took any concomitant medications since the previous visit.  
In CHB participants who consent to LFNAs: a LFNA will be performed within the screening 
period, after screening tests have shown eligibility, as directed by the Principal Investigator or 
delegated physician. These aspirates and subsequent assessments are optional 
NB. Coagulation profile must be assessed prior to repeat LFNA 
6.2 
Treatment Day Assessments (Day 0) 
The following will be performed pre-vaccination: 
• 
Re-check of eligibility criteria 
• 
A urine pregnancy test will be performed 
• 
Blood samples will be taken for haematology (including PT/INR and aPTT), 
biochemistry and LFTs 

 
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• 
A full physical examination will be performed 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
• 
A baseline assessment of local and systemic reactogenicity will be performed 
• 
Blood samples will be taken for immunogenicity assessments (including neutralising 
antibodies for cohorts 5 and 6 only) 
Participants will then receive study vaccine by intramuscular injection according to Table 1. 
All participants will be assessed for at least 30 minutes in the clinic after receiving the vaccine 
injection in case of immediate adverse events. The first participant in each cohort will be 
observed for 1 hour.  
The following will be performed post-vaccination: 
• 
The vaccination site will be covered with a sterile dressing during the observation 
period; it will then be removed and disposed of as GMO waste 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured at the end of 
the observation period 
• 
Local and systemic reactogenicity will be assessed at the end of the observation period 
• 
On Day 0, an eDiary, tape measure and thermometer will be provided to perform 
self-assessment of local and systemic reactogenicity for 3 days after the vaccination. 
On Day 0 participants will be reminded to do the following daily for the next 3 days: 
− 
Take and record their temperature  
− 
Measure and record the size of vaccination site redness 
− 
Assess the other solicited adverse events listed in the eDiary 
6.3 
Follow-up Period Assessments 
6.3.1 
Telephone Call: Day 1  
• 
eDiary to collect local and systemic reactions during 3 consecutive days 
post-vaccination 
6.3.2 
Clinic Visit: 7 
• 
A symptom-directed physical examination will be performed if required 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
• 
Blood samples will be taken for haematology (including PT/INR and aPTT), 
biochemistry and LFTs 
6.3.3 
Clinic Visit: Day 14 
• 
A symptom-directed physical examination will be performed if required 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
• 
Blood samples will be taken for haematology (including PT/INR and aPTT), 
biochemistry and LFTs 
• 
Blood samples will be taken for immunogenicity assessments 

 
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6.3.4 
Clinic Visit: Days 28, 56 (Cohorts 1-4) and 168 (End of Study Visit 
Cohorts 1-4) 
• 
A urine pregnancy test will be performed 
• 
A symptom-directed physical examination will be performed if required 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
• 
Blood samples will be taken for haematology (including PT/INR and aPTT), 
biochemistry and LFTs 
• 
Blood samples will be taken for immunogenicity assessments 
6.3.5 
Clinic Visit: Day 84 (including End of Study Visit Cohorts 5 and 6) 
• 
A symptom-directed physical examination will be performed if required 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
• 
Blood samples will be taken for haematology (including PT/INR and aPTT), 
biochemistry and LFTs 
• 
Blood samples will be taken for immunogenicity assessments (including neutralising 
antibodies for cohorts 5 and 6 only) 
• 
In CHB participants who consent to LFNAs: an LFNA will be performed with 
additional PT/INR and aPTT testing, as directed by the Principal Investigator or 
delegated physician. These aspirates and subsequent assessments are optional 
6.4 
Assessments at Unscheduled Visits 
Unscheduled visits may be required according to the participant’s condition; assessments 
performed will be recorded in the eCRF. 
6.5 
Participant Discontinuation 
Participants have the right to withdraw from the study at any time for any reason, including 
their future care. The Investigator should however try to find out why a participant withdraws 
from the study and document the reason for withdrawal in the source documents and eCRF. 
If there is a medical reason for withdrawal, the participant will remain under the supervision of 
the Investigator until satisfactory health has returned. 
Participants who are withdrawn from the study prior to completion of the scheduled study 
procedures for any reason should complete the end of study visit assessments as far as possible.  

 
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7 
DETAIL OF STUDY ASSESSMENTS  
7.1 
Demographic and Baseline Assessments 
The following will be collected at screening to determine eligibility and baseline status of the 
participant. Baseline safety assessments will also be performed as detailed in Section 7.3. 
7.1.1 
Demographic Data and Baseline Variables 
Demographic data will include age, gender and race/ethnicity, smoking history, use of alcohol 
and drugs of abuse. Height and weight will also be measured. 
7.1.2 
Medical and Disease History  
Disease history (including date of diagnosis) and any allergies or other clinically significant 
diseases and surgeries will be recorded. 
7.1.3 
Prior Medications and Therapies 
All prior therapies and procedures will be recorded. 
All 
other 
prior 
medications 
(e.g. prescription 
drugs, 
over the counter 
drugs, 
herbal/homeopathic remedies, nutritional supplements) used by the participant in the 28 days 
before the screening visit will also be recorded (see Section 5.9). 
7.1.4 
Laboratory Eligibility Tests 
Haematology, biochemistry, LFTs and viral serology blood tests and urinalysis will be 
performed at screening for all participants. All of these samples will be analysed at the local 
laboratory in the hospital. Results from tests must be reviewed by the Investigator (or a 
designee who is a medically qualified study team member) and managed in accordance with 
the study centre procedures. The clinical significance of all results outside of the normal range 
will be determined by the Investigator to determine eligibility. 
Abnormal results and findings will be discussed as applicable with the participant and the 
participant will be referred for follow-up with their healthcare provider if necessary. 
 
Haematology 
A sample of venous blood will be collected according to the local laboratory procedures.  
The following will be measured: full blood count, haemoglobin, haematocrit, erythrocytes, 
mean cell volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin 
concentration, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
fibrinogen, PT/INR, APTT and platelets. 
 
Biochemistry and Liver Function Tests 
A sample of venous blood will be collected according to the local laboratory procedures. 
The following biochemistry parameters will be measured: sodium, potassium, urea, creatinine 
and albumin and LFTs (ALP, GGT, ALT, AST and total bilirubin).  

 
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HIV, HBV, HCV and HDV Diagnostic Testing 
Blood samples will be tested for: 
• 
In all participants: 
− 
HIV antibodies 
− 
HCV antibodies 
• 
In Healthy Volunteers: qualitative HBsAg, HBsAb, HBcAb 
• 
In CHB participants: quantitative HBsAg, HBeAg, HBcAg, anti-HBs, anti-HBe, anti-
HBc, HBV DNA, pgRNA, HDV serology 
 
Urinalysis 
A urine sample will be collected in a sterile container for dipstick urinalysis. The following 
will be tested: blood, bilirubin, glucose, ketones, leucocytes, nitrite, pH, protein, specific 
gravity and urobilinogen. The Investigator may order additional urine tests to be performed. 
7.1.5 
Urine Pregnancy Test 
A urine pregnancy test will be performed in female participants of childbearing potential at 
screening and confirmed to be negative pre-vaccination on Day 0, as per local standard 
procedures and at each of the timepoints according to Table 2. 
7.2 
Immunogenicity Assessments 
Immunogenicity samples (PBMCs) will be taken for planned and potential exploratory 
analyses at each of the timepoints according to Table 2. 
Immunogenicity studies will include (but are not limited to) analysis of samples ex vivo by 
multiparameter flow cytometry (including Mean Fluorescence Intensity measurements) and 
ex vivo IFN-γ ELISpot assays. The latter will be used for epitope mapping. Innate immune 
responses will be measured primarily by RNA sequencing of blood and may be assessed in 
other assays if cell numbers permit. Additional immunogenicity assessments may be 
performed. 
7.2.1 
Secondary Outcomes in Blood Samples 
Peripheral blood mononuclear cells will be isolated from blood samples taken at each of the 
timepoints according to Table 2, and tested for recognition of overlapping HBV peptide pools 
using ICS for multiple cytokines including, and not limited to IFN-γ, and will be analysed by 
multiparameter flow cytometry to obtain frequencies of HBV-specific T cells within CD4+ and 
CD8+ T cell subsets before and after vaccination (magnitude of vaccine-induced response). 
The mean/median fluorescence intensity of cytokine signals will be determined to provide a 
composite assessment of HBV-specific T cell avidity. 
Serum blood samples in CHB participants will be used for analysis of HBV DNA, HBeAg, 
HBeAb, HBsAg and HBsAb. 
Blood samples of healthy participants in cohorts 5 and 6 will be used for analysis of total T cell 
response to ChAdOx1-HBV antigens using a peptide-stimulated ELISpot assay. 

 
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7.2.2 
Exploratory Analysis 
 
Exploratory Analysis in Blood Samples 
HBV-specific CD4+ and T cell subsets within PBMC will be further defined by phenotypic 
markers of activation, differentiation and memory. Peripheral blood mononuclear cells will 
also be used in IFN-γ ELISpot assays to determine the breadth of HBV-specific T cell 
responses (defined by number of peptide pools or individual peptides recognised). These data 
may be used to build immunologic models of the immune system. 
Blood samples will be used for extraction of RNA and subsequent unbiased analysis of innate 
immune responses before and after vaccination by RNA sequencing. 
Serum blood samples will be used for analysis of pgRNA and HBcAg.  
 
Exploratory Analysis in Liver Fine Needle Aspirates 
Liver fine needle aspirate assays will be used to quantify and characterise intrahepatic immune 
and parenchymal cells and/or HBV DNA and RNA transcripts. The local immune landscape at 
Day 84 will be compared with baseline. Additional exploratory assessments may be performed. 
This is an optional procedure for CHB participants only. The Principal Investigator will provide 
a separate consent for this procedure which will explain the procedure in full and all associated 
risks. 
7.3 
Safety Assessments 
7.3.1 
Adverse Events  
Recording and reporting of adverse events is described in detail in Section 8.2. 
 
Solicited Adverse Events 
Solicited adverse events are events the participant is specifically asked about. These adverse 
events are commonly observed soon after receipt of vaccines and relate to local and systemic 
signs and symptoms. Solicited adverse events will be collected for 3 days post-vaccination1. 
These will be recorded daily in the eDiary for all participants. 
For this study, solicited adverse events to be collected include:  
• 
Vaccination site reactions: pain, induration, warmth, erythema (redness) 
• 
Systemic adverse events: feverishness, chills, myalgia, fatigue, headache, nausea, 
arthralgia, malaise  
Participants will be asked to record the presence of these symptoms and grade the severity as 
described in Section 8.2.3.1. Oral temperature will be measured using the thermometer 
provided and the diameter of induration will be measured with the tape measure provided. 
 
Unsolicited Adverse Events 
Unsolicited adverse events are other events meeting the criteria for adverse events (see 
Section 8.2.1) apart from those the participant is specifically asked about. Unsolicited 
 
 
1 In the event that they persist longer than 3 days then an adverse event will be recorded 

 
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non-serious adverse events will be collected from the date the informed consent is signed to 
28 days post-vaccination. Hospitalisations, other SAEs and AESIs will be collected for the 
duration of the study. 
Participants will collect unsolicited adverse events in the eDiary and these will be reviewed 
during clinic visits with the participant and relevant information (event term, start and end date, 
severity, causality, outcome and seriousness) collected and entered into the eCRF as described 
in Section 8.2.3. 
7.3.2 
Laboratory Safety Tests 
Laboratory safety tests will be performed at each of the timepoints according to Table 2, as per 
Sections 7.1.4.1 and 7.1.4.2. Extra laboratory safety tests may be performed if the Investigator 
deems them to be necessary to fully evaluate an adverse event. In the event that the Investigator 
elects to order non-protocol-specified laboratory tests, the Investigator must record the 
rationale for the tests and a determination of clinical significance of the result in the source 
documents. The Investigator must keep the local Medical Monitor informed of adverse events 
of clinical significance. 
Abnormal results and findings will be discussed as applicable with the participant, and the 
participant will be referred for follow-up with their healthcare provider if necessary. 
Results from the LFTs obtained on the study must be reviewed by the Investigator (or a 
designee who is a medically qualified study team member) and managed in accordance with 
the study centre procedures. The clinical significance of all results outside of the normal range 
will be determined by the Investigator and may be reported as an adverse event at the discretion 
of the Investigator. 
7.3.3 
Physical Examination  
A skin, respiratory, cardiovascular, abdominal and lymphatic system examination will be 
performed at screening and pre-vaccination on Day 0. A symptom-directed physical 
examination will be performed at all other clinic visits if required. Results will be recorded as 
normal, abnormal and not clinically significant or abnormal and clinically significant. 
7.3.4 
Vital Signs 
Vital signs will be performed at screening, pre-vaccination and post-vaccination (at the end of 
the observation period) at the vaccination visit, at all visits during the follow-up and the end of 
study visit. At each timepoint blood pressure, pulse rate and oral temperature, will be measured 
after the participant has been in a sitting position for 5 minutes. 

