A Phase II/III Partially Double-Blinded, Randomised, Multinational, Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults to Determine the Safety and Immunogenicity of AZD2816, a Vaccine for the Prevention of COVID-19 Caused by Variant Strains of SARS-CoV-2
Phase: PHASE2
Conditions: COVID-19, SARS-CoV-2
Sponsor: AstraZeneca

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Clinical Study Report Appendix 16.1.1
Drug Substance
AZD2816
Study Code
D7220C00001
Appendix 16.1.1
Protocol and Protocol Amendments

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VERSION OF PROTOCOL OR PROTOCOL AMENDMENT
Global Document Name
Version No 
Version Date
Global Clinical Study Protocol
1.0
14 May 2021
Amendment 1 Global Clinical Study Protocol
2.0
02 Jun 2021
Amendment 2 Global Clinical Study Protocol
3.0
29 Jul 2021
Amendment 3 Global Clinical Study Protocol
4.0
11 Oct 2021
Local Document Name 
Great Britain
Version No
Version Date
Global Clinical Study Protocol
1.0
14 May 2021
Amendment 1 Great Britain Clinical Study Protocol
1.0
03 Jun 2021
Amendment 2 Great Britain Clinical Study Protocol 
2.0
30 Jul 2021
Amendment 3 Great Britain Clinical Study Protocol
3.0
12 Oct 2021

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Clinical Study Protocol
Study Intervention
AZD2816
Study Code
D7220C00001
Version
1
Date
14 May 2021
TITLE PAGE
A Phase II/III Partially Double-Blinded, Partially Randomised, Multinational, 
Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults to 
Determine the Safety and Immunogenicity of AZD2816, a Vaccine for the Prevention 
of COVID-19 Caused by Variant Strains of SARS-CoV-2
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Number: D7220C00001
Study Intervention: AZD2816
Study Phase: II/III
Short Title: Phase II/III Study of AZD2816, a Vaccine for the Prevention of COVID-19 in 
Adults
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator:  Professor Andrew Pollard

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS...................................................................................................... 3
1
PROTOCOL SUMMARY.................................................................................. 9
1.1
Synopsis ............................................................................................................. 9
1.2
Schema............................................................................................................. 14
1.3
Schedule of Activities....................................................................................... 15
2
INTRODUCTION............................................................................................ 21
2.1
Study Rationale ................................................................................................ 21
2.2
Background ...................................................................................................... 21
2.3
Benefit/Risk Assessment................................................................................... 24
2.3.1
Risk Assessment............................................................................................... 24
2.3.2
Benefit Assessment........................................................................................... 25
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 25
3
OBJECTIVES AND ENDPOINTS................................................................... 26
4
DESIGN........................................................................................................... 30
4.1
Overall Design.................................................................................................. 30
4.1.1
COVID-19 Assessments ................................................................................... 32
4.1.2
Screening.......................................................................................................... 32
4.1.3
Vaccination Visit .............................................................................................. 32
4.1.4
Follow-up visits................................................................................................ 33
4.2
Scientific Rationale for Study Design ............................................................... 33
4.2.1
Rationale for Study Design and Participant Population ..................................... 33
4.2.2
Rationale for Study Endpoints .......................................................................... 34
4.3
Justification for Dose........................................................................................ 35
4.4
End of Study Definition.................................................................................... 36
5
STUDY POPULATION ................................................................................... 36
5.1
Inclusion Criteria .............................................................................................. 36
5.1.1
All Participants:................................................................................................ 36
5.1.2
Previously COVID-19 Vaccinated Participants................................................. 38
5.2
Exclusion Criteria ............................................................................................. 38
5.3
Lifestyle Considerations ................................................................................... 40
5.4
Screen Failures ................................................................................................. 40
6
STUDY INTERVENTION............................................................................... 41
6.1
Study Interventions Administered..................................................................... 41
6.1.1
Investigational Products.................................................................................... 41
6.1.2
Dosing Instructions........................................................................................... 42
6.2
Preparation/Handling/Storage/Accountability ................................................... 42
6.2.1
Dose Preparation and Administration................................................................ 43

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6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 43
6.3.1
Randomization.................................................................................................. 43
6.3.2
Blinding............................................................................................................ 44
6.3.3
Procedures for Unblinding ................................................................................ 45
6.4
Study Intervention Compliance......................................................................... 45
6.5
Concomitant Therapy........................................................................................ 46
6.5.1
Permitted Concomitant Medications ................................................................. 46
6.5.2
Prohibited Concomitant Medications ................................................................ 46
6.6
Dose Modification ............................................................................................ 47
6.7
Intervention After the End of the Study............................................................. 47
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 47
7.1
Discontinuation of Study Intervention............................................................... 47
7.2
Participant Withdrawal from the Study ............................................................. 48
7.3
Lost to Follow-up ............................................................................................. 48
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 49
8.1
Efficacy Assessments........................................................................................ 49
8.2
Safety Assessments........................................................................................... 49
8.2.1
Physical Examinations...................................................................................... 50
8.2.2
Vital Signs........................................................................................................ 50
8.2.3
Clinical Laboratory Assessments ...................................................................... 50
8.3
Adverse Events and Serious Adverse Events..................................................... 51
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 51
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 52
8.3.3
Causality Collection.......................................................................................... 53
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 53
8.3.5
Adverse Events Based on Examinations and Tests............................................ 53
8.3.6
Hy’s Law.......................................................................................................... 54
8.3.7
Solicited Adverse Events .................................................................................. 54
8.3.8
COVID-19 Assessment..................................................................................... 55
8.3.9
Medically-Attended Adverse Events................................................................. 55
8.3.10
Adverse Events of Special Interest.................................................................... 56
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest ................................ 56
8.3.10.2
Potential Neurological Adverse Events of Special Interest ................................ 56
8.3.11
Reporting of Serious Adverse Events................................................................ 59
8.3.12
Pregnancy......................................................................................................... 59
8.3.12.1
Maternal Exposure............................................................................................ 59
8.3.13
Medication Error............................................................................................... 60
8.4
Overdose .......................................................................................................... 60
8.5
Human Biological Samples............................................................................... 61
8.5.1
Pharmacokinetics.............................................................................................. 61
8.5.2
Immunogenicity Assessments ........................................................................... 61

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8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 62
8.5.2.2
8.5.2.3
8.5.2.4
8.5.3
Pharmacodynamics........................................................................................... 63
8.6
Human Biological Sample Biomarkers ............................................................. 63
8.7
Optional Genomics Initiative Sample................................................................ 63
8.8
Medical Resource Utilization and Health Economics ........................................ 63
9
STATISTICAL CONSIDERATIONS............................................................... 63
9.1
Statistical Hypotheses....................................................................................... 63
9.2
Sample Size Determination............................................................................... 63
9.3
Populations for Analyses .................................................................................. 68
9.4
Statistical Analyses........................................................................................... 69
9.4.1
General Considerations..................................................................................... 70
9.4.2
Safety ............................................................................................................... 71
9.4.2.1
Primary Endpoints ............................................................................................ 71
9.4.2.2
Other Safety Endpoints..................................................................................... 71
9.4.3
Immunogenicity................................................................................................ 72
9.4.3.1
Immunogenicity Endpoints ............................................................................... 72
9.4.4
Data Safety Monitoring Board .......................................................................... 79
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 79
11
REFERENCES............................................................................................... 102
CCI
CCI
CCI

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LIST OF TABLES
Table 1
Schedule of Activities: Screening ............................................................ 15
Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine . 16
Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated  Participants Receiving Vaccination with a 4-Week 
Dosing Interval........................................................................................ 17
Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 12-Week 
Dosing Interval........................................................................................ 19
Table 5
Study Objectives and Endpoints............................................................... 26
Table 6
Highly Effective Methods of Contraception............................................. 37
Table 7
Investigational Products........................................................................... 41
Table 8
Laboratory Safety Variables..................................................................... 50
Table 9
Predefined Solicited Adverse Events for Reactogenicity Assessment....... 54
Table 10
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)...... 64
Table 11
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set) .......................... 64
Table 12
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes........... 65
Table 13
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponses Rates based on Historic Seroconversion Rates and 
Proposed Sample Sizes ............................................................................ 65
Table 14
Probability of detecting 1 or more safety events (N = 300)....................... 66
Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio .................................................................... 67
Table 16
Power for Non-inferiority Using -10% as the Upper Bound of the 
Difference in Seroresponse Rate .............................................................. 68
Table 17
Populations for Analysis .......................................................................... 68
Table 18 
Description of the Analysis Keys for Tables 19 and 20 ............................ 74
Table 19
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 75

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Table 20
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 76
Table 21
Immunogenicity Comparisons for Previously Unvaccinated Groups........ 77
Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups............ 78
Table 23
Tables for Clinical Abnormalities: Local Reactions to Injectable Product 91
Table 24
Tables for Clinical Abnormalities: Vital Signs......................................... 92
Table 25
Tables for Clinical Abnormalities: Systemic (General or Illness) ............. 93
Table 26
Adverse Events of Special Interest........................................................... 94
Table 27
List of Potential Immune-mediated Medical Conditions........................... 95
LIST OF FIGURES
Figure 1
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants.............................................................................................. 14
Figure 2
Study Design for Unvaccinated Seronegative/Seropositive Participants ... 14
Figure 3
Neurology Testing Algorithm .................................................................. 58

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 80
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 85
Appendix C
Handling of Human Biological Samples .................................................. 89
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ............................. 91
Appendix E
Adverse Events of Special Interest........................................................... 94
Appendix F
Actions Required in Cases of any Thrombotic Events With 
Thrombocytopenia and/or Bleeding ......................................................... 98
Appendix G
Abbreviations ........................................................................................ 100
Appendix H
Protocol Amendment History................................................................. 101

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A phase II/III partially double-blinded, partially randomised, multinational,  
active-controlled study in both previously vaccinated and unvaccinated adults to determine the 
safety and immunogenicity of AZD2816, a vaccine for the prevention of COVID-19 caused 
by variant strains of SARS-CoV-2.
Short Title: Phase II/III study of AZD2816, a vaccine for the prevention of COVID-19 in 
adults.
Rationale: Recently, several variants of the SARS-CoV-2 virus with increased
transmissibility have emerged, including B.1.1.7, first identified in the UK, P.1, first identified 
in Brazil, and B.1.351, first identified in South Africa.  In an ongoing clinical trial of 
AZD1222 in South Africa, interim results failed to show protection against mild to moderate 
disease caused by the B.1.351 variant; protection against severe disease could not be 
determined as no severe cases were identified (Madhi et al 2021). 
Based on available evidence about vaccine effectiveness and molecular epidemiology of 
emerging variants, B.1.351 is estimated to have a potential to escape vaccine-induced 
immunity. B.1.351 carries sequence mutations in common with other variants of concerns; 
immunity to B.1.351 therefore has the potential to provide some cross-immunity against other 
emerging strains. Development of candidate vaccines that include the B.1.351 S-protein 
variant is underway.  AstraZeneca is developing AZD2816, a vaccine against the B.1.351 
SARS-CoV-2 variant using the same ChAdOx1 platform and manufacturing processes used 
for AstraZeneca’s currently available COVD-19 vaccine, AZD1222.
Objectives and Endpoints:
The purpose of this study is to demonstrate the safety and characterize the immunogenicity of 
AZD2816, AstraZeneca’s candidate ChAdOx1 vector vaccine against SARS-CoV-2 variant 
strain B.1.351, when administered:
!
As a single dose to SARS-CoV-2 seronegative individuals who previously received a 
primary 2-dose vaccination against SARS-CoV-2 with AZD1222 or an mRNA vaccine
!
As a 2-dose primary series to SARS-CoV-2 seronegative individuals who are 
unvaccinated (ie, have neither been infected with SARS-CoV-2 nor been vaccinated 
against SARS-CoV-2).

