A Platform Study Evaluating the Efficacy and Safety of Investigational Therapies in Participants With Chronic Hepatitis B Infection (PREVAIL)
Phase: PHASE1
Conditions: Hepatitis B, Chronic
Sponsor: Vir Biotechnology, Inc.

Official Title: A Phase 2 Study Evaluating the Efficacy and Safety of VIR-3434 and/or VIR-2218 
Containing Regimens in HBeAg-negative Participants with Low Viral Burden of Chronic Hepatitis B 
Infection (THRIVE) 
NCT Number: NCT05612581
Document Date: 26 January 2024, Version 1.0

PREVAIL PLATFORM CLINICAL STUDY 
SUB-PROTOCOL B (THRIVE) 
PROTOCOL AMENDMENT 3 
This sub-protocol should be read and conducted in conjunction with the 
PREVAIL Master Protocol 
Study Title 
A Phase 2 Study Evaluating the Efficacy and Safety of VIR-3434 and/or 
VIR-2218 Containing Regimens in HBeAg-negative Participants with 
Low Viral Burden of Chronic Hepatitis B Infection (THRIVE) 
Brief Title 
A Phase 2 Study to Evaluate VIR-3434 and/or VIR-2218 Containing 
Regimens for Treatment of Chronic Hepatitis B Infection 
Master Study Number 
VIR-MHB1-V200 
Sub-Study Number 
VIR-SHB1-V202 
Compounds 
VIR-3434 (tobevibart), VIR-2218 (elebsiran), and tenofovir disoproxil 
fumarate (TDF) 
Indication 
Chronic Hepatitis B Infection 
Study Phase 
2 
Study Sponsor 
Vir Biotechnology, Inc. 
1800 Owens Street, Suite 900 
San Francisco, CA 94158, USA 
Regulatory Agency 
Identifying Numbers 
IND: TBD 
EudraCT: 2022-002014-16 (under Master Protocol) 
NCT: 05612581 (under Master Protocol) 
Protocol Date 
26 January 2024, Version 1.0 
This study will be conducted in compliance with International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP), including the archiving of essential documents 
CONFIDENTIALITY STATEMENT  
This document contains confidential information that is the property of Vir Biotechnology, Inc. This confidential 
information is being provided to you, your staff, the applicable Institutional Review Board/Independent Ethics 
Committee, and applicable regulatory authorities solely for the purpose of evaluating or conducting this clinical 
study. This confidential information will be protected by you and your staff against disclosure to or use by third 
parties, except as necessary for the evaluation or conduct of the study. 

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INVESTIGATOR SIGNATURE PAGE 
VIR BIOTECHNOLOGY, INC 
1800 OWENS STREET, SUITE 900 
SAN FRANCISCO, CA 94158 
STUDY ACKNOWLEDGMENT 
A Phase 2 Study Evaluating the Efficacy and Safety of VIR-3434 and/or VIR-2218 
Containing Regimens in HBeAg-negative Participants with Low Viral Burden of Chronic 
Hepatitis B Infection (THRIVE) 
This sub-protocol has been approved by Vir Biotechnology, Inc. The following signature 
documents this approval.  
Printed Name 
Signature and Date 
INVESTIGATOR STATEMENT 
I have read the Master Protocol, current sub-protocol, including all appendices, and I agree that it 
contains all necessary details for me and my staff to conduct this study as described. I will 
conduct this study as outlined herein and will make a reasonable effort to complete the study 
within the time designated.  
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Vir Biotechnology, Inc. I will discuss this material with them to ensure 
they are fully informed about the drugs and the study.  
Principal Investigator Printed Name 
Signature 
Date 
PPD

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PROTOCOL AMENDMENT 3 (26 JANUARY 2024) SUMMARY OF CHANGES TABLE 
Table 1: 
Protocol Document History 
Summaries of changes for previous amendments are provided in Section 10.5. 
Table 2: 
Protocol Amendment 3 Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis (Number of 
Participants), 4.1.1. Number of 
Participants, 9.2. Sample Size 
Determination, 9.5. Interim Analysis 
Clarified that floater participants may be added at any 
time at Sponsor’s discretion. As a result of this 
clarification, language in Section 9.5 (Interim 
Analysis) was updated for consistency 
To clarify when floater participants can be 
added during the study 
2.3.1. Risk Assessment 
Updated risk information for hypersensitivity reactions 
and immunogenicity for VIR-3434 
To provide updated risk assessment 
information for VIR-3434 per the most recent 
IB  
4.1.3. NRTI Treatment 
Clarified that confirmatory test for HBV DNA 
> 20,000 IU/mL should occur no later than 7 calendar
days after initial result is received. Also clarified that
central laboratory testing is preferred, but local
laboratory results will be accepted if it is not feasible
to collect central laboratory results in time.
To ensure retesting is done promptly for 
safety management of participants who may 
be recommended to start NRTI therapy in 
follow-up period 
5.1. Inclusion Criteria 
Clarified that participants must have HBV DNA 
≤ 2,000 IU/mL and > LLOQ to be eligible 
Participants must have quantifiable HBV 
DNA to be eligible 
Document 
Date 
Amendment 3 
26 January 2024 
Amendment 2 
11 October 2022 
Amendment 1 
16 May 2022 
Original Protocol 
01 April 2022 

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Section # and Name 
Description of Change 
Brief Rationale 
7.2. Discontinuation of Study 
Intervention(s) 
Added the following additional treatment 
discontinuation criteria:  
Serum ALT or aspartate aminotransferase (AST) 
> 3 × ULN with:
serum albumin <3.0g/dL or
ascites, hepatic encephalopathy, or liver-related 
symptoms (eg, severe fatigue, nausea, vomiting, right 
upper quadrant pain in the absence of an alternative 
medical explanation) 
Also added study intervention may be discontinued in 
the occurrence of a condition that in the opinion of the 
Investigator significantly jeopardizes the wellbeing 
and safety of the participant. Investigator must 
promptly inform the Sponsor Medical Monitor if any 
such condition arises. 
This change was made to include additional 
criteria for treatment discontinuation and 
clarification for when the Investigator may 
stop study intervention. This change was 
previously made in Addendum France-1 of 
VIR-SHB1-V202 (THRIVE) Amendment 2, 
Version 3.0 in response to a request made by 
ANSM of France and is being added to 
VIR-SHB1-V202 (THRIVE) Amendment 3 to 
harmonize into a single global protocol. 
8.8. Pharmacokinetic Assessments 
Clarified that PK assessments are exploratory and may 
or may not be analyzed, and specific assays used for 
these assessments may be changed at the Sponsor’s 
discretion based on emerging data 
To allow for appropriate analyses of 
exploratory PK assessments based on 
emerging data 
10.2. Appendix 2: Clinical 
Laboratory Tests, 10.7. Appendix 7: 
Additional Assessments in 
Participants That Experience ALT 
Elevation Meeting ECI Criteria 
Added serum phosphate to the protocol-required safety 
laboratory tests 
To align with renal monitoring guidance in 
the Viread® SmPC. This change was 
previously made in Addendum-1 and 
Addendum France-1 of VIR-SHB1-V202 
(THRIVE) Amendment 2, Version 3.0 and is 
being added to VIR-SHB1-V202 (THRIVE) 
Amendment 3 to harmonize into a single 
global protocol. 

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Section # and Name 
Description of Change 
Brief Rationale 
10.2. Appendix 2: Clinical 
Laboratory Tests 
Added footnote to clarify creatinine clearance 
calculation for study visits where weight is not 
measured (creatinine clearance will be calculated using 
the value measured from the most recent study visit) 
To provide further guidance for creatinine 
clearance calculation. This clarification was 
described in Protocol Administrative Letter 1 
for VIR-SHBV1-V202 (THRIVE) 
Amendment 2, Version 3.0 and is being added 
to VIR-SHB1-V203 (THRIVE) Amendment 3 
to harmonize into a single global protocol. 
Entire document 
Other administrative, formatting, and other minor 
changes 
These changes were made to clarify, ensure 
consistency, provide up-to-date information, 
or rectify typographical errors. 

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2
1.
PROTOCOL SUMMARY ..........................................................................................11
1.1.
Synopsis ......................................................................................................................11
1.2.
Study Schema .............................................................................................................14
1.3.
Schedule of Activities .................................................................................................14
2.
INTRODUCTION ......................................................................................................15
2.1.
Background .................................................................................................................15
2.2.
Study Rationale ...........................................................................................................16
2.3.
Benefit/Risk Assessment ............................................................................................17
2.3.1.
Risk Assessment .........................................................................................................17
2.3.2.
Benefit Assessment .....................................................................................................21
2.3.3.
Overall Benefit Risk Conclusion ................................................................................21
3.
OBJECTIVES AND ENDPOINTS ............................................................................22
4.
STUDY DESIGN .......................................................................................................24
4.1.
Overall Study Design ..................................................................................................24
4.1.1.
Number of Participants ...............................................................................................24
4.1.2.
Intervention Groups and Duration ..............................................................................24
4.1.2.1.
Intervention Groups ....................................................................................................24
4.1.2.2.
Cohort Initiation ..........................................................................................................25
4.1.2.3.
Duration ......................................................................................................................25
4.1.3.
NRTI Treatment ..........................................................................................................25
4.1.4.
Long-term and Follow-Up Care .................................................................................26
4.2.
Scientific Rationale for Study Design ........................................................................26
4.2.1.
Rationale for VIR-3434 for the Treatment of Chronic HBV Infection ......................26
4.2.2.
Rationale for VIR-2218 for the Treatment of Chronic HBV Infection ......................28
4.2.3.
Rationale for VIR-3434 + VIR-2218 + TDF for the Treatment of Chronic 
HBV Infection ............................................................................................................29
4.3.
Justification for Dose ..................................................................................................29
4.3.1.
VIR-3434 Dose Selection ...........................................................................................29
4.3.2.
VIR-2218 Dose Selection ...........................................................................................31
4.3.3.
TDF Dose Selection ....................................................................................................32
4.4.
End of Study Definition ..............................................................................................32

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5.
STUDY POPULATION .............................................................................................33
5.1.
Inclusion Criteria ........................................................................................................33
5.2.
Exclusion Criteria .......................................................................................................34
5.3.
Lifestyle Considerations .............................................................................................36
5.3.1.
Meals and Dietary Restrictions ...................................................................................36
5.3.2.
Caffeine, Alcohol, and Tobacco .................................................................................36
5.3.3.
Activity .......................................................................................................................36
5.4.
Screen Failures ............................................................................................................36
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................37
6.1.
Study Intervention(s) Administered ...........................................................................37
6.2.
Preparation, Handling, Storage, and Accountability ..................................................38
6.3.
Randomization and Blinding ......................................................................................38
6.4.
Study Intervention Compliance ..................................................................................38
6.5.
Dose Modification ......................................................................................................38
6.5.1.
Dose Modifications for TDF ......................................................................................38
6.6.
Concomitant Therapy .................................................................................................38
6.6.1.
Concomitant Therapy Not Permitted During the Study .............................................38
7.
DISCONTINUATION OF STUDY, STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................40
7.1.
Study Stopping Rules .................................................................................................40
7.2.
Discontinuation of Study Intervention(s) ...................................................................40
7.3.
Participant Discontinuation/Withdrawal from the Study ...........................................41
7.4.
Replacement of Participants .......................................................................................41
7.5.
Lost to Follow-up .......................................................................................................41
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................41
8.1.
Screening Period .........................................................................................................41
8.2.
Efficacy Assessments .................................................................................................41
8.3.
Safety Assessments .....................................................................................................41
8.3.1.
Physical Examinations ................................................................................................41
8.3.2.
Vital Signs ..................................................................................................................41
8.3.3.
Clinical Safety Laboratory Tests ................................................................................41
8.3.4.
Pregnancy Testing ......................................................................................................42
8.3.5.
Local Tolerability .......................................................................................................42

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8.4.
Assessment of Viral Parameters, Antiviral Activity, and Resistance 
Surveillance ................................................................................................................42
8.5.
.42
8.6.
Exploratory Assessments ............................................................................................42
8.6.1.
Exploratory Analysis Samples ....................................................................................42
8.6.2.
42
8.6.2.1.
43
8.6.2.2.
.43
8.6.2.3.
.43
8.6.3.
43
8.7.
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................43
8.7.1.
Time Period and Frequency for Collecting AE and SAE Information .......................43
8.7.2.
Follow-up of AEs and SAEs .......................................................................................43
8.7.3.
Regulatory Reporting Requirements for SAEs ...........................................................43
8.7.4.
Adverse Events of Interest ..........................................................................................43
8.7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
or SAEs .......................................................................................................................43
8.7.6.
Laboratory Events of Clinical Interest ........................................................................44
8.7.7.
Special Situation Reports ............................................................................................44
8.7.7.1.
Pregnancy ...................................................................................................................44
8.8.
Pharmacokinetic Assessments ....................................................................................44
8.9.
Immunogenicity Assessments ....................................................................................44
8.10.
Electrocardiogram .......................................................................................................44
8.11.
Liver Elastography (eg, FibroScan) ............................................................................44
9.
STATISTICAL CONSIDERATIONS .......................................................................45
9.1.
Statistical Hypotheses .................................................................................................45
9.2.
Sample Size Determination ........................................................................................45
9.3.
Analysis Sets ...............................................................................................................46
9.4.
Statistical Analyses .....................................................................................................46
9.4.1.
General Considerations ...............................................................................................46
9.4.2.
Primary Endpoint(s) Analysis .....................................................................................46
9.4.2.1.
Target Population ........................................................................................................46
CCI
CCI
CCI
CCI
CCI
CCI

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9.4.2.2.
Population Level Summary ........................................................................................46
9.4.3.
Secondary Endpoint(s) Analysis.................................................................................47
9.4.4.
Exploratory Endpoint(s) Analysis ..............................................................................47
9.4.5.
Missing Data ...............................................................................................................47
9.4.6.
Other Safety Analyses ................................................................................................47
9.5.
Interim Analysis ..........................................................................................................47
9.6.
Pharmacokinetic Analyses ..........................................................................................48
9.7.
Immunogenicity Analyses ..........................................................................................48
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................49
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................49
10.1.1.
Regulatory and Ethical Considerations ......................................................................49
10.1.2.
Financial Disclosure ...................................................................................................49
10.1.3.
Informed Consent Process ..........................................................................................49
10.1.4.
Data Protection ...........................................................................................................49
10.1.5.
Confidentiality ............................................................................................................49
10.1.6.
Committees Structure .................................................................................................49
10.1.6.1.
Liver Flare Adjudication Committee (LFAC) ............................................................49
10.1.7.
Dissemination of Clinical Study Data ........................................................................49
10.1.8.
Data Quality Assurance ..............................................................................................49
10.1.9.
Source Documents ......................................................................................................49
10.1.10.
Electronic Case Report Forms (eCRF) .......................................................................49
10.1.11.
Study and Site Start and Closure ................................................................................50
10.1.12.
Publication Policy .......................................................................................................50
10.2.
Appendix 2: Clinical Laboratory Tests .......................................................................51
10.3.
Appendix 3: AEs, SAEs, SSRs and AEIs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................................53
10.4.
Appendix 4: List Abbreviations and Definitions of Terms ........................................54
10.5.
Appendix 5: Summaries of Changes for Previous Protocol Amendments .................56
10.6.
Appendix 6: Contraceptive and Barrier Guidance ......................................................62
10.7.
Appendix 7: Additional Assessments in Participants That Experience ALT 
Elevation Meeting ECI Criteria ..................................................................................64
10.8.
Appendix 8: Anaphylaxis, Cytokine Release Syndrome, And Immune 
Complex Disease Supportive Measures .....................................................................66