 
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8 
SAFETY MANAGEMENT 
8.1 
Responsibilities for Ensuring the Safety of Study Participants 
The national Competent Authority, the study Sponsor, the Institution through which the 
research is performed, and all members of the Investigator’s study team share responsibility 
for ensuring that participants in this study are exposed to the least possible risk of adverse 
events that may result from participation in this protocol.  
8.1.1 
Investigator 
The Investigator has a personal responsibility to closely monitor study participants and an 
inherent authority to take whatever measures necessary to ensure their safety. The Investigator 
may delay a participant’s study vaccine administration or pause study vaccine administration 
in the whole study if they have some suspicion that the study vaccine might place a participant 
at significant risk. The Investigator determines severity and causality for each adverse event.  
Responsibilities of the Investigator may be assigned to a designee who is a medically qualified 
study team member, however the accountability for the specific task remains with the 
Investigator. 
8.1.2 
Study Sponsor 
The Sponsor also has an institutional responsibility to ensure participant safety. This 
responsibility is vested in the local Medical Monitor and an SMC. 
8.1.3 
Local Medical Monitor 
The local Medical Monitor (LMM) is the Sponsor’s medical representative. The LMM reviews 
safety information collected throughout the study.  The LMM can add another causality to the 
Investigator’s causality assessment, however the causality assessment given by the Investigator 
must not be downgraded by the LMM. If the LMM disagrees with the Investigator’s causality 
assessment, the opinion of both the Investigator and the Sponsor should be provided with the 
report. 
8.1.4 
Safety Monitoring Committee 
The SMC will constitute the Sponsor Representative, the Principal Investigator at each centre, 
the local Medical Monitor and the Chief Investigator. The SMC will operate in accordance 
with the study-specific charter, which will be agreed prior to the start of enrolment. 
An SMC will be appointed to review the study data and make recommendations concerning 
the continuation, modification, or termination of the study. The SMC will perform the 
following: 
• 
Scheduled evaluation of study conduct, progress and review of the safety data. 
Scheduled meetings will take place as follows: 
− Kick off meeting before the first participant is enrolled 
− At least 48 hours after the first healthy participant is dosed in cohort 1 
− At least 48 hours after cohort 1 dosing is complete 
− At least 48 hours after cohort 2 dosing is complete 
− At least 48 hours after the first CHB participant is dosed in cohort 3 
− At least 48 hours after cohort 3 dosing is complete 

 
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• 
The SMC will be notified within 24 hours of the Investigators’ being aware of any 
severe local or systemic reaction or vaccine-related SAE. If a severe local or systemic 
reaction or vaccine-related SAE occurs at any time point during the study, the SMC 
will review the case immediately.  
• 
The SMC will be convened if any of the stopping or holding rules are met (see 
Section 3.1.3) 
The SMC has the power to place the study on hold if deemed necessary 
8.1.5 
Data Monitoring Committee 
A DMC will be appointed to perform unscheduled reviews of the available data including 
safety and tolerability study data and make recommendations concerning the continuation, 
modification, or termination of the study if one of the study stopping or holding rules defined 
in Section 3.1.3 is met. 
There will be a minimum of three appropriately qualified independent committee members of 
whom one will be the designated chair. The DMC will operate in accordance with the 
study-specific charter, which will be agreed prior to the start of enrolment. 
The DMC will be notified within 24 hours of the Sponsor being aware of any study stopping 
or holding rules.  
The chair of the DMC may be contacted for advice and independent review by the Investigator 
or Sponsor in any other situation where the Investigator or Sponsor feels independent advice 
or review is important. 
8.1.6 
Research Ethics Committee 
The HRA/REC has institutional responsibility for the safety of participants in clinical studies. 
The HRA/REC has the authority to terminate, suspend or require changes to a clinical study. 
8.1.7 
Competent Authority 
Since the Competent Authority receives all expedited safety reports for the study it also has the 
authority to terminate, suspend or require changes to a clinical study. 
8.2 
Adverse Events  
8.2.1 
Definitions  
 
Adverse Event 
An adverse event is: 
• 
Any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment 
• 
An adverse event can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use 
of study vaccine, whether or not considered related to the investigational product 
An adverse event includes but is not limited to: 
• 
Any clinically significant worsening of a pre-existing condition 

 
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• 
An adverse event occurring from overdose (i.e. a dosage higher than that prescribed by 
a healthcare professional for clinical reasons, or a dosage higher than that described in 
the Investigator’s Brochure or on the marketed product label) of an investigational or 
marketed product, whether accidental or intentional 
• 
An adverse event occurring from abuse (e.g. use for non-clinical reasons) of an 
investigational or marketed product 
• 
An event related to a medical procedure or associated with the discontinuation of the 
previous use of an investigational or marketed product required by protocol 
(protocol-related adverse event) 
• 
Not all vital sign or laboratory abnormalities will be considered an adverse event. 
Usually these will be considered as an adverse event: 
− If Grade 3 (severe) or greater in severity 
− If judged to be clinically significant by the Investigator 
− If accompanied by clinical symptoms 
− If meeting the definition of a SAE 
− If resulting in dose modification, interruption or discontinuation of study vaccine 
− If requiring specific treatment 
 
Adverse Reaction 
An adverse reaction is defined as any untoward and unintended response to study vaccine 
related to any dose administered. 
An unexpected adverse reaction is an adverse reaction in which the nature or severity of which 
is not consistent with the Investigator’s Brochure or Prescribing Information. 
 
Serious Adverse Event 
SAEs are adverse events meeting at least one of the following criteria: 
• 
It results in death (i.e. the adverse event caused or led to the fatality). Serious does not 
describe an event which hypothetically might have caused death if it were more severe 
• 
It was immediately life-threatening (i.e. the adverse event placed the participant at 
immediate risk of dying. It does not refer to an event which hypothetically may have 
led to death if it were more severe) 
• 
It required inpatient hospitalisation or prolonged hospitalisation beyond the expected 
length of stay. Hospitalisations for scheduled treatments and elective medical/surgical 
procedures related to a pre-existing condition that did not increase in severity or 
frequency following receipt of study vaccine, are not serious by this criterion. 
Hospitalisation is defined as a hospital admission or an emergency room visit for a 
period greater than 24 hours 
• 
It resulted in a persistent or significant disability/incapacity (i.e. substantial reduction 
of the participant’s ability to carry out activities of daily living) 
• 
It resulted in a congenital anomaly or birth defect (i.e. an adverse finding in a child 
or foetus of a participant exposed to the study vaccine prior to conception or during 
pregnancy) 

 
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• 
Other medically important conditions that may not result in death, threaten life or 
require hospitalisation (i.e. the adverse event does not meet any of the above serious 
criteria) may be considered an SAE when, based on appropriate medical judgment, they 
may jeopardise the participant and require medical or surgical intervention to prevent 
one of the serious outcomes listed in these criteria (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in hospitalisation, or the development of drug dependency or drug 
abuse) 
An SAE is an adverse event meeting the outcome criteria for seriousness regardless of 
relationship to the study vaccine. The following are not (and should not be reported as) SAEs: 
hospitalisation for scheduled treatments and elective medical/surgical procedures related to a 
pre-existing condition that did not increase in severity or frequency following receipt of study 
vaccine, and admissions for social reasons. 
 
Suspected Unexpected Serious Adverse Reaction 
A SUSAR is any suspected adverse reaction related to the study vaccine that is both unexpected 
and serious. 
8.2.2 
Study Reporting Period for Adverse Events 
The reporting period for all adverse events begins on the date the informed consent is signed. 
Solicited adverse events are recorded in the eDiary up to 3 days post-vaccination. All other 
events are recorded in the eCRF up until Day 28. All SAEs and or Adverse events of special 
interest are recorded until at least 168 days after the last study vaccination dose and for all 
serious or study vaccine-related adverse events until these are resolved or until participant 
contact discontinues. 
Adverse event information will be collected at study visits and participant will be instructed to 
call study team members to report any abnormalities during the intervals between study visits 
and to come to the study centre if medical evaluation is needed and the urgency of the situation 
permits.  
8.2.3 
Recording and Assessment of Adverse Events by the Investigator 
Solicited adverse events are recorded in the eDiary up to 3 days post-vaccination. All other 
adverse events are recorded in the eCRF up to until Day 28. All adverse events, both those 
observed by study team members and those spontaneously reported by the participant, will be 
recorded in the eCRF. Solicited adverse events will be reported using pre-defined terms. 
Unsolicited adverse events will be reported using a recognised medical term or diagnosis that 
accurately reflects the event.  
Adverse events will be assessed by the Investigator, or a medically qualified study team 
member, for severity, relationship to study vaccine, action taken, outcome and whether the 
event meets criteria as an SAE according to the following guidelines: 

 
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Assessment of Severity  
The severity of adverse events will be graded according to the toxicity table in Appendix 1. 
The scale shown in Table 3 will be used to assess severity of adverse events not listed in 
Appendix 1. 
Table 3 
Severity Grading of Adverse Events not listed in the Toxicity Table for 
Clinical and Laboratory Abnormalities 
Grade 
Severity 
1 
Mild  
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated; no disruption of normal daily activity. 
2 
Moderate 
Minimal, local, or non-invasive intervention indicated; discomfort 
sufficient to reduce or affect daily activity. 
3 
Severe 
Severe or medically significant, but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; inability to 
work or perform normal daily activity. 
4 
Life-threatening 
Represents an immediate threat to life. 
5 
Fatal 
Death as a result of this adverse event 
A change in severity of an adverse event will not be recorded as a new adverse event. Only the 
highest severity level that occurs during the entire period of the adverse event will be recorded 
on the eCRF with the onset and resolution dates encompassing the entire duration of the event.  
Note: It is important to distinguish between serious and severe adverse events. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 8.2.1.3. 
 
Assessment of Relationship 
Solicited adverse events of vaccination site reactions will be considered causally related to 
study vaccine. 
For all other adverse events, the Investigator will determine a causal relationship to the study 
vaccine. A number of factors will be considered in making this assessment, including: 1) the 
temporal relationship of the event to the administration of the study vaccine 2) whether an 
alternative aetiology has been identified and 3) biological plausibility.  
Causality of all adverse events should be assessed by the Investigator using the following 
question: 
“Is there a reasonable possibility that the adverse event may have been caused by the study 
vaccine?” 
• 
YES (related): There is a reasonable possibility that the study vaccine contributed to 
the adverse event 
• 
NO (not related): There is no reasonable possibility that the adverse event is causally 
related to the administration of the study vaccine. There are other, more likely causes 
and administration of the study vaccine is not suspected to have contributed to the 
adverse event 
The Investigator determines causality. The Sponsor and LMM can add another causality 
assessment to the Investigator’s causality assessment. The causality assessment given by the 
Investigator must not be downgraded by the Sponsor. If the Sponsor disagrees with the 

 
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Investigator’s causality assessment, the opinion of both the Investigator and the Sponsor should 
be provided with the report. 
Every effort should be made by the Investigator to determine the existence of any pre-existing 
conditions (e.g. headache in adults or rashes in infants on study Day 0 with onset prior to study 
vaccination) that must be taken into consideration when assessing causal relationship of an 
adverse event. Pre-existing conditions should be recorded in the eCRF as baseline history and 
substantiated by appropriate source documentation. Intermittent conditions such as headaches 
in adults or irritability in infants may not be present on study Day 0 but may represent an 
adverse event if the intensity or duration of the event is worse than usual following study 
vaccine. 
 
Action Taken with Study Vaccine  
The action taken with the study vaccine will be recorded as None, as only one dose is given. 
 
Assessment of Outcome 
The outcome of the adverse event will be assessed as: 
• 
Recovered/resolved 
• 
Recovered/resolved with sequelae 
• 
Not recovered/resolved 
• 
Unknown 
• 
Fatal 
8.2.4 
Reporting Requirements and Procedures for Serious Adverse Events 
All SAEs are reported to the Sponsor for the entire study period. Suspected, unexpected, serious 
adverse reactions are reported even after the study is over, if the Sponsor, local Medical 
Monitor or Principal Investigator becomes aware of them. The study centre will be provided 
with specific reporting procedures including the SAE paper form and any supplemental 
reporting forms to be used. SAEs will be reported on the SAE paper form and the adverse event 
eCRF using a recognised medical term or diagnosis that accurately reflects the event. 
SAEs will be assessed for severity, causal relationship to the study vaccine or alternative 
aetiology by the Sponsor and Investigator. The onset and resolution dates of the event and 
medical care taken in response to the event will be documented. If the event has not resolved 
by the end of the study is enrolled into, it will be documented as “ongoing” on the eCRF, 
however, follow-up of the SAE must continue until resolved or the condition has stabilised. 
Information recorded on the eCRF must be substantiated in the source documents. 
The SAE form for that event must be completed by the Investigator, within 24 hours of the 
study centre becoming aware of the event. The SAE form should be completed with all 
information known at the time and scanned and emailed to the local Medical Monitor and to 
 
Fatal or life-threatening SAEs that the Investigator suspects are related to the study vaccine 
should be telephoned to the local Medical Monitor immediately upon the Investigator’s 
awareness of the event. If the local Medical Monitor is required by the protocol or chooses to 
suspend enrolment s/he shall immediately create a written memorandum for record to the study 
file and telephonically notify the Sponsor of this act. 

 
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Contact information for all safety personnel are contained in the Team Contact List, which will 
be stored at the study centre in the ISF and maintained by the study Sponsor. 
Investigators must not wait to collect additional information to fully document the event before 
notifying the local Medical Monitor of an SAE. The initial notification should include the 
following (at minimum):  
• 
Protocol number and name and contact number of the Investigator 
• 
Participant identification number (and initials and date of birth, if available) 
• 
Investigational product 
• 
SAE(s)  
The Sponsor will notify the DMC of all SUSARs within 24 hours of becoming aware of an 
event and will provide all follow-up information in a timely manner. 
 