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The following table lists the primary and secondary endpoints:
Objectives
Endpoints
Safety Objectives
- Primary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 7 
days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with 2 doses of a SARS-CoV2 
mRNA vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with 2 doses of AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with 2 doses of a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with 2 doses of AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD1222 with a 
! Incidence of local and systemic solicited AEs for 
7 days post-dose

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4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD1222 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
- Primary (descriptive)
Previously vaccinated seronegative participants
To assess the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To assess the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with 2-doses of a SARS-CoV-
2 mRNA vaccine
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To assess the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 variant strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres 
Unvaccinated seronegative participants

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To describe the humoral immune response against 
the B.1.351 and Wuhan-Hu-1 variant strains induced 
by a 2-dose primary vaccination with AZD1222 with 
a 4-week interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 variant strains induced by 
a 2-dose primary vaccination with AZD2816 with a 
12-week interval in unvaccinated seronegative
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (comparative)
Previously vaccinated seronegative participants receiving 1 dose versus unvaccinated seronegative participants 
receiving 2 doses
To evaluate the immune responses against the 
B.1.3.51 variant strain and Wuhan-Hu-1 strain 
elicited by 1 dose of AZD2816 in seronegative 
participants previously vaccinated with 2 doses of 
AZD1222 relative to the response elicited by a 2-
dose primary vaccination with AZD1222 with a 4-
week dosing interval in unvaccinated seronegative
participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 variant strain and Wuhan-Hu-1 strain 
elicited by 1 dose of AZD2816 in seronegative 
participants previously vaccinated with 2 doses of a 
SARS-CoV-2 mRNA vaccine relative to the 
response elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Previously vaccinated seronegative participants
To evaluate the immune response against the B.1.351 
variant strain and the Wuhan-Hu-1 strain elicited by 
1 dose of AZD2816 as relative to the response with 1 
dose of AZD1222 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune response against the B.1.351 
and Wuhan-Hu-1 variant strain elicited by 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with a mRNA vaccine relative to the 
response with 1 dose of AZD1222 in seronegative 
participants previously vaccinated with 2 doses of 
AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
Unvaccinated seronegative participants
To evaluate the immune response against the B.1.351 
and Wuhan-Hu-1 variant strain elicited by a primary 
2-dose vaccination with AZD2816 with a 4-week 
dosing interval relative to the response elicited by a 
primary 2-dose vaccination with AZD1222 with a 4-
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)

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week interval in previously unvaccinated 
seronegative participants
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 variant strain and the Wuhan-Hu-1 strain 
elicited by a 2-dose primary vaccination with 
AZD2816 with a 12-week dosing interval relative to 
the response elicited by a 2-dose primary vaccination 
with AZD2816 with a 4-week interval in previously 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
SAEs: serious adverse events; MAAEs: medically attended adverse events; AESIs: adverse events of special 
interest.
a
At least a 4-fold increase in geometric mean titre from baseline
Overall Design: This is a phase II/III, multinational, partially randomized, partially double-
blind, controlled study in both previously vaccinated and unvaccinated participants. 
Disclosure Statement: This is a parallel-group preventive study with 6 treatment arms.
Number of Participants: Approximately 1650 SARS-CoV-2 nucleocapsid seronegative 
participants will be assigned to study intervention to support the primary and secondary 
objectives of this study. In addition, participants that are SARS-Cov-2 nucleocapsid 
seropositive at screening will be enrolled and assigned to study intervention for an exploratory 
analysis, with a cap of 10% of the seronegative population (ie, approximately 165 total 
participants).
Intervention Groups and Duration: Previously vaccinated individuals will receive 1 dose of 
AZD1222 or AZD2816 on Day 1.  Previously unvaccinated participants will receive 2 doses 
of AZD1222 or AZD2816: one dose on Day 1 and one dose on either Day 29 or Day 85.  
Participants will be followed up for safety for 180 days after last study vaccine administration.
Data Monitoring Committee: A Data Safety Monitoring Board will provide oversight to 
ensure safe and ethical conduct of the study.
Statistical Methods:
Sample sizes of 300 seronegative participants per group (or 150 for the AZD2816 primary 
vaccination with a 12-week dosing interval group) are deemed appropriate based upon 
available immunogenicity data from previous clinical studies with AZD1222 for the primary 
and secondary objectives of this study.  
The safety analysis set for adverse events consists of all participants who have received at 
least one dose of study intervention.  The immunogenicity analysis set includes all participants 
in the safety analysis set who have no protocol deviations or intercurrent events judged to 
have the potential to interfere with the generation or interpretation of an immune response.

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An interim analysis will be performed on data from 28 days after first dose to support 
assessment of 1 dose in both previously vaccinated and unvaccinated participants.  A primary 
analysis will be performed on data from 28 days after the second dose of the 4-week dosing 
intervals to support assessment of these 2-dose primary vaccinations.  A secondary analysis 
will be performed on data from 28 days after the second dose of the 12-week dosing interval 
to support assessment of this 2-dose primary vaccination.  The final analysis will be 
performed on data from 6 months follow-up after participant's vaccination.  
1.2
Schema
Figure 1
Study Design for Previously Vaccinated Seronegative/Seropositive
Participants
Figure 2
Study Design for Unvaccinated Seronegative/Seropositive Participants
Note:  In addition to the approximately 1650 seronegative participants enrolled to support the primary/secondary objectives,
seropositive participants will also be enrolled in the study to support exploratory objectives in this patient population, with a 
cap of 10% of the planned seronegative participants (ie, a maximum of 165 seropositive participants).

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1.3
Schedule of Activities
Table 1
Schedule of Activities: Screening 
Procedure
Day -14 to Day 1
See Section
Informed consent
X
5.1, Appendix A 3
Demography
X
-
Medical and surgical history
X
-
Prior and concomitant medications
X
6.5
Complete physical examination, including height and weight
X
8.2.1
Vital signs
X
8.2.2
Urine pregnancy test (for women of childbearing potential only) 
X
8.2.3
Clinical safety laboratory assessments
X
8.2.3
Assessment of serious adverse events
X
8.3, Appendix B
Blood sample for SARS-CoV-2 antibody testing (lateral flow test)
X
8.5.2
Verify eligibility criteria
X
5.1, 5.2
Note:  Screening activities can occur at same visit as initial vaccination with investigational product (ie, Visit 1 in 
Table 2, Table 3, and Table 4).

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Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine
Procedure
Treatment and Follow-up Period
Section
Day
1
8
15
29
180
Window (days)
-
±2
±2
±3
±14
Medical and surgical history
X
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
-
-
6.1.1
Immunological assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
-
8.3.7
e-Diary collected
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xab
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: 
serious adverse event

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated  Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
Urine pregnancy test
(women of childbearing potential)
X 
-
-
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
X 
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample for SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample for additional immunogenicity
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
X
-
-
-
8.3.7

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated  Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
X
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
-
X
X
X
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X
-
-
-
X
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X
-
-
-
X
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
X
-
-
-
8.3.7

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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2
INTRODUCTION
AZD2816 is being developed for the prevention of COVID-19.  It is a modified version of the 
current AstraZeneca SARS-CoV-2 vaccine (referred to as AZD1222 in clinical
documentation) that has been modified to also provide immunity against the newly emerging 
SARS-CoV-2 variant strain B.1.351.  Like AZD1222, AZD2816 is a recombinant replication-
defective chimpanzee adenovirus vector (ChAdOx1) expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tissue plasminogen activator leader sequence at the 
N terminus.  AZD2816 differs from AZD1222 in that the S glycoprotein gene sequence used 
is from the B.1.351 variant strain instead of the original Wuhan-Hu-1 variant.
2.1
Study Rationale
The aim of the study is to assess the safety and immunogenicity of AZD2816 for prevention 
of COVID-19 as both a primary 2-dose vaccination in previously unvaccinated participants 
and a 1-dose vaccination in participants previously vaccinated against the original Wuhan-Hu-
1 strain of SARS-CoV-2.  A safe and effective vaccine for COVID-19 prevention, including 
against the B.1.351 variant, would have significant global public health impact. 
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (Zhou et al 2020).  The disease these patients contracted was subsequently 
named Coronavirus Disease 2019 (COVID-19).  The World Health Organization declared the 
novel coronavirus a pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the 
novel coronavirus SARS-CoV-2, has resulted in significant global morbidity and mortality as 
well as major disruption to healthcare systems.  Measures to change the course of the 
pandemic have included the accelerated development vaccines against the original Wuhan-
Hu-1 strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes.  SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus,
and it is the seventh COVID virus known to cause human infections and the third known to 
cause severe disease after SARS-CoV and MERS-CoV. One fourth of the viral genome is 
responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 
and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 spike (S) glycoprotein is a type I trimeric, transmembrane protein that is 
located at the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s 

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subunits are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the 
receptor binding domain and subsequent fusion of virus and cell membranes, thereby
mediating the entry of SARS-CoV-2 into the target cells.  The S protein has an essential role 
in virus entry and determines tissue and cell tropism, as well as host range.  The roles of the 
S-protein in receptor binding and membrane fusion have made it a desirable target for vaccine 
and antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947 
(ie, the Wuhan-Hu-1 isolate).
To date, 5 vaccines that rely upon the expression of the SARS CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 
NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b).  Immunogenicity data indicate that a 
single dose of AZD1222 elicits both humoral and cellular immunogenicity responses and that 
antibody responses are boosted after a second dose.  In a pooled analysis of the 4 studies 
conducted in the United Kingdom, Brazil, and South Africa (DCO2 database lock 07 
December 2020), the vaccine was highly immunogenic; seroresponse of S binding antibody 
was > 98% after a single dose of AZD1222.  Seroresponse of live neutralising antibody was 
82.4% after 1 dose, which rose to 99.4% after a second dose.  Efficacy analyses of the pooled 
DCO2 data demonstrated effective protection of AZD1222 against COVID-19 with a vaccine 
efficacy of 66.73% (95.84% CI: 57.41%, 74.01%) (p < 0.001) from 15 days after the second 
dose in seronegative participants receiving 2 doses.  The DCO2 data also demonstrated that 
the standard dose of AZD1222 (5 x 1010 viral particles) provides complete protection against 
COVID-19 hospital admission ≥ 22 days after the first dose in the seronegative analysis set 
(0 versus 14 cases in the control group, 2 of which were severe, including one with a fatal
outcome).  Vaccine efficacy was similar in participants with pre-existing comorbidities, being 
those at greatest risk of severe outcomes of COVID-19, compared to that in the general 
population.  Recently available primary analysis data from a Phase III study performed in the 
United States and Latin America showed primary endpoint vaccine efficacy of 76% (95% CI: 
67.60%, 82.22%; p-value < 0.001). 