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10.9.
Appendix 9: Schedule of Activities ............................................................................68
11.
REFERENCES ...........................................................................................................80
LIST OF TABLES 
Table 1:
Protocol Document History ..........................................................................................3
Table 2:
Protocol Amendment 3 Summary of Changes .............................................................3
Table 3:
Intervention Groups ....................................................................................................24
Table 4:
Study Intervention (s) Administered ..........................................................................37
Table 5:
Study Arm(s) ..............................................................................................................37
Table 6:
Protocol-Required Safety Laboratory Tests ...............................................................51
Table 7:
Assessments in Participants That Experience ALT Elevation Meeting ECI 
Criteria ........................................................................................................................64
Table 8:
Schedule of Activities: Cohort 1b ...............................................................................68
Table 9:
Schedule of Activities: Cohort 2b ...............................................................................72
Table 10:
Schedule of Activities for Follow-Up Period for all Cohorts .....................................77
LIST OF FIGURES 
Figure 1:
Study Schema .............................................................................................................14
Figure 2:
Dosing Scheme by Cohort ..........................................................................................14
Figure 3:
Stages of Chronic HBV Infection ...............................................................................15
Figure 4:
VIR-3434 Observed and Projected Mean Concentration Profile in Healthy 
Volunteers in the Absence of HBsAg .........................................................................30

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1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Study Title 
A Phase 2 Study Evaluating the Efficacy and Safety of VIR-3434 and/or VIR-2218 containing 
regimens in HBeAg-negative Participants with Low Viral Burden of Chronic Hepatitis B 
Infection (THRIVE) 
Brief Title 
A Phase 2 Study to Evaluate VIR-3434 and/or VIR-2218 Containing Regimens for Treatment of 
Chronic Hepatitis B Infection  
Background and Rationale 
Chronic HBV infection remains an important global public health problem with significant 
morbidity and mortality (Trepo 2014). Chronic HBV infection is a dynamic process 
characterized by the interplay of viral replication and the host immune response. Patients can be 
divided into different stages of the disease based on the levels of Hepatitis B e antigen (HBeAg), 
HBV DNA, alanine aminotransferase (ALT), and liver inflammation (EASL 2017; Sarin 2015; 
Terrault 2018). 
Among the 300 million patients infected chronically with HBV, those who are HBeAg-negative 
represent the largest subgroup. These patients range from being inactive carriers to having 
chronic active hepatitis that can progress to serious liver complications including hepatocellular 
carcinoma (HCC). Inactive carriers are HBeAg-negative and anti-HBe-positive with persistently 
low levels of HBV DNA (≤ 2,000 IU/mL) and normal ALT maintained for at least 1 year. These 
patients have a good long-term prognosis with low rates of histological progression, low risk of 
cirrhosis or HCC, and high rates of long-term Hepatitis B surface antigen (HBsAg) clearance 
(EASL 2017; Invernizzi 2016; Terrault 2018; Yeo 2020). Inactive carriers lack indications for 
currently available treatments aimed at HBV DNA suppression, but they may be most likely to 
achieve functional cure, thereby becoming non-infectious with a lower risk of disease 
reactivation. 
VIR-3434 is a monoclonal antibody targeting HBsAg with multiple potential mechanisms of 
action including strong neutralizing activity and enhanced immunologic activity due to Fc 
domain engineering. VIR-2218 is small interfering RNA (siRNA) that targets all HBV RNA 
transcripts and is associated with substantial reductions in HBsAg in patients with chronic HBV 
infection. VIR-3434 and TDF with or without VIR-2218 has the potential to achieve a functional 
cure of chronic HBV infection. 

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Primary and Secondary Objectives and Endpoints:  
The objectives and endpoints specific to this sub-protocol are listed in the table. 
Objectives 
Endpoints 
Primary 
•
To evaluate the efficacy of VIR-3434 and
tenofovir disoproxil fumarate (TDF) with or
without VIR-2218
•
Proportion of participants achieving
suppression of HBV DNA (< LLOQ) with
HBsAg loss (< 0.05 IU/mL) at the end of
treatmenta
Secondary 
In addition to the Master Protocol, 
•
To assess the effect of VIR-3434 and TDF
with or without VIR-2218 on HBV DNA
•
To assess the effect of VIR-3434 and TDF
with or without VIR-2218 on HBsAg
•
To assess the immunogenicity of VIR-3434
In addition to the Master Protocol secondary 
endpoints 1-8, 
9.
Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) with
HBsAg loss (< 0.05 IU/mL) after
discontinuation of all treatment
a.
at 24 weeks
b.
at 48 weeks
10. Proportion of participants achieving HBsAg
loss (< 0.05 IU/mL)
a.
at end of treatmenta
b.
at 24 weeks post-end of treatmenta
11. Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) after
discontinuation of all treatment
a.
at 24 weeks
b.
at 48 weeks
12. Incidence and titers of anti-drug antibodies
(ADA; if applicable) to VIR-3434
13. Mean change in serum HBsAg level from
baseline across timepoints in the study
14. Proportion of participants achieving HBV
DNA (< LLOQ)
a End of treatment as defined in SOA 

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Overall Study Design 
This sub-protocol (THRIVE) should be read and conducted in conjunction with the PREVAIL 
Master Protocol. The Master Protocol provides a study framework: study outline, populations, 
common objectives and endpoints, common inclusion and exclusion criteria, statistical 
methodology, assessments and planned analyses for all sub-protocols. This sub-protocol is a 
Phase 2, multi-center, open-label study designed to evaluate the safety and efficacy of regimens 
containing VIR-3434 and NRTI with or without VIR-2218 in non-cirrhotic adult participants 
with low viral burden of chronic HBV infection. 
Brief Summary 
This sub-protocol is intended to evaluate 24- to 48- week regimens of VIR-3434 and TDF with 
or without VIR-2218 in participants with chronic HBV infection. Study population IV as defined 
in the Master Protocol (and table below) as participants that are HBeAg negative with low HBV 
DNA (≤ 2,000 IU/mL) and ALT levels ≤ ULN within the 1-year period prior to screening will be 
included in this sub-protocol.  
Master Protocol Population 
HBeAg Status 
HBV DNA Level 
ALT Level 
IV 
Negative 
≤ 2,000 IU/mL 
≤ ULN 
Number of Participants 
Up to 60 participants are planned to enroll in this sub-protocol. Cohorts 1b and 2b will each 
enroll approximately 15 participants initially. Additionally, up to 30 floater participants may be 
added to any of the cohorts in the sub-protocol at any time at Sponsor’s discretion. 
Intervention Groups and Duration 
Cohort 
Study 
Intervention 
Dose 
Route 
Number of 
Doses 
Frequency of Dosing 
1b 
VIR-3434 
300 mg 
SC 
12 
Every 4 weeks 
TDF 
300 mg a 
Oral 
308 
Every day 
2b 
VIR-3434 
300 mg 
SC 
12 
Every 4 weeks 
VIR-2218 
200 mg 
SC 
12 
Every 4 weeks 
TDF 
300 mg a 
Oral 
308 
Every day 
a Tenofovir disoproxil fumarate (TDF) dose will be 300 mg per label. Supply outside the United States may be 
tenofovir disoproxil (TD) 245 mg per label 
The total duration in the study for all participants will be up to 100 weeks. This includes the 
Screening Period up to 56 days (8 weeks), the Treatment Period of 44 weeks, and a Follow-Up 
Period of 48 weeks. 

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Liver Flare Adjudication Committee (LFAC): 
The Liver Flare Adjudication Committee (LFAC) will provide hepatic safety oversight by 
performing periodic reviews of data pertaining to participants who meet certain prespecified 
criteria for ALT elevations (Section 8.7.6). The LFAC membership composition, laboratory 
criteria to trigger patient case evaluation by the LFAC, and data review requirements are 
described in detail in the LFAC Charter. (See Section 10.1.6.1) 
1.2.
Study Schema 
Eligible participants will be enrolled via an interactive response technology (IRT) into 1 of the 
open cohorts. The overall study scheme is shown in Figure 1, and the dosing scheme for all 
cohorts are shown in Figure 2 . The SOA for Cohorts 1b and 2b are provided in Table 8 and 
Table 9. Table 10 shows the SOA for the Follow-Up Period.  
Figure 1: 
Study Schema 
Figure 2: 
Dosing Scheme by Cohort 
FU: Follow-Up; EOT: End of Treatment; Q4W: Every 4 weeks; TDF: Tenofovir disoproxil fumarate; 
HBsAg = Hepatitis B surface antigen; HBV DNA = Hepatitis B virus DNA; LLOQ = lower limit of quantitation 
See Section 4.1 for more details. 
1.3.
Schedule of Activities 
Schedules of activities (SOA) are provided in Section 10.9. 

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2.
INTRODUCTION
This sub-protocol should be read and conducted in conjunction with the PREVAIL Master 
Protocol (VIR-MHB1-V200). 
2.1.
Background 
Chronic HBV infection remains an important global public health problem with significant 
morbidity and mortality (Trepo 2014). Chronic HBV infection is a dynamic process 
characterized by the interplay of viral replication and the host immune response. Patients can be 
divided into different stages of the disease based on the levels of Hepatitis B e antigen (HBeAg), 
Hepatitis B virus (HBV) DNA, ALT, and liver inflammation (EASL 2017; Sarin 2015; 
Terrault 2018). 
Chronic HBV infection is a dynamic process and depends on the relationship between viral 
replication and host immune responses. Patients may oscillate between different phases of the 
disease, and serial monitoring of biomarkers such as HBV DNA, ALT, and HBV antigens helps 
determine the natural history of the disease. (Figure 3) 
Figure 3: 
Stages of Chronic HBV Infection 
Among the 300 million patients infected chronically with HBV, those who are HBeAg-negative 
represent the largest subgroup. These patients range from being immune inactive (also referred to 
as “inactive carriers” or “inactive hepatitis”) to having chronic active hepatitis that can progress 
to serious liver complications including hepatocellular carcinoma (HCC). Inactive carriers are 
HBeAg-negative and anti-HBe-positive with persistently low levels of HBV DNA 
(< 2,000 IU/mL) and normal ALT maintained for at least 1 year. These patients have a good 
long-term prognosis with low rates of histological progression, low risk of cirrhosis or HCC, and 
high rates of long-term HBsAg clearance (EASL 2017; Invernizzi 2016; Terrault 2018; 
Yeo 2020). Inactive carriers lack indications for currently available treatments aimed at HBV 
DNA suppression, but they may be most likely to achieve functional cure, thereby becoming 
non-infectious with a lower risk of disease reactivation. 
Immune 
Tolerant
Immune 
active
Inactive 
carrier
Reactivation
HBV DNA
ALT

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2.2.
Study Rationale 
VIR-3434 is a monoclonal antibody (mAb) targeting Hepatitis B surface antigen (HBsAg) with 
multiple potential mechanisms of action, including strong neutralizing activity and enhanced 
immunologic activity due to Fc domain engineering. In patients with chronic HBV infection, 
prior studies have shown that restoration of HBV-specific CD8+ T cell function by PD-1 
blockade in immune inactive patients is linked to T cell differentiation (Bengsch 2014). Reports 
from this study suggest that the potential to revive HBV-specific T cells in an immune inactive 
population may be feasible with VIR-3434’s proposed mechanism as a vaccinal mAb with T cell 
engagement activity. VIR-2218 is a siRNA that is associated with substantial reductions in 
HBsAg in patients with chronic HBV infection. VIR-3434 and an NRTI, with or without 
VIR-2218, have the potential to achieve a functional cure of chronic HBV infection. 
See Section 4.2 for additional scientific rationale for the different investigational regimens in this 
sub-protocol.

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2.3.
Benefit/Risk Assessment 
Detailed information about the known and potential benefits and risks of VIR-2218 and VIR-3434 may be found in the respective 
Investigator’s Brochures (IBs). 
2.3.1.
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: VIR-2218 
Injection site reactions (ISRs) 
Based on available preliminary clinical data 
from studies VIR-2218-1001 and 
VIR-2218-1006, ISRs are a recognized risk of 
subcutaneous (SC) administered siRNA 
therapies and are typically transient. 
Participants are monitored for local tolerability after 
injection and all AEs will be collected to reflect any 
ISRs that may be reported. Routine safety 
monitoring and reporting procedures are in place to 
provide safety overview. 
Immunogenicity: Immunogenicity is 
a potential risk associated with 
siRNA molecules. In general, the 
development of anti-drug antibodies 
(ADA) may impact safety, efficacy, 
or both. 
Immunogenicity data from Parts B/C of the 
VIR-2218-1001 study indicated a low 
immunogenicity risk based on all confirmed 
participants yielding negative titers. 
While there were no apparent clinical consequences 
related to the presence of VIR-2218 ADA, 
immunogenicity will continue to be assessed in 
Parts D/F of study VIR-2218-1001. 
Liver function test abnormalities: 
VIR-2218 is targeted for delivery to 
the liver, and transient transaminase 
elevations have been observed with 
SC administration with other 
GalNAc-conjugated siRNA 
therapeutics.  
Based on available preliminary clinical data 
from studies VIR-2218-1001 and 
VIR-2218-1006, minor ALT elevations (Grade 
1 or Grade 2) have been observed in participants 
receiving VIR-2218 monotherapy. However, 
none of the participants met Hy’s law and the 
majority resolved the ALT elevations by the end 
of treatment. 
Monitoring of liver function is recommended. In 
addition, ALT flares in chronic HBV patients may 
be a sign of restoration of HBV-targeted immunity, 
therefore close monitoring of liver function and 
HBV-viral parameters may be warranted. 
Low probability: Events of Clinical Interest (ECI) 
defined as ALT elevations >3x ULN, must be 
reported within 5 business days of Investigator 
notification. The Sponsor will monitor ECI and an 
independent Liver Flare Adjudication Committee 
(LFAC) reviews the liver safety and assesses 
etiology to recommend changes in study conduct. 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: VIR-3434 
Probability of significant non-target 
mediated toxicity: Hypersensitivity 
reactions (including injection site 
reactions [ISRs] and anaphylaxis): 
Hypersensitivity reactions (including 
ISRs and anaphylaxis), which may be 
severe or life-threatening, are a 
potential risk associated with the 
mAb class. The distinct risk of 
developing such conditions after 
dosing with VIR-3434 is unknown. 
Based on data from completed study 
VIR-3434-1002 and available preliminary data 
from ongoing study VIR-2218-1006, VIR-3434 
has been generally well tolerated in healthy 
participants and in participants with chronic 
HBV infection. ISRs that are Grade 1 or 2 in 
severity and transient have been observed with 
SC administration of VIR-3434. Most ISRs 
were considered unrelated to VIR-3434.   
Low probability: participants will be closely 
monitored to evaluate any patterns of non-target 
mediated toxicity. 
Participants are monitored for local tolerability after 
injection and all AEs will be collected to reflect any 
hypersensitivity reactions that may be reported. 
Routine safety monitoring and reporting procedures 
are in place to provide safety overview. 
Immunogenicity: Immunogenicity is 
a potential risk associated with the 
mAb class. VIR-3434 is a human 
immunoglobulin G (IgG) mAb; 
therefore, the development of ADA 
may impact its safety, efficacy, or 
both. 
In completed study VIR-3434-1002, there was 
no observable effect of ADA on PK, safety, and 
efficacy in the participants with treatment-
emergent ADA. 
Immunogenicity data will continue to be monitored 
and assessed in relation to associated VIR-3434 PK 
and clinical safety measures. 
Potential target-mediated risks: 
immune complex disease and 
hepatotoxicity due to the elimination 
of infected hepatocytes via cytotoxic 
T-cells induced via a vaccinal effect.
As no or only low levels of HBsAg is
detected on the surface of infected
hepatocytes, antibody-dependent
cellular cytotoxicity (ADCC)/
antibody-dependent cellular
phagocytosis (ADCP)-mediated
elimination of hepatocytes is possible
but unlikely to occur.
In study VIR-3434-1002, single doses up to 
300 mg were well tolerated. No clinically 
significant changes in laboratory parameters 
were observed, and no participant developed 
clinical or laboratory evidence of immune 
complex disease. 
These preliminary results are consistent with 
prior clinical experience supporting the safety of 
anti-HBsAg mAb. HBV-ABXTL, a mixture of 
two anti-HBsAg monoclonal antibodies, was 
evaluated at doses up to 80 mg administered 
weekly for 4 doses in patients with baseline 
HBsAg ranging from approximately 20 to 
Low probability: participants will be closely 
monitored to evaluate any patterns of non-target 
mediated toxicity. 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
80,000 IU/mL, and no signs of immune 
complex disease or hepatotoxicity were 
observed (Galun 2002). Additionally, several 
studies have evaluated the use of hepatitis B 
immune globulin (HBIG) in patients with 
chronic HBV infection and reported favorable 
safety and tolerability (Perrillo 2013, 
Reed 1973, Tsuge 2016). In the largest study, 
64 patients with baseline HBsAg ranging from 
0.09 to 11,214 IU/mL (mean 1,965 IU/mL) 
received HBIG therapy for multiple weeks, and 
no clinical manifestations of immune complex 
disease or other safety concerns were observed 
(Perrillo 2013).  
Study Intervention: VIR-3434 + VIR-2218 + TDF 
Hepatotoxicity 
The combination of these study interventions 
may result in hepatotoxicity (eg, elevated ALT). 
Based on available preliminary clinical data 
from ongoing studies VIR-2218-1001 and 
VIR-2218-1006 and completed study 
VIR-3434-1002: VIR-2218 or VIR-3434 
monotherapy in virally suppressed participants 
have resulted in minor ALT elevations (Grade 1 
or Grade 2). However, none of the participants 
met Hy’s law, and the majority of ALT 
elevations resolved after the end of treatment. 
Addition of NRTI (TDF [tenofovir disoproxil 
fumarate]) to the treatment regimen to suppress 
viral replication 
Excluding patients with significant fibrosis or 
cirrhosis, significant chronic liver disease (except 
HBV infection), history of hepatic decompensation. 
Routine safety monitoring and reporting procedures 
ECI; defined as ALT elevations >3x ULN must be 
reported within 5 business days of Investigator 
notification. Sponsor monitors ECI and an 
independent Liver Flare Adjudication Committee 
(LFAC) reviews the liver safety and assesses 
etiology to recommend changes in study conduct 
Stopping criteria for study interventions have been 
provided in Section 7.1.  