Follow-up Information on an SAE 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, should be instituted. Appropriate consultation and follow-up evaluations should be 
carried out until the event has resolved or is otherwise explained by the Investigator. For all 
SAEs, the Investigator is obligated to pursue and provide information to the Sponsor. In 
addition, an Investigator may be requested by the Sponsor to obtain specific information in an 
expedited manner. This information may be more detailed than that captured on the SAE form. 
In general, this will include a description of the adverse event in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality. 
Information on other possible causes such as concomitant medication and illnesses must be 
provided. 
After the initial SAE report, the Investigator is required to follow each participant proactively 
and to report new significant follow-up by submitting an updated SAE report form to the 
Sponsor (or designee). New significant information includes, but is not limited to, the 
following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results and hospital records if applicable 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Required Follow-up for SAEs 
There should be attempted follow-up until the end of the study in all participants. If an SAE 
continues after this period, then the participant must be followed up until the event resolves or 
stabilises. The local Medical Monitor may specify a longer period of time, if required to assure 
the safety of the participant. 

 
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Medical Review and Reporting by the Sponsor 
The Sponsor (or designee) will determine expedited reporting requirements for each reported 
SAE according to local requirements based upon: 
• 
Investigator's assessment of causality and seriousness 
• 
Expectedness  
The expectedness of an SAE is assessed by the Sponsor in the overall classification of SAEs 
for expedited reportability. As no clinical data are available with ChAdOx1-HBV, all serious 
adverse reactions will be considered unexpected for the purposes of expedited reporting.  
 
Sponsor Responsibility for Expedited Safety Reports 
The Sponsor (or designee) will notify Investigators of all reportable SAEs. This notification 
will be in the form of an expedited safety report. Upon receiving such notices, the Investigator 
must review and retain the notice with other study related documentation.  
The Investigator should also comply with the HRA/REC procedures for reporting any other 
safety information. 
The Sponsor will ensure that SAEs are reported to the HRA/REC and Competent Authority 
according to local requirements.  
Suspected, unexpected, serious adverse reactions and other significant safety issues reported 
from the development programme shall be reported to the relevant Competent Authorities 
according to local regulations (either as expedited safety reports and/or in aggregate reports), 
by the Sponsor (or designee). 
8.2.5 
Follow-up of Participants after Adverse Events 
 
Investigator Follow-up 
Treatment of any adverse events will be determined by the Investigator using his/her best 
medical judgment and according to current clinical practice guidelines. All applied measures 
as well as follow-up will be recorded in the appropriate eCRF. 
The Investigator will continue follow-up on adverse events, including laboratory abnormalities 
and solicited adverse events, until the event has resolved, is otherwise satisfactorily explained, 
or the participant completes the study. The resolution date will be recorded on the eCRF as the 
last date on which the participant experienced the adverse event. If an adverse event resolution 
date is uncertain the Investigator should estimate the completion date based on medical 
judgment and interview of the participant. Approximate dates of resolution from phone or other 
communications may be taken as adverse event resolution dates. Some examples of estimation 
of adverse event resolution are: 1) an asymptomatic laboratory abnormality on one visit that 
has not been followed-up between visits but has resolved by the next visit may be assumed to 
have resolved by the midpoint of the inter-visit interval; 2) A resolved adverse event that was 
treated may be assumed to have been resolved by the end of treatment.  
Adverse events that are still present at the end of the study should be recorded as ongoing.  
Information recorded on the eCRF must be substantiated in the source documents. If an adverse 
event evolves into a condition that becomes “serious,” it will be designated as serious on the 
adverse event eCRF and a supplemental SAE report form will be completed. 

 
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Follow-up for SAEs must continue until resolution and the outcome reported to the Sponsor, 
even if this extends beyond the SAE reporting period. 
8.2.6 
Post-study Adverse Events 
At the final study visit, the Investigator should instruct each participant to report to the 
Investigator any subsequent adverse events that the participant’s personal physician believes 
could be related to study vaccine or study procedures.   
The Investigator should notify the Sponsor (or designee) of any death, SAE or other adverse 
event of concern occurring at any time after a participant has discontinued study vaccine if the 
event is believed to be related to study vaccine or study procedures. The Sponsor (or designee) 
should also be notified if the Investigator becomes aware of the development of cancer or a 
congenital anomaly/birth defect in a subsequently conceived offspring of a participant that 
participated in this study. 
The Investigator should record the event in the eCRF; if the eCRF is no longer available, the 
Investigator should report the event directly to the Sponsor (or designee). 
8.3 
Other Events of Special Interest 
Adverse events of special interest represent a subset of adverse events that include autoimmune 
diseases and other systemic disorders of interest which could potentially have an autoimmune 
aetiology. The Investigator should use clinical and scientific judgment in deciding whether 
other adverse events (i.e. events not listed here) could have an autoimmune origin and should 
therefore be reported as AESIs (see Section 8.2.4). 
8.4 
Overdoses or Incorrect Administration 
Study vaccine overdose is the accidental or intentional use of the study vaccine in an amount 
higher than the dose being studied. An overdose or incorrect administration of study vaccine is 
not an adverse event unless it results in untoward medical effects: 
• 
Any study vaccine overdose or incorrect administration of study vaccine should be 
recorded in the eCRF as part of the study vaccine administration information  
• 
Any untoward medical effects associated with an overdose or incorrect administration 
of study vaccine should be recorded in the eCRF as an adverse event.  
If the associated adverse event fulfils serious criteria, the event should be reported to the 
Sponsor (or designee) within 24 hours of knowledge of the event 
8.5 
Management of Pregnancy  
8.5.1 
Notification and Follow-up  
Any pregnancies occurring during the study or within 6 months after the last dose of study 
vaccine must be reported to the Sponsor (or designee) within 24 hours of knowledge of the 
event. The paper pregnancy form should be completed with all information known at the time 
and scanned and emailed to 
 
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the reporting window and must be immediately 
discontinued from study vaccine. The Investigator should counsel the participant, discussing 

 
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the risks of the pregnancy and the unknown effects on the foetus. Monitoring of the participant 
should continue until conclusion of the pregnancy. 
Male participants will be instructed to immediately inform the Investigator if their partner 
becomes pregnant during the reporting window. Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male participant exposed 
to study vaccine. The pregnant partner will need to sign an authorisation for use and disclosure 
of pregnancy health information to allow for follow-up on her pregnancy. The Investigator may 
provide information on the risks of the pregnancy and the unknown effects on the foetus, to 
support an informed decision in cooperation with the treating physician and/or obstetrician. 
8.5.2 
Outcome 
Additional information on the course and outcome of the pregnancy should be provided to the 
Sponsor (or designee) when available using the pregnancy report form. 
The following pregnancy outcomes will be considered to be SAEs and should be reported 
according to the procedure in Section 8.2.4. Pregnancy is not considered an adverse event 
unless one of these criteria is met: 
• 
Spontaneous abortion (as the Sponsor considers spontaneous abortions to be medically 
significant events) 
• 
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male participant 

 
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9 
DATA QUALITY ASSURANCE AND QUALITY CONTROL 
9.1 
Protocol Violations and Deviations 
Major protocol deviations are defined as those that result in harm to the study participants or 
significantly affect the scientific value of the reported results of the study. Other deviations will 
be considered minor.  
Protocol deviations will be recorded on the source documents and with an explanation for the 
deviation. All protocol deviations will also be recorded as specified in the monitoring plan and 
statistical analysis plan (SAP). 
Major protocol deviations that meet the criteria for a serious breach of ICH GCP [34] should 
be reported to the Sponsor immediately. No deviation from the inclusion/exclusion criteria will 
be permitted.  
9.2 
Monitoring and Source Document Verification 
The Sponsor will arrange for the study to be monitored in accordance with the principles of 
ICH GCP [34]. The frequency of monitoring visits will be determined by the rate of participant 
recruitment. 
The following are examples of items that will be reviewed at these visits: 
• 
Compliance with the protocol 
• 
Consent procedure 
• 
Source documents 
• 
Adverse event procedures 
• 
Storage and accountability of study vaccine 
The monitoring visits also provide the Sponsor with the opportunity to ensure that timely 
participant accrual and the other Investigator’s obligations and all applicable requirements are 
being fulfilled. 
The Investigator must permit the Study Monitor, the HRA/REC, the Sponsor’s auditors and 
representatives from Competent Authorities direct access to all source documents 
(see Section 11.1) for confirmation of the accuracy and reliability of data contained within the 
eCRF (source document verification). Participant confidentiality will be protected at all times. 
The Study Monitor will carry out source document verification at regular intervals. This is an 
essential element of quality control, as it allows the rectification of transcription errors and 
omissions. 
9.3 
Data Management and Coding 
Data for each participant will be recorded on an eCRF. Data collection must be completed for 
each participant who signs an informed consent form and receives at least one dose of study 
vaccine. 
Electronic CRFs will be designed and produced by the Sponsor (or designee) and should be 
completed in accordance with instructions. The Investigator is responsible for maintaining 
adequate and accurate medical records from which accurate information will be transcribed 
directly into the eCRFs using a secure internet connection. The eCRFs should be filled out 
completely by the Investigator (or designee) as stated on the delegation of responsibilities form. 

 
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The eCRF system will be Food and Drug Administration (FDA) Code of Federal Regulations 
(CFR) 21 Part 11 compliant. 
The eCRFs must be reviewed and approved by the Investigator. 
Data entered into the eCRF will be validated as defined in the data validation specifications. 
Validation includes, but is not limited to, validity checks (e.g. range checks), consistency 
checks and customised checks (logical checks between variables to ensure that study data are 
accurately reported) for eCRF data and external data (e.g. laboratory data). A majority of edit 
checks will be triggered during data entry and will therefore facilitate efficient ‘point of entry’ 
data cleaning.  
Data management personnel will perform both manual eCRF review and review of electronic 
edit checks to ensure that the data are complete, consistent and reasonable. The electronic edit 
checks will run continually throughout the course of the study and the issues will be reviewed 
manually online to determine what action needs to be taken. 
Manual queries may be added to the system by clinical data management, local Medical 
Monitor or Study Monitor. Clinical Data Managers and Study Monitors are able to remotely 
and proactively monitor the eCRFs to improve data quality. 
External data will be transferred electronically into the study database. Discrepancies will be 
queried to the study centre and/or the laboratory until the electronic data and the database are 
reconciled.  
All updates to queried data will be made by authorised study team members only and all 
modifications to the database will be recorded in an audit trail. Once all the queries have been 
resolved, eCRFs will be locked. Any changes to locked eCRFs will be approved by the 
Investigator. 
Once the full set of eCRFs has been completed and locked, and SAE reconciliation has been 
completed, the Sponsor will authorise database lock and all electronic data will be sent to the 
designated statistician for analysis. Subsequent changes to the database will then only be made 
only by written agreement of the Sponsor. The Investigator will be provided with a copy of the 
eCRFs in a non-editable format. 
Adverse events and medical/cancer history terms will be coded from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA) 
(Version 22.0 or later). Prior and concomitant medications and therapies will be coded 
according to the World Health Organisation drug dictionary (Version Drug B3 Global 
September 2019). Coding review will be performed by the Sponsor (or designee) prior to 
database lock. 
The clinical data (in SAS® dataset format) will be transferred to the Sponsor at the end of the 
study.  

 
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10 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN  
10.1 
Sample Size Determination 
No formal sample size calculation for cohorts 1 to 4 was performed and sample size is based 
upon feasibility considerations. The chosen number of participants is considered sufficient to 
meet the objectives for the study. 
The sample size for cohorts 5 and 6 is based on the ELISpot results of ChAdOx1-HBV 
administered to healthy adults at a dose of 2.5 x 1010 which resulted in a mean of 1,000 +/-500 
spot forming units in three adults who had samples examined by same day analysis at Oxford 
University. Assuming the same response in 15 volunteers in each cohort, the sample size is 
powered to detect a 45% decrease in the T cell response in the participants receiving prior 
AZD1222 compared to the Pfizer/Moderna mRNA COVID-19 vaccine. 
10.2 
Statistical and Analytical Plans 
This section presents a summary of the planned statistical analyses. Full details of the analysis 
will be described in the SAP that will be approved before database lock. Any analysis that 
deviates from the SAP will be documented and justified in the clinical study report.   
The computer program package SAS System for Windows® (Version 9.4 or later) will be used 
for statistical analysis.  
10.2.1 
Analysis Sets 
• 
The intent-to-treat/safety analysis set will consist of all participants who received at 
least one vaccination (data will be summarised according to the vaccination actually 
received) 
• 
The per-protocol analysis set will consist of all participants in the safety analysis set 
who received the correct study vaccine and who had no major protocol deviations 
• 
The immunogenicity analysis set will consist of all participants in the per-protocol set 
and have available immunogenicity data to evaluate the immunogenicity endpoints and 
did not have any major protocol deviations that would impact on the results of the 
immunological analysis 
Allocation of participant to the analysis sets (and whether any participant or specific data from 
a participant will be excluded) will be determined at the pre-database lock Data Review 
meeting. 
10.2.2 
Study Analyses 
 
General Principles  
The majority of the analysis will be descriptive in nature. Unless stated otherwise, continuous 
variables will be summarised using descriptive statistics (number of participants, mean, 
standard deviation, median, minimum and maximum values) and the number and percentage 
of participants will be used for categorical variables. 
Data will be summarised by study vaccine, participant group and where appropriate, overall. 
Immunogenicity and efficacy data may be subjected to additional statistical analysis, which 
will be detailed in the SAP. 

 
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Disposition 
Participant disposition, including reasons for study withdrawal if applicable, will be 
summarised descriptively. 
 