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A sharp rise in COVID-19 cases was reported in late 2020, which was attributed to the 
emergence of new SARS-CoV-2 variant strains: B.1.1.7 in the United Kingdom, B.1.351 
in South Africa, and P.1 in Brazil.  These variant strains carry a number mutations in the 
S protein sequence: 9 amino acids in B.1.1.7, 10 amino acids in B.1.351, and 12 amino acids 
in P.1 compared with the Wuhan-Hu-1 sequence.  These mutations may result in an increase 
of transmissibility and/or reduced vaccine effectiveness.  Variant B.1.351 was first identified 
in South Africa in October 2020.  Its attributes include approximately 50% increased
transmission and moderate impact of neutralization by monoclonal antibody therapeutics, 
convalescent plasma and vaccine sera.  In vitro neutralization assays suggest that the B.1.351 
lineage viruses may be the most antigenically distinct from the original Wuhan-like strains 
(Zhou et al 2021).  In addition, evidence suggests that AZD1222 may afford diminished 
protection against mild-moderate COVID-19 disease arising from the B.1.351 variant which 
is also antigenically the most different from the Wuhan-Hu-1 virus (Madhi et al 2021).  
The development of candidate vaccines that would be effective against the B.1.351 variant 
strain is underway.  AZD2816 is being developed as an updated ChADOx-nCOv19 vaccine 
designed to provide protective immunity against the newly arising B.1.351 variant strain, 
using the same ChAdOx1 platform and manufacturing processes used for AstraZeneca’s 
currently approved COVID-19 vaccine, AZD1222.
The purpose of this Phase II/III, multinational, randomized, partially double-blind, active-
controlled study is to demonstrate the safety and characterize the immunogenicity of 
AZD2816, AstraZeneca’s candidate ChAdOx1 vector vaccine against B.1.351, when 
administered:
•
As a single dose vaccination in SARS-CoV-2 seronegative individuals who have 
previously received a 2-dose primary vaccination series (AZD1222 or an mRNA vaccine) 
against SARS-CoV-2 
•
As a 2-dose primary vaccination to SARS-CoV-2 seronegative individuals who have not 
been vaccinated previously. 
SARS-CoV-2 seropositive participants will be enrolled in separate cohorts to support a 
parallel exploratory analysis in these participants.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD1222 and 
AZD2816 is provided in the respective Investigator’s Brochures.

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2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD2816 and AZD1222 can be found in the respective Investigators Brochures.
2.3.1
Risk Assessment
AZD2816 has been developed using the same vaccine vector, ChAdOx1, as AZD1222 and 
only differs in the sequence for SARS-CoV-2 S glycoprotein that is inserted in the vector.  
The anticipated safety profile of AZD2816 is the same as the observed safety profile of 
AZD1222.  Risks associated with AZD2816 are thus the same as the risks associated with 
AZD1222, and no additional risks are anticipated due to the change in the targeted sequence.
A number of essentially mild and moderate adverse reactions to AZD1222 have been 
identified and resemble reactions frequently observed after many vaccines.  Based on pooled 
clinical data from studies with AZD1222, the most commonly expected local solicited AEs for 
participants in this study are vaccination site pain and tenderness.  The most commonly 
expected systemic solicited AEs are fatigue, headache, and malaise.  The majority of reported 
events have been mild or moderate in severity and resolved within 1 to 7 days.  Following the 
second dose, a general attenuation in the incidence and severity of local and systemic solicited 
AEs was observed. 
Post-authorisation hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk.
A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, 
has been observed very rarely following vaccination with COVID-19 Vaccine during post-
authorisation use. No events have been observed in the AZD1222 clinical development 
programme.  Thrombosis in combination with thrombocytopenia is thus considered to be an 
important identified risk.  This includes cases presenting as venous thrombosis, including 
unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as well as 
arterial thrombosis, concomitant with thrombocytopenia.  Considering the frequency of this 
rare event and the size of this study, the risk for participants in this trial is considered to be 
low.  The protocol includes exclusion criteria and instructions for heightened vigilance and 
thorough investigations for suspected cases to mitigate against further the risk for these rare 
event. 
Important potential risks are 1) neurologic events and potential immune-mediated neurologic 
conditions and 2) vaccine-associated enhanced disease, including vaccine-associated enhanced 
respiratory disease. 

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2.3.2 Benefit Assessment
All participants will receive active treatment: either AZD1222, which has been shown to be 
effective in providing protection against SARS-CoV-2, or AZD2816, which as a modified 
form of AZD1222 designed to be effective against the emergent B.1.351 variant strain and 
may also provide participants with protection.  The information gained from this study will 
inform development decisions with regard to the efficacy of AZD2816 as both a primary 
2-dose vaccination in participants that have not been previously vaccinated and a 1-dose 
booster vaccination in participants previously vaccinated against SARS-CoV-2.
2.3.3 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria and close monitoring of participants to 
minimize known and potential risks. 
An independent Data Safety Monitoring Board will provide study oversight, evaluating 
cumulative safety and other clinical data at regular intervals. 
Taking these measures into account, the potential risks identified in association with the 
administration of AZD2816 and AZD1222 are justified by the anticipated benefit that may be 
afforded to participants for the prevention of COVID-19.

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3
OBJECTIVES AND ENDPOINTS
Table 5 describes the objectives and endpoints of this study.  Co-primary objectives were 
chosen to characterise the safety and humoral immune response against selected strains of 
AZD2816 and AZD1222 when administered as either a primary vaccination series in 
previously unvaccinated participants or as a booster to participants who have been previously 
primed with 2 doses of AZD1222 or an approved mRNA COVID-19 vaccine.  All primary 
and secondary objectives/endpoints are descriptive; there will be no hypothesis testing in this 
study. Estimates of neutralizing antibody geometric mean titre ratio and difference in 
seroresponse rates (and 95% confidence interval) will be generated as secondary analyses to 
support the assessment of relative immune responses between selected study groups.
Table 5
Study Objectives and Endpoints
Objectives
Endpoints
Safety Objectives
- Primary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 7 
days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with 2 doses of a SARS-CoV2 
mRNA vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose

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To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with 2 doses of AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with 2 doses of a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with 2 doses of AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD1222 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD1222 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
- Primary (descriptive)
Previously vaccinated seronegative participants
To assess the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To assess the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)

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previously vaccinated with 2-doses of a SARS-CoV-
2 mRNA vaccine
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To assess the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 variant strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres 
Unvaccinated seronegative participants
To describe the humoral immune response against 
the B.1.351 and Wuhan-Hu-1 variant strains induced 
by a 2-dose primary vaccination with AZD1222 with 
a 4-week interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 variant strains induced by 
a 2-dose primary vaccination with AZD2816 with a 
12-week interval in unvaccinated seronegative
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (comparative)
Previously vaccinated seronegative participants receiving 1 dose versus unvaccinated seronegative participants 
receiving 2 doses
To evaluate the immune responses against the 
B.1.3.51 variant strain and Wuhan-Hu-1 strain 
elicited by 1 dose of AZD2816 in seronegative 
participants previously vaccinated with 2 doses of 
AZD1222 relative to the response elicited by a 2-
dose primary vaccination with AZD1222 with a 4-
week dosing interval in unvaccinated seronegative
participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 variant strain and Wuhan-Hu-1 strain 
elicited by 1 dose of AZD2816 in seronegative 
participants previously vaccinated with 2 doses of a 
SARS-CoV-2 mRNA vaccine relative to the 
response elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres

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Previously vaccinated seronegative participants
To evaluate the immune response against the B.1.351 
variant strain and the Wuhan-Hu-1 strain elicited by 
1 dose of AZD2816 as relative to the response with 1 
dose of AZD1222 in seronegative participants 
previously vaccinated with 2 doses of AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune response against the B.1.351 
and Wuhan-Hu-1 variant strain elicited by 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with a mRNA vaccine relative to the 
response with 1 dose of AZD1222 in seronegative 
participants previously vaccinated with 2 doses of 
AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
Unvaccinated seronegative participants
To evaluate the immune response against the B.1.351 
and Wuhan-Hu-1 variant strain elicited by a primary 
2-dose vaccination with AZD2816 with a 4-week 
dosing interval relative to the response elicited by a 
primary 2-dose vaccination with AZD1222 with a 4-
week interval in previously unvaccinated 
seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 variant strain and the Wuhan-Hu-1 strain 
elicited by a 2-dose primary vaccination with 
AZD2816 with a 12-week dosing interval relative to 
the response elicited by a 2-dose primary vaccination 
with AZD2816 with a 4-week interval in previously 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
Exploratory
Previously vaccinated and unvaccinated participants (seronegative and seropositive at screening)
To explore antibody response to selected SARS-
CoV-2 variants of interest/variants of concern 
following 2-dose primary vaccination with AZD2816 
or AZD1222 in a sub-group of seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding titres (geometric mean titre) for selected 
variants of concern/variants of interest
! Seroresponsea rate of SARS-CoV-2 specific     
antibody binding titres for selected variants of 
concern/variants of interest
To explore B-cell and T-cell responses following 2-
dose primary vaccination with AZD2816 or 
AZD1222 in a sub-group of seronegative participants
! Intracellular cytokine staining and flow cytometry 
for T-cell responses over time
! Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 B.1.351 or Wuhan-Hu-1 S protein 
from day of dosing baseline over time
! Breadth and depth of peripheral blood B-cell and T-
cell repertoire over time through immunosequencing
To monitor the incidence of SARS-CoV-2 infection 
following 1 dose of AZD2816 or 1 dose of AZD1222
in previously vaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by 
the presence of nucleocapsid antibodies occurring  
post-dose of study intervention 