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Injection site reactions 
Combination of VIR-3434 +/- VIR-2218 may 
result in ISRs such as injection site pain, 
bruising, itching, rash. In the completed 
VIR-3434-1002 study and ongoing 
VIR-2218-1001 and VIR-2218-1006 studies, 
these interventions alone on or in combination 
have resulted in ISRs Grade 1 or 2 in severity 
that usually resolve within a few days to weeks. 
There is no potential cumulative risk for the 
combination intervention of 
VIR-3434 + VIR-2218. 
Participants are monitored for local tolerability after 
injection and all AEs will be collected to reflect any 
ISRs that may be reported. Routine safety 
monitoring and reporting procedures are in place to 
provide safety overview. 

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2.3.2.
Benefit Assessment 
Single doses of VIR-2218 up to 900 mg in healthy volunteers and up to 6 doses of up to 200 mg 
administered every 4 weeks (ie, the highest dose tested) in participants with chronic HBV 
infection were well tolerated and exhibited safety profiles supportive of continued clinical 
development (VIR-2218 Investigator’s Brochure). Regardless of hepatitis B e antigen (HBeAg) 
status, VIR-2218 was associated with a -1.96 log10 IU/mL mean decrease in HBsAg after 
6 every 4-week (Q4W) doses (Lim 2022). 
VIR-3434 has the potential to further reduce HBsAg, inhibit the intrahepatic spread of HBV via 
entry inhibition, eliminate infected hepatocytes, and stimulate an adaptive immune response 
against HBV. Lower HBsAg levels that may be achieved by lead-in or concomitant 
administration of VIR-2218 have the potential to augment the effects of VIR-3434 and achieve a 
functional cure of chronic HBV infection. Additionally, multiple-dose regimens of VIR-3434 
may produce rapid and sustained reductions of HBsAg in the absence of VIR-2218 and 
potentially achieve functional cure of chronic HBV infection as monotherapy.  
In the ongoing VIR-2218-1001 study, monotherapy with 6 doses of VIR-2218 is being evaluated 
in virally suppressed (on NRTI) participants with chronic HBV infection. Preliminary safety and 
tolerability data suggest VIR-2218 monotherapy was generally well-tolerated (Yuen 2021). 
Additionally, substantial sustained reductions in HBsAg were observed, compared to 2 doses of 
VIR-2218 in Parts B-C (Lim 2022). In this sub-protocol, it is hypothesized that the addition of 
VIR-3434 to VIR-2218 will lead to higher rates of HBsAg loss and functional cure.  
2.3.3.
Overall Benefit Risk Conclusion 
The patient population in this study will have low level viremia and liver inflammation. This 
study will provide information on the safety, tolerability, and efficacy of VIR-3434 and NRTI 
(TDF) in combination with VIR-2218. The study is designed to test the hypothesis that regimens 
containing VIR-3434 and TDF with or without VIR-2218 may lead to a functional cure of 
chronic HBV infection by reducing HBsAg and stimulating a host immune response. Compared 
to the current standard of care, the regimens in this study offer the potential benefits of finite 
duration, pangenotypic activity, and the potential to achieve functional cure, which may be 
associated with a reduction in serious HBV-associated sequelae such as cirrhosis, liver failure, 
HCC, or death.  
The mechanistic rationale, together with available clinical data, supports a favorable risk-benefit 
profile for evaluation of regimens containing VIR-3434, TDF, and/or VIR-2218 in patients with 
chronic HBV infection. 

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3.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints 
Primary 
•
To evaluate the efficacy of VIR-3434 and TDF
with or without VIR-2218
•
Proportion of participants achieving
suppression of HBV DNA (< LLOQ) with
HBsAg loss (< 0.05 IU/mL) at the end of
treatmenta
Secondary 
In addition to the Master Protocol objectives, 
•
To assess the effect of VIR-3434 and TDF
with or without VIR-2218 on HBV DNA
•
To assess the effect of VIR-3434 and TDF
with or without VIR-2218 on HBsAg
•
To assess the immunogenicity of VIR-3434
In addition to the Master Protocol secondary 
endpoints 1-8, 
9.
Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) with
HBsAg loss (< 0.05 IU/mL) after
discontinuation of all treatment
a.
at 24 weeks
b.
at 48 weeks
10. Proportion of participants achieving HBsAg
loss (< 0.05 IU/mL)
a.
at end of treatment
b.
at 24 weeks post-end of treatmenta
11. Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) after
discontinuation of all treatment
a.
at 24 weeks
b.
at 48 weeks
12. Incidence and titers of ADA (if applicable) to
VIR-3434
13. Mean change in serum HBsAg level from
baseline across timepoints in the study
14. Proportion of participants achieving HBV
DNA (< LLOQ)

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Objectives 
Endpoints 
Exploratory 
In addition to the Master Protocol objectives, 
•
To evaluate proportion of participants meeting
criteria for nucleos(t)ide reverse transcriptase
inhibitor (NRTI) treatment after
discontinuation of all treatments
•
To assess the effect of the VIR-3434 and TDF
with or without VIR-2218 on HBV DNA
•
To characterize the pharmacokinetics (PK) of
VIR-3434
•
To characterize the PK of VIR-2218 (for
cohorts with VIR-2218)
•
To assess the immunogenicity of VIR-2218
(for cohorts with VIR-2218)
•
To assess the effect of duration of treatment of
VIR-3434 and TDF with or without VIR-2218
•
To assess potential virological relapse
In addition to the Master Protocol exploratory 
endpoints 1-6, 
7.
Proportion of participants meeting criteria for
NRTI treatment in Follow-Up Period
8.
HBV DNA levels and change from baseline
across timepoints in the study
9.
Nadir and maximum change of HBV DNA
levels from baseline in the study
10. VIR-3434 PK parameters
11. VIR-2218 PK parameters (for cohorts with
VIR-2218)
12. Incidence and titers of ADA (if applicable) to
VIR-2218 (for cohorts with VIR-2218)
13. Proportion of participants with virological
relapse (defined as either (1) an increase of
≥ 1 log10 HBV DNA IU/mL above nadir for
at least 2 consecutive visits OR
(2) quantifiable HBV DNA of ≥ 1 log10
IU/mL above LLOQ for at least 2 consecutive
visits after being < LLOQ)
a End of treatment as defined in SOA 

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4.
STUDY DESIGN
4.1.
Overall Study Design 
The THRIVE sub-protocol should be read and conducted in conjunction with the PREVAIL 
Master Protocol. The Master Protocol provides a study framework: study outline, populations, 
common objectives and endpoints, common inclusion and exclusion criteria, statistical 
methodology, assessments and planned analyses for all sub-protocols. THRIVE is a Phase 2, 
multi-center, open-label study designed to evaluate the safety and efficacy of regimens 
containing VIR-3434 and NRTI with or without VIR-2218 in non-cirrhotic adult participants 
with low viremic burden of chronic HBV infection currently not on treatment. The study is 
planned to be conducted at multiple clinical investigative sites globally.  
The THRIVE sub-protocol is intended to evaluate up to 48-week regimens of VIR-3434 in 
combination with tenofovir disoproxil fumarate (TDF) with or without VIR-2218 in participants 
with chronic HBV infection. Study population IV as defined in the Master Protocol (and table) 
that are HBeAg negative with low HBV DNA (≤ 2,000 IU/mL) and ALT levels ≤ ULN within 
the 1-year period prior to screening will be included in this sub-protocol.  
Master Protocol Population 
HBeAg Status 
HBV DNA Level 
ALT Level 
IV 
Negative 
≤ 2,000 IU/mL 
≤ ULN 
4.1.1.
Number of Participants 
Up to 60 participants are planned to enroll in this sub-protocol. Cohorts 1b and 2b will each 
enroll approximately 15 participants initially. An additional 30 participants may be added to any 
of the cohorts in this sub-protocol at any time at Sponsor’s discretion. 
4.1.2.
Intervention Groups and Duration 
4.1.2.1.
Intervention Groups 
There are 2 cohorts planned in this sub-protocol (Table 3). 
Table 3: 
Intervention Groups  
Cohort 
Study 
intervention 
Dose 
Route 
Number of 
Doses 
Frequency of Dosing 
1b 
VIR-3434 
300 mg 
SC 
12 
Every 4 weeks 
TDF 
300 mg a 
Oral 
308 
Every day 
2b 
VIR-3434 
300 mg 
SC 
12 
Every 4 weeks 
VIR-2218 
200 mg 
SC 
12 
Every 4 weeks 
TDF 
300 mg a 
Oral 
308 
Every day 
a Tenofovir disoproxil fumarate (TDF) dose will be 300 mg per label. Supply outside the United States may be 
Tenofovir disoproxil (TD) and the corresponding dose will be 245 mg per label. 

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4.1.2.2. 
Cohort Initiation 
Cohorts in this study may be enrolled in parallel. Cohorts may be opened, closed, or discontinued 
at the Sponsor’s discretion.  
4.1.2.3. 
Duration 
The total duration for participants in Cohorts 1b and 2b will be up to 100 weeks inclusive of the 
Screening Period, Treatment Period, and Follow-Up Period. 
4.1.2.3.1. Screening Period  
The Screening Period for all participants will be up to 56 days (8 weeks). 
4.1.2.3.2. Treatment Period  
The Treatment Period will be 44 weeks for Cohorts 1b and 2b. 
4.1.2.3.3.  Follow-Up Period 
Once participants complete the Treatment Period per their respective cohort, they will enter the 
Follow-Up Period. The maximum duration of the Follow-Up Period is 48 weeks after the last 
dose of the study intervention(s).  
4.1.3.
NRTI Treatment 
It is recommended that commercial NRTI therapy be reinitiated in participants at any time during 
the Follow-Up Period if they meet any of the following criteria: 
•
HBV DNA increase ≥ 2 log10 IU/mL within a 2-week period
•
HBV DNA > 100,000 IU/mL at any Follow-Up Period visit (regardless of other
biochemical parameters or ALT values)
•
Confirmed increase of HBV DNA > 20,000 IU/mL (ie, at 2 consecutive collections,
regardless of other biochemical parameters or ALT values)
−
Note: The repeat HBV DNA test should be performed as soon as possible and no
later than 7 calendar days after the initial result is received. Central laboratory
testing is preferred, but local laboratory results will be accepted if it is not feasible
to collect central laboratory results in time.

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•
HBV DNA > 2,000 IU/mL concurrent with any of the following criteria at the same
visit:
−
Confirmed total bilirubin > 2x ULN and ALT > ULN
−
Any sign of hepatic decompensation (including, but not limited to, confirmed
increase in prothrombin time [PT] ≥ 2 or international normalized ratio [INR]
≥ 0.5 from baseline, jaundice, ascites, encephalopathy, etc)
−
ALT > 10x ULN
−
ALT > 2x ULN persisting for ≥ 12 consecutive weeks
−
ALT > 5x ULN persisting for ≥ 4 consecutive weeks
•
Confirmed HBeAg seroreversion (ie, HBeAg positive after being HBeAg negative)
•
Any other clinically significant event(s) warranting initiation of NRTI therapy in the
opinion of the investigator after discussion with Sponsor
Participants who start NRTI therapy in the Follow-Up period should continue to be followed per 
the SOA for the Follow-Up Period (Table 10) through the Week 48 visit. Participants with HBV 
DNA increase ≥ 2 log10 IU/mL within a 2-week period should:  
•
return to the site for an unscheduled visit to measure HBV DNA levels and liver
function tests as soon as possible after the investigator becoming aware of the HBV
DNA increase
•
continue returning weekly until HBV DNA levels stabilize (do not increase
≥ 1 log10 IU/mL over 4-week period or start decreasing for at least 2 consecutive
visits) after which they should continue per the SOA for the Follow-Up Period
If any unscheduled visits needed as outlined above coincide with an existing visit per the 
Follow-Up Period SOA then the Follow-Up visit assessments should be conducted.  
4.1.4.
Long-term and Follow-Up Care 
Once a participant has completed the study, long-term care should be determined by the 
Investigator or primary treating physician based on local clinical guidelines. 
4.2.
Scientific Rationale for Study Design 
4.2.1.
Rationale for VIR-3434 for the Treatment of Chronic HBV Infection 
VIR-3434 offers a novel strategy for the treatment of chronic HBV infection by neutralizing 
HBV viral and subviral particles through the targeting of HBsAg and inhibition of viral entry 
into hepatocytes. Additionally, the Fc region of VIR-3434 is engineered to increase binding 
affinity to the neonatal Fc receptor (FcRn) and promote the Fc-gamma receptor (FcγR) binding 
profile towards the activating receptors. These modifications may prolong serum half-life, 
increase potency, and induce a “vaccinal” effect (the induction of antigen-specific T cell 
responses).  