Protocol Deviations 
Protocol deviations will be listed including: nature (missed procedure(s), early or late 
procedure(s), missed visits, visit performed out of protocol defined window, prohibited 
medication taken, study vaccine dosing deviation, inclusion/exclusion criteria violation, 
participants not withdrawn but meeting withdrawal criteria, biological sample handling error, 
other) overall and categorised by major and minor. 
 
Demographics and Baseline Data 
The safety analysis set will be used for the analysis of demographic and baseline data. 
Demographics and baseline characteristics will be listed and summarised descriptively. 
Medications and therapies will be summarised by anatomic therapeutic chemical classification. 
 
Immunogenicity Analyses 
The following endpoints will be presented by study vaccine and participant group: 
• 
A multi-parameter index made of CD4+ magnitude, CD4+ avidity, and 
CD8+ magnitude 
• 
Reduction in HBsAg titre at Week 12 and Week 24 post-vaccination (last visit) 
• 
Proportion of subjects with HBeAg and HBsAg loss  
• 
Proportion of HBeAg and HBsAg seroconversion 
• 
Reduction of hepatitis B DNA level 
• 
Effect on hepatitis core-related antigen (HBcAg) 
• 
Effect of hepatitis B circulation pre-genomic RNA (pgRNA) 
• 
Liver fine needle aspirate assays will include measures of immune and parenchymal 
cell frequency, function and phenotype, HBV cccDNA and RNA transcripts 
• 
Additional exploratory analysis can be performed on blood samples and LFNAs, 
including comparing the local immune landscape at Day 84 with baseline 
 
Safety Data 
Safety data will be summarised descriptively. 
10.2.2.6.1 Adverse Events 
All adverse events will be listed, including the verbatim description and MedDRA preferred 
terms and system organ class (SOC).  
Treatment emergent adverse events (TEAEs) are defined as those occurring after the study 
vaccine administration. 

 
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TEAEs will be summarised by SOC and by preferred term. The incidence of TEAEs will be 
based on the numbers and percentages of participants with events and number of events. 
TEAEs will be further summarised by severity and relationship to study vaccine.  
An overall summary of adverse event incidence will also be presented by study vaccine dose 
and overall to include the number and percentage of participants with at least one: TEAE, 
vaccine-related TEAE, Grade 3 to Grade 5 TEAE, death, SAE, vaccine-related SAE, AESI, 
vaccine-related AESI, TEAE leading to study vaccine discontinuation and TEAE leading to 
study discontinuation. 
Narratives will be written for any deaths, other SAEs, AESIs, TEAEs leading to study vaccine 
discontinuation and TEAEs leading to study discontinuation. 
10.2.2.6.2 Laboratory Safety Tests 
Severity grading using the toxicity table in Appendix 1 will be assigned to laboratory safety 
values where applicable. Laboratory results in reported units and standard international (SI) 
units will be listed, including high and low flags, severity grades where applicable, the 
corresponding normal range and clinical significance. 
Laboratory safety tests summaries will be based on results in SI units. Absolute and change 
from baseline results, including the worst change for each variable for each participant will be 
summarised using descriptive statistics.  
Treatment emergent out of range results with the corresponding severity grade, normal ranges, 
baseline results and clinical significance will be separately listed. Shift tables will be used to 
show changes from baseline at each timepoint and the worst change in each participant and 
scatterplots of the worst change will be produced. The number of participants showing shifts 
of at least two severity grades will be summarised.  
The number of participants with treatment emergent clinically significant laboratory safety test 
results and laboratory safety test results of Grade 3 or 4 will be summarised. 
10.2.2.6.3 Vital Signs 
Absolute and change from baseline vital sign results, including the worst change for each 
variable for each participant will be summarised using descriptive statistics. Treatment 
emergent out of range results with the corresponding normal ranges, baseline results and 
clinical significance will be separately listed. Shift tables will be used to show changes from 
baseline at each timepoint and the worst change in each participant and scatterplots of the worst 
change will be produced. The number of participants with treatment emergent clinically 
significant results will be summarised. 
10.2.2.6.4 Physical Examination  
Treatment emergent abnormal physical examination with the corresponding clinical 
significance will be listed. Shift tables will be used to show changes in physical examination 
status from baseline at each timepoint and the worst shift in each participant will be included. 
10.2.3 
Interim Analyses 
No interim analyses are planned. 

 
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10.2.4 
Handling Missing, Unused or Spurious Data 
The SAP will describe and account for the occurrence of and extent of missing data, and its 
possible impact on the study analysis. 

 
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11 
STUDY DOCUMENTATION, INSPECTIONS AND RECORD KEEPING 
11.1 
Study Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 
should contain all essential documents required by ICH GCP [34] and include: 
1. 
ISF (e.g. protocol and amendments, HRA/REC and Competent Authority approval with 
correspondence, sample informed consent, study vaccine accountability records, staff 
curriculum vitae and authorisation forms, correspondence) 
2. 
Participant source documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation, including medical notes. All source documents produced in this 
study will be maintained by the Investigator and made available for inspection. Source 
data include, but is not limited to, the following and will be identified in a source data 
location log: 
• 
Screening/enrolment log 
• 
Medical notes - which should be updated after each visit to include visit dates, 
medical history and cancer history, concomitant medication, any clinically relevant 
findings of clinical examinations or clinically relevant adverse events/medication 
changes, SAEs and information on participant withdrawal 
• 
Informed consent form 
• 
Safety laboratory reports 
• 
Visit dates  
• 
Study vaccine accountability and inventory forms 
3. 
Participant eCRF data (which includes an audit trail containing a complete record of all 
changes to data) will be sent to the Investigator at the end of the study 
11.2 
Audits and Study Centre Inspections 
Authorised personnel from Competent Authorities and the Sponsor quality assurance function 
may carry out inspections and audits respectively. The purpose of an audit or inspection is to 
ensure that ethical, regulatory and quality requirements are fulfilled in Sponsor studies. 
If an audit or inspection occurs, the Investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his time and the time 
of his staff to the auditor or inspector to discuss findings and any relevant issues. 
11.3 
Retention of Records 
Records and documents pertaining to the conduct of this study and the distribution of study 
vaccine, including eCRFs, informed consent forms, laboratory safety test results and study 
vaccine inventory and accountability records, must be retained by the Investigator for at least 
15 years after completion or discontinuation of the study, or according to local requirements, 
whichever is longer. After that period of time, the documents may be destroyed, subject to local 
regulations.   

 
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No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to another party 
or moving them to another location. 

 
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12 
FINANCE AND INSURANCE  
Financial arrangements are detailed in the Investigator Agreement between the Sponsor and 
Investigator. 
Details of the Sponsor’s arrangement for clinical study insurance to provide for compensation 
to participant for any claim for bodily injury or death arising from participation in the clinical 
study are provided in the informed consent form.  

 
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13 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Local Regulations/Declaration of Helsinki 
The Investigator will ensure that this study is conducted in full conformance with the protocol 
and the principles of the “Declaration of Helsinki” [38] or with the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 
individual.  
The study must fully adhere to ICH GCP [34] or with local regulations if they afford greater 
protection to the participant. 
13.2 
Competent Authority Approval 
The study will not commence before approval from the Competent Authority been granted 
according to local requirements. The Sponsor (or designee) will be responsible for the 
preparation, submission and confirmation of receipt of any Competent Authority approvals 
required prior to release of study vaccine for shipment to the study centre. 
During the study, the Sponsor (or designee) is also responsible for submitting subsequent 
amendments and notifications to the Competent Authority according to local requirements.  
13.3 
Research Ethics Committee Approval 
The Investigator will be responsible for submitting submit all documents required by the 
HRA/REC e.g. this protocol, the informed consent form relevant supporting information and 
all types of study specific participant recruitment information (including advertisements) and 
any other written information to be provided to participants, to the HRA/REC for review. The 
Investigator or Sponsor should also provide the HRA/REC with a copy of the Investigator’s 
Brochure or product labelling, information to be provided to participants and any updates. If 
the HRA/REC requires modification of the submitted information, the documentation 
supporting this requirement must be provided to the Sponsor (or designee). 
The study must have the initial and at least annual (when required) approval of an HRA/REC. 
The signed approval letter must identify the exact protocol title and number, documents 
approved and the date of approval of the protocol and the informed consent document. The 
Sponsor will not ship clinical supplies until a signed approval letter has been received and a 
Clinical Trial Agreement has been signed by the Sponsor and the study centre. 
A list of HRA/REC members must be provided to the Sponsor (or designee). 
The Investigator or Sponsor should provide the HRA/REC with reports, updates and other 
information (e.g. expedited safety reports, amendments and administrative letters) according 
to regulatory requirements or study centre procedures. 
The Sponsor (or designee) will ensure the HRA/REC is notified of any adverse events meeting 
the criteria for expedited reporting, annual updates and when the study has been completed 
according to local requirements. The Sponsor (or designee) will provide information to the 
Investigator who will be responsible for forwarding this to the HRA/REC. 
13.4 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from participants 
prior to conducting any study related procedures. All consent documentation must be in 
accordance with applicable regulations and ICH GCP [34]. Each participant is requested to 

 
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sign and date the informed consent form after (s)he has received and read the participant 
information sheet and received an explanation of what the study involves, including but not 
limited to: the objectives, potential benefits and risk, inconveniences and the participant’s 
rights and responsibilities. participants will be given adequate time to evaluate the information 
given to them before signing and dating the informed consent form. The informed consent form 
also be signed and dated by the person obtaining consent. The original signed informed consent 
form for each participant will be retained on file by the Investigator and the second signed 
original given to the participant. 
Informed consent forms must be retained for enrolled participants and for participants who are 
not subsequently enrolled and must be available for verification by the Study Monitor at any 
time.  
In the event of changes to the informed consent form during the study, the Investigator must 
always use the most current HRA/REC approved form for documenting written informed 
consent. 
CHB participants will also be asked whether they would like to undergo a liver fine needle 
aspirate procedure. This is an optional test and the PI will provide a separate consent form for 
this procedure which will explain the procedure in full and all associated risks. 
13.5 
Protocol Amendments 
The protocol (and other supporting documents that have received approval before the start of 
the study e.g. informed consent form) may not be modified without written approval from the 
Sponsor. In the event that an amendment to the protocol (and/or supporting documents) is 
required, it will be classified into one of the following categories by the Sponsor: 
• 
Substantial amendments are those considered ‘substantial’ to the conduct of the clinical 
study and are likely to have a significant impact on e.g. the safety or physical or mental 
integrity of the participants, the scientific value of the study, the conduct or 
management of the study or the quality or safety of the study vaccine used in the study 
• 
Non-substantial amendments only involve administrative or logistical changes, 
typographical errors 
The Sponsor will determine if Competent Authority and/or HRA/REC review is required prior 
to the implementation of the amendment according to local regulations. In general, substantial 
amendments may not be initiated without approval except when necessary to eliminate 
immediate hazards to the participants or when the change(s) involves. Non-substantial 
amendments do not require approval. 
The Sponsor (or designee) is responsible for obtaining approval for substantial amendments 
from the Competent Authority. The Investigator is responsible for promptly informing the 
HRA/REC of any substantial amendments and providing documentation of favourable opinion 
to the Sponsor (or designee). 
13.6 
Confidentiality of Study Documents and Participant Records 
The Investigator must ensure that participant’s anonymity will be maintained and that their 
identities are protected from unauthorised parties. The Sponsor (or designee) will maintain 
confidentiality standards by assigning a unique coded identification number to each participant 
included in the study. Participant names will never be included in data sets that are transmitted 

 
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to the Sponsor or their representatives or to third parties as permitted by the informed consent 
form.  
Participants should be identified by an identification code rather than by their names on eCRFs 
or other documents submitted to the Sponsor. The Investigator should keep a participant 
enrolment log relating codes to the names of participants. The Investigator should maintain 
documents not for submission to the Sponsor e.g. informed consent forms, in strict confidence. 
Records will not be destroyed without giving the Sponsor prior written notice and the 
opportunity to further store such records, at the Sponsor’s cost and expense. 
Participant medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the informed consent form signed by the participant, 
unless permitted or required by law. 

 
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14 
STUDY COMPLETION 
All materials or supplies provided by the Sponsor will be returned to the Sponsor upon study 
completion. The Investigator will notify the HRA/REC when the study has been completed. 
The study will be considered complete when the last participant completes their final follow-up 
visit and all the data clarification forms have been resolved. This report should be made within 
3 months of the completion or termination of the study. The final report sent to the HRA/REC 
should also be sent to the Sponsor and, along with the completed eCRFs, constitutes the final 
summary to the Sponsor, thereby fulfilling the Investigator’s regulatory responsibility.  

 
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15 
PUBLICATION OF DATA 
The final study report will be made available to the Investigator for purposes of publications. 
The Investigator and study team must send all manuscripts, abstracts, and presentations using 
data from this study to the Sponsor for review prior to their submission. The Sponsor reserves 
the right to delete any part or parts of such materials deemed to be confidential or proprietary. 

 
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2020;5:94. 
31. 
Barouch DH, Tomaka FL, Wegmann F, et al. Evaluation of a mosaic HIV-1 vaccine in 
a multicentre, randomised, double-blinded, placebo-controlled, phase 1/2a clinical trial 
(APPROACH) and in rhesus monkeys. Lancet 2018;392:232-243. 
32. 
Goldstein N, Bockstal V, Bart S, et al. Safety and immunogenicity of heterologous and 
homologous two dose regimens of Ad26- and MVA-vectored Ebola vaccines: a 
randomized, controlled phase 1 Study. J Infect Dis. 2020; jiaa586. 