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To monitor the incidence of COVID-19 following 1 
dose of AZD2816 or AZD 1222 in previously 
vaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To monitor the incidence of SARS-CoV-2 infection 
following vaccination with 2 doses of AZD2816 or 2 
doses of AZD1222 in unvaccinated seronegative 
participants
! The incidence of SARS-CoV-2 infection defined by 
the presence of nucleocapsid antibodies occurring 
post-second dose of study intervention 
To monitor the incidence of COVID-19 following 2 
doses of AZD2816 or AZD 1222 in unvaccinated 
seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune response against the 
B.1.351 and Wuhan-Hu-1 variant strains induced by 
a 2-dose primary vaccination with AZD1222 or 
AZD2816 in sub-groups of seronegative and 
seropositive participants
! Magnitude of SARS-CoV-2 neutralization titres 
(geometric mean titre) as determined by a live virus 
neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres as determined by a 
live virus neutralization assay
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following 2 doses of AZD2816 or 
AZD1222 in sub-groups of seronegative and 
seropositive participants
! Magnitude of ChAdOx1 nAb titres (geometric mean 
titre)
! Seroresponse rate of ChAdOx1 neutralizing antibody 
titres
! Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody 
titres, 1 month after both Dose 1 and Dose 2
To explore additional immune responses following 
2 doses of AZD1222 or AZD2816 in sub-groups of 
seronegative and seropositive participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity data
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.
4
DESIGN
4.1
Overall Design
This is a multi-country Phase II/III study to evaluate the safety and immunogenicity of 
AZD2816 as single-dose vaccination in previously vaccinated adult participants and as a 
2-dose primary vaccination in previously unvaccinated adult participants. 
A total of approximately 1650 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled across these 2 patient 
populations with the goal of 900 previously vaccinated participants receiving single-dose 
vaccination and 750 unvaccinated participants receiving primary 2-dose vaccination. In 
addition, seropositive patients will be enrolled (with a cap of 10% of the seronegative 
population or 165 participants) to support exploratory analysis is these participants. 
The enrollment and randomization strategy is intended to minimize group differences in terms 
of age, gender and the presence of comorbidities.

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In both the single-dose treatment regimen and primary 2-dose vaccination treatment regimen, 
participants will receive study intervention consisting of intramuscular administration of either 
AZD1222 (5 ×1010 viral particles) or AZD2816 (5 ×1010 viral particles). 
Approximately 600 seronegative participants previously vaccinated with AZD1222 will be 
randomised 1:1 to receive a single intramuscular dose of either AZD1222 or AZD2816 in a 
double-blinded fashion. 
Approximately 300 seronegative participants previously vaccinated with an approved mRNA 
based vaccination will receive a single intramuscular open-label dose of AZD2816.
Approximately 750 seronegative, previously unvaccinated participants will be randomised 
2:2:1 to receive a 2-dose primary vaccination of either 2 doses of AZD1222 or AZD2816 with 
a 4-week dosing interval in a double-blinded fashion or 2 doses of open-label AZD2816 with 
a 12-week dosing interval. 
In addition, a smaller population seropositive participants (approximately 10% of the 
seroronegative population), will be randomised or assigned to treatment in a similar manner as 
above.
Immunogenicity (ie, anti-Wuhan-Hu-1 and anti-B.1.351 immune responses including 
S-binding antibody titres and neutralizing antibody levels [pseudoneutralization]) will be 
assessed in serum samples collected pre-dose on the day of each vaccination (baseline levels 
before vaccination), 14 and 28 days after each vaccination, and 180 days after the last 
vaccination.
All participants will be given an axillary thermometer, tape measure or ruler, and a proprietary 
e-diary application designed for use with a smart device with instructions for use.  All 
participants will be asked to report on solicited signs and symptoms for 7 days following 
vaccination (Days 1-8 for all participants and Days 29-36 for the 4-week dosing interval and 
Days 85-92 for the 12-week dosing interval).  An e-diary will be used to collect information 
on the timing and severity of the solicited signs and symptoms.
Follow-up visits will take place as per the schedule of assessment within respective windows.  
All participants will be assessed for local and systemic AE, physical examination, review of 
e-diaries at these time points as detailed in the schedule of assessment.  Blood will also be 
taken for safety assessments and immunology purposes.
All study participants will be followed for safety for 180 days after administration of their last 
vaccination dose.  In every participant, solicited local and systemic events will be reported for 
up to 7 days after each dose, all unsolicited AEs will be reported for up to 28 days after each 

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dose, and SAEs and AEs of special interest will be evaluated through study completion 
(up to 180 days after the last study vaccination).  
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, 
to ensure safe and ethical conduct of the study.
4.1.1
COVID-19 Assessments
Occurrence of COVID-19 in the trial will be reported as safety events, including monitoring 
of the potential risk of vaccine-induced enhanced disease as an AE of special interest (see 
Appendix E).  COVID-19 will be diagnosed and treated as per standard medical practice.  
In addition, experimental treatments are permitted.  Detailed information will be collected in 
a standard way and reported on a specific case report form. 
4.1.2
Screening 
All potential participants will be screened, which may take place at a visit up to 14 days prior 
to Day 1 or on Day 1 itself.  
Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the screening procedures specified in the Schedule of Activities (Section 1.3) will be 
undertaken including a medical history, physical examination, height and weight, a 
SARS-CoV-2 screening test and clinical safety laboratory assessments.  Baseline information 
collected in the previously vaccinated participants will include which vaccine was received, 
immunization dose interval, and time since last vaccination.
For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled.  (Note: Women with urine test results that are positive or undetermined will not be 
enrolled and should be advised to seek medical attendance outside the context of the trial if 
pregnancy is suspected.) 
The eligibility of the participants will be reviewed at the end of the screening visit and again 
when all results from the screening visit have been considered.  Decisions to exclude the 
participant from enrollment or to withdraw a participant from the study will be at the 
discretion of the Investigator.
4.1.3
Vaccination Visit
Participants will be considered enrolled at the point of vaccination.  Before vaccination, the 
eligibility of the participant will be reviewed.  Body temperature will be observed and a 
medical history and physical examination will be undertaken before the first vaccination to 
determine need to postpone vaccination or screen fail the participant.  A negative pregnancy

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test (urine test) will need to be obtained from women of childbearing potential before 
vaccination.  Baseline blood samples will be obtained before the first vaccination.
Participants will receive 1 dose of AZD2816 or AZD1222 at vaccination visits, administered 
by intramuscular injection.  Previously immunized participants will have a single vaccination 
visit, Day 1.  Participants that have not been previously vaccinated at baseline will have a 
second vaccination visit on Day 29 (4-week interval) or Day 85 (12-week interval).  
All participants will be given an axillary thermometer, tape measure or ruler, and a proprietary 
e-diary application designed for use with a smart device with instructions for use.  All 
participants will be asked to report on solicited signs and symptoms for 7 days following 
vaccination (Days 1 to 8 and Days 29 to 36 or Days 85 to 92 when applicable).
4.1.4
Follow-up visits
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3).  All 
participants will be assessed for local and systemic AE, physical examination, review of the 
e-diary and blood tests at these time points as detailed in the Schedule of Activities.  Blood 
will also be taken for safety and immunogenicity assessments.
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate way until the last 
study visit in order to collect information on any SAEs/AE of special interest.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population includes adults ≥18 years of age.  Persons who are healthy or have 
medically stable underlying conditions will be eligible.  Adults with medically-stable chronic 
diseases may participate if, according to the judgement of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Some seropositive participants 
(capped at 10% of the seronegative participant population) will be enrolled to support an 
exploratory analysis.  
Those enrolled in the single-dose vaccination part of the study must have received 2 doses of 
AZD1222 (with a dosing interval of 4-12 weeks) or 2 doses of an mRNA COVID-19 vaccine 
(with a dosing interval of 3-12 weeks for the BNT162b2 mRNA vaccine [Pfizer-BioNTech] 
and 4-12 weeks for the mRNA-1273 vaccine [Moderna]) with the second doses administered 
at least 3 months prior to first study intervention administration. 

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Pregnant/breastfeeding women, persons with severe immunodeficiency or severe underlying 
disease will be excluded from participation in the study.  Persons previously vaccinated with 
AZD1222 in the context of an AZD1222 vaccine trial are eligible for enrollment as previously 
vaccinated participants in the trial.  Persons who have previously received any other 
investigational product for the prevention of COVID-19 will be excluded from participation in 
this study.
Participants with known risk factors for thrombosis and thrombocytopenia (excluding 
contraceptive hormonal therapy or replacement hormonal therapy) are excluded.
4.2.2
Rationale for Study Endpoints
There is no statistical hypothesis testing planned for this study.  Descriptive statistics will 
support evaluation of safety, reactogenicity, and immunogenicity.
An interim analysis will occur when all vaccinated participants have completed their Day 29 
visit. 
The primary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants randomized to a 4-week dosing interval have 
completed their Day 57 visit (ie, 28 days after their second dose).
A secondary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants (including those randomized to either a 4-week or a 
12-week dosing interval) have completed their Day 57/Day 113 visit (ie, 28 days after their
second dose).
The final analysis will occur when data from all vaccinated participants are available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants/180 days after the second dose for unvaccinated participants).
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination 
will be summarized by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be 
summarized by system organ class and preferred term, and by relationship to 
vaccination as assessed by the investigator.
!
SAEs and AEs of special interest following the first vaccination and throughout the 
study duration will be summarized by system organ class and preferred term and by 
relationship to vaccination as assessed by the investigator.