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The normal serum half-life of IgG is approximately 21 days and regulated by a balance of 
FcRn-mediated endocytosis and recycling versus endosomal degradation. To produce a product 
with sustained activity against HBV, the well characterized LS modification (M428L and 
N434S) (Gaudinski 2018; Ko 2014; Zalevski 2010) was included in the Fc region of VIR-3434. 
The LS modification increases IgG1 binding to FcRn only at the acidic pH of the endosomal 
compartment thereby increasing IgG recycling back into circulation. Monoclonal antibodies 
containing the LS mutation have previously been studied in humans (Gaudinski 2018). For 
example, VRC01LS, a mAb against the CD4 binding site of the HIV-1 glycoprotein, was 
deemed safe and well tolerated at doses of 5 to 40 mg/kg IV and 5 mg/kg SC in healthy 
volunteers. No anti-drug antibodies (ADAs) were detected out to 48 weeks. VIR-3434 is 
similarly anticipated to have an extended half-life in humans, resulting in a prolonged duration of 
exposure. In vitro data for VIR-3434 suggests that the LS mutation is not anticipated to interfere 
with the additional Fc modifications described below.  
The Fc region of VIR-3434 was also engineered to include a modification which modulates 
binding to human FcγRs by enhancing binding to the activating receptors FcγRIIa and FcγRIIIa, 
while diminishing binding to the inhibitory receptor FcγRIIb. This Fc modification is designed to 
enhance ADCP of HBsAg and HBV virions and antigen presentation and, as a result, promote 
the induction of T cell responses (“vaccinal effect”). The impact of similar modifications on 
mAb efficacy have been studied in a FcγR-humanized lymphoma mouse model. In this model, 
anti-CD20 antibodies promoted direct killing of tumor cells via engagement of FcγRIIIa on 
macrophages and monocytes. In addition, anti-CD20-immune complexes induced CD8+ T cell 
responses via FcγRIIa-dependent presentation of tumor antigens by dendritic cells. Overall, 
Fc-engineering of anti-CD20 antibodies to increase FcγRIIa and FcγRIIIa binding (GASDALIE 
mutation) had superior therapeutic activity (DiLillo 2015). Parallel reduction of binding to the 
inhibitory FcγRIIb has the potential to further augment this vaccinal effect (DiLillo 2015). 
Available data regarding the use of HBsAg-directed antibodies in the treatment of patients with 
chronic HBV infection suggest that these molecules have the potential to reduce HBsAg levels 
while maintaining an acceptable safety and tolerability profile. GC1102, a fully human 
anti-HBsAg mAb in development for chronic HBV infection and prevention of recurrent HBV 
following liver transplantation, effectively lowered HBsAg by 2-3 log10 IU/mL and was well 
tolerated in a Phase 1 study in patients with chronic HBV infection, with no evidence of serious 
sequelae such as immune complex disease (Lee 2018). HBV-ABXTL (HepeX-B), a mixture of 
two human anti-HBsAg mAbs, was administered to 27 patients with levels of HBsAg ranging 
from approximately 20 to 85,000 IU/mL. HBV-ABXTL was found to have a favorable safety and 
tolerability profile at doses up to 80 mg administered weekly for 4 doses, and no signs of 
immune complex disease or hepatotoxicity were reported (Galun 2002). Similarly, no adverse 
events were reported in two studies of chronic HBV patients receiving high doses of hepatitis B 
immune globulin (HBIG) to prevent re-infection following liver transplantation (Reed 1973; 
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Clinical data from the oncology setting suggests that Fc engineering designed to enhance 
ADCC/ADCP, and antigen presentation may improve efficacy without compromising safety or 
tolerability (Im 2018). Margetuximab is a modified version of trastuzumab that has been 
approved by FDA for the treatment of HER2-positive carcinomas. Margetuximab contains 
modifications designed to enhance ADCC/ADCP and antigen presentation. Margetuximab was 
well tolerated in a first-in-human (FIH) Phase 1 study in patients with HER-2 positive 
carcinomas. Common toxicities were primarily ≤ Grade 2, including no evidence of 
cardiotoxicity (Bang 2017), which has been observed with the non-Fc modified parent mAb, 
trastuzumab, in late-stage clinical trials (Ponde 2016; Riccio 2016).  
Taken together, these data suggest that mAbs that are Fc engineered to prolong serum half-life 
and optimize immune effector cell activity have the potential to improve the efficacy of 
therapeutic mAbs without compromising safety. VIR-3434 is predicted to decrease serum 
HBsAg, inhibit intrahepatic viral spread, eliminate infected hepatocytes, and stimulate 
HBV-specific immune responses. Therefore, VIR-3434 has the potential to achieve a functional 
cure of chronic HBV infection, with or without other agents such as VIR-2218 and an NRTI 
(TDF). 
VIR-3434 has been evaluated in VIR-3434-1002 and is being evaluated in VIR-2218-1006 in 
participants with chronic HBV infection. Cohort 1b will assess the contribution of VIR-3434 to 
combination therapies and its potential to achieve functional cure in the absence of any other 
investigational agents. To assess participant responses and a potential vaccinal effect from 
VIR-3434, peripheral blood mononuclear cells (PBMCs) will be collected to perform evaluation 
of host cellular immune responses (eg, T cells) against HBV antigens.  
4.2.2. 
Rationale for VIR-2218 for the Treatment of Chronic HBV Infection  
The use of siRNA offers a novel strategy for the treatment of chronic HBV infection. siRNAs are 
19-21 base-pair RNA duplexes that exploit the endogenous RNA-interference pathway to enable
sequence-specific RNA cleavage and degradation. One siRNA can have multiple antiviral
effects, including degradation of the pgRNA, thus inhibiting viral replication, and degradation of
all viral messenger RNA (mRNA) transcripts, thereby preventing expression of viral proteins.
This may result in the return of a functional immune response directed against HBV, either alone
or in combination with other therapies.
By contrast, NRTIs act at a distinct part of the viral life cycle and have a different mechanism of 
action than VIR-2218. NRTIs inhibit the HBV polymerase, blocking the reverse transcription of 
the viral pgRNA to viral DNA and preventing the production of infectious virions. NRTIs, 
however, do not directly impact the production of viral proteins such as HBsAg.  
VIR-2218 is a GalNAc conjugated siRNA that targets all HBV viral RNA and thereby inhibiting 
production and secretion of virions and subviral particles. In the ongoing VIR-2218-1001 and 
VIR-2218-1006 studies, VIR-2218 alone and in combination with other agents (PEG-IFN or 
VIR-3434) has been shown to induce significant reductions in HBsAg levels in participants with 
chronic HBV infection. 
Reduction of HBsAg-containing noninfectious subviral particles by VIR-2218 is considered an 
important differentiator from currently available treatments.  

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4.2.3.
Rationale for VIR-3434 + VIR-2218 + TDF for the Treatment of Chronic HBV 
Infection  
Emerging clinical data suggests that a combination of multiple therapeutic modalities may be 
necessary to achieve functional cure in the majority of chronic HBV patients (Revill 2019; 
Zoulim 2015). The excessive secretion of non-virion incorporated HBsAg in chronic HBV 
infection is thought to contribute to T and B cell dysfunction and to impair the host’s ability to 
clear or control the virus (Bertoletti 2016; Burton 2018; Maini 2016). Therefore, development of 
functional cure is likely to require a reduction or elimination of HBsAg in conjunction with the 
induction of host immunity against the infection.  
When administered individually, VIR-2218 and VIR-3434 are associated with substantial 
reductions in HBsAg in patients with chronic HBV infection (Gane 2021; Yuen 2021). The 
combination of VIR-2218 and VIR-3434 is thus anticipated to result in deep, sustained 
reductions in HBsAg. This is supported by AAV-HBV mouse model of chronic HBV infection, 
in which combination treatment with VIR-2218 and VIR-3434 was associated with marked 
reductions in HBsAg. Additionally, lower HBsAg levels achieved by prior or concomitant 
treatment with VIR-2218 may augment the effect of VIR-3434.  
Reduction in HBsAg may also augment the potential immunologic effects of VIR-3434. The Fc 
modifications of VIR-3434 are designed to enhance ADCP of HBsAg and HBV virions and 
antigen presentation and, as a result, promote the induction of T cell responses. Given the 
putative impact of HBsAg on immune function, these potential effects of VIR-3434 may be 
enhanced in the setting of lower HBsAg, which can be achieved with lead-in and/or concurrent 
treatment with VIR-2218. Longer durations of VIR-3434 dosing may also enhance these effects. 
The participant population included in this sub-protocol have a low viral burden and normal 
ALT, and are not indicated for treatment with NRTI. However, NRTIs such as TDF help reduce 
viral replication and thereby reduce the HBV DNA levels. Therefore, they are included as part of 
all regimens in this sub-protocol in addition to VIR-3434 to allow these participants with low 
HBV DNA levels to achieve HBV DNA < LLOQ along with VIR-3434 which has potential 
immune-modulatory effects to ultimately achieve sustained suppression of HBV DNA with or 
without HBsAg loss.  
4.3.
Justification for Dose 
4.3.1.
VIR-3434 Dose Selection 
Available PK, safety, and antiviral activity from the VIR-3434-1002 and VIR-2218-1006 studies 
were considered for selection of the VIR-3434 dosing regimens.  
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VIR-3434 has a half-life (t1/2) of approximately 25 days, with measurable concentrations up to 
24 weeks after a single SC dose of 90-900 mg in healthy volunteers (Gupta 2021). 
Dose-proportional increases in Cmax and AUCinf were observed across the SC dose range 
evaluated. A similar t1/2 was observed following a single IV injection of 3,000 mg. 
Nonparametric superposition was employed to predict the concentration time profile and PK 
exposures following 13 SC doses of VIR-3434 300 mg administered every 4 weeks. As seen in 
Figure 4, the projected Cmax of 50 µg/mL for this regimen would not exceed the observed Cmax of 
a single 3,000 mg IV dose of 1,076 µg/mL. Similarly, the projected AUCinf associated with this 
regimen (5,148 day*µg/mL) does not exceed the observed mean AUCinf of the 3,000 mg IV dose 
(11,842 day*µg/mL). Additionally, due to target-mediated drug disposition, the PK exposure in 
healthy volunteers is anticipated to be an overestimate compared to participants with chronic 
HBV infection, as VIR-3434 is expected to be eliminated more rapidly in the presence of 
HBsAg. 
Figure 4: 
VIR-3434 Observed and Projected Mean Concentration Profile in Healthy 
Volunteers in the Absence of HBsAg 
Mean concentration of VIR-3434 observed over time in healthy volunteers in VIR-3434-1002 administered single 
dose of VIR-3434 either 300 mg SC (green solid line) or 3000 mg IV (red solid line). The projected mean 
concentration profile of VIR-3434 following 13 doses of 300 mg SC administered every 4 weeks in the absence of 
HBsAg and assuming a 25-day half-life is depicted in blue.  
Data from VIR-3434-1002 demonstrated that single doses of up to 300 mg VIR-3434 were 
generally well tolerated with no safety concerns in participants with chronic HBV infection. The 
majority of AEs were Grade 1 or 2. There were no study discontinuations due to AEs. In the 
ongoing VIR-2218-1006 study, combination regimens of VIR-3434 are being evaluated in 
participants with chronic HBV infection who are on NRTIs. No significant safety concerns have 
been identified to date for VIR-3434 up to 12 doses of up to 75 mg administered weekly. The 
cumulative exposure following 13 SC doses of VIR-3434 every 4 weeks at 300 mg is not 
anticipated to exceed the maximum exposure associated with a single dose of 3,000 mg 
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Based on antiviral data in study VIR-3434-1002, VIR-3434 is associated with HBsAg reductions 
> 1 log10 IU/mL in the majority of study participants following a single SC dose of 6 to 300 mg
in a dose dependent manner (Agarwal 2021; Agarwal 2022). The 300 mg dose level was
associated with the largest and most durable HBsAg reductions, with mean reductions from
baseline of >2 log10 at Week 4 and > 1.5 log10 at Week 8. Repeat administration of VIR-3434
may enhance the reduction of HBsAg, increase the likelihood of eliciting the potential
immunomodulatory effects of its Fc domain modifications, and prolong the duration of viral
entry inhibition.
In summary, the observed PK, HBsAg kinetics and absence of safety signals in the ongoing 
single dose and multiple dose studies, along with the potential for multiple doses of VIR-3434 to 
further lower HBsAg, support the dose level, frequency, and duration of VIR-3434 regimens 
selected for this sub-protocol. 
4.3.2.
VIR-2218 Dose Selection 
Available safety, tolerability, antiviral activity, and pharmacokinetic data from Parts A-F of 
study VIR-2218-1001 were considered when selecting dose regimens for VIR-2218.  
In Part A of the VIR-2218-1001 study, a single SC dose of VIR-2218 was administered to 
healthy volunteers over the dose range of 50 to 900 mg. In Parts B and C of the study, 2 doses of 
VIR-2218 given 4 weeks apart, ranging from 20 to 200 mg were administered to participants 
with chronic HBV infection. In healthy volunteers, VIR-2218 was absorbed after SC injection 
with a median Tmax of 4-7 hours and was not measurable in plasma beyond 48 hours for any 
participant (Gupta 2021). Available PK data from HBV participants were similar to healthy 
adults. No accumulation of VIR-2218 in plasma was evident following a second dose of 
VIR-2218 administered 4 weeks apart in participants with chronic HBV infection.  
In Cohort 2b of this study, VIR-2218 will be administered as a SC injection of 200 mg every 
4 weeks for 12 doses. The duration of VIR-2218 treatment in each cohort was selected to ensure 
suppression of HBsAg by VIR-2218 for the entire duration of concomitant treatment with 
VIR-3434. Regimens containing varying durations up to 12 doses of 200 mg VIR-2218 
administered every 4 weeks will be evaluated to assess the impact of more sustained HBsAg 
suppression on the outcome of functional cure.  
The VIR-2218 dose level of 200 mg was selected based on results from Parts B and C of the 
VIR-2218-1001 study. In participants with chronic HBV infection, a regimen of 2 doses of 
VIR-2218 administered 4 weeks apart was associated with dose-dependent reductions in HBsAg 
across a dose range of 20-200 mg (Gane 2021; Lim 2022). The largest reductions in HBsAg 
were observed in the 200 mg cohort.  
The VIR-2218 regimens selected for this study are supported by the safety profile of VIR-2218 
in the ongoing VIR-2218-1001 (Yuen 2021) and VIR-2218-1006 studies. In VIR-2218-1001 
Cohorts 1d and 1f, up to 6 doses of 200 mg VIR-2218 administered every 4 weeks either as 
monotherapy or in combination with PEG-IFNα is well tolerated and associated with deep, 
sustained reductions in HBsAg in patients in chronic HBV infection. In both the VIR-2218-1001 
and VIR-2218-1006 studies, up to 13-dose regimens of VIR-2218 200 mg administered every 
4 weeks in combination with VIR-3434 are being evaluated.  

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In summary, PK, safety, and antiviral activity support the VIR-2218 regimens selected for this 
study. 
4.3.3.
TDF Dose Selection 
TDF will be administered at a dose of 300 mg (or TD 245 mg) daily, the FDA-approved dose 
level and frequency for the treatment of chronic HBV infection. The optimal duration of TDF 
treatment is unknown and not reported in the prescribing information 
(VIREAD® Prescribing Information), and the patient population of the current study are not 
indicated for treatment. Therefore, TDF dosing will continue until the last dose of VIR-3434 
and/or VIR-2218 per the respective cohort.  
4.4.
End of Study Definition 
The end of study for this sub-protocol is defined as the date of the last observation of the last 
participant. 
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5.
STUDY POPULATION
Participants that fulfil the following inclusion and exclusion criteria at screening are eligible for 
participation in this sub-protocol. Participants may be re-screened after consultation with the 
Sponsor. 
p
. To achieve these characteristics, screening and/or 
enrollment may be restricted by the Interactive Response Technology (IRT) at any time.  
5.1.
Inclusion Criteria 
Inclusion criteria per Master Protocol, details provided for sub-protocol B in bold 
1. Age ≥ 18 (or age of legal consent, whichever is older) to < 66 years
2. Chronic HBV infection defined as a positive serum HBsAg, HBV DNA, or HBeAg on
2 occasions at least 6 months apart based on previous or current laboratory documentation
(any combination of these tests performed 6 months apart is acceptable)
In addition, as defined in Table 3 of the Master Protocol for population IV, the 
participants must be/have the following, within the 1-year period prior to 
screening: 
a. HBeAg negative
b. HBV DNA ≤ 2,000 IU/mL and > LLOQ
c.
ALT ≤ ULN
3. Besides chronic infection with HBV, must be in good health, determined from medical
history, and no clinically significant findings from physical examination, vital signs, and
laboratory values
4. Female participants must have a negative pregnancy test or confirmation of
postmenopausal status. Post-menopausal status is defined as 12 months with no menses
without an alternative medical cause (see Section 10.6 for additional details). Women of
child-bearing potential (WOCBP) must have a negative blood pregnancy test at screening
and a negative urine pregnancy test on Day 1, cannot be breast feeding, and must be
willing to use highly effective methods of contraception (Section 10.6) 14 days before
study intervention administration through 48 weeks after the last dose of VIR-3434 or
VIR-2218. Female participants must also agree to refrain from egg donation and in vitro
fertilization from the time of study intervention administration through 48 weeks after the
last dose of VIR-3434 or VIR-2218.
5. Male participants with female partners of child-bearing potential must agree to meet 1 of
the following contraception requirements from the time of study intervention
administration through 48 weeks after the last dose of VIR-3434 or VIR-2218:
documentation of vasectomy or azoospermia, or male condom use plus partner use of 1 of
the contraceptive options listed for contraception for WOCBP (Section 10.6). Male
participants must also agree to not donate sperm from the time of first study intervention
administration through 48 weeks after the last dose of VIR-3434 or VIR-2218.
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6. Able to understand and comply with the study requirements and able to provide written
informed consent
Additional Inclusion Criteria for Sub-Protocol B 
7. HBsAg > lower limit of detection at screening
8. Body Mass Index (BMI) ≥ 18 kg/m2 to ≤ 35 kg/m2
5.2.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Exclusion Criteria per Master Protocol 
1. History of clinically significant liver disease from non-HBV etiology
2. History or current evidence of hepatic decompensation, including ascites, hepatic
encephalopathy, and/or esophageal or gastric varices
3. History or current suspicion of malignancy diagnosed or treated within 5 years (localized
treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical
carcinoma in situ is allowed if appropriately treated prior to screening); participants under
evaluation for malignancy are not eligible.
4. History of bone marrow or solid organ transplant
5. Known active infection other than chronic HBV infection or any clinically significant
acute condition such as fever (> 38° C) or acute respiratory illness within 7 days prior to
Day 1
6. Co-infection with human immunodeficiency virus (HIV), hepatitis A virus (HAV),
hepatitis C virus (HCV), hepatitis D virus (HDV) or hepatitis E virus (HEV). Participants
who are HCV antibody or HDV antibody positive, but have a documented negative HCV
RNA or HDV RNA, respectively, are eligible. Participants with positive HAV
immunoglobulin M (IgM) or HEV IgM but asymptomatic and with a positive HAV
immunoglobulin G (IgG) or HEV IgG are eligible.
7. History or clinical evidence of alcohol or drug abuse within the 12 months before
screening or a positive drug screen at screening unless it can be explained by a prescribed
medication (the diagnosis and prescription must be approved by the investigator). Note:
cannabis use is permitted
8. Received an investigational agent within 90 days or 5 half-lives (if known), whichever is
longer, before study intervention administration or are active in the follow-up phase of
another clinical study involving interventional treatment. Participants must also agree not
to take part in any other interventional study at any time during their participation in this
study, inclusive of the Follow-Up Period.