 
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33. 
Wilkie M, Satti I, Minhinnick A, et al. A phase I trial evaluating the safety and 
immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime 
– MVA85A boost in healthy UK adults. Vaccine 2020;38:779-789. 
34. 
International Conference on Harmonisation. ICH E6(R2). Integrated addendum to ICH 
E6(R1) Guideline for Good Clinical Practice. 11 June 2015. 
35. 
EU Guidelines to Good Manufacturing Practice. Medicinal Products for Human and 
Veterinary Use Annex 13. 
36. 
Ewer KJ, Lambe T, Rollier CS, Spencer AJ, Hill AV, Dorrell L. Viral vectors as vaccine 
platforms: from immunogenicity to impact. Curr Opin Immunol. 2016;41:47-54.  
37. 
de Barra E, Hodgson SH, Ewer KJ, et al. A Phase Ia study to assess the safety and 
immunogenicity of new malaria vaccine candidates ChAd63 CS administered alone and 
with MVA CS. PLoS One. 2014;9(12):e115161. 
38. 
World Medical Association, Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects as amended by the 59th World Medical Association 
General Assembly, Seoul, Korea, October 2008. 
 
 
 

 
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APPENDICES 
Appendix 1 
Toxicity Table for Clinical and Laboratory Abnormalities 
 

 
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Appendix 2 
Details of Changes Made in Protocol Amendments 
Details of Changes Made in Protocol Amendment 8 (Protocol Version 9.0, 24 Nov 21) 
1.5.1 Rationale for Investigation of Dosing Interval With Respect to COVID-19 Vaccines 
To support this interval, this study aims to produce data of the response in healthy volunteers 
to our ChAdOx-1 HBV vaccine following the use of the AZD1222 vaccine. T cell responses 
(the critical immunological factor in chronic HBV infection) will be compared in participants 
who have received who have received either a prior two-dose series of AZD1222 with those 
who have received at least two prior doses of either the Pfizer mRNA COVID 19 vaccine 
(Comirnaty®) or the Moderna COVID-19 vaccine (Spikevax). Due to the recommendation to 
use the AZD1222 in those over the age of 40 years, we will confine our study to 40-60 years 
of age and keep the interval from the second latest COVID-19 vaccine in to a narrow window 
of 10-18 weeks. No interference on HBV-focused T cell responses is expected from either the 
Pfizer vaccine or the Moderna vaccine, so the interval from the second latest COVID-19 
vaccine will be between 6 to 30 weeks 
 
3.1.1 Study Design 
This is a Phase 1, first in human study of ChAdOx1-HBV. The study will be conducted in 
40 healthy participants and 12 participants with CHB and virally suppressed with oral antiviral 
medication. This will be an open-label, non-randomised dose escalation study comparing the 
safety, tolerability and immunogenicity of 2 different doses of ChAdOx1-HBV vaccine. T cell 
responses in healthy participants who have received a prior two dose series of AZD1222 or at 
least two doses of Pfizer or Moderna mRNA COVID-19 vaccines will also be analysed. The 
study design is shown in Figure 2. 
 
3.1.2 Study Methodology 
…. 
Thirty healthy participants (15 who have received two doses of AZD1222 [cohort 5] and 
15 who have received at least two doses of either Pfizer or Moderna mRNA COVID-19 
vaccine [cohort 6]) will be dosed in parallel with the high dose used in cohorts 2 and 4. 
 
4.1 Number of participants 
…. 
A total of 10 healthy participants and 12 participants with CHB infection is considered 
sufficient to confirm the safety, tolerability and immunogenicity of ChAdOx1-HBV and to 
answer the objectives of the study before progressing to larger studies. An additional 30 healthy 
participants (15 who have received two doses dose of AZD1222 and 15 who have received at 
least two dose of either Pfizer or Moderna mRNA COVID-19 vaccine) will be recruited to 
assess whether prior receipt of AZD1222 results in decreased T cell responses to ChAdOx1-
HBV. 
 
4.2 Inclusion Criteria 

 
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Healthy participants (cohort 6): 
16. Completed second Received the latest dose of Pfizer (Comirnaty®) or Moderna 
(Spikevax) mRNA COVID 19 vaccine 6 to 30 weeks before enrolment 
 
Details of Changes Made in Protocol Amendment 7 (Protocol Version 8.0, 22 Sep 2021) 
 
1.5.1 
Rationale for Investigation of Dosing Interval With Respect to COVID-19 
Vaccines 
….. 
To support this interval, this study aims to produce data of the response in healthy volunteers 
to our ChAdOx-1 HBV vaccine following the use of the AZD1222 vaccine. T cell responses 
(the critical immunological factor in chronic HBV infection) will be compared in participants 
who have received a prior two-dose series of AZD1222 with those who have received either 
the Pfizer mRNA COVID-19 vaccine (Comirnaty®) or Moderna COVID-19 vaccine 
(Spikevax). Due to the recommendation to use the AZD1222 in those over the age of 40 years, 
we will confine our study to 40-60 years of age and keep the interval from the second COVID 
19 vaccine in a narrow window of 10-18 weeks. No interference on HBV-focused T cell 
responses is expected from the Pfizer or Moderna vaccine, so the interval from the second 
COVID-19 vaccine will be between 6 to 30 weeks. 
 
3.1.1 
Study Design 
This is a Phase 1, first in human study of ChAdOx1-HBV. The study will be conducted in 
1040 healthy participants and 12 participants with CHB and virally suppressed with oral 
antiviral medication. This will be an open-label, non-randomised dose escalation study 
comparing the safety, tolerability and immunogenicity of 2 different doses of ChAdOx1-HBV 
vaccine. T cell responses in healthy participants who have received a prior two-dose series 
of either AZD1222 or the Pfizer or Moderna mRNA COVID-19 vaccines will also be 
analysed. The study design is shown in Figure 2. 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=6) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 1 (N=5) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Cohort 2 (N=5) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Healthy Participants 
CHB Participants 
Cohort 3 (N=6) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Healthy Participants 
Cohort 5 AZD1222 
(N=15) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 6 Pfizer/Moderna
mRNA (N=15) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 

 
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3.1.2 
Study Methodology 
…. 
Thirty healthy participants (15 who have received two doses of AZD1222 [cohort 5] and 
15 who have received two doses of Pfizer/Moderna mRNA COVID-19 vaccine [cohort 6]) 
will be dosed in parallel with the high dose used in cohorts 2 and 4. 
 
4.1 
Number of Participants 
…. 
A total of 10 healthy participants and 12 participants with CHB infection is considered 
sufficient to confirm the safety, tolerability and immunogenicity of ChAdOx1-HBV and to 
answer the objectives of the study before progressing to larger studies. An additional 30 healthy 
participants (15 who have received two doses of AZD1222 and 15 who have received two 
doses of Pfizer/Moderna mRNA COVID-19 vaccine) will be recruited to assess whether prior 
receipt of AZD1222 results in decreased T cell responses to ChAdOx1-HBV. 
 
4.2 
Inclusion criteria 
Healthy participants (cohort 6): 
14. Considered to be healthy with no current conditions that may significantly impair 
participant safety or influence study results, in the opinion of the Investigator 
15. Adult males or females aged ≥40 to ≤60 years at screening 
16. Completed second dose of Pfizer (Comirnaty®) or Moderna (Spikevax) mRNA 
COVID-19 vaccine 6 to 30 weeks before enrolment 
 
5.7 
Method of Assigning Participants to Treatment Groups 
In cohorts 1-4, the healthy and CHB participants will be allocated to low dose or high dose 
treatment depending on the treatment schedule prepared by statistician. 
As cohorts 5 and 6 were introduced following completion of enrolment of the healthy 
participants in cohorts 1 and 2, all further healthy participants enrolled under protocol 
version 7.0 and 8.0 will receive high dose treatment. 
 
The Synopsis is updated to reflect the changes above. 
 
Details of Changes Made in Protocol Amendment 6 (Protocol Version 7.0, 08 Jul 2021) 
Front Page 
Sponsor's Authorised Representative: 
  

 
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Chief Scientific Officer 
 
ADMINISTRATIVE AND CONTACT INFORMATION 
Immunogenicity Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory 
(for pgRNA and HBcAg analysis) 
 
 
 
 
 
 
 
 
 
 
 
1.5.1 
Rationale for Investigation of Dosing Interval With Respect to COVID-19 
Vaccines 
There are concerns that the prior use of a vectored vaccine may result in anti-vector responses, 
which would decrease the response to a subsequent use of the same vector. Specifically, there 
have been concerns raised that the use of the AstraZeneca ChAdOx1-SARS-CoV-2 vaccine 
(AZD1222 or Vaxzevria®) might reduce either the antibody or T cell response to a subsequent 
vaccine using the same vector. This potential decrease has been attributed to the induction of a 
neutralising cross-reactive T cell response to the viral vector.  
For adenoviral vectors, prior infection with a replicating adenovirus of the same strain (e.g., 
human adenoviral 5) does appear to have an effect on the subsequent T cell and antibody 
response. However, this neutralisation is primarily directed against the fibre protein. This 
interference was a primary motivating factor in the development of replication-incompetent 
adenoviral vectors based on simian strains (chimpanzee, bonobo, and gorilla). In contrast, the 
neutralisation resulting from the use of the replication incompetent adenoviral vectors 
themselves is directed primarily to the abundant hexon capsid protein, and this response may 
have only minor effect on cell entry and immunogenicity, mainly mediated by the fibre.  

 
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In studies of AZD1222, there was no statistical relation between the level of neutralisation 
response following the first immunisation, and the resultant antibody or T cell response (as 
measured by IFN-γ ELISpot) following a second immunisation [27]. Likewise prior receipt of 
a ChAdOx1 vaccine (either ChAdOx1-MERs or ChAdOx1-mening) had no effect on the 
response to AZD1222.  
However, the improvement of antigen-specific immunogenicity of a delayed interval is 
supported by reports in the literature of clinical trials assessing homologous or heterologous 
prime-boost regimes with adenoviral vectors [28-33]. In summary, the longer the interval 
between first and second dose of the adenoviral vector, the better the antigen-specific boosting 
capacity of the second dose. This has been mostly studied with antibody responses to the same 
adenoviral vector encoding the same antigen. This has been in part attributed to declining titres 
of vector-neutralising and vector-binding antibodies with time. Specifically, antigen-specific 
antibodies were boosted 3-fold when the boosting interval was 4 weeks, but this increased to 
10-fold when the interval between the two vaccines was 24 weeks [29]. In another study, 
antibody titres were boosted 10-fold after a prime-boost interval of 12 weeks, and T cells were 
also boosted [28]. Nonetheless, it is well-known that increasing interval may boost responses, 
and the association of the increase in titres with increasing intervals has not been clearly shown 
in any of the cited studies to be attributed to the level of anti-vector neutralizing antibodies.  
It is important to note that all previous clinical experience with second administration of the 
same adenoviral vector has been in the context of a single antigen, for example, Ad26-gag 
prime followed by Ad26-gag boost. This is in contrast to the scenario discussed here, where a 
possible administration of the ChAdOx1-nCoV-19 vaccine is followed by administration of a 
ChAdOx1 vector encoding HBV antigens. This is not a prime-boost scenario per se but rather 
the re-use of the same vector platform in a different indication.  
Given this uncertainty and the improved responses seen three months after initial immunization 
compared to one month in studies of homologous prime-boost of the same antigen, and lacking 
clear data, the Sponsor has advised that participants not receive the ChAdOX1 vaccine in this 
and other 
-sponsored trials until at least three months after receiving the AZD1222 
or J&J hAd26, and that a three-month interval should also be advised if the COVID-19 vaccine 
follow entry into our study. However, this is not based on firm data, and either a shorter or 
longer interval may indeed be warranted. 
To support this interval, this study aims to produce data of the response in healthy volunteers 
to our ChAdOx-1 HBV vaccine following the use of the AZD1222 vaccine. T cell responses 
(the critical immunological factor in chronic HBV infection) will be compared in participants 
who have received a prior two-dose series of AZD1222 with those who have received either 
the Pfizer mRNA COVID-19 vaccine (Comirnaty®) or Moderna COVID-19 vaccine 
(Spikevax). Due to the recommendation to use the AZD1222 in those over the age of 40 years, 
we will confine our study to 40-60 years of age and keep the interval from the second COVID 
19 vaccine in a narrow window of 10-18 weeks. No interference on HBV-focused T cell 
responses is expected from the Pfizer or Moderna vaccine, so the interval from the second 
COVID-19 vaccine will be between 6 to 30 weeks. 