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Solicited AEs will be collected for 7 days after each dose of study intervention, a period that 
has proven adequate to describe reactogenicity events in previous vaccine studies.  For all 
participants, AEs will be collected through 28 days after each dose of study intervention.  
SAEs, medically-attended AEs, and AEs of special interest and will be collected from Day 1 
through end of the study.  AEs of special interest include terms identified by the Brighton 
Collaboration involving events associated with vaccination in general (SPEAC 2020).
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean titre
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean titre from baseline
Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of 
interest.
Immunogenicity against SARS-CoV-2 Wuhan-Hu-1 and B.1.351 strains will be characterized 
through the quantification of Spike-binding antibodies, pseudo-neutralization and, in a subset 
of participants, live neutralization.  Exploratory analysis of immunogenicity against other 
strains and induction of other immune effectors including cell-mediated immunity will be 
conducted. 
4.3
Justification for Dose
The AZD2816 nominal dose of 5 × 1010 viral particles is the same dose as the approved dose 
for AZD1222, which was based on the accumulated non-clinical data and clinical data from 
the AZD1222 clinical studies, as well as from other SARS-CoV-2 vaccines in development. 
Safety and immunogenicity data from an additional clinical study, MERS001(NCT03399578), 
using the same ChAdOx1 vector, also helped inform dose selection. MERS001 was the first 
clinical study of a ChAdOx1-vectored vaccine expressing the full-length S protein from a 
separate, but related, beta-coronavirus.  ChAdOx1 MERS has been given to 31 participants to 
date at doses ranging from 5 × 109 viral particles to 5 × 1010 viral particles.  Despite higher 
reactogenicity observed at the 5 × 1010 viral particles, this dose was safe, with self-limiting 
AEs and no serious adverse reactions recorded.  The 5 × 1010 viral particles was the most 
immunogenic, in terms of inducing neutralizing antibodies against MERS-CoV using a live 
virus assay (Folegatti et al 2020).  Given the immunogenicity findings and safety profile 
observed with the ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 viral particles 
dose was chosen for AZD1222.  
Based on accumulating nonclinical and clinical data gathered for AZD1222, a 2-dose regimen 
was selected for vaccination of unvaccinated participants with AZD2816 (AZD1222 

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Investigators Brochure).  A single dose vaccination has been selected for participants 
previously vaccinated in line with both FDA and EMA guidance (FDA 2021, EMA 2021).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities (Section
1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as a protocol waiver or exemption, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1
All Participants: 
Age
1
Adult, ≥ 18 years of age at the time of consent
COVID-19
For inclusion in the SARS-CoV-2 seronegative population supporting the primary and 
secondary objectives: 
2
No history of laboratory-confirmed SARS-CoV-2 infection (ie, no positive nucleic acid 
amplification test and no positive antibody test).
3
Seronegative for SARS-CoV-2 at screening (lateral flow test to detect reactivity to the 
nucleoprotein).
Note, patients failing to meet criteria 2 and/or 3 may be included in the separate seropositive 
population supporting the seropositive exploratory objectives. 
Type of Participant 
4
Medically stable such that, according to the judgment of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up
- A stable medical condition is defined as disease not requiring significant change in 
therapy or hospitalization for worsening disease during the 3 months prior to enrollment

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5
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator
6
Signed informed consent obtained before conducting any study-related procedures
Reproduction
7
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants:
(a) Women of childbearing potential must:
!
Have a negative pregnancy test on the day of screening and on days of 
vaccination
!
Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
30 days following administration of the last dose of study intervention.  A highly 
effective method of contraception is defined as one that can achieve a failure rate 
of less than 1% per year when used consistently and correctly (see Table 6).  
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy) or 
!
Post-menopausal:
!
For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥ 12 months amenorrhea prior to randomization, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and
o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal
range, the participant is to be considered of childbearing potential
!
For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomization, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.
Table 6
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing systema
Bilateral tubal occlusion
Vasectomized partner b
Combined (oestrogen- and progestogen-containing 
hormonal contraception
      Oral (combined pill)
      Intravaginal
     Transdermal (patch)

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Table 6
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Sexual abstinence c
Progestogen-only hormonal contraception
     Oral 
     Injectable
     Implantable
a
This is also considered a hormonal method 
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse from 28 days prior to Day 1 through 30 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant
5.1.2
Previously COVID-19 Vaccinated Participants
8
Prior completion of a 2-dose primary homologous vaccination regimen against SARS-
CoV-2 with either AZD1222 (2 standard doses as authorized vaccine or as investigational 
product in a clinical trial with a 4 to 12-week dosing interval) or with an mRNA vaccine 
approved for emergency or conditional use (eg, BNT162b2  vaccine [Pfizer-BioNTech] 
with a 3- to 12-week dosing interval or mRNA-1273 vaccine [Moderna] with a 4- to 12-
week dosing interval).  The second dose in all cases should have been administered at 
least 3 months prior to first administration of study intervention.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of allergy to any component of AZD1222/AZD2816.
2
History of Guillain-Barré syndrome, any demyelinating disease, or any other 
neuroimmunologic condition
3
Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) on the 
day prior to or day of randomization 
4
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia or HIV/AIDS.
5
Recurrent severe infections and use of immunosuppressant medication within the past 
6 months (≥ 20 mg per day of prednisone or its equivalent, given daily or on alternate 
days for ≥ 15 days within 30 days prior to administration of study intervention)
The following exceptions are permitted:  
∀
Topical/inhaled steroids or short-term oral steroids (course lasting ≤14 days)
6
History of primary malignancy except for:

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(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or for metastasis (for example, indolent 
prostate cancer) in the opinion of the site investigator.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
(c) Adequately treated uterine cervical carcinoma in situ without evidence of disease
(d) Localized prostate cancer
7
History of thrombocytopenia and/or thrombosis, including participants who have 
experienced major venous and/or arterial thrombosis in combination with 
thrombocytopenia following vaccination with any COVID-19 vaccine
8
History of heparin-induced thrombocytopenia, congenital thrombophilia (ie, factor V 
Leiden, prothrombin G20210A, antithrombin III deficiency, protein C deficiency and 
protein S deficiency, factor XIII mutation, familial dysfibrinogenemia), auto-immune 
thrombophilia (antiphospholipid syndrome, anti-cardiolipin antibodies, anti-β2-
glycoprotein 1 antibodies), or paroxysmal nocturnal haemoglobinuria.
9
Clinically significant bleeding (eg, factor deficiency, coagulopathy, or platelet disorder), 
or prior history of significant bleeding or bruising following intramuscular injections or 
venepuncture
10 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, or neurological illness, as judged 
by the Investigator (note, mild/moderate well-controlled comorbidities are allowed)
11 Any other significant disease, disorder, or finding that may significantly increase the risk 
to the participant because of participation in the study, affect the ability of the participant 
to participate in the study, or impair interpretation of the study data
12 Any autoimmune conditions, except mild psoriasis and vitiligo
Note: The AEs of special interest as outlined in Appendix E (including Table 27) should be 
considered when evaluating a participant for exclusion criteria as the presence of these AEs of 
special interest, especially if untreated or uncontrolled, may be a safety risk to the participant, 
affect the ability of the participant to participate in the study, and/or impair interpretation of 
the study data.  Investigators should review and consider the list of conditions in Appendix E.  
If any of these conditions are present in a participant, the Investigator is asked to utilize 
his/her clinical judgment in determining the participant’s eligibility for the study.  Should the 
participant have conditions as outlined in Appendix E and the participant is enrolled, the 
Investigator is asked to document notes on site regarding the final rationale for enrollment.
Prior/Concomitant Therapy
13 Receipt of or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 with the exception of prior vaccination with 
AZD1222 or an mRNA COVID-10 vaccine (2 doses of the same vaccine within an 

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approved dosing interval, see Section 5.1.2), which is allowed for participants in the 
previously vaccinated cohort 
Note: For participants who develop COVID-19, receipt of licensed treatment options 
and/or participation in investigational treatment studies is permitted
14 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to or after administration of study intervention
15 Receipt of any influenza vaccine (licensed or investigational) within 7 days prior to and 
after administration of AZD1222/AZD2816.
16 Receipt of immunoglobulins and/or any blood products within 3 months prior to 
administration of study intervention or expected receipt during the period of study 
follow-up
Other Exclusions
17 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)
18 Women who are currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, having given birth less than 3 months before or planning pregnancy during 
the study. 
19 Has donated ≥ 450 mL of blood products within 30 days prior to randomization or 
expects to donate blood within 90 days of administration of second dose of study 
intervention
20 Participants with a history of chronic alcohol or drug abuse or any condition associated 
with poor compliance.
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements or 
if vaccination would interfere with the participant’s ongoing treatment.
22 Previous enrollment in the present study.
5.3
Lifestyle Considerations
1
Participants must follow the contraception requirements outlined in Section 5.1
2
Restrictions relating to concomitant medications are described in Section 6.5
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 

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queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Only a single rescreening is allowed in the study.  Rescreened participants are 
required to sign a new ICF (Appendix A 3), and will be assigned a new participant number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical device utilized by a study participant according to 
the study protocol.  Study intervention is defined as AZD2816 or AZD1222 (Table 7).
6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 7
Investigational Products
Intervention 
Name
AZD2816
AZD1222
Type 
Vaccine
Vaccine
Dose Formulation
Unit Dose Strength
1 × 1011 viral particles/mL
1 × 1011 viral particles/mL
≥5 × 108 infectious units/mL
≥5 × 108 infectious units/mL
Dosage Level
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
≥2.5 × 108 infectious units
≥2.5 × 108 infectious units
Route
Intramuscular
Intramuscular
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labelling
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Current/Former 
Name
-
Previous clinical documentation:
ChAdOx1 nCoV-19
Current tradename: Vaxzevria
IMP: investigational medicinal product; NIMP: non-investigational medical product; w/v: weight/volume.
CCI
CCI

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AZD2816
AZD2816 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD2816 has 
a label-claim volume of 5 mL and can provide up to ten 0.5 mL doses.
AZD1222
AZD1222 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD1222 has 
a label-claim volume of 4 mL and can provide up to eight 0.5 mL doses.
Unopened vial must be stored at 2-8 oC (36-46 oF) for the duration of the assigned shelf-life 
and must not be frozen.  Both investigational products must be kept in original packaging until 
use to prevent prolonged light exposure. 
6.1.2
Dosing Instructions
Previously unvaccinated participants will receive 2 doses of either AZD1222 or AZD2816, 
with the first dose administered on Day 1 and the second dose on Day 29 (for a 4-week dosing 
interval) (Table 3) or Day 85 (for a 12-week dosing interval) (Table 4). 
Previously vaccinated participants will receive 1 dose of either AZD1222 or AZD2816
(Table 2)
It is recommended that the study interventions be administered as an intramuscular injection 
into the deltoid of the non-dominant arm. Other injection sites may be used if necessary.
All study participants will be observed in the clinic for at least 15 minutes after vaccination.
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical
equipment to treat acute anaphylactic reactions must be immediately available, and study
personnel must be trained to recognize and treat anaphylaxis.
6.2
Preparation/Handling/Storage/Accountability
The procedures for preparation, handling, storage, and accountability are identical for 
AZD2816 and AZD1222.
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 

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automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual or specified handling instructions.
6.2.1
Dose Preparation and Administration
Doses of AZD2816 and AZD1222 must be prepared by the unblinded pharmacist (or designee 
in accordance with local and institutional regulations) using aseptic technique. Each dose is 
prepared by withdrawing 0.5 mL from a vial of AZD2816 or AZD1222 in a sterile syringe.
AZD2816 and AZD1222 do not contain preservatives. Each vial must be assigned a beyond-
use-date of 6 hours at 2-30 °C (36-86 °F) from first needle puncture of the vial, after which 
any unused portion must be discarded.
Once an AZD2816 or AZD1222 dose is drawn into a syringe for administration, the dose must 
be administered within the beyond-use-date of the vial. If dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
The study contains 2 randomised cohorts and 1 non-randomised cohort: 
!
Participants that have previously been vaccinated with 2 doses of AZD1222 will be 
randomised 1:1 to 1 dose of AZD2816 or 1 dose of AZD1222.
!
Participants that have been previously vaccinated with an mRNA COVID-19 vaccine will 
not be randomised; all will receive 1 dose of AZD2816.  
!
Vaccination naïve participants that will be randomised 2:2:1 to 2 doses of AZD2816 with 
a 4-week dosing interval, 2 doses of AZD1222 with a 4-week dosing interval, or 2 doses 
of AZD2816 with a 12-week dosing interval.
Separate populations of SARS-CoV-2 seronegative participants (supporting the primary and 
secondary objectives) and SARS-CoV-2 seropositive participants (supporting exploratory 
objectives) will be randomised/included in the above cohorts.