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9. Any clinically significant medical or psychiatric condition that may interfere with study
intervention, assessment, or compliance with the protocol or otherwise makes the
participant unsuitable for participation in the study, as determined by the investigator.
Additional Exclusion Criteria for Sub-Protocol B 
10. Significant fibrosis or cirrhosis as defined by having either a FibroScan (or
sponsor-approved equivalent) result of > 8.5 kPa at screening or a liver biopsy within
1 year with Metavir F3 fibrosis or F4 cirrhosis.
11. History of immune complex disease
12. History of an autoimmune disorder
13. History of HBV-related extrahepatic disease, including but not limited to HBV-related
rash, arthritis, or glomerulonephritis
14. History of allergic reactions, hypersensitivity, or intolerance to monoclonal antibodies,
antibody fragments, or any excipients of VIR-3434
15. Prior NRTI therapy within 24 weeks prior to Day 1 or any prior therapy with PEG-IFNα
16. Use of any of the following systemic medications within 14 days before study intervention
administration and throughout the study:
a.
Paracetamol (acetaminophen) ≥ 3 g/day
b. Isoniazid
c.
Systemic steroids (prednisone equivalent of > 10 mg/day) or other immunosuppressive
agents (Note: corticosteroid administration for the treatment of immune-mediated AEs
is allowed.)
17. Receipt of an oligonucleotide (eg, siRNA, antisense oligonucleotide) with activity against
HBV within 48 weeks before study intervention administration
18. Receipt of VIR-3434 within 24 weeks prior to Day 1
19. Participant has the following laboratory parameters at screening by laboratory testing:
a.
ALT > ULN at screening and any time in the 12 months prior to study enrollment
b. HBeAg positive at screening and any time in the 12 months prior to study enrollment
c.
HBV DNA >2,000 IU/mL at screening and any time in the 12 months prior to study
enrollment
d. Direct bilirubin or international normalized ratio (INR) > 1.5 ULN
20. Creatinine clearance (CLcr) < 30 mL/min as calculated by the Cockcroft-Gault formula at
screening
21. Clinically significant abnormalities on 12-lead ECG at screening (as determined by the
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5.3.
Lifestyle Considerations 
Lifestyle considerations are not applicable to this study. 
5.3.1. 
Meals and Dietary Restrictions  
There are no dietary restrictions in this study. 
5.3.2.
Caffeine, Alcohol, and Tobacco 
Participants that regularly consume more than 10 units of alcohol per week (1 unit = 1 glass of 
wine [125 mL] = 1 measure of spirits [30 mL] = one-half pint of beer [284 mL]), or more than 
2 units of alcohol per day, are excluded from this sub-protocol. There are no limitations on the 
use of caffeine and tobacco in this study.  
5.3.3. 
Activity  
There are no limitations on physical activity in this sub-protocol. 
5.4.
Screen Failures 
Participants that screen fail will not be eligible to enroll in the study. Participants may be 
re-screened after discussion with the Sponsor. 

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6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
6.1.
Study Intervention(s) Administered 
Table 4: 
Study Intervention (s) Administered 
Intervention Label 
VIR-3434 
VIR-2218 
TDF /TD 
Intervention Name 
VIR-3434 
VIR-2218 
Tenofovir disoproxil 
fumarate/ Tenofovir 
disoproxil 
Type 
Biologic 
Oligonucleotide 
Drug 
Dose Formulation 
Lyophilized powder in 
vial 
Liquid in vial 
Tablet 
Unit Dose 
Strength(s) 
300 mg/vial 
200 mg/mL at 0.5mL 
300 mg tablet (TDF) 
245mg tablet (TD) 
Dosage Level(s) 
300 mg Q4W-Q12W 
200 mg Q4W 
300 mg QD (TDF) or 
245 mg QD (TD) based 
on supply source 
Route of 
Administration 
SC 
SC 
Oral 
Use 
Experimental 
Experimental 
Experimental 
IMP and 
NIMP/AxMP 
IMP 
IMP 
IMP 
Sourcing 
Sponsor 
Sponsor 
Sponsor 
Packaging and 
Labeling 
Single-use vial labeled 
as required by country 
requirement. 
Single-use vial labeled 
as required by country 
requirement. 
Bottle labeled as 
required per country 
requirement. 
Current or trade 
name(s) 
VIR-3434 
VIR-2218 
Viread® 
Table 5: 
Study Arm(s) 
Arm Title 
Cohort 1b 
Cohort 2b 
Arm Type 
Experimental 
Experimental 
Arm Description 
Participants will receive VIR-3434 
300 mg Q4W and 300 mg TDF 
(or TD 245 mg) QD from Day 1 to 
Week 44 
Participants will receive VIR-3434 
300 mg Q4W, VIR-2218 200 mg 
Q4W and 300 mg TDF QD (or TD 
245 mg) from Day 1 to Week 44 
Associated 
Intervention Labels 
VIR-3434, TDF/TD 
VIR-3434, VIR-2218, TDF/TD 

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6.2.
Preparation, Handling, Storage, and Accountability 
Detailed instructions for all study intervention/drugs will be provided in the Pharmacy Manual. 
6.3.
Randomization and Blinding 
This is an open-label study, participants will be enrolled to one of the open cohorts in the sub-
protocol. 
6.4.
Study Intervention Compliance 
Participants are expected to comply with the dosing schedule of the investigational therapies. 
TDF may be taken home by the participant to be administered daily per protocol. Participants 
will be asked to keep a treatment diary noting the day and date they take their study intervention 
and any adverse events. They will be asked to bring their treatment diary to each study visit 
along with all used and unused study intervention containers. 
6.5.
Dose Modification 
6.5.1.
Dose Modifications for TDF 
It is recommended that TDF dose modifications be performed in accordance with the VIREAD® 
approved local product label.  
6.6.
Concomitant Therapy 
6.6.1.
Concomitant Therapy Not Permitted During the Study 
Use of NRTIs before Day 1 is prohibited. While on the study, participants will receive TDF per 
protocol. No other NRTIs are permitted during the course of the Treatment Period. If participants 
require NRTI therapy during Follow-Up Period, Investigator may start commercial NRTI. 
Use of any of the following systemic medications is prohibited within 14 days before study 
intervention administration and throughout the study: 
•
Systemic steroids (prednisone equivalent of > 10 mg/day) or other
immunosuppressive agents (Note: corticosteroid administration for the treatment of
immune-mediated AEs is allowed.)
•
Paracetamol (acetaminophen) ≥ 3 g/day
•
Isoniazid

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Additionally, the administration of any potentially hepatotoxic medications during the study 
should be considered only if no therapeutic alternative can be identified and after a careful 
consideration of the potential risks and benefits for the participant. Medications that are 
potentially hepatotoxic or associated with drug-induced liver injury include, but are not limited 
to, the following (Björnsson 2016): 
•
Aspirin > 3 g/day or ibuprofen ≥ 1.2 g/day
•
Tricyclic antidepressants
•
Valproate
•
Phenytoin
•
Amiodarone
•
Anabolic steroids
•
Allopurinol
•
Amoxicillin-clavulanate
•
Minocycline
•
Nitrofurantoin
•
Sulfamethoxazole/trimethoprim
•
Erythromycin
•
Rifampin
•
Azole antifungals
•
Herbal or natural remedies

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7.
DISCONTINUATION OF STUDY, STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Study Stopping Rules
If either of the following criteria as met, dosing will be paused, and an ad hoc medical 
monitoring meeting will be convened with the study investigator or their representative and/or 
LFAC (if related to an ECI): 
•
3 or more participants experience Grade 3 or higher study intervention-related AEs in
the same System Organ Class (SOC)
•
2 or more participants experience Grade 4 or higher study intervention-related AEs in
the same SOC
Following an assessment of all available safety data, the committee will vote to discontinue, 
modify (including discontinuation of one or more cohorts), or continue the study unchanged. 
7.2.
Discontinuation of Study Intervention(s) 
Participants that have received at least 1 dose of VIR-3434 or VIR-2218 will not receive 
additional doses of either study intervention if any the following criteria are met:  
•
Any clinical manifestations of hepatic decompensation
•
Grade 3 or higher study intervention-related AE of anaphylaxis, cytokine release
syndrome, or immune complex disease
•
Serum ALT > 10 × ULN
•
Serum ALT or AST > 3 × ULN with any of the following laboratory results or
clinical symptoms:
−
total bilirubin > 2 × ULN or
−
INR > 1.5 × ULN (erroneously elevated INR due to incorrect blood volume
collection should be ruled out) or
−
serum albumin < 3.0g/dL or
−
ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue,
nausea, vomiting, right upper quadrant pain in the absence of an alternative
medical explanation)
The investigator should notify the medical monitor immediately in the event that any of the 
above criteria are met. Upon documented agreement with the investigator and the Sponsor 
Medical Monitor, the participant may be considered to continue receiving study intervention. 
Study intervention may be discontinued in the occurrence of a condition that in the opinion of the 
Investigator significantly jeopardizes the wellbeing and safety of the participant. Investigator 
must promptly inform the Sponsor Medical Monitor if any such condition arises. 
Participants who become pregnant during the Treatment Period will not receive additional doses 
of any study intervention. See Master Protocol for additional details.  

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Participants who discontinue all study interventions prematurely (eg, due to meeting a stopping 
rule) will undergo assessments for the EOT visit at the time of discontinuation. These 
participants will continue to the Follow-Up Period SOA.  
7.3.
Participant Discontinuation/Withdrawal from the Study 
Refer to Master Protocol. 
7.4.
Replacement of Participants 
Refer to Master Protocol. 
7.5.
Lost to Follow-up 
Refer to Master Protocol. 
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in SOA (Section 10.9). Refer to Master 
Protocol for additional details 
8.1.
Screening Period 
Refer to Master Protocol. 
8.2.
Efficacy Assessments 
 Refer to Master Protocol. 
8.3.
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SOA. 
8.3.1. 
Physical Examinations  
Refer to Master Protocol. In addition to the Master Protocol: 
•
At screening, body weight and height will be measured, and BMI will be calculated.
•
Body weight will also be measured at study visits as indicated in the SOA.
8.3.2.
Vital Signs 
Refer to Master Protocol. 
8.3.3.
Clinical Safety Laboratory Tests 
Clinical laboratory tests that will be performed in this study are presented in Section 0. In the 
event of an unexplained clinically relevant (in the opinion of the investigator) abnormal 
laboratory test occurring after study intervention administration, the test may be repeated and 
followed up at the discretion of the investigator until it has returned to the normal range or 
stabilized, and/or a diagnosis is made to adequately explain the abnormality. 

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8.3.4. 
Pregnancy Testing  
Please refer to Master Protocol. 
8.3.5.
Local Tolerability 
If a local reaction around the injection site occurs, photographs may be obtained. Participants 
should be instructed to monitor for local and systemic ISRs, including signs and symptoms of 
anaphylaxis and instructed to seek emergency medical care, if needed. Oral analgesics may be 
used to manage mild to moderate local pain or tenderness. More extensive or severe symptoms 
(eg, suspected anaphylaxis, cytokine release syndrome, or immune complex disease) should be 
evaluated by the study investigator and treated as deemed appropriate by the investigator and per 
local standards of care. See Section 10.8 for additional details. 
8.4.
Assessment of Viral Parameters, Antiviral Activity, and Resistance 
Surveillance  
In addition to Master Protocol, assessments of antiviral activity performed after screening will 
include: HBsAg (quantitative), anti-HBs (quantitative), HBeAg (qualitative or quantitative as 
specified in the SOA), anti-HBe, and HBV DNA. 
Assessments of exploratory viral markers or other viral analyses may also be performed after 
screening as described in the Master Protocol.  
Resistance surveillance to monitor for the potential development of resistance to NRTI (TDF), 
VIR-3434, or VIR-2218 will be conducted for all participants who receive study intervention. 
HBV genome sequencing will be attempted in participants with HBV DNA rebound as defined 
by HBV DNA ≥ 500 IU/mL. As it will not be known at the time of visit if a participant has 
virologic rebound, samples for resistance surveillance will be collected at all study visits noted in 
the SOA. Samples collected for resistance surveillance may be used to perform additional viral 
analyses, including but not limited to viral sequencing. 
Details regarding the processing and shipping of the samples are provided in the Laboratory 
Manual. 
8.5.
 Time points for assessments are 
provided in the SOA for each applicable cohort. 
8.6.
Exploratory Assessments 
8.6.1.
Exploratory Analysis Samples 
Refer to Master Protocol. 
8.6.2.
Details regarding the processing, shipping, and analysis of these samples are provided in the 
Laboratory Manual. 
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8.6.2.1.
Refer to Master Protocol. 
8.6.2.2.
Refer to Master Protocol. 
8.6.2.3.
Refer to Master Protocol. 
8.6.3.
 Samples 
will be collected at certain time points per the SOA for a given cohort. Details regarding sample 
processing, shipping, and storage are provided in the Laboratory Manual and Vir Immunology 
Sample Manual (if applicable). 
. Based on emerging data, the Sponsor may restrict enrollment to certain sites or cohorts. 
8.7.
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting  
Refer to Master Protocol. 
8.7.1.
Time Period and Frequency for Collecting AE and SAE Information 
Refer to Master Protocol. 
8.7.2.
Follow-up of AEs and SAEs 
Refer to Master Protocol. 
8.7.3.
Regulatory Reporting Requirements for SAEs 
Refer to Master Protocol. 
8.7.4.
Adverse Events of Interest 
Not applicable 
8.7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs or 
SAEs  
Refer to Master Protocol. 
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8.7.6. 
Laboratory Events of Clinical Interest  
Laboratory ECI for this study are defined as instances of ALT > 3x ULN. 
An ECI is considered resolved when ALT returns to ≤ ULN. 
All ECIs must be reported to the Sponsor Medical Monitor within 5 business days of the 
investigator becoming aware of the ECI. In addition, the assessments outlined in Section 10.7 
should be performed as soon as possible and no later than two weeks after the initial ALT value 
meeting criteria for a laboratory ECI.  
8.7.7.
Special Situation Reports 
Refer to Master Protocol. 
8.7.7.1. 
Pregnancy  
Refer to Master Protocol. 
8.8.
Pharmacokinetic Assessments 
Blood samples will be collected to assess concentrations of VIR-3434 and VIR-2218 (for cohorts 
receiving VIR-2218). Timepoints for the collection of samples for VIR-3434 and VIR-2218 PK 
analysis are provided in the SOA. Concentrations of VIR-3434 and VIR-2218 PK will be 
quantified using a validated bioanalytical assay. These assessments are exploratory and may or 
may not be analyzed. Specific assays used for these assessments may be changed at the 
Sponsor’s discretion based on emerging data. Details regarding the processing, shipping, and 
analysis of the samples are provided in the Laboratory Manual. 
8.9.
Immunogenicity Assessments 
Blood samples will be collected for analysis of immunogenic responses to determine 
presence/absence and titers of ADA as applicable, according to the timepoints defined in the 
SOA. Samples may also be characterized for neutralizing potential of anti-VIR-3434 antibody 
(NAb), as appropriate. Details regarding the processing, shipping, and analysis of the samples 
are provided in the Laboratory Manual.  
8.10. 
Electrocardiogram 
12-lead safety ECGs will be recorded and reviewed on-site by the investigator. ECGs will be
obtained using an ECG machine that automatically calculates the heart rate and measures PR,
QRS, QT, and QTc intervals. All ECGs should be measured in the supine position after the
participant has rested comfortably for approximately 10 minutes. ECG should be measured
before blood sample collection and administration of study intervention(s), where applicable.
8.11. 
Liver Elastography (eg, FibroScan) 
To exclude the presence of cirrhosis, participants will have a liver elastography (eg, FibroScan or 
other sponsor-approved method) evaluation. This is not required to be performed if the 
participant has had a liver elastography in the 6 months prior to screening or liver biopsy in the 
year prior to screening that confirmed the absence of Metavir F3 fibrosis or F4 cirrhosis. 