 
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2 
STUDY OBJECTIVES 
Objectives 
Endpoints 
Secondary 
Secondary 
• 
Cohorts 5 and 6 only: Assess whether the 
receipt of prior ChAdOx1 SARS-CoV-2 
vaccine (AZD1222) results in decreased 
T cell responses to ChAdOx1-HBV, when 
administered 
10-18 
weeks 
prior 
to 
ChAdOx1-HBV 
• 
Total T cell response to the 
antigens encoded by ChAdOX1-
HBV as measured in a peptide-
stimulated ELISpot assay 
Exploratory 
 
Determine the effect of ChAdOx1-HBV on 
virological and immunological systemic and 
intrahepatic changes in participants with CHB 
infection and virally suppressed with oral 
antiviral medication. 
• 
 
• 
Effect of prior AZD1222 on the 
CD4+ 
and 
CD8+ 
T cell 
magnitude and phenotype as 
measured 
by 
multiparameter 
flow cytometry 
 
3.1.1 
Study Design 
This is a Phase 1, first in human study of ChAdOx1-HBV. The study will be conducted in 
1040 healthy participants and 12 participants with CHB and virally suppressed with oral 
antiviral medication. This will be an open-label, non-randomised dose escalation study 
comparing the safety, tolerability and immunogenicity of 2 different doses of ChAdOx1-HBV 
vaccine. T cell responses in healthy participants who have received a prior two-dose series 
of either AZD1222 or the Pfizer or ModernamRNA COVID-19 vaccines will also be 
analysed. The study design is shown in Figure 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=6) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 1 (N=5) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Cohort 2 (N=5) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Healthy Participants 
CHB Participants 
Cohort 3 (N=6) LD 
ChAdOx1-HBV 
2.5 x 109 vp 
Healthy Participants 
Cohort 5 AZD1222 
(N=15) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 
Cohort 6 
Pfizer/Moderna mRNA
(N=15) HD 
ChAdOx1-HBV 
2.5 x 1010 vp 

 
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Five reviews of the safety, tolerability and available immunogenicity data will be performed 
by a Safety Monitoring Committee (SMC): 
• 
 
No SMC review is required for cohorts 5 and 6 as the dose administered has been assessed 
in the previous cohorts of healthy participants. 
 
3.1.2 
Study Methodology 
The study will investigate response to study vaccine as shown in Table 2. On Day 0, an 
electronic diary (eDiary), tape measure and thermometer will be provided to perform 
self-assessment of local and systemic reactogenicity. All participants will then have a 
follow-up telephone call on Day 1 and return to the clinic for study assessments on Days 
7, 14, 28, 84. Participants in cohorts 1-4 only, will also have follow up visits on Day 56 and 
Day 168.  End of study visit procedures will be performed at the final visitParticipants will 
then have a follow-up telephone call on Day 1 and return to the clinic on Days 7, 14, 28, 56, 
84 and 168 for study assessments, with end of study visit procedures performed at the final 
visit. 
Five healthy participants will be administered the low dose first (cohort 1). Dose escalation 
will only be initiated in the remainingnext 5 healthy participants (cohort 2) following SMC 
review. 
Six CHB participants will be administered the low dose (cohort 3) before the dose escalation 
is initiated in the remaining 6 CHB participants (cohort 4). 
Thirty healthy participants (15 who have received two doses of AZD1222 [cohort 5] and 
15 who have received two doses of Pfizer/Moderna mRNA COVID-19 vaccine [cohort 6]) 
will be dosed in parallel with the high dose used in cohorts 2 and 4. 
The first participant in each of cohorts 1-4 will be assessed for 1 hour in the clinic 
post-vaccination in case of immediate adverse events (timed after the end of study vaccine 
administration). TheAll other participants will be assessed for 30 minutes. 
The safety and immunogenicity assessments to be performed in cohorts 1-4 are: 
• 
 
For participants in cohorts 5 and 6, all assessments on Days 0, 7, 14, 28 and 84 above will 
be performed. In addition, neutralising antibodies to ChadOx1 will be assessed on Days 0 
and 84. 
 
3.1.4.1 
Duration for Each Participant 
Cohorts 1-4: Up to 8 months (up to 1.5 months for screening and 6.5 months on the study with 
study vaccine given on Day 0). 
Cohorts 5 and 6: Up to 4.5 months (up to 1.5 months for screening and 3 months on the 
study with study vaccine given on Day 0). 
 

 
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3.2 
Discussion of Study Design 
This is a first in human study of the ChAdOx1 vaccine and is designed to assess the safety in 
both healthy adults, as well as in the target CHB population. As T cell responses to natural 
infection are blunted or exhausted in participants with CHB, it will be important to determine 
how responses in CHB compare to healthy participants. Given the uncertainty around prior 
use of a vectored vaccine resulting in anti-vector responses, this study will also assess the 
response of healthy participants who have previously received AZD1222 to ChAdOx1-
HBV. 
 
4.1 
Number of Participants 
It is planned that 1040 healthy participants and 12 participants with CHB infection and virally 
suppressed with oral antiviral medication will be enrolled in the study. Chronic HBV 
participants will be recruited/deemed eligible by hepatologists, infectious disease specialists or 
physicians experienced in treating CHB participants. Centres not meeting the enrolment 
expectations will be considered for replacement with or addition of a new site. If participants 
leave the study before all follow-up visits are completed (for any reason), then these may be 
replaced at the discretion of the study team. A log of all participants enrolled into the study (i.e. 
having given informed consent) will be maintained in the Investigator’s Site File (ISF) at the 
study centre irrespective of whether they have treated with vaccine or not. 
The number of participants is based on feasibility considerations rather than formal sample size 
calculations. A total of 10 healthy participants and 12 participants with CHB infection is 
considered sufficient to confirm the safety, tolerability and immunogenicity of ChAdOx1-HBV 
and to answer the objectives of the study before progressing to larger studies. An additional 
30 healthy participants (15 who have received two doses of AZD1222 and 15 who have 
received two doses of Pfizer/Moderna mRNA COVID-19 vaccine) will be recruited to 
assess whether prior receipt of AZD1222 results in decreased T cell responses to 
ChAdOx1-HBV. 
 
4.2 
Inclusion criteria 
Participants must meet all the following criteria to be eligible for the study: 
5. If female: Not pregnant and one of the following: 
• 
 
• 
Sexual abstinence, only if the participant refrains from heterosexual 
intercourse during the entire study period and it is the usual lifestyle of the 
participant 
 
Healthy participants (cohort 5): 
11. Considered to be healthy with no current conditions that may significantly impair 
participant safety or influence study results, in the opinion of the Investigator 
12. Adult males or females aged ≥40 to ≤60 years at screening 
13. Completed second dose of COVID-19 AZD1222 vaccine 10 to 18 weeks before 
enrolment 

 
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Healthy participants (cohort 6): 
14. Considered to be healthy with no current conditions that may significantly impair 
participant safety or influence study results, in the opinion of the Investigator 
15. Adult males or females aged ≥40 to ≤60 years at screening 
16. Completed second dose of Pfizer/Moderna mRNA COVID-19 vaccine 6 to 30 weeks 
before enrolment 
 
4.3 
Exclusion Criteria 
8. 
Cohorts 1-4: Receipt of any adenoviral vaccine within 3 months prior to administration 
of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-based vaccine within 
3 months after Day 0 
Cohorts 5 and 6: Receipt of any adenoviral vaccine (other than AZD1222 per 
inclusion criterion 13) within 3 months prior to administration of ChAdOx1-HBV 
on Day 0, or plan to receive an adenoviral-based vaccine within 3 months after 
Day 0 
 
Additionally, for healthy participants (cohorts 1, 2, 5 and 6) 
18. 
HBsAg positive 
 
5.1 
Study Vaccines Administered 
The study vaccine to be given in each treatment group are shown in Table 1. 
Table 1 
Study Vaccine Treatment Groups in HBV001 
Treatment Cohort 
Vaccine Single Dose 
N 
Cohort 1 LD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 109 vp 
5 
Cohort 2 HD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 1010 vp 
5 
Cohort 3 LD 
Participants with CHB 
ChAdOx1-HBV 
2.5 x 109 vp 
6 
Cohort 4 HD 
Participants with CHB 
ChAdOx1-HBV 
2.5 x 1010 vp 
6 
Cohorts 5 and 6 HD 
Healthy Participants 
ChAdOx1-HBV 
2.5 x 1010 vp 
30 
Abbreviations: ChAdOx1-HBV=chimpanzee adenovirus-vectored hepatitis B virus vaccine; CHB=chronic 
hepatitis B virus; HD=high dose; LD=low dose; vp=viral particles 
 
5.7 
Method of Assigning Participants to Treatment Groups 
In cohorts 1-4, Tthe healthy and CHB participants will be allocated to low dose or high dose 
treatment depending on the treatment schedule prepared by statistician. 

 
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As cohorts 5 and 6 were introduced following completion of enrolment of the healthy 
participants in cohorts 1 and 2, all further healthy participants enrolled under protocol 
version 7.0 will receive high dose treatment. 
 
6 
STUDY PROCEDURES AT EACH VISIT/SCHEDULE OF ASSESSMENTS 
The study consists of the following: 
• 
A 42-day screening period before the start of the study period 
• 
A study period of 168 days, consisting of a vaccination day on Day 0, a follow-up 
telephone call on Day 1 and follow-up visits on Days 7, 14, 28, 56 and end of study 
visit on Day 168. Participants in cohorts 1-4 only, will also have follow up visits on 
Day 56 and Day 168. End of study visit procedures will be performed at the final 
visit. 

 
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Table 2 
Overall Schedule of Assessments at Each Study Visit 
Visit/Call 
Screen 
Vaccination 
Follow-up 
End of Study 
Timepoint 
Day-42 to -1 
Day 0 
Day 1 
Day 7±1 
Day 14±1 
Day 28±2 
Day 56±3 
(cohorts 1-4) 
Day 84±7[a] 
Day 168±7 
(cohorts 1-4) 
Pre- 
0 
Post- 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Baseline/eligibility variables 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
X 
X 
 
 
 
 
 
 
 
 
 
HIV Ab, HCV Ab, HBsAg, HDV Ab(a)[b]
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (β-hCG) [c]  
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Laboratory eligibility and safety tests 
 
 
 
 
 
 
 
 
 
 
 
Haematology [d]  
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Biochemistry[d]  
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Liver function tests[e]  
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Study vaccination 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
 
X 
 
 
 
 
 
 
 
 
Post-vaccination observation[f]  
 
 
 
X 
 
 
 
 
 
 
 
Other Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
Directed physical examination if required 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signs[g]  
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Local/systemic reactogenicity [h]  
 
X 
 
X 
X 
X 
 
 
 
 
 
Unsolicited adverse events [i]  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serious adverse events and adverse events 
of special interest  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for HBV disease markers  
 
 
 
 
 
 
 
 
 
 
 
Healthy participants (HBsAb, HbcAb) 
 
X 
 
 
 
 
 
 
 
 
X[j] 
CHB (HBV DNA, HBsAg quantitative) 
X 
X 
 
 
 
 
 
X 
X 
X 
X 

 
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Visit/Call 
Screen 
Vaccination 
Follow-up 
End of Study 
Timepoint 
Day-42 to -1 
Day 0 
Day 1 
Day 7±1 
Day 14±1 
Day 28±2 
Day 56±3 
(cohorts 1-4) 
Day 84±7[a] 
Day 168±7 
(cohorts 1-4) 
Pre- 
0 
Post- 
CHB ( HBeAg, anti-HBe, anti-HBs, 
pgRNA, HBcAg, anti-HBc) 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Immunogenicity assessments 
 
 
 
 
 
 
 
 
 
 
 
Blood for cellular immunogenicity [k] 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Blood for neutralising antibodies 
(cohorts 5 and 6 only) 
 
 
X 
 
 
 
 
 
 
X 
 
Liver fine needle aspirates[l]† 
X 
X 
 
 
 
 
 
 
 
X 
 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine transaminase; aPTT=activated partial thromboplastin time; AST=aspartate transaminase; CHB=chronic hepatitis B virus; 
DNA=desoxyribonucleic acid; GGT=gamma-glutamyl transpeptidase; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; β-hCG=beta human chorionic gonadotrophin; 
HBcAg=hepatitis B core-related antigen; HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HBsAg=hepatitis B surface antigen; HCV=Hepatitis C virus; HDV=Hepatitis D virus; 
HIV=human immunodeficiency virus; ICS=intracellular cytokine staining; INR= international normalised ratio; LFNA=liver fine needle aspirate; pgRNA=pre-genomic RNA; 
PBMCs=peripheral blood mononuclear cells; PT=prothrombin time 
†Optional assessments 
 
[a] 
End of Study Visit for cohorts 5 and 6 
[b] 
HDV Ab serology and HBsAg quantitative test will be done in CHB participants only; HBsAg qualitative test will be done in healthy participants; all participants will be tested for HIV 
and HCV serology 
[c] 
Female participants only 
[d] 
Full haematology (including PT/INR and aPTT) and biochemistry panel  
[e] 
Measurement of ALP, GGT, ALT, AST and total bilirubin 
[f] 
The first participant in each cohort will be assessed for 1 hour in case of immediate adverse events (timed after the end of study vaccine administration). The other participants will be 
assessed for 30 minutes 
[g] Pulse, blood pressure and temperature 
[h] Captured during clinic visits and then via eDiary for 3 days post-vaccination 
[i] 
Recorded in the eCRF from the date the informed consent is signed, at all clinic visits to cover the period since the previous visit and during the visit and up to 28 days post-vaccination 
[j] 
If negative at baseline, at discretion of the investigator 
[k] To be processed into PBMCs for analysis by ICS 
[l] 
Only in CHB participants who consent to LFNAs after confirming eligibility. Coagulation profile must be assessed prior to repeat LFNA on Day 84. For those consenting to LFNAs, 
blood for PT/INR and aPTT testing must be collected 
 

 
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6.2 
Treatment Day Assessments (Day 0) 
The following will be performed pre-vaccination: 
• 
 
• 
Blood samples will be taken for immunogenicity assessments (including neutralising 
antibodies for cohorts 5 and 6 only) 
 
6.3.4 
Clinic Visit: Days 28, 56 (Cohorts 1-4) and 168 (End of Study Visit Cohorts 1-4) 
 
6.3.5 
Clinic Visit: Day 84 (including End of Study Visit Cohorts 5 and 6) 
• 
 
• 
Blood samples will be taken for immunogenicity assessments (including neutralising 
antibodies for cohorts 5 and 6 only) 
 
7.2.1 
Secondary Outcomes in Blood Samples 
Blood samples of healthy participants in cohorts 5 and 6 will be used for analysis of total 
T cell response to ChAdOx1-HBV antigens using a peptide-stimulated ELISpot assay. 
 