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Randomization will be stratified based on age, gender, and presence of the following
comorbidities that are known risk factors for severe illness from COVID-19 (based on the 
participant’s past and current medical history):
!
Obesity (BMI ≥ 30 kg/m2 at baseline)
!
Significant cardiovascular disease (eg, heart failure, coronary artery disease, congenital 
heart disease, cardiomyopathies, or pulmonary hypertension)
!
Chronic lung disease (eg, chronic obstructive pulmonary disease, idiopathic pulmonary 
disease, cystic fibrosis, or moderate to severe asthma)
!
Diabetes (Type 1 or Type 2).  
To maintain comparability between randomised groups (previously vaccinated with AZD1222 
and previously unvaccinated participants) and the non-randomised group (previously
vaccinated with mRNA participants), the randomisation stratification factors will be 
monitored during the enrolment period, and if required a recruitment cap on a particular level 
of a factor may be stipulated.
The randomised participants will be centrally assigned to randomized study intervention using 
an Interactive Response Technology (IRT)/Randomisation and Trial Supply Management.  
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 
the log in information & directions for the Randomisation and Trial Supply Management will 
be provided to each site.
Where a participant does not meet all the eligibility criteria but incorrectly received study 
intervention, the investigator should inform the Study Physician immediately, and a discussion 
should occur between the Study Physician and the investigator regarding whether to continue 
or discontinue the participant.
6.3.2
Blinding
Treatment will be double-blinded for previously AZD1222 vaccinated participants 
randomised to a single dose of either AZD2816 or AZD1222 and for previously unvaccinated 
participants randomised to either AZD2816 or AZD1222 given as 2 dose regimen with a 
4-week dosing interval.  Participants previously vaccinated with an  mRNA COVID-19 
vaccine will receive an open-label booster dose of AZD2816, and previously unvaccinated 
participants receiving a primary 2-dose vaccination of AZD2816 with a 12-week dosing 
interval in this study will also receive treatment in an open-label fashion.
For the double-blinded treatments, neither the participant nor any of the investigators or 
Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
participants will be aware of the study intervention received.  Since AZD2816 and AZD1222 
are visually distinct prior to dose preparation (due to differences in container closure), 
investigational product will be handled by an unblinded pharmacist (or designee in accordance 

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with local and institutional regulations) at the study site. Once drawn into syringes for 
administration, AZD2816 and AZD1222 are not visually distinct from each other.
The IRT will provide the investigators with a dose tracking number to be allocated to the 
participant at the dispensing visit.  Routines for this will be described in the IRT user manual 
that will be provided to each study site.
For participants receiving double-blinded treatments, the randomization code should not be 
broken except in medical emergencies when the appropriate management of the participant 
requires knowledge of the treatment randomization.  The investigator documents and reports 
the action to the Sponsor, without revealing the treatment given to participant to the Sponsor 
staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities.  Randomization codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.
6.3.3
Procedures for Unblinding
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
in which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment 
is warranted.  Participant safety must always be the first consideration in making such a 
determination.  If a participant’s intervention assignment is unblinded for safety, the Sponsor 
must be notified within 24 hours after breaking the blind. 
In the event that a study participant is contacted about receiving a licensed and/or authorized 
COVID-19 vaccine outside of this clinical study, unblinding instructions are being provided to 
the sites.  If the participant is unblinded, the Sponsor needs to be notified within 24 hours, and 
this should be documented in the site source documents.
6.4
Study Intervention Compliance
Participants are dosed at the study site, receiving study intervention directly from the 
investigator or designee, under medical supervision.  The date, and time if applicable, of dose 
administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.

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6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the period specified in the 
Schedule of Activities (Section 1.3), must be recorded in the eCRF along with the information 
listed below.  Vitamins and/or herbal supplements are not to be recorded.
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
!
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance.
!
Primary care providers, or where appropriate investigators, should prescribe appropriate 
concomitant medications or treatments deemed necessary to provide full supportive care 
and comfort during the study.
!
Participants who develop COVID-19 after receiving study intervention should be treated 
with licensed medications and interventions according to standard of care.  All routine 
vaccinations other than influenza are permitted beginning > 30 days after last dose of 
study intervention.  Licensed influenza vaccines are permitted 7 days before and 7 days 
after administration of study intervention.
!
Topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 days) are 
permitted
6.5.2
Prohibited Concomitant Medications
The following medications are prohibited and the Sponsor must be notified if a participant 
receives any of these prohibited medications.  The use of the following concomitant 
medications and/or vaccines, however, will not definitively require withdrawal of the
participant from the study, but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis set.
!
Primary or booster vaccinations, other than AZD2816 or AZD1222, for prevention of 
SARS-CoV-2 or COVID-19.
Note: Participants choosing to receive a licenced and/or authorized COVID-19 vaccine 
should inform the Investigator so it can be properly documented.  Participants, who 
receive a licenced and/or authorized COVID-19 vaccine outside the study, should be 
encouraged to continue study conduct to be followed for safety reporting and all 
assessments.

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!
Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention.  Thirty days after 
the second vaccination, other routine vaccinations are permitted as clinically indicated.
!
Glucocorticoids at a dose ≥ 20 mg/day of prednisone or equivalent given daily or on
alternate days for ≥ 14 consecutive days between randomization and the participant’s
scheduled final visit
!
Other systemically administered drugs with significant immunosuppressive activity,
such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy
between randomization and the participant’s scheduled final visit
!
Immunoglobulins and/or any blood product.
If a participant receives a prohibited concomitant medication, the investigator in consultation 
with the Sponsor will evaluate any potential impact on receipt of study intervention based on 
time the medication was administered, the medication’s pharmacology and pharmacokinetics, 
and whether the medication will compromise the participant’s safety or interpretation of the 
data (see Section 7.1). 
6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.  Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive the first or second dose (if applicable) of study 
intervention if any of the following occur in the participant in question:
1
Withdrawal of consent after signing informed consent
2
Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 
3
Participant is pregnant or nursing
4
Any grade 3 or greater allergic reaction including anaphylaxis that is assessed as related 
to study intervention 
5
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6
Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardize the safety of the study participant 
7
Receipt of a prohibited concomitant medication that may jeopardize the safety of the 
study participant or interpretation of the data
Each participant who has received at least 1 dose of study intervention will be followed for the 
full study period unless consent is withdrawn specifically from further study participation, or 
the participant is lost to follow-up.  Participants who have not received study intervention, 
regardless of reason, will not be followed.
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine 
during the study, AstraZeneca needs to be notified within 24 hours and this should be 
documented in the site source documents. Participants who have received study intervention, 
regardless of reason, will be followed for the full study period.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken should be 
carried out in line with what was stated in the informed consent and local regulation.  
The investigator must document the decision on use of existing samples in the site study 
records and inform the Sponsor Study Team.  If the participant does not specifically 
request withdrawal of consent for use of samples, then the samples collected prior to the 
consent withdrawal will be destroyed once per protocol analysis is complete.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

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!
The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the Schedule of Activities (Section
1.3).  Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities.
8.1
Efficacy Assessments
Not applicable.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).

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8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.  Each clinically significant 
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history, 
clinical signs, and symptoms and will include signs of thrombosis and/or 
thrombocytopenia.  Each clinically significant abnormal finding following vaccination 
will be recorded as an AE.
!
All physical examinations will be performed by a licensed healthcare provider 
(eg, physician, physician assistant, or licensed nurse practitioner). 
8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3).  The participant should be 
resting prior to the collection of vital signs.  On vaccination days, vital signs should be 
assessed prior to vaccine administration.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3).  Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the investigator, with the 
date and time of collection recorded in the appropriate eCRF.
The standard clinical chemistry and haematology analysis will be performed at a local 
laboratory at or near to the investigator site.  Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.  
The following laboratory variables will be measured:
Table 8
Laboratory Safety Variables
Blood
Serum/Plasma
Haemoglobin
Activated partial thromboplastin time
Leukocyte count
Prothrombin time
Leukocyte differential count (absolute count)
Fibrinogen
Platelet count
D-dimer

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-
Creatinine
-
Bilirubin, total
-
Alkaline phosphatase
-
Aspartate aminotransferase 
-
Alanine aminotransferase
In case a participant shows an aspartate aminotransferase or alanine aminotransferase 
≥3 × upper limit of normal together with total bilirubin ≥2 × the upper limit of normal, please 
refer to Section 8.3.6
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the Schedule of Activities (Section 1.3).  Urine pregnancy tests for 
#-human chorionic gonadotropin may be performed at the site using a licensed dipstick test.  
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a e-diary (Section 8.3.7), and will be assessed separately 
from the (unsolicited) AEs collected during the study.  General information for AEs in this 
protocol excludes the reporting of solicited AEs via e-diary unless otherwise noted..
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
AEs will be recorded for 28 days after each dose of study intervention. 
Solicited AEs will be recorded for 7 days after each dose of study intervention (ie, Day 1 
through Day 8). If a solicited AE is not resolved within the e-diary reporting period, the event 

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will be reported as a non-solicited adverse event in the eCRF, with a start date of when started 
and the actual stop date.
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact. 
See the Schedule of Activities for the scheduled timepoints (Section 1.3). 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Severity grade/maximum severity grade/changes in severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge

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!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA 2007) will be utilized for all unsolicited events with an 
assigned severity grading including Grade 5. 
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol-mandated vital signs and laboratory safety 
assessments will be summarized in the Clinical Study Report. 
Deterioration as compared to baseline in protocol-mandated vital signs and laboratory safety 
assessment should therefore only be reported as AEs if they fulfil any of the SAE or 
medically-attended AE criteria or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or 
non-planned visits were required).