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9.
STATISTICAL CONSIDERATIONS
This section provides a summary of the planned statistical analyses. Details of the statistical 
analyses will be provided in the Statistical Analysis Plan (SAP), which will be finalized prior to 
first interim analysis and database lock. 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the SAP and/or the clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate. 
9.1.
Statistical Hypotheses 
The null hypothesis is that the response rate, defined as the proportion of participants achieving 
sustained suppression of HBV DNA (< LLOQ) with HBsAg loss (< 0.05 IU/mL) at EOT, is 
≤ 2%, which is the assumed rate of HBsAg loss in NRTI-suppressed patients. The alternative 
hypothesis is that the response rate is greater than 2%. 
This study is exploratory in nature. No multiplicity adjustment will be made. 
9.2.
Sample Size Determination 
A sample of 15 in each cohort will provide approximately 76% statistical power for each cohort 
to reject the null hypothesis, if the true HBsAg loss rate is 25%, using a 1-sided exact binomial 
test with a significance level of 2.5%.  
Up to 30 participants will be enrolled in this sub-protocol initially. Additionally, up to 30 floater 
participants may be added to the cohorts at any time at Sponsor’s discretion. As described in 
Section 9.5, this addition may be based on the data from interim analysis. No more than 
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9.3.
Analysis Sets 
In addition to the Master Protocol, the following analysis sets will apply to this sub-protocol: 
Analysis Sets 
Description 
PK Analysis Set 
The PK Analysis Set includes all participants in the Full 
Analysis Set who had at least one measurable postdose 
concentration.  
The PK Analysis Set will be used for all PK analyses. 
Immunogenicity Analysis Set 
Immunogenicity Analysis Set includes all participants in the Full 
Analysis Set who had at least 1 postdose measurement of 
immunogenicity, including screening, titer, or neutralizing 
characterization, as applicable  
The Immunogenicity Analysis Set will be used for analyses of the 
immunogenicity endpoints. 
Details of immunogenicity analyses will be provided in the SAP. 
9.4.
Statistical Analyses 
9.4.1.
General Considerations 
Refer to the Master Protocol. 
TEAE definition for this sub-protocol: An AE that is reported with an onset date on or after the 
start of study intervention(s) until end of Follow-Up Period. 
Prior to the final analysis, interim analyses will be conducted, and the analyses may be submitted 
for publication or to regulatory agencies to seek guidance for the overall clinical development 
program. 
9.4.2.
Primary Endpoint(s) Analysis 
The primary efficacy endpoint is the proportion of participants achieving suppression of HBV 
DNA (< LLOQ) with HBsAg loss (< 0.05 IU/mL) at EOT. 
9.4.2.1. 
Target Population  
All eligible participants with chronic HBV infection, as defined in the Full Analysis Set. 
9.4.2.2. 
Population Level Summary 
The proportion of participants who achieved suppression of HBV DNA (< LLOQ) with HBsAg 
loss (< 0.05 IU/mL) at EOT and the corresponding two-sided 95% exact Clopper-Pearson 
confidence intervals. 

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9.4.3. 
Secondary Endpoint(s) Analysis  
Refer to the Master Protocol for the safety data analysis. 
The key secondary efficacy endpoints (see Section 3 in this protocol and the PREVAIL Master 
Protocol) including the effect of the study intervention on HBsAg, anti-HBs, HBeAg, and HBV 
DNA in the Full Analysis Set will be summarized. 
9.4.4.
Exploratory Endpoint(s) Analysis 
Missing data due to withdrawal or all other events will not be imputed. 
9.4.5.
Missing Data 
Values for missing safety laboratory data will not be imputed. However, a missing baseline result 
(defined as predose Day 1) will be replaced with a screening result, if available.  
If no pre-treatment laboratory value is available, the baseline value will be assumed to be normal 
(ie, no grade [Grade 0]) for the summary of graded laboratory abnormalities. If safety laboratory 
results for a participant are missing for any reason at a time point, the participant will be 
excluded from the calculation of summary statistics for that time point. 
9.4.6. 
Other Safety Analyses  
Refer to the Master Protocol for other safety data analysis. 
9.5.
Interim Analysis 
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9.6.
Pharmacokinetic Analyses 
VIR-2218 and VIR-3434 concentration data from all sparse samples may be pooled with data 
from other studies and may be used for estimation of population PK parameters. 
PK/pharmacodynamic analyses will be conducted to explore exposure-response relationships 
between PK parameters and selected antiviral variables. These analyses may include graphical 
plots, tabular summaries, and various linear and/or nonlinear analyses. Details of the analysis 
will be provided in a separate analysis plan. 
9.7.
Immunogenicity Analyses 
For all study parts, immunogenicity data will be listed and summarized using descriptive 
statistics, including incidence, titers, and neutralization data, as applicable. 
Correlations between immunogenicity data and safety, efficacy, and PK data will be explored. 
These analyses may include graphical plots, tabular summaries, and various linear and/or 
nonlinear analyses. Details of immunogenicity analyses will be provided in the SAP. 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1.
Regulatory and Ethical Considerations 
Refer to Master Protocol. 
10.1.2.
Financial Disclosure 
Refer to Master Protocol. 
10.1.3.
Informed Consent Process 
Refer to Master Protocol. 
10.1.4.
Data Protection 
Refer to Master Protocol. 
10.1.5.
Confidentiality 
Refer to Master Protocol. 
10.1.6.
Committees Structure 
10.1.6.1.
Liver Flare Adjudication Committee (LFAC) 
The LFAC will provide hepatic safety oversight by performing periodic reviews of data 
pertaining to participants who meet certain prespecified criteria for transaminase elevations 
Section 8.7.6 . Additionally, the Sponsor may request LFAC evaluation of specific patient data at 
any time. The LFAC will be governed by an LFAC Charter that will be finalized prior to 
screening the first participant. The LFAC membership composition, laboratory criteria to trigger 
patient case evaluation by the LFAC, and data review requirements are described in detail in the 
LFAC Charter. 
10.1.7.
Dissemination of Clinical Study Data 
Refer to Master Protocol. 
10.1.8.
Data Quality Assurance 
Refer to Master Protocol. 
10.1.9.
Source Documents 
Refer to Master Protocol. 
10.1.10.
Electronic Case Report Forms (eCRF) 
Refer to Master Protocol. 

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10.1.11. 
Study and Site Start and Closure 
Refer to Master Protocol. 
10.1.12. 
Publication Policy 
Refer to Master Protocol.

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10.2. 
Appendix 2: Clinical Laboratory Tests 
Table 6: 
Protocol-Required Safety Laboratory Tests 
Chemistry 
Hematology 
Albumin 
Blood urea nitrogen (BUN) 
Calcium 
Bicarbonate 
Chloride 
Creatine kinasea 
Creatinine 
Creatinine clearance (calculated)b  
Gammaglutamyltransferase (GGT) 
Glucose (non-fasting) 
Lactate dehydrogenase (LDH) 
Phosphate 
Potassium 
Sodium 
Liver Function Tests: Alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin 
(total and direct)  
Complement (C3, C4, CH50)c 
Platelet count 
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
White blood cell (WBC) count with differential: neutrophils, 
lymphocytes, monocytes, eosinophils, basophils 
RBC indices: mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), % reticulocytes 
Coagulation Parameters 
Pregnancy Testing 
International normalized ratio (INR) 
Prothrombin time (PT) 
Highly sensitive (serum/plasma or urine) human chorionic 
gonadotropin (hCG) pregnancy test (as needed for women of 
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Urinalysis 
Additional Screening Tests 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Microscopy (if blood or protein is abnormal) 
Nitrite 
pH 
Proteins 
RBCs 
Specific gravity 
Urobilinogen 
Visual inspection for appearance and color 
Urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines) 
Serology:  
Hepatitis Ad, B, Ce, Df and Ed  
Human immunodeficiency virus I and II 
Lipase 
Amylase 
Follicle stimulating hormone (FSH)g 
Hemoglobin A1c (HbA1c) 
Thyroid stimulating hormone (TSH)  
Free T4 
HBV genotyping    
a Only required if ALT and/or AST is elevated > 2x the predose Day 1 baseline value 
b Please note the following clarification for the creatinine clearance calculation: for study visits where weight is not measured, creatinine clearance will be 
calculated using the value measured from the most recent study visit. 
c As indicated in the Schedule of Activities (Section 10.9)  
d Participants with positive HAV IgM or HEV IgM but asymptomatic and with a positive HAV IgG or HEV IgG are eligible. 
e Participants with positive HCV screening serology may have HCV RT-PCR performed to determine eligibility. 
f Participants with positive HDV screening serology may have HDV RNA performed to determine eligibility. 
g Required for confirmation of menopause only as applicable

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10.3. 
Appendix 3: AEs, SAEs, SSRs and AEIs: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting 
Refer to Master Protocol. 

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10.4. 
Appendix 4: List Abbreviations and Definitions of Terms 
ADA 
anti-drug antibodies 
ADCC/ADCP 
antibody dependent cellular toxicity/antibody dependent cellular 
phagocytosis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BUN 
blood urea nitrogen 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECI 
events of clinical interest 
EOT 
end of treatment 
FcRn 
Fc receptor 
FSH 
follicle stimulating hormone 
GGT 
gammaglutamyltransferase 
HAV 
hepatitis A virus 
HBcrAg 
hepatitis B correlated antigen 
HBeAg 
hepatitis B e antigen 
HBIG 
hepatitis B immune globulin 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRR 
infusion related reaction 
IRT 
Interactive Response Technology 
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ISR 
injection site reaction 
LDH 
lactate dehydrogenase 
LFAC 
Liver Flare Adjudication Committee 
mAb 
monoclonal antibody 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
NAb 
neutralizing antibodies 
NRTI 
nucleos(t)ide reverse transcriptase inhibitors 
NSAID 
non-steroidal anti-inflammatory drug 
PBMC 
peripheral blood mononuclear cells 
PEG-IFNα 
peginterferon-alfa-2a 
PK 
pharmacokinetics 
PT 
prothrombin time 
QD 
once a day 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 
RBC 
red blood cell 
SAP 
Statistical Analysis Plan 
siRNA 
small interfering ribonucleic acid 
SOA 
Schedule of Activities 
SRC 
safety review committee 
TD 
tenofovir disoproxil 
TDF 
tenofovir disoproxil fumarate 
TND 
target not detected 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCBP 
women of child-bearing potential 

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10.5. 
Appendix 5: Summaries of Changes for Previous Protocol Amendments 
Protocol Amendment 2 (11 October 2022) Summary of Changes Table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3. Objectives and Endpoints
9. Statistical Considerations
Added assessment of hepatitis B virus (HBV) DNA 
suppression (< lower limit of quantitation [LLOQ]) at 
the end of treatment to the primary endpoint 
Added proportion of participants achieving hepatitis B 
surface antigen (HBsAg loss (< 0.05 IU/mL) at the end 
of treatment to the secondary endpoints. 
The prior primary endpoint to evaluate 
proportion of participants achieving HBsAg 
loss (<0.05 IU/mL) at the end of treatment 
was moved to be a secondary endpoint and 
the primary endpoint was modified to include 
HBV DNA suppression (<LLOQ) and HBsAg 
loss (<0.05 IU/mL) at the end of treatment for 
better understanding of the effect of the study 
interventions on both viral parameters and 
better align with the FDA HBV clinical 
guidance (FDA 2022). 
1.1. Synopsis 
1.2. Study Schema 
3. Objectives and Endpoints
4.1.2.1. Intervention Groups
4.1.2.3.2. Treatment Period
4.2.1. Rationale for VIR-3434 for the 
Treatment of Chronic HBV Infection 
4.2.3. Rationale for VIR-3434 + 
VIR-2218 + TDF for the Treatment 
of Chronic HBV Infection 
6.1. Study Intervention(s) 
Administered 
9.4.1. General Considerations 
10.9. Appendix 9: Schedule of 
Activities 
Removed option for participants to discontinue study 
intervention at Week 20 and move into the Follow-up 
Period if they achieve undetectable HBsAg and HBV 
DNA < LLOQ at 2 consecutive visits by Week 20. 
As a result of this change, dosing of study intervention 
and duration of treatment was updated for Cohorts 1b 
and 2b, and the exploratory endpoint assessing 
proportion of participants with HBsAg loss maintained 
24 weeks post-end of treatment (EOT) of Week 20 was 
removed. 
Removal of the option to discontinue 
treatment early would allow for all 
participants within the cohort to receive the 
same duration of treatment and thereby allow 
consistency of analyses of the regimen. 

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Section # and Name 
Description of Change 
Brief Rationale 
2.3.1. Risk Assessment 
Updated immunogenicity risks for VIR-2218 and VIR-
3434. 
Additional edits were made to terminology and 
definitions to align with the most recent VIR-2218 and 
VIR-3434 Investigator’s Brochures (IBs). 
To provide updated risk assessment 
information for VIR-2218 and VIR-3434 per 
the most recent IBs.  
4.1.3. NRTI Treatment 
Added additional criteria for which commercial 
nucleos(t)ide reverse transcriptase inhibitors (NRTI) 
therapy be initiated in participants at any time during 
the Follow-up Period  
Additional criteria were added to ensure 
prompt identification of participants that may 
be at a risk for safety complications. 
Recommendation for treatment with NRTI 
and additional safety monitoring for these 
participants are outlined in Section 4.1.3. 
5.2. Exclusion Criteria 
8.11. Liver Elastography (new 
section)  
10.9. Appendix 9: Schedule of 
Activities 
Clarified that, in addition to FibroScan, liver 
elastography can be assessed with other Sponsor-
approved methods  
Some study sites may not have access to 
FibroScan to measure liver elastography. 
Sponsor may approve alternate methods to 
determine fibrosis in these cases. 
5.2. Exclusion Criteria 
8.10. Electrocardiogram 
10.9. Appendix 9: Schedule of 
Activities 
Added Exclusion Criterion #21: Clinically significant 
abnormalities on 12-lead electrocardiogram (ECG) at 
screening (as determined by the investigator) 
In addition to at screening, added 12-lead safety ECGs 
assessments at Day 8 in the Treatment Period and 
Follow-up Period. 
Screening and post-dose safety ECG 
assessments have been added to assess cardiac 
safety. 