8.2.4 
Reporting Requirements and Procedures for Serious Adverse Events 
The SAE form for that event must be completed by the Investigator, within 24 hours of the 
study centre becoming aware of the event. The SAE form should be completed with all 
information known at the time and scanned and emailed to the local Medical Monitor and to 
 
 
The Synopsis is updated to reflect the changes above. 
 

 
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Details of Changes Made in Protocol Amendment 5 (Protocol Version 6.0, 01 Mar 2021) 
 
ADMINISTRATIVE AND CONTACT INFORMATION 
 
Sponsor Medical Oversight 
 
 
 
 
 
 
 
 
 
  
 
 
4.3 Exclusion Criteria 
1. Presence of any significant acute or chronic, uncontrolled medical/psychiatric illness 
2. 
Hepatitis C virus (HCV) antibody positive….. 
……..  
8. Any History of receipt of any adenoviral vaccine within 3 months prior to 
administration of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-based 
vaccine within 3 months after Day 0 
 
3.3 Benefit Risk Assessment 
……. 
With any new treatment there is always a possibility of an unexpected adverse events. 
The administration of ChAdOx1-HBV in this study may interfere with the effectiveness 
of other vaccines subsequently administered to the participant. The ChAdOx1 vector 
induces anti-vector immunity in addition to an antigen-specific immune response. Of 
particular concern are neutralising antibodies directed against the capsid structure of the 
vector, which may have a negative effect on subsequent immunisations with the same or 
related adenoviral vector by neutralising the vector before it has a chance to transduce 
target cells.  This effect decreases with longer interval between the vaccines [Error! 
Reference source not found.,Error! Reference source not found.].  In particular, there is a 
concern that the ChAdOx1-HBV administered in this study could decrease the response 
to the AstraZeneca Covid19 vaccine, which has the same viral vector, especially if it is 
administered within 3 months of ChAdOx1-HBV. The Janssen (Johnson & Johnson) 
Covid19 vaccine is also made with an adenovirus, and some interference cannot be ruled 
out. Therefore it is recommended that participants in this study receive an alternative 
type of Covid19 vaccine, such as an mRNA or protein vaccine, at least 2 weeks before and 
after ChAdOx1-HBV in this study. 
There are also routinely scheduled reviews of safety and efficacy data throughout the study by 
the SMC…… 

 
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8.2.4 Reporting Requirements and Procedures for Serious Adverse Events 
……. 
Investigators must not wait to collect additional information to fully document the event before 
notifying the local Medical Monitor of an SAE. The initial notification should include the 
following (at minimum):  
• 
Protocol number and name and contact number of the Investigator 
• 
Participant identification number (and initials and date of birth, if available) 
• 
Date participant received iInvestigational product 
• 
SAE(s) and date of event onset 
• 
Current status of participant 
 
Details of Changes Made in Protocol Amendment 4 (Protocol Version 5.0, 29 Oct 2020) 
 
4.2 Inclusion Criteria 
Participants must meet all the following criteria to be eligible for the study: 
1. Adult males or females aged ≥18 to ≤65 years at screening 
2. Body Mass Index ≤30kg/m2………….. 
…………. 
10. HBsAg <400010000IU/mL 
 
 
Details of Changes Made in Protocol Amendment 3 (Protocol Version 4.0, 24 Feb 2020) 
ADMINISTRATIVE AND CONTACT INFORMATION 
 
Sponsor Medical Oversight 
 
  
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
  
 

 
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3.1.2  Study Methodology 
Participants will be screened in the period Day -42 to Day -1. Informed consent will be 
obtained before any study specific procedures are performed. Eligible participants will then 
attend the clinic to receive study vaccine on Day 0. Participants will be enrolled sequentially.  
…. 
• 
HBV disease markers in serum: 
o  Healthy participants: HBsAg will be tested at screening, hepatitis B surface 
antibody (HBsAb) and HBcAb will be tested at Day 0, and repeated at the 
end of the trial if negative at baseline, or at discretion of the Investigator 
o CHB participants: HBV DNA and quantitative HBsAg will be tested at 
screening and repeated on Days 0 28, 56, 84 and 168. The following 
parameters will be analysed on Days 0, 28, 56, 84 and 168: HBeAg, HBcAg, 
anti-HBs, anti-HBe, anti-HBc, pgRNA HBsAg, HBeAg, HBcAg, anti-HBs, 
anti-HBe, anti-HBc, HBV DNA, pgRNA will be analysed at screening, pre 
vaccination on Day 0 and on Days 14, 56, 84 and 168 
o … 
In CHB participants who consent to LFNAs, these will be taken pre-vaccination within  the 
screening period on Day 0 and at the clinic visit on Day 84. Liver fine needle aspirate assays 
may be used to quantify and characterise intrahepatic immune and parenchymal cells and/or 
HBV DNA and RNA transcripts. These aspirates and subsequent LFNA assessments are 
optional. 
 
4.3  Exclusion criteria 
Additionally, for participants with well controlled CHB (cohorts 3 and 4) 
21. ALT >3 × ULN, INR >1.5 unless the participant was stable on an anticoagulant regimen 
affecting INR, albumin <35 g/L, total bilirubin >34.2 µmol/L 2mg/dL, platelet count 
<100 x 109/L 100,000/mL 
 
 
5 
STUDY VACCINE 
The Investigator must ensure that study vaccine is handled only by study team members who 
have been appropriately trained for the conduct of this clinical study and that dosing is only 
performed by study team members who fully understand the procedures outlined in this section, 
the Investigator's Brochure and the Pharmacy Investigational Product (IP) Handling Manual. 

 
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A Delegation of Authority Log will be maintained by the study centre and will identify the 
individual(s) authorised to prepare and administer the study vaccine. 
 
5.2 
Identity of Study Vaccine 
ChAdOx1-HBV will be manufactured to Good Manufacturing Practice, labelled according to 
local regulations, including Annex 13 of the Good Manufacturing Practice Directive [28] as 
detailed in the Pharmacy IP Handling Manual.  
ChAdOx1-HBV is formulated in an A438 buffer comprising of 10 mM histidine, 35 mM NaCl, 
7.5% sucrose (w/v), 1 mM MgCl2, 0.1% (w/v) PS-80, 0.1 mM ethylenediaminetetraacetic acid 
(EDTA), 0.5% ethanol (v/v), pH 6.6 to a target concentration of 1 x 1011 vp/mL. 
ChAdOx1-HBV will be supplied at a target sterile volume of 0.65 mL in 3 mL Type 1 
borosilicate glass vials allowing 0.5mL to be drawn by syringe for dilution into high dose HBV 
vaccine and low dose HBV vaccine. Dilution to both low and high doses will be detailed in the 
Pharmacy IP Handling Manual. The vials are stoppered with sterilised European 
Pharmacopoeia/United States Pharmacopoeia Type 1 chlorobutyl, rubber stopper and sealed 
with aluminium/copolymer caps. The vaccine is clear to slightly opaque in appearance 
The study vaccines will be released by a qualified person. 
 
5.3 
Labelling, Packaging and Shipping 
At the start of the study, a sufficient number of study vaccine vials will be shipped to each 
study centre based on projected recruitment at each centre with approximately 20% overage in 
case of spillage or breakage. Further study vaccine supplies may be requested following the re 
supply process in the Pharmacy IP Handling Manual. 
 
5.7 
Method of Assigning Participants to Treatment Groups 
At the screening visit, participants will be sequentially allocated a screening participant  
number once written, informed consent has been obtained. They will be identified by this 
number until entry intothroughout the study. 
The healthy and CHB participants will be allocated to low dose or high dose treatment 
depending on the treatment schedule prepared by statistician. 
Participants fulfilling entry criteria will be allocated an enrolment number and allocated to 
treatment based on a treatment schedule.  
Once screening and enrolmentparticipant numbers have been assigned, no attempt will be 
made to use those numbers again. If an enrolment  participant number is allocated incorrectly, 
no attempt will be made to remedy the error once the study vaccine has been dispensed. Any 
participants that are withdrawn prior to vaccination will be replaced on a case by case basis 
following discussion with the Sponsor. Discontinued participants following vaccination who 
do not complete all follow up visits will be replaced at the determination of the Sponsor. 
Any replacement participants will be given the next sequential participant number. 
The treatment schedule list will be held by the statistician during the study. 
 

 
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5.8.2.2  
Study Vaccine Preparation and Administration 
ChAdOx1-HBV vials will be allowed to reach room temperature before use.  
Doses of ChAdOx1 HBV will be prepared by serial dilution according to the procedure in the 
Pharmacy IP Handling Manual. Dilution kits of commercially available equipment will be 
provided by the Sponsor. 
All vaccinations will be made by a suitably qualified health professional. A second study team 
member will be present to account for each vaccination given. 
The suitably qualified healthcare professional will wear gloves, eye protection and an apron or 
laboratory coat/gown during the procedure. The vaccination site will be covered with a sterile 
dressing to minimise dissemination of the recombinant virus into the environment. This should 
absorb any virus that may leak out through the needle track. The sterile dressing will be 
removed approximatelykept on the vaccination site at least 10 minutes  after vaccination. 
The dressing will be discarded as GMO waste. 
 
 
6 
STUDY PROCEDURES AT EACH VISIT/SCHEDULE OF ASSESSMENTS

 
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Table 2 
Overall Schedule of Assessments at Each Study Visit 
Visit/Call 
Screen 
Vaccination 
Follow-up 
End of Study 
Timepoint 
Day-42 to -1 
Day 0 
Day 1 
Day 7±1 
Day 14±1 
Day 28±2 
Day 56±3 
Day 84±7 
Day 168±7 
Pre- 
0 
Post- 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Baseline/eligibility variables 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
X 
X 
 
 
 
 
 
 
 
 
 
HIV Ab, HCV Ab, HBsAg, HDV Ab(a),
HBV, HDV serology 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (β-hCG) [c] 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Laboratory eligibility and safety tests 
 
 
 
 
 
 
 
 
 
 
 
Haematology [d] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Biochemistry[d] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Liver function tests[e] 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Study vaccination 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
 
X 
 
 
 
 
 
 
 
 
Post-vaccination observation[f] 
 
 
 
X 
 
 
 
 
 
 
 
Other Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
Directed physical examination if required 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signs[g] 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Local/systemic reactogenicity [h] 
 
X 
 
X 
X 
X 
 
 
 
 
 
Unsolicited adverse events [i] 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serious adverse events and adverse events 
of special interest  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for HBV disease markers  
 
 
 
 
 
 
 
 
 
 
 
Healthy participants (HBsAb, HbcAb) 
 
X 
 
 
 
 
 
 
 
 
X[i] 
CHB (HBV DNA, HBsAg quantitative) 
X 
X 
 
 
 
 
 
X 
X 
X 
X 

 
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CHB ( HBeAg, anti-HBe, anti-HBs, 
pgRNA, HBcAg, anti-HBc) 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Immunogenicity assessments 
 
 
 
 
 
 
 
 
 
 
 
Blood for cellular immunogenicity [k] 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Liver fine needle aspirates[l]† 
X 
X 
 
 
 
 
 
 
 
X 
 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine transaminase; aPTT=activated partial thromboplastin time; AST=aspartate transaminase; CHB=chronic hepatitis B virus; 
DNA=desoxyribonucleic acid; GGT=gamma-glutamyl transpeptidase; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; β-hCG=beta human chorionic gonadotrophin; 
HBcAg=hepatitis B core-related antigen; HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HBsAg=hepatitis B surface antigen; HCV=Hepatitis C virus; HDV=Hepatitis D virus; 
HIV=human immunodeficiency virus; ICS=intracellular cytokine staining; INR= international normalised ratio; LFNA=liver fine needle aspirate; pgRNA=pre-genomic RNA; 
PBMCs=peripheral blood mononuclear cells; PT=prothrombin time 
†Optional assessments 
 
[m] HDV Ab serology and HBsAg quantitative test will be done in CHB participants only; HBsAg qualitative test will be done in healthy participants; all participants will be tested 
for HIV and HCV serology 
[n] 
Female participants only 
[o] 
Full haematology (including PT/INR and aPTT) and biochemistry panel  
[p] 
Measurement of ALP, GGT, ALT, AST and total bilirubin 
[q] 
The first participant in each cohort will be assessed for 1 hour in case of immediate adverse events (timed after the end of study vaccine administration). The other participants will be 
assessed for 30 minutes 
[r] Pulse, blood pressure and temperature 
[s] Captured during clinic visits and then via eDiary for 3 days post-vaccination 
[t] Recorded in the eCRF from the date the informed consent is signed, at all clinic visits to cover the period since the previous visit and during the visit and up to 28 days post-vaccination 
[u]  If negative at baseline, at discretion of the investigator healthy participants: HBsAg, HBsAb, HBcAb. In CHB participants: HBsAg, HBeAg, HBcAg, anti-HBs, anti-HBe, anti-
HBc, HBV DNA, pgRNA 
[v] To be processed into PBMCs for analysis by ICS 
[w] Only in CHB participants who consent to LFNAs after confirming eligibility. Coagulation profile must be assessed prior to repeat LFNA on Day 84. For those consenting to 
LFNAs, blood for PT/INR and aPTT testing must be collected 
 