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If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an SAE or medically-attended AE, and the associated vital sign 
will be considered as additional information. 
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation.  Any occurrences of aspartate aminotransferase or alanine aminotransferase 
≥3 × the upper limit of normal together with total bilirubin ≥2 × upper limit of normal at any 
point during the study following the administration of study medication should be reported to 
the Sponsor as a potential Hy's Law SAE within 1 day with a serious criteria of ‘Important 
medical event’ and causality assessment ‘yes/related’.
The study physician will contact the investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 9) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention via e-diary collection. If a solicited AE is not resolved within the e-diary 
reporting period, the event will be also reported as a non-solicited adverse event in the eCRF,
with a start date of when started and the actual stop date.
Solicited AEs should not be reported as unsolicited AEs unless they fulfil the criteria for SAEs 
or medically-attended AEs(see Sections 8.3 and 8.3.8, respectively).
Table 9
Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic 
Pain at the site of the injection 
Fever (> 100 °F/37.8 °C)
Redness/erythema at the site of the injection
Chills
Tenderness at the site of the injection
Muscle pains
Induration/swelling at the site of the injection 
Fatigue (physical or mental tiredness/exhaustion)
-
Headache
-
Malaise (general feeling of discomfort or uneasiness)
-
Nausea
-
Vomiting

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Solicited AE e-Diary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given an oral thermometer, tape measure or ruler, and access to the 
Solicited AE e-Diary, with instructions on use, along with the emergency 24-hour telephone 
number to contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms. 
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorized representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix D.  Because 
solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention. 
8.3.8 COVID-19 Assessment
This study will describe the incidence of  COVID-19 adverse events reported from Day 1 to 
180 days after the participant’s last/only dose of vaccine.
COVID-19 is defined as SARS-CoV 2-RT-PCR positive symptomatic illness.  At all clinic 
visits following the initial vaccination, participants will be asked if they have had a diagnosis 
of COVID-19 since their last clinic visit (see Schedule of Activities in Section 1.3). Medical 
records will be obtained for confirmation of a patient-reported diagnoses of COVID-19.  
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea.  Events will be reported as AEs/SAEs.
If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed 
using RT-PCR.
8.3.9 Medically-Attended Adverse Events
Medically-attended AEs will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3).
Medically-attended AEs are defined as AEs leading to medically-attended visits that were not 
routine visits for physical examination or vaccination, such as an emergency room visit, or an 
otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. 
AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
illness visits will not be considered medically-attended AEs.

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8.3.10
Adverse Events of Special Interest
AEs of special interest will be collected according to the timepoints specified in the Schedule 
of Activities (Section 1.3). 
AEs of special interest are events of scientific and medical interest specific to the further 
understanding of study intervention safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor.  AEs of special interest are based on 
Brighton Collaboration case definitions (SPEAC 2020), clinical experience, and scientific 
interest.  A list of events is provided in Appendix E.
An AE of special interest can be serious or non-serious.  All AEs of special interest will be 
recorded in the eCRF.  If any AE of special interest occurs in the course of the study, 
investigators or other site personnel will inform the appropriate Sponsor representatives within 
1 day ie, immediately but no later than 24 hours of when he or she becomes aware of it.  
Serious AEs of special interest will be recorded and reported as per Section 8.3.11.
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest
The investigator should remain vigilant for the occurrence of thrombotic events with 
thrombocytopenia and/or bleeding.  If a participant experiences new onset thromboembolic 
events with thrombocytopenia, there should be prompt evaluation with a thorough 
haematological investigation.  COVID-19 testing, including PCR and serology (nucleoprotein 
antibodies), should also be performed.  See Appendix F for further guidance on investigation 
and management of suspected events.
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and whole genome 
sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events.
8.3.10.2
Potential Neurological Adverse Events of Special Interest
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation, including referral to a neurology specialist for further 
evaluation and testing, as clinically indicated.  Testing can include evaluation for peripheral 
demyelinating conditions (eg, electromyography).  In cases of concern for spinal cord disease, 
see Figure 3 for a recommended testing algorithm. 

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An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AEs of special interest occurring 
in the AZD1222 clinical development program (see Appendix A 5).  

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Figure 3
Neurology Testing Algorithm
a
Adapted from Rovira et al 2015
Ab: antibody; ACE: angiotensin converting enzyme; ADC: apparent diffusion coefficient; ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibodies; AQP4: 
aquaporin 4; CMV: cytomegalovirus; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebral spinal fluid; CT: computed tomography; DWI: diffusion-weighted 
image; EBV: Epstein-Barr virus; ED: emergency department; ENA: extractable nuclear antigen antibodies; ESR: erythrocyte sedimentation rate; FLAIR: fluid-attenuated inversion 
recovery; GRE: gradient echo; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IgG: immunoglobulin G; MOG: myelin oligodendrocyte glycoprotein; MRI: 
magnetic resonance image; PCR: polymerase chain reaction; RF: rheumatoid factor; RPR: rapid plasma reagin; STIR: short T1 inversion recovery; SWI: susceptibility-weighted 
imaging; TSH: thyroid stimulating hormone; TM: transverse myelitis; VDRL: Venereal Disease Research Laboratories; VZV: varicella-zoster virus. 

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8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedures.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Sponsor representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 1 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available.
The Sponsor representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness is the AZD1222 Investigators 
Brochure, Section 5.6. 
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor, except if the pregnancy is discovered 
before the participant has received any study intervention.
8.3.12.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2).  Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the study intervention may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 

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spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the participant was discontinued 
from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.11) and within 30 days for all other pregnancies 
that are not associated with an SAEs.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module may be used to report the outcome of the pregnancy.
8.3.13
Medication Error
If a medication error occurs, then the investigator or other site personnel informs the 
appropriate Sponsor representatives within 1 day, ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 3. 
8.4
Overdose
For this study, any dose of study intervention exceeding that specified in the protocol will be 
considered an overdose.
There is no specific treatment for an overdose with AZD2816 or AZD1222.  If overdose 
occurs, the participant should be treated supportively with appropriate monitoring as 
necessary.

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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose occurs in the course of the study, the investigator or other site personnel inform 
appropriate Sponsor representatives immediately, but no later than 24 hours after when he or 
she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual.  Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality.  Further details on Handling of Human 
Biological Samples are provided in Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a 
maximum of 15 years following issue of the Clinical Study Report.  Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses, eg, exploratory immunology, such 
as systems serology and profiling of B- and T-cell repertoire.  The results from further 
analysis will not be reported in the Clinical Study Report.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).  Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual.  Results for exploratory immunogenicity analyses may 
be reported separately from the CSR.

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8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the Schedule of Activities (Section 1.3).  Authorized laboratories 
will assess serologic responses to AZD1222 and AZD2816 using validated (or qualified, 
where appropriate) assays.  Serologic assessment to the S protein from different SARS-CoV-2 
variants (which include Wuhan-Hu-1, B.1.351, B.1.1.7, and P.1) will be assessed 
quantitatively using a validated multiplexed ECL based immunoassay.  Additionally, 
seroresponse will be assessed for each antigen over time.  The rate of SARS-CoV-2 infection 
in participants receiving AZD2816 versus AZD1222 will be determined by seroconversion in 
a SARS-CoV-2 nucleocapsid antigen in a multiplexed electrochemiluminescence-based assay 
performed at an authorized laboratory. Additional exploratory assessments may be performed 
to measure binding antibodies to SARS-CoV-2 variants of interest (which may include 
B.1.429, B.1.525, B.1.526, P.2, P.3, B.1.617, and the Q677H mutation observed in multiple 
variants).
8.5.2.2
 
 
 
 
 
 
 
 
 
8.5.2.3
 
 
 
 
 
CCI
CCI
CCI
CCI

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8.5.2.4
 
 
 
 
 
 
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Already collected samples may be analysed for biomarkers thought to play a role in 
COVID-19 severity or outcomes based upon emerging immunogenicity and 
pharmacodynamic analysis from this or other studies involving the study interventions. These 
analyses include but are not limited to serum or plasma cytokines, quantification of RNA, 
micro-RNA, and/or non-coding RNA using quantitative reverse transcriptase polymerase 
chain reaction (RT-PCR), microarray, sequencing, or other technologies in blood, or 
peripheral blood mononuclear cells to evaluate their association with AZD1222/2816 and 
observed clinical responses to these study interventions.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
There is no statistical hypothesis testing planned for this study.  Descriptive analyses will 
support evaluation of safety, reactogenicity and immunogenicity.
9.2
Sample Size Determination
Primary Objective: Characterise Immunogenicity (Precision)
Historical data were available for the immunogenicity responses to AZD1222 from the pooled 
COV001/002/003/005 studies.  Table 10 presents the log transformed immunogenicity 
responses (ie, geometric mean titres) by assay for participants that received 2 standard doses 
CCI
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of AZD1222.  These results indicate that the pseudo-neutralising antibodies exhibited the 
largest variation (standard deviation of 1.20 and 1.10 for the 4-week and 12-week dosing 
intervals respectively), while live-neutralising antibodies had the lowest (standard deviation of 
0.72 for the 4-week dosing interval).
Table 10
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 4-
week dosing intervala
Post-2nd dose with a 12-
week dosing intervalb
Assay
N
Mean
Std Dev
N
Mean
Std Dev
N
Mean
Std Dev
Pseudo
476
4.3
1.34
166
5.3
1.20
113
5.4
1.10
Live
51
4.9
1.15
42
6.2
0.72
0
-
-
S protein
1139
9.1
1.14
293
10.1
0.96
302
10.7
0.83
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval
Table 11 presents the seroresponse (ie, > 4 fold increase from baseline) by assay.  These 
results indicate that the pseudo-neutralising antibodies exhibited the lowest proportion of 
seroresponse (59.7% and 85.5% for the 4-week and 12-week dosing intervals respectively), 
while both live-neutralising and spike-binding seroresponse rates exceeded 95%.
Table 11
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 4-week 
dosing intervala
Post-2nd dose with a 12-
dose week intervalb
Assay
N
Proportion
N
Proportion
N
Proportion
Pseudo
499
32%
382
59.7%
117
85.5%
Live
96
75%
95
96.8%
-
-
Spike
940
96.6%
636
95.9%
304
99.3%
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval 
Under the assumption that the immunogenicity responses (ie, geometric mean antibody titres) 
associated with AZD2816 will be similar to the responses associated with AZD1222 in 
participants that received 2 standard doses in the pooled COV001/002/003/005 studies, in 
which standard deviations ranged from 0.72 to 1.2 (Table 10), 150 participants will provide a 
95% confidence interval half-width between 0.115 and 0.192 (see Table 12).  Similarly, 300 
participants will provide a 95% confidence interval half-width between 0.081 and 0.136.