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Section # and Name 
Description of Change 
Brief Rationale 
7.1. Study Stopping Rules 
Added study stopping rules 
Criteria were added to trigger an ad hoc 
medical monitoring meeting in which a 
recommendation to discontinue, modify, or 
continue the study will be made. 
8.3.1. Physical Examinations 
10.9. Appendix 9: Schedule of 
Activities 
In addition to at screening, body weight measurements 
were also added at study visits as indicated in the 
Schedule of Activities.  
Body weight is required to calculate 
creatinine clearance. 
9.3. Analysis Sets 
Modified pharmacokinetic (PK) Analysis Set to 
include all participants in the Full Analysis Set 
(previously All Enrolled Set) who received at least one 
dose of study drug and had at least one measurable 
postdose concentration.  
Modified Immunogenicity Analysis Set to include all 
participants in the Full Analysis Set (previously Safety 
Analysis Set) who had at least one postdose 
measurement of immunogenicity. 
To align with the updated definition of the 
Full Analysis Set in the master protocol. The 
Full Analysis Set includes all participants who 
received at least one dose of study 
intervention(s) irrespective of post-dose 
assessments. 
9.6. Pharmacokinetic Analyses 
Clarified that VIR-2218 and VIR-3434 concentration 
data from all sparse PK samples may be pooled with 
data from future studies and may be used for 
estimation of population PK parameters. 
To provide updated PK analyses plan 
10.6. Appendix 6: Contraceptive and 
Barrier Guidance 
Clarified that an elevated follicle stimulating hormone 
(FSH) in the post-menopausal range should be used to 
confirm a post-menopausal state in women not using 
hormonal contraception or hormone replacement 
therapy. 
To correct FSH criteria used to confirm a 
post-menopausal state. 
10.9. Appendix 9: Schedule of 
Activities 
Added additional visits in the Follow-up Period at 
Weeks 2, 6, 10, 28, 32, 40, and 44. 
More frequent visits after completion of 
treatment period were added to ensure prompt 
identification of any participants that may be 
at a risk for safety complications. 
Entire document 
Other administrative, formatting, and other minor 
changes 
These changes were made to clarify, ensure 
consistency, provide up-to-date information, 
or rectify typographical errors.  

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Protocol Amendment 1 (16 May 2022) Summary of Changes Table 
Section # and Name 
Description of Change 
Brief Rationale 
Study title 
Modified study title to “A Phase 2 Study 
Evaluating the Efficacy and Safety of VIR-3434 
and/or VIR-2218 containing regimens in 
HBeAg-negative Participants with Low Viral 
Burden of Chronic Hepatitis B Infection 
(THRIVE)” 
Study title was modified to be concise 
1.1 Synopsis 
3. Objectives, endpoints and
estimands
9.4.2 Primary Endpoint 
Analysis 
Moved one co-primary endpoint (Proportion of 
participants with HBsAg loss at 24 weeks post-
end of treatment) to be a secondary endpoint, 
making “Proportion of participants with HBsAg 
loss (< 0.05 IU/mL) at the end of treatment” the 
only primary endpoint 
This modification was made to focus the primary endpoint 
of the study to understand the proportion of participants 
that achieve HBsAg loss on-treatment. The sustained 
HBsAg loss and any additional off-treatment HBsAg loss 
will be evaluated as secondary endpoints in this study. 
1.1 Synopsis 
3. Objectives, endpoints and
estimands
Added secondary endpoints #10 and 14 and 
modified #11 
# 10 Proportion of participants achieving 
sustained suppression of HBV DNA (< LLOQ) 
after discontinuation of all treatment  
at 24 weeks 
at 48 weeks 
#11 Proportion of participants achieving 
sustained suppression of HBV DNA (< LLOQ) 
with HBsAg loss (< 0.05 IU/mL) after 
discontinuation of all treatment 
at 24 weeks 
at 48 weeks 
#14 Mean change in serum HBsAg level from 
baseline across timepoints in the study 
Endpoints 10, and 11 were added/modified to conform 
with the FDA HBV clinical guidance (FDA 2022). 
Endpoint 14 was added for better understanding of the 
change in HBsAg levels through the study. 

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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3. Objectives, endpoints and
estimands
Moved these secondary endpoints and the 
respective objectives to exploratory endpoints 
•
Proportion of participants meeting criteria
for NRTI treatment in Follow-Up Period
•
HBV DNA levels and change from baseline
across timepoints in the study
•
Nadir and maximum change of HBV DNA
levels from baseline in the study
These endpoints will provide additional understanding of 
the changes in the HBV DNA and of participants needing 
NRTI treatment after end of treatment. Therefore, they 
were better suited as exploratory endpoints 
1.1 Synopsis 
3. Objectives, endpoints and
estimands
Added exploratory objective and corresponding 
endpoint #11 Proportion of participants with 
virological relapse (defined as either (1) an 
increase of ≥ 1 log10 HBV DNA IU/mL above 
nadir for at least 2 consecutive visits OR (2) 
quantifiable HBV DNA of ≥ 1 log10 IU/mL above 
LLOQ for at least 2 consecutive visits after being 
< LLOQ) 
This endpoint was added to conform to the FDA HBV 
clinical guidance to evaluate any virological relapse. This 
will distinguish virological relapse from transient 
increases in HBV DNA that are possible after 
discontinuing NRTI (FDA 2022).  
1.1 Synopsis 
3. Objectives, endpoints and
estimands
Other minor clarifications to primary and 
secondary endpoints: 
Defining HBsAg loss as < 0.05 IU/mL 
Modifying TND or undetectable HBV DNA 
across different secondary endpoints as < LLOQ 
These changes were made to provide clarifications to the 
level of viral marker referenced. The HBV DNA level was 
modified from being TND (target not detected) to 
< LLOQ to conform to the FDA guidance (FDA 2022) 
4.1 Overall study design 
Table 
Participant population including in this sub-
protocol was modified from HBV DNA 
< 2,000 IU/mL and ALT < ULN to be HBV DNA 
≤ 2,000 IU/mL and ALT ≤ ULN 
This modification was made to include participants that 
may have the limit values and to align with major clinical 
practice guidelines (Terrault 2018 and EASL 2017)  
4.1.2.3.2 Treatment Period 
Criteria to stop study interventions at W20 for 
Cohorts 1b and 2b were modified to include HBV 
DNA < LLOQ in addition to undetectable HBsAg 
This criterion was added to ensure that participants that 
stop study interventions have achieved HBV DNA 
suppression and thereby increasing the probability of long-
term sustained suppression off-treatment. 

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Section # and Name 
Description of Change 
Brief Rationale 
4.1.2.3.4 NRTI treatment 
during Follow-Up 
Added criteria to consider starting NRTI in the 
Follow-Up Period if “any other clinically 
significant event(s) warranting the NRTI therapy 
in the opinion of the investigator occur”.  
This criterion was added to ensure investigator had the 
option to start NRTI treatment with any clinical event(s) 
that in their opinion may affect participant safety after 
discontinuation of all study treatments.  
5.2 Exclusion criteria 
Exclusion criterion #23 from “Prior NRTI 
therapy” to 
“Prior NRTI therapy within 24 weeks prior to 
Day 1 or any prior therapy with PEG-IFNα” 
This criterion was modified to allow inclusion of 
participants that may have had prior NRTI therapy but 
have been off NRTIs for at least 24 weeks prior to dosing 
in the current study. 
Prior PEG-IFNα was added as an exclusion to allow 
assessment of participants that were not 
PEG-IFNα-experienced and provide a clear understanding 
of the safety and efficacy of the current study regimens  
9.3 Analysis Sets 
Clarified that the PK and immunogenicity 
analysis sets will include all participants from the 
Safety Analysis Set who received at least one 
dose of study drug and had at least 
one measurable post-dose concentration or at 
least one post-dose immunogenicity measurement 
respectively.  
Modified to provide clarity 
Entire document 
Other administrative, formatting, and other minor 
changes 
These changes were made to clarify, ensure consistency, 
or rectify typographical errors.  

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10.6. 
Appendix 6: Contraceptive and Barrier Guidance 
WOCBP may be included in this study and include any female participant who has experienced 
menarche and who is not post-menopausal or permanently sterilized (eg, bilateral tubal 
occlusion, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy). 
•
WOCBP must be willing to use highly effective methods of contraception from
14 days before the first dose of study intervention to 48 weeks after the final dose of
VIR-3434 or VIR-2218. After the end of study, use of TDF in WOCBP should be
determined per the VIREAD® approved local product label.
Highly effective methods of birth control are defined as those that result in a low failure rate 
(ie, less than 1% per year). Birth control methods which are considered highly effective include: 
•
Established use of combined (estrogen and progestogen containing) oral, intravaginal,
or transdermal hormonal methods of contraception associated with inhibition of
ovulation OR established use of progestogen-only oral, injectable, or implantable
hormonal methods of contraception associated with inhibition of ovulation. It is not
currently known whether VIR-2218 or VIR-3434 will impact the effectiveness of
hormonal contraceptive methods; therefore, it is recommended to use an additional
form of contraception (ie, barrier method) for 48 weeks after the last administration of
VIR-3434 or VIR-2218. After the end of study, use of TDF in WOCBP should be
determined per the VIREAD® approved local product label.
•
Placement of an intrauterine device
•
Placement of an intrauterine hormone-releasing system
•
Surgical sterilization of male partner (with the appropriate documentation of
vasectomy or the absence of sperm in the ejaculate; for female participants on the
study, the vasectomized male partner should be the sole partner for that participant)
•
True sexual abstinence from heterosexual contact, when in line with the preferred and
usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post ovulation methods) and withdrawal are not acceptable methods
of contraception. Abstinent participants must agree to use 1 of the above-mentioned
contraceptive methods for 48 weeks after last dose of VIR-3434 or VIR-2218 if they
start heterosexual relationships during the study. After the end of study, use of TDF in
WOCBP should be determined per the VIREAD® approved local product label.
•
Barrier method in combination with hormonal contraceptive, as described above
Post-menopausal status is defined as 12 months with no menses without an alternative medical 
cause. An elevated follicle stimulating hormone (FSH) level in the post-menopausal range 
should be used to confirm a post-menopausal state in women not using hormonal contraception 
or hormone replacement therapy (HRT). In the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.  

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Female participants must also agree to refrain from egg donation and in vitro fertilization from 
the time of study intervention administration through 48 weeks after the last dose of VIR-3434 or 
VIR-2218. After the end of study, use of TDF in WOCBP should be determined per the 
VIREAD® approved local product label. 
Male participants with female partners of child-bearing potential must agree to meet 1 of the 
following contraception requirements from the time of study treatment administration until 
48 weeks after the last administration of VIR-3434 or VIR-2218. After the end of study, use of 
TDF in males with female partners of child-bearing potential should be determined per the 
VIREAD® approved local product label. 
•
Documentation of azoospermia or vasectomy
•
Male condom plus partner use of 1 of the contraceptive options listed above for
contraception for WOCBP (hormonal contraceptive, intrauterine device)
Male participants must also agree not to donate sperm from the first dose of study intervention 
through 48 weeks after the last dose of VIR-3434 or VIR-2218. After the end of study, use of 
TDF in males donating sperm should be determined per the VIREAD® approved local product 
label. 

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10.7. 
Appendix 7: Additional Assessments in Participants That Experience 
ALT Elevation Meeting ECI Criteria 
Additional assessments will be performed in participants who experience ALT elevations 
meeting ECI criteria as outlined in Section 8.7.6. Following the occurrence of elevated ALT 
meeting ECI criteria per central laboratory, the assessments in Table 7 will be performed as soon 
as possible and no later than 2 weeks after the initial ALT value meeting criteria for a laboratory 
ECI.  
The full panel of assessments should only be performed once per ECI occurrence. An ECI 
occurrence is considered resolved when ALT returns to ≤ ULN.  
Individual assessments may be repeated per investigator discretion, as needed. 
Participants who meet ECI criteria will continue to receive study intervention unless criteria for 
study intervention discontinuation are met. Criteria for individual patient discontinuation from 
further dosing are described in Section 7.1. 
Table 7: 
Assessments in Participants That Experience ALT Elevation Meeting ECI 
Criteria  
Chemistry 
Hematology 
Albumin 
Blood urea nitrogen (BUN) 
Calcium 
Bicarbonate 
Chloride 
Calcium 
Creatine kinase 
Creatinine 
Creatinine clearance (calculated) 
Gammaglutamyltransferase (GGT) 
Glucose  
Lactate dehydrogenase (LDH) 
Phosphate 
Potassium 
Sodium 
Uric acid 
Lipase 
Liver Function Tests: Alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bilirubin (total and 
direct) 
Platelet count 
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
White blood cell (WBC) count with 
differential: neutrophils, lymphocytes, monocytes, 
eosinophils, basophils 
RBC indices: mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), 
% reticulocytes 
Coagulation Parameters 
Exploratory testing 
International normalized ratio (INR) 
Prothrombin time (PT) 
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Extended Hepatic Panel 
Imaging 
Quantitative HBsAg 
HBV DNA 
Quantitative HBeAg 
HAV antibody IGM 
HCV antibody  
HCV RNA PCR (qualitative and quantitative) 
HDV antibody or RNA 
HEV antibody IgM 
Epstein-Barr Virus antibodies (IgM and IgG) 
Cytomegalovirus antibodies (IgM and IgG)  
Varicella Zoster Virus antibodies IgG 
HSV-I and II IgG 
IgG 
Phosphatidylethanol 
Aldolase 
Anti-nuclear antibodies 
Anti-Smooth muscle antibodies 
Anti-LKM1 antibody 
Anti-mitochondrial antibodies 
Anti-SLA antibodies 
Ferritin 
Ceruloplasmin 
IgM 
Urinary ethylglucuronide 
Acetaminophen 
Abdominal ultrasound, including doppler flow if 
available (CT or MRI is acceptable in place of 
ultrasound if clinically indicated) 
Focused Medical History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter 
medications and herbal remedies 
Exposure to other potentially hepatotoxic agents 
including any work-related exposures (eg, 
solvents, pesticides, etc.) 
Alcohol consumption and drugs of abuse 
Travel history 
Exercise History 

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10.8. 
Appendix 8: Anaphylaxis, Cytokine Release Syndrome, And Immune 
Complex Disease Supportive Measures 
The following equipment or agents may be needed in the event of a suspected anaphylactic 
reaction or cytokine release syndrome: 
•
ECG monitor
•
Blood pressure monitor
•
Oxygen saturation monitor
•
Thermometer
•
Tourniquet
•
Oxygen
•
Mechanical ventilator
•
Renal replacement therapy
•
IV infusion solutions, tubing, catheters, and tape
•
Fresh-frozen plasma and/or cryoprecipitate
•
Epinephrine
•
Antihistamines, such as diphenhydramine
•
Corticosteroids, such as hydrocortisone, prednisolone, and methylprednisolone
The following are procedures that may be followed in the event of a suspected anaphylactic 
reaction or cytokine release syndrome: 
•
Maintain an adequate airway
•
Stop study intervention injection (if reaction occurs during injection)
•
Call for additional medical assistance
•
Apply a tourniquet proximal to the injection site to slow systemic absorption of study
intervention (if reaction occurs during injection). Do not obstruct arterial flow in the
limb.
•
Ensure appropriate monitoring is in place, such as continuous ECG and pulse
oximetry monitoring
•
Administer epinephrine, antihistamines, corticosteroids or other medications/products
as necessary based on the status of the participant and as directed by the physician
•
Draw local laboratory samples as appropriate, possibly including evaluation of
cytokines
•
The following equipment or agents may be needed in the event of suspected immune
complex disease
•
Thermometer