 
Pr ot oc ol H B V -0 0 1  
Versi o n 9. 0 : 2 4 N o v  2 0 2 1  
 
V accitec h Lt d  
C O N FI D E N TI A L  
P a ge 1 1 3  of 1 1 8  
 
 
6. 1 
Scree ni n g a n d B aseli ne Pre -D ose Assess me nts  
Writte n i nf or me d c o nse nt f or partici pati o n i n t he st u d y m ust be o btai ne d bef ore perf or mi n g 
a n y st u d y s pecific scree ni n g tests or e val uati o ns acc or di n g t o t he pr ocess i n Secti o n 1 3. 4.  
….. 
•  
A bl o o d sa m ple will be ta ke n f or HI V, H C V, H B V,  a n d i n C H B p artici p a nts o nl y,  
he patitis D V ir us ( H D V) dia g n ostic testi n g   
… 
C o nc o mita nt me dicati o ns will be rec or de d t hr o u g h o ut t he st u d y b y q uesti o ni n g t he partici pa nt 
at eac h visit w het her t he y t o o k a n y c o nc o mita nt me dicati o ns si nce t he pre vi o us visit.  
I n  C H B  p artici p a nts  w h o  c o nse nt  t o  L F N As:  a n  L F N A  will  be  perf or me d  wit hi n  
scree ni n g peri o d , after scree ni n g tests h a ve s h o w n eli gi bilit y , as directe d b y t he Pri nci p al 
I n vesti g at or or dele g ate d p h ysici a n. T hese as pir ates a n d s u bse q ue nt assess me nts are 
o pti o n al 
N B. C o a g ul ati o n pr ofile m ust be assesse d pri or t o re pe at L F N A  
 
6. 2 
Tre at me nt D a y Assess me nts ( D a y 0)  
T he f oll o wi n g will be perf or me d pre - vacci nati o n: 
• 
I n C H B  partici pa nts  w h o  c o nse nt  t o  L F N As:  a n  L F N A  will  be  perf or me d  wit h  
a d diti o nal P T/I N R a n d a P T T testi n g, as directe d b y t he Pri nci pal I n vesti gat or or dele gate d 
p h ysicia n. T hese as pirates a n d s u bse q ue nt assess me nts are o pti o nal  
 
7. 1. 4. 3 HI V, H B V, H C V a n d H D V Di a g n ostic Testi n g  
Bl o o d sa m ples will be teste d f or:  
• 
I n all partici pa nts: 
 
HI V a nti b o dies 
  
H C V a nti b o dies 
• 
I n Healt h y V ol u nteers: q u alit ati ve  H Bs A g, H Bs A b, H Bc A b  
• 
I n C H B partici pa nts: q u a ntit ati ve  H Bs A g, H Be A g, H Bc A g, a nti -H Bs, a nti -H Be, a nti -
H Bc, H B V D N A, p g R N A, H D V ser ol o g y  
 
8. 2. 1. 3 Seri o us A d verse E ve nt  
A n  S A E  is  a n  a d verse  e ve nt  meeti n g  t he  o utc o me  criteria  f or  seri o us ness  re gar dless  of  
relati o ns hi p t o t he st u d y vacci ne. T he f oll o wi n g are n ot ( a n d s h o ul d n ot be re p orte d as) 
S A Es: h os pit alis ati o n f or sc he d ule d tre at me nts a n d electi ve me dic al/s ur gic al  pr oce d ures 
rel ate d t o a pre -e xisti n g c o n diti o n t h at di d n ot i ncre ase i n se verit y or  fre q ue nc y f oll o wi n g 
recei pt of st u d y v acci ne, a n d a d missi o ns f or s oci al re as o ns.  
 
 

 
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Details of Changes Made in Protocol Amendment 2 (Protocol Version 3.0, 04Dec2019) 
4.2 
Inclusion Criteria 
The following text in bold has been added: 
5. If female: Not pregnant and one of the following: 
− Hormonal (oral, intravaginal, transdermal, implantable or injectable):  
− Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
− Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
− oral 
− injectable 
− implantable 
− An intrauterine hormone-releasing system 
4.3.1.2  
Study Discontinuation 
The following text in bold has been clarified: 
Participants may choose to discontinue study assessments by withdrawal of consent. If 
the participant discontinues from taking the study vaccine but does not withdraw 
consent, the Investigator or research worker should attempt to continue safety follow-up 
assessments. 
Participants may be withdrawn from taking the study vaccine, but followed up for safety, in 
the event of: 
• 
A severe adverse event or SAE 
• 
Difficulties in obtaining blood or other samples 
• 
Failure of the participant to comply with the protocol requirements or to cooperate with 
the Investigator 
• 
For safety reasons, it being in the best interest of the participant that he/she be 
withdrawn, in the Investigator’s opinion 
• 
A positive pregnancy test or if the participant is non-compliant with the 
contraception requirements (see Section 4.2) 
• 
Development of a medical condition that requires concomitant treatment with a 
potentially toxic therapy 
Participants must be withdrawn from the study in the event of: 
• 
Withdrawal of consent 
• 
For safety reasons, it being in the best interest of the participant that he/she be 
withdrawn, in the Investigator’s opinion 
• 
A positive pregnancy test or if the participant is non-compliant with the contraception 
requirements (see Section 4.2) 

 
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• 
Development of a medical condition that requires concomitant treatment with a 
potentially toxic therapy 
8.1.3 Local Medical Monitor 
The following text in bold has been added: 
The local Medical Monitor (LMM) is the Sponsor’s medical representative and is a 
credentialed physician or surgeon in their country of residence with the necessary expertise to 
act in such capacity. The LMM local Medical Monitor reviews the safety of the product for 
protocols in a specific region and, in conjunction with the Sponsor, determines expectedness 
of study vaccine-related SAEs. The local Medical Monitor, in consultation with the Sponsor, 
may assess the causality for adverse events and may upgrade the causality determined by the 
Investigatorcan add another causality to the investigator’s causality assessment, however 
the causality assessment given by the investigator must not be downgraded by the LMM. 
If the LMM disagrees with the investigator’s causality assessment, the opinion of both the 
investigator and the sponsor should be provided with the report.  
8.2.3.2  
Assessment of Relationship 
The following text in bold has been added: 
For all other adverse events, the Investigator and the Sponsor (the local Medical Monitor) will 
determine a causal relationship to the study vaccine. 
 
The Investigator and the Sponsor both determines causality. It is expected that communication 
and consultation may occur in the assessment of the causality of adverse eventsThe Sponsor 
and LMM can add another causality assessment to the Investigator’s causality 
assessment. The causality assessment given by the investigator must not be downgraded 
by the Sponsor. If the Sponsor disagrees with the Investigator’s causality assessment, the 
opinion of both the Investigator and the Sponsor should be provided with the report. 
8.2.4.3  
Medical Review and Reporting by the Sponsor 
The following text has been clarified: 
The Sponsor (or designee) will determine expedited reporting requirements for each reported 
SAE according to local requirements based upon: 
• 
Investigator's assessment of causality and seriousness, with allowance for upgrading 
following independent review by the Sponsor (or designee) as needed 
The Synopsis is updated to reflect the changes above. 
 
 

 
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Details of Changes Made in Protocol Amendment 1 (Protocol Version 2.0, 13Nov2019) 
ADMINISTRATIVE AND CONTACT INFORMATION  
The following text in bold has been added: 
 
Central Laboratory (for pgRNA and 
HBcrAg HBcAg analysis)  
 
 
 
 
 
  
 
 
2 STUDY OBJECTIVES AND ENDPOINTS 
The following text in bold has been added: 
 
Exploratory  
Determine the effect of ChAdOx1-HBV on 
virological and immunological systemic and 
intrahepatic changes in participants with CHB 
infection and virally suppressed with oral antiviral 
medication.  
 
 
 
Exploratory  
• Effect on serum hepatitis B core-related antigen 
(HBcrAgHBcAg)  
 
 
3.1.1 
Study Design 
The following text in bold has been added: 
A Data Safety Monitoring Committee (DSMC) will be appointed to perform unscheduled 
reviews of the available safety, and tolerability, efficacy and immunogenicity study data and 
make recommendations concerning the continuation, modification or termination of the study 
if one of the study stopping or holding rules defined in Section 3.1.3 is met. 
3.1.2 
Study Methodology 
The following text in bold has been added: 
The study will investigate response to study vaccine as shown in Table 2. On Day 0, an 
electronic diary (eDiary), tape measure and thermometer will be provided to perform 
self-assessment of local and systemic reactogenicity. Participants will then have a follow-up 
telephone call on Day 1 and return to the clinic on Days 1, 7, 14, 28, 56, 84 and 168 for study 
assessments, with end of study visit procedures performed at the final visit. 
 
• 
HBV disease markers in serum (HBV DNA, HBeAg, in healthy participants: HBsAg, 
hepatitis B surface antibody (anti-HBsHBsAb), HBcAb; in CHB participants: 
HBsAg, HBeAg, HBcrAg HBcAg, anti-HBs), anti-HBe, anti-HBc, HBV DNA, 
pgRNA) will be analysed at screening, pre-vaccination on Day 0 and on Days 14, 56, 
84 and 168 in the CHB cohorts 
6 
STUDY PROCEDURES AT EACH VISIT/SCHEDULE OF ASSESSMENTS 
The following text in bold has been added: 
A study period of 168 days, consisting of a vaccination day on Day 0, a follow-up telephone 
call on Day 1 and follow-up visits on Days 1, 7, 14, 28, 56 and end of study visit on Day 168 

 
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Table 1 
Overall Schedule of Assessments at Each Study Visit 
Visit/Call 
Scre
en 
Vaccination 
Follow-up 
End of 
Study 
Timepoint 
Day-42 
to -1 
Day 0 
Day 1 
Day 7±1 Day 14±1 Day 28±2 Day 56±3 Day 84±7 Day 168±7 
Pre- 
0 
Post- 
Other Safety 
assessments 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
Directed physical 
examination if required 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs [g] 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
assessments 
 
 
 
 
 
 
 
 
 
 
 
Transcriptomics  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine transaminase; aPTT=activated partial thromboplastin time; 
AST=aspartate transaminase; CHB=chronic hepatitis B virus; DNA=desoxyribonucleic acid; GGT=gamma-glutamyl 
transpeptidase; HBcAb=hepatitis B core antibody; anti-HBsHBsAb=hepatitis B surface antibody; β-hCG=beta human 
chorionic gonadotrophin; HBcrAgHBcAg=hepatitis B core-related antigen; HBV=hepatitis B virus; HBeAg=hepatitis B 
e antigen; HBsAg=hepatitis B surface antigen; HCV=Hepatitis C virus; HDV=Hepatitis D virus; HIV=human 
immunodeficiency virus; ICS=intracellular cytokine staining; INR= international normalised ratio; LFNA=liver fine needle 
aspirate; pgRNA=pre-genomic RNA; PBMCs=peripheral blood mononuclear cells; PT=prothrombin time 
 
[h] 
In allhealthy participants: HBsAg, HBsAb, HBcAb. In CHB participants only HBV DNA,: HBsAg, HBeAg, 
HBcAg, anti-HBs, anti-HBe, anti-HBsHBc, HBV DNA, pgRNA, HBcrAg 
 
6.3.1 
Clinic VisitTelephone Call: Day 1  
The following text has been clarified: 
• 
A symptom-directed physical examination will be performed if required 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
• 
Blood samples will be taken for immunogenicity assessment [transcriptomics only] 
• 
eDiary to collect local and systemic reactions during 3 consecutive days 
post-vaccination 
6.3.2 
Clinic Visit: 7 
The following text has been clarified: 
• 
A symptom-directed physical examination will be performed if required 
• 
Vital signs (pulse rate, blood pressure and temperature) will be measured 
• 
Blood samples will be taken for haematology (including PT/INR and aPTT), 
biochemistry and LFTs 
• 
Blood samples will be taken for immunogenicity assessment [transcriptomics only] 
7.1.4.3 
HIV, HBV, HCV and HDV Diagnostic Testing 
Blood samples will be tested for: 
• 
In all participants: 
− 
HIV antibodies 
− 
HCV antibodies 
− 
HBsAg 

 
Protocol HBV-001 
Version 9.0: 24 Nov 2021 
 
Vaccitech Ltd 
CONFIDENTIAL 
Page 118 of 118 
 
• 
In Healthy Volunteers: HBsAg, HBsAb, HBcAb 
• 
In CHB participants only: HDV serology, HBV DNA,: HBsAg, HBeAg, HBcAg, 
anti-HBe antibody-HBs, anti-HBs antibody-HBe, anti-HBc, HBV DNA, pgRNA, 
HDV serology 
7.2 
Immunogenicity Assessments 
The following text has been clarified: 
Immunogenicity samples (PBMCs) will be taken for planned and potential exploratory 
analyses and transcriptomics at each of the timepoints according to Table 2. 
7.2.2.1 
Exploratory Analysis in Blood Samples 
The following text in bold has been added: 
Serum blood samples will be used for analysis of pgRNA and HBcrAgHBcAg. 
7.3 
Secondary Outcomes in Blood Samples 
The following text in bold has been added: 
Serum blood samples in CHB participants will be used for analysis of HBV DNA, HBeAg, 
anti-HBe antibody, HBsAg and anti-HBs antibodyHBsAb.  
8.1.5 
Data Safety Monitoring Committee 
The following text in bold has been added: 
A DSMC will be appointed to perform unscheduled reviews of the available safety, and 
tolerability, efficacy and immunogenicity study data and make recommendations concerning 
the continuation, modification, or termination of the study if one of the study stopping or 
holding rules defined in Section 3.1.3 is met.