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•
Analgesic and antipyretic agents, such as non-steroidal anti-inflammatory drugs
(NSAIDs)
•
Antihistamines, such as diphenhydramine
•
Corticosteroids, such as prednisone and methylprednisolone
•
In extreme cases, equipment for plasmapheresis may be needed
The following are procedures that may be followed in the event of suspected immune complex 
disease: 
•
Though unlikely to occur acutely, stop study intervention injection (if reaction occurs
during injection)
•
Ensure temperature is appropriately monitored
•
Monitor for most common manifestations, including rheumatic (arthralgias) and
dermatologic (pruritic rash) findings
•
Administer NSAIDs, antihistamines, corticosteroids, or other medications/products as
necessary based on the status of the participant and as directed by the physician
•
Draw local laboratory samples as appropriate, possibly including complete blood
count, erythrocyte sedimentation rate, C-reactive protein, urinalysis, serum chemistry,
and evaluation of complement
•
In extreme cases, plasmapheresis may be employed

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10.9. 
Appendix 9: Schedule of Activities 
Assessments in bold are in addition to those listed in the PREVAIL Master Protocol. 
Table 8: 
Schedule of Activities: Cohort 1b 
Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44/ 
EOTb 
Visit Day ± Visit Window 
D-56 to D-1 
D1 
D8 ±2 
D29±2 D57±2 D85±2 D113±2 D141±2 D169±2 D197±2 D225±2 D253±2 D281±2 D309±2 
Study Procedures 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Xc
Demography 
X 
Physical examination 
X 
X 
Body Weight 
X 
Medical history 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review/record e
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver elastography (eg, Fibroscan) f 
X 
12-lead safety ECGg
X 
X 
ECI surveillanceh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-3434 local tolerability i 
X 
Drug Administration 
VIR-3434 administration j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TDF administration (QD) k 
X 

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Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44/ 
EOTb 
Visit Day ± Visit Window 
D-56 to D-1 
D1 
D8 ±2 
D29±2 D57±2 D85±2 D113±2 D141±2 D169±2 D197±2 D225±2 D253±2 D281±2 D309±2 
Treatment Diary 
X 
Laboratory Assessmentsm 
Pregnancy test n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening viral serology o 
X 
Liver function tests p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation parameters p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis pq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine for drugs of abuse r 
X 
HBsAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBs qualitative 
X 
Anti-HBs quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg qualitative 
X 
HBeAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBe qualitative 
X 
HBV DNA quantification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV genotyping 
X 
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Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44/ 
EOTb 
Visit Day ± Visit Window 
D-56 to D-1 
D1 
D8 ±2 
D29±2 D57±2 D85±2 D113±2 D141±2 D169±2 D197±2 D225±2 D253±2 D281±2 D309±2 
Complement testing q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-3434 PK s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-3434 immunogenicity t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory Assessments 
D = day; EOT = end of treatment; W = week  
a On days in which study intervention is administered, assessments performed predose unless otherwise specified. 
b If a participant discontinues treatment or withdraws prematurely from the study prior to the Week 44 visit, EOT assessments should be performed. 
c Prior to study intervention administration on Day 1, participant eligibility will be confirmed. 
d Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 
10 minutes. 
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e After signing of the informed consent form (ICF), but prior to initiation of study intervention, AEs/SAEs related to protocol-mandated procedures will be 
reported. Following initiation of study intervention, all AEs/SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study. 
Further details can be found in Section 8.7.  
f Does not need to be performed if the participant has had a liver elastography (eg, FibroScan or other sponsor-approved method) in the 6 months prior to 
screening or liver biopsy in the year prior to screening that confirmed the absence of METAVIR F3 fibrosis or F4 cirrhosis. 
g 12-lead safety ECG will be recorded and should be measured in the supine position after the participant has rested comfortably for approximately 10 minutes. 
Further details can be found in Section 8.10.  
h Participants will be monitored for ECI, and additional assessments may be performed if indicated. See Section 10.7 and Section 8.7.6 for more information. 
i On Day 1, local tolerability should be assessed approximately 1 hour after VIR-3434 administration. At the discretion of the investigator, unscheduled visits are 
permitted as needed for follow-up of any unresolved local tolerability symptoms. Local tolerability symptoms occurring at other visits should be reported as 
AEs. 
j VIR-3434 will be administered via SC injection. Participants will be monitored for at least 1 hour after VIR-3434 administration. 
k TDF will be administered daily orally. 
m Screening laboratory tests may be repeated (eg, for values thought to be erroneous) with Sponsor approval. 
n WOCBP are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and a urine pregnancy test will be performed at 
subsequent visits. Negative pregnancy test must be confirmed prior to study intervention administration. 
o See Section 8.4 for viral serology parameters.
p Clinical laboratory and urinalysis parameters are described in Section 0.
q Additional samples for urinalysis and complement testing will be collected at any time if fever, rash, or arthralgia are observed in a participant without
alternative explanation per the assessment of the investigator, or if immune complex disease is suspected by the investigator based on other signs or symptoms 
consistent with immune complex disease. Other signs and symptoms consistent with immune complex disease include, but are not limited to, decreased 
complement, hematuria, proteinuria, and/or decreased renal function. Urinalysis parameters are described in Section 0. 
r Drugs of abuse included in the panel are described in Section 0. 
s At all visits during the Treatment Period where PK collection is required, samples will be collected predose only. On Day 8, VIR-3434 will not be dosed, 
therefore, PK sample can be collected at any time. VIR-3434 PK sample collection includes samples for free and total PK assays, as applicable. Predose 
samples will be collected within 1 hour prior to dose. Further details can be found in Section 8.8.  
t Includes samples for ADA and neutralizing antibodies (NAb), as applicable for VIR-3434. Samples will be collected prior to dosing and at each indicated 
timepoint thereafter. Additional samples for immunogenicity analysis may be collected if a persistent drug related immunologic event is suspected. 
u See Section 8.4 for more information.
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Table 9: 
Schedule of Activities: Cohort 2b 
Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
W4 
W8 
W12 
W16 
W20  
W24 
W28 
W32 
W36 
W40 
W44/ 
EOTb
Visit Day ± Visit Window 
D-56 to
D-1
D1 
D2 
D8 
±2 
D29 
±2 
D57 
±2 
D85 
±2 
D113 
±2 
D141 
±2 
D169 
±2 
D197 
±2 
D225 
±2 
D253 
±2 
D281 
±2 
D309 
±2 
Study procedures 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Xc
Demography 
X 
Physical examination 
X 
X 
Body weight 
X 
Medical history 
X 
Vital signs d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review/record e
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver elastography (eg, Fibroscan) f 
X 
12-lead safety ECGg
X 
X 
ECI surveillance h
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-3434 local tolerability i 
X 
Drug Administration 
VIR-3434 and VIR-2218 
administrationj
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TDF administration (QD) k 
X 

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Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
W4 
W8 
W12 
W16 
W20  
W24 
W28 
W32 
W36 
W40 
W44/ 
EOTb
Visit Day ± Visit Window 
D-56 to
D-1
D1 
D2 
D8 
±2 
D29 
±2 
D57 
±2 
D85 
±2 
D113 
±2 
D141 
±2 
D169 
±2 
D197 
±2 
D225 
±2 
D253 
±2 
D281 
±2 
D309 
±2 
Treatment Diary 
X 
Laboratory Assessmentsm 
Pregnancy test n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening viral serology o 
X 
Liver function tests p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation parameters q
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis pq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine for drugs of abuse r 
X 
HBsAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBs qualitative 
X 
Anti-HBs quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg qualitative 
X 
HBeAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBe qualitative 
X 
HBV DNA quantification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV genotyping 
X 
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Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
W4 
W8 
W12 
W16 
W20  
W24 
W28 
W32 
W36 
W40 
W44/ 
EOTb
Visit Day ± Visit Window 
D-56 to
D-1
D1 
D2 
D8 
±2 
D29 
±2 
D57 
±2 
D85 
±2 
D113 
±2 
D141 
±2 
D169 
±2 
D197 
±2 
D225 
±2 
D253 
±2 
D281 
±2 
D309 
±2 
Complement testing q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-3434 PK predose s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-3434 PK postdose 
Xt 
Xu 
VIR-2218 PK predose v 
X 
X 
X 
VIR-2218 PK postdose 
Xw
Xx 
Xw 
Xw 
VIR-3434 immunogenicityy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-2218 immunogenicityz
X 
X 
X 
X 
X 
X 
X 
Exploratory Assessments 
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Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
W4 
W8 
W12 
W16 
W20  
W24 
W28 
W32 
W36 
W40 
W44/ 
EOTb
Visit Day ± Visit Window 
D-56 to
D-1
D1 
D2 
D8 
±2 
D29 
±2 
D57 
±2 
D85 
±2 
D113 
±2 
D141 
±2 
D169 
±2 
D197 
±2 
D225 
±2 
D253 
±2 
D281 
±2 
D309 
±2 
D = day; EOT = end of treatment; W = week  
a On days in which study intervention is administered, assessments performed predose unless otherwise specified. 
aa See Section 8.4 for more information. 
b If a participant discontinues treatment or withdraws prematurely from the study prior to the Week 44 visit, EOT assessments should be performed. 
c Prior to study intervention administration on Day 1, participant eligibility will be confirmed. 
c
e After signing of the informed consent form (ICF), but prior to initiation of study intervention, AEs/SAEs related to protocol-mandated procedures will be 
reported. Following initiation of study intervention, all AEs/SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study. 
Further details can be found in Section 8.7  
f Does not need to be performed if the participant has had a liver elastography (eg, FibroScan or other sponsor-approved method) in the 6 months prior to 
screening or liver biopsy in the year prior to screening that confirmed the absence of Metavir F3 fibrosis or F4 cirrhosis. 
g 12-lead safety ECG will be recorded and should be measured in the supine position after the participant has rested comfortably for approximately 10 minutes. 
Further details can be found in Section 8.10. 
h Participants will be monitored for ECI, and additional assessments may be performed if indicated. See Section 10.7 and Section 8.7.6 for more information. 
i On Day 1, local tolerability should be assessed approximately 1 hour after VIR-3434 administration. At the discretion of the investigator, unscheduled visits are 
permitted as needed for follow-up of any unresolved local tolerability symptoms. Local tolerability symptoms occurring at other visits should be reported as 
AEs. 
j VIR-3434 and VIR-2218 will be administered via SC injection. Participants will be monitored for at least 1 hour after VIR-3434 administration. 
k TDF will be administered daily orally. 
l Patient reported outcomes surveys will be administered as described in Section 8.5.
m Screening laboratory tests may be repeated (eg, for values thought to be erroneous) with Sponsor approval.
n WOCBP are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and a urine pregnancy test will be performed at
subsequent visits. Negative pregnancy test must be confirmed prior to study intervention administration. 
o See Section 8.4 for viral serology parameters.
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p Clinical laboratory and urinalysis parameters are described in Section 0. 
q Additional samples for urinalysis and complement testing will be collected at any time if fever, rash, or arthralgia are observed in a participant without 
alternative explanation per the assessment of the investigator, or if immune complex disease is suspected by the investigator based on other signs or symptoms 
consistent with immune complex disease. Other signs and symptoms consistent with immune complex disease include, but are not limited to, decreased 
complement, hematuria, proteinuria, and/or decreased renal function. Urinalysis parameters are described in Section 0. 
r Drugs of abuse included in the panel are described in Section 0. 
s VIR-3434 PK sample collection includes samples for free and total PK assays, as applicable. Predose samples will be collected within 1 hour prior to dose. 
Further details can be found in Section 8.8.  
t Day 2 VIR-3434 PK postdose sample will be collected between 22 to 28 hours post D1 dose. 
u VIR-3434 PK postdose sample can be collected at any time during the D8 visit.
v VIR-2218 PK predose samples will be collected within 1 hour prior to dose. Further details can be found in Section 8.8.
w Day 1, Week 20, and Week 44 VIR-2218 PK postdose samples will be collected between 2 to 6 hours post-dose.
x Day 2 VIR-2218 PK sample will be collected between 22 to 28 hours post D1 dose.
y Includes samples for ADA and neutralizing antibodies (NAb), as applicable for VIR-3434. Samples will be collected prior to dosing and at each indicated
timepoint thereafter. Additional samples for immunogenicity analysis may be collected if a persistent drug related immunologic event is suspected. 
z Includes samples for ADA of VIR-2218. Samples will be collected prior to dosing and at each indicated timepoint thereafter. Additional samples for 
immunogenicity analysis may be collected if a persistent drug related immunologic event is suspected. 

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Table 10: 
Schedule of Activities for Follow-Up Period for all Cohorts 
Study Stage 
Follow-Up Period 
Follow up Visit 
F1 
F2 
F4 
F6 
F8 
F10 
F12 
F16 
F20 
F24 
F28 
F32 
F36 
F40 
F44 
F48/ 
EOFU 
Visit Day ± Visit 
Window 
D8 
±2 
D15 
±2 
D29 
±7 
D43 
±7 
D57 
±7 
D71 
±7 
D85 
±7 
D113 
±7 
D141 
±7 
D169 
±7 
D197 
±7 
D225 
±7 
D253 
±7 
D281 
±7 
D309 
±7 
D337 
± 7 
Study Procedures 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
review/recorda 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead safety ECGb
X 
ECI surveillancec
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
Pregnancy teste
X 
X 
X 
X 
X 
Liver function testsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
parametersf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisfg 
X 
X 
X 
X 
HBsAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Stage 
Follow-Up Period 
Follow up Visit 
F1 
F2 
F4 
F6 
F8 
F10 
F12 
F16 
F20 
F24 
F28 
F32 
F36 
F40 
F44 
F48/ 
EOFU 
Visit Day ± Visit 
Window 
D8 
±2 
D15 
±2 
D29 
±7 
D43 
±7 
D57 
±7 
D71 
±7 
D85 
±7 
D113 
±7 
D141 
±7 
D169 
±7 
D197 
±7 
D225 
±7 
D253 
±7 
D281 
±7 
D309 
±7 
D337 
± 7 
Anti-HBs quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBe qualitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV DNA 
quantification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement testingg 
X 
X 
VIR-3434 PKh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VIR-3434 
immunogenicityi 
X 
X 
X 
X 
X 
X 
X 
VIR-2218 
immunogenicityj 
X 
X 
X 
X 
X 
X 
X 
Exploratory Assessments 
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Study Stage 
Follow-Up Period 
Follow up Visit 
F1 
F2 
F4 
F6 
F8 
F10 
F12 
F16 
F20 
F24 
F28 
F32 
F36 
F40 
F44 
F48/ 
EOFU 
Visit Day ± Visit 
Window 
D8 
±2 
D15 
±2 
D29 
±7 
D43 
±7 
D57 
±7 
D71 
±7 
D85 
±7 
D113 
±7 
D141 
±7 
D169 
±7 
D197 
±7 
D225 
±7 
D253 
±7 
D281 
±7 
D309 
±7 
D337 
± 7 
D = day; EOFU = End of Follow-Up; F = Follow-Up Week  
a In the Follow-Up Period, all AEs/SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study. Further details can be found in 
Section 8.7.  
b 12-lead safety ECG will be recorded and should be measured in the supine position after the participant has rested comfortably for approximately 10 minutes. 
Further details can be found in Section 8.10. 
c Participants will be monitored for ECI, and additional assessments may be performed if indicated. See Section 10.7 for more information. 
e WOCBP are required to have pregnancy tests. A urine pregnancy test will be performed. 
f Clinical laboratory and urinalysis parameters are described in Section 0. 
g Additional samples for urinalysis and complement testing will be collected at any time if fever, rash, or arthralgia are observed in a participant without 
alternative explanation per the assessment of the investigator, or if immune complex disease is suspected by the investigator based on other signs or symptoms 
consistent with immune complex disease. Other signs and symptoms consistent with immune complex disease include, but are not limited to, decreased 
complement, hematuria, proteinuria, and/or decreased renal function. Urinalysis parameters are described in Section 0. 
h VIR-3434 PK sample collection includes samples for free and total PK assays, as applicable. Further details can be found in Section 8.8. 
i Includes samples for ADA and neutralizing antibodies (NAb), as applicable for VIR-3434. Additional samples for immunogenicity analysis may be collected if 
a persistent immunologic related event is suspected. 
j Includes samples for ADA of VIR-2218. Additional samples for immunogenicity analysis may be collected if a persistent drug related immunologic event is 
suspected. 
k See Section 8.4 for more information. 
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11.
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PPD

PPD