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Table 12
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes
Standard Deviation
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
0.72
150
0.115
300
0.081
0.83
150
0.133
300
0.094
0.96
150
0.154
300
0.109
1.1
150
0.176
300
0.124
1.2
150
0.192
300
0.136
Under the assumption that the seroresponse rates associated with AZD2816 will be similar to 
the response rates in adults that received 2 standard doses of AZD1222 in the pooled 
COV001/002/003/005 studies (Table 11), 150 participants will provide a 95% confidence 
interval half-width between 1.33% and 7.85%, and 300 participants will provide a 95% 
confidence interval half-width between 0.94% and 5.55% (Table 13). 
Table 13
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponses Rates based on Historic Seroconversion Rates and 
Proposed Sample Sizes
Observed 
seroconversion rate
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
59.7%
150
7.85%
300
5.55%
85.5%
150
5.63%
300
3.98%
95.9%
150
3.17%
300
2.24%
96.8%
150
2.82%
300
1.99%
99.3%
150
1.33%
300
0.94%

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For a fixed sample size, the precision with which the 95% confidence interval of the binary 
seroresponse rate can be estimated is a function of the response rate.  Table 13 provides the 
lower bounds of the 95% confidence interval for selected response proportions for alternate 
sample sizes.  For a given response rate, we can be 95% confident that the true seroresponse 
rate is at least as large as the lower bound of the confidence interval.
Primary Objective: Safety
Table 14 indicates the probability of observing 1 or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 
particular type for participants in each treatment arm.  With the sample size of 300 
participants, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 95%.
Table 14
Probability of detecting 1 or more safety events (N = 300)
Event Frequency
Probability (> 1 event)
≥ 10% (Very Common)
> 99%
≥ 1% (Common)
95%
≥ 0.1% (Uncommon)
26%
≥ 0.01% (Rare)
3%
Secondary Objective: Compare Immunogenicity
Although this study will describe and compare the immune responses between AZD2816 and 
AZD1222 for selected group pairs, no-formal non-inferiority margin for either the geometric 
mean titre ratio or the difference in seroresponse is prospectively defined. 
Under the assumption that there is no difference between treatment arms of interest (ie, a ratio 
of 1, difference on the log scale of 0), the power conferred by 150 and 300 participants 
respectively for the comparison of geometric mean titre ratio using a noninferiority margin of 
1.5 (equivalent to a difference on the log scale of 0.405) is presented in Table 15.

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Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
Sides
Null 
difference
Assumed 
mean 
treatment 
difference
Assumed 
standard 
deviation
N of 
participants in 
comparator 
group
N of 
participants 
in reference 
group
Alpha
Power
Upper
ln1.5 = 0.405
0
0.72
150
300
0.05
> 0.999
300
300
> 0.999
0.83
150
300
0.999
300
300
> 0.999
0.96
150
300
0.995
300
300
> 0.999
1.10
150
300
0.979
300
300
0.998
1.20
150
300
0.958
300
300
0.994
Similarly, if there is no difference between treatment arms of interest (ie, a ratio of 1) in the 
proportion of seroresponders, 300 participants provides 80% power for to establish non-
inferiority to within margin of -10% if the seroresponse rate is > 75%.  The observed pseudo-
neutralising response rates (> 4 fold increase from baseline) from the COV001/002/003/005 
studies for AZD1222 were 59.7% and 85.5% for the 4-week and 12-week dosing interval 
respectively (Table 11).  A population of 300 participants provides 70% power to detect non-
inferiority (using a non-inferiority margin of -10%) if the observed response rate is 59.7% 
(Table 16).

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Table 16
Power for Non-inferiority Using -10% as the Upper Bound of the 
Difference in Seroresponse Rate
Sides
Null 
proportion 
difference
Assumed 
proportion of 
seroresponders 
in both groups
Assumed 
difference in 
proportion of 
seroresponders 
N in 
comparator 
group
N in 
reference 
group
Alpha
Power
Lower
-0.1
0.597
0
150
300
0.05
0.665
300
300
0.805
0.855
150
300
0.904
300
300
0.963
0.959
150
300
0.999
300
300
> 0.999
0.968
150
300
> 0.999
300
300
> 0.999
0.993
150
300
> 0.999
300
300
> 0.999
9.3
Populations for Analyses
The following populations are defined:
Table 17
Populations for Analysis
Population
Description
All participants analysis set 
All participants screened for the study, to be used for reporting disposition and 
screening failures.
Seronegative full analysis 
set
All randomized seronegative participants who received at least 1 dose of study 
intervention, irrespective of their protocol adherence and continued participation in 
the study.  Participants will be analysed according to their randomized treatment 
irrespective of whether or not they have prematurely discontinued, according to the 
intent-to-treat principle.  Participants who withdraw consent to participate in the 
study will be included up to the date of their study withdrawal.
Safety analysis set
The safety analysis set consists of all participants (seropositive and seronegative at 
screening) who have received at least 1 dose of study intervention.  Erroneously-
treated participants (eg, those randomized to one treatment but actually received 
another treatment) are accounted for in this analysis set by assigning them to the 
treatment they actually received.  A participant who has on one or several occasions 
received active study intervention is classified as active for all summaries, including 
summaries by dose.  This will be the primary analysis set for all safety analyses.  

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Table 17
Populations for Analysis
Population
Description
Seronegative 
immunogenicity analysis set
The immunogenicity analysis population will include all seronegative participants 
in the safety analysis set who have no protocol deviations or intercurrent events 
judged to have the potential to interfere with the generation or interpretation of an 
immune response.  Examples of such protocol violations will be documented in the 
Statistical Analysis Plan.  This will be the primary analysis set for all 
immunogenicity analyses.
Participants that are SARS-CoV-2 seropositive at screening will be included in seropositive 
analysis sets analogous to the above seronegative analysis sets. Further definition is provided 
in the Statistical Analysis Plan.
9.4
Statistical Analyses
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints.  A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to the interim analyses.
An interim analysis will occur when all participants have completed their Day 29 visit (ie, 
28 days after first dose for all participants).  It is estimated that this early analysis has the 
potential to provide clear signals about whether AZD2816 provides a strong neutralizing 
response against the B.1.351 strain while retaining immunogenicity against the Wuhan strain, 
and thereby influence programmatic decisions early.  Sample size re-estimation may be 
performed at the interim analysis, full details of the methods and procedures are presented in 
the statistical analysis plan.
The primary analysis will occur when all participants have completed their Day 29 visit AND
safety and immunogenicity data from all previously unvaccinated participants randomized to a 
4-week dosing interval are available through completion of their visit 28 days after the second 
priming dose.
A secondary analysis will occur when all participants have completed their Day 29 visit AND
safety and immunogenicity data from all previously unvaccinated participants (including those 
randomized to a 12-week dosing interval) are available through completion of the visit 
28 days after the second priming dose. 
The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).

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To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.
9.4.1 General Considerations
An interim analysis will occur when all participants have completed their Day 29 visit (ie, 
28 days after first dose for all participants).  It is estimated that this early analysis has the 
potential to provide clear signals about whether AZD2816 provides a strong neutralizing 
response against the B.1.351 strain while retaining immunogenicity against the Wuhan strain, 
and thereby influence programmatic decisions early.  Sample size re-estimation may be 
performed at the interim analysis, full details of the methods and procedures are presented in 
the statistical analysis plan.
The primary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants randomized to a 4-week 
dosing interval are available through completion of their visit 28 days after the second priming 
dose.
A secondary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants (including those 
randomized to a 12-week dosing interval) are available through completion of the visit 28 
days after the second dose. 
The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).
To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.

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9.4.2 Safety
9.4.2.1
Primary Endpoints
Overview
Descriptive analyses will support evaluation of safety, reactogenicity and immunogenicity. 
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination will 
be summarised by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be summarised 
by system organ class and preferred term, and by relationship to vaccination as assessed 
by the investigator.
!
MAAEs, SAEs, and AESIs following the first vaccination and throughout the study 
duration will be summarised by system organ class and preferred term and by relationship 
to vaccination as assessed by the investigator. 
!
The change from baseline for safety laboratory measures at 7 and 28 days after 
vaccination.
AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities.  AEs will be presented for each treatment group by system organ class 
and preferred term.  Summaries will include the number and percentage of participants 
reporting at least one event, number of events and exposure adjusted rates, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs.  Summaries will present the relationship to 
study intervention as assessed by the investigator, maximum intensity, seriousness, and death.
A listing will cover details for each individual AE.  Full details of all AE analyses will be 
provided in the Statistical Analysis Plan, including intercurrent events for safety due to 
potential unblinding of participants for administration of licensed and/or approved SARS-
CoV-2 or COVID-19 vaccine.
At the time of the interim analysis, group assignment will not be presented when safety event 
data has the potential to unblind participant’s study group attribution.
9.4.2.2
Other Safety Endpoints
Vital Signs
Vital sign measurements will be performed as specified in the Schedule of Activities (Section 
1.3).  The set of assessments will include pulse oximetry, blood pressure, and body 
temperature.  

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Details of all vital sign analyses will be provided in the Statistical Analysis Plan, which will 
include descriptive statistics presented for observed values for all vital sign parameters. 
COVID-19
This study will describe the incidence of COVID-19 adverse events from the first dose of the 
vaccine to study end (180 days post-vaccination). Descriptive statistics will be produced 
based on the safety analysis set. Full details will be documented in the statistical analysis plan.
9.4.3
Immunogenicity
9.4.3.1
Immunogenicity Endpoints
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean antibody titre.
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean antibody titre from 
baseline
Both the geometric mean antibody titre and seroresponse of participants will be summarized 
descriptively by strain, treatment arm, and timepoint for the immunogenicity population.
9.4.3.1.1
Estimand framework for immunogenicity descriptions and comparisons
Target populations: 
1) Previously unvaccinated participants 
a.
Seronegative Analysis Set: and with no evidence of prior or current infection  
2) Participants who previously received SARS-CoV-2 vaccination with either AZD1222 
or a licensed mRNA vaccine according to the authorized dose and dosing regimen at 
least 3 months prior to first study intervention (see Section 5.1.2).
Outcome variable: neutralizing antibody and binding titres to SARS-CoV-2 at 28 days after 
each treatment administration (1 treatment administration for the previously vaccinated 
population and 2 planned treatment administrations for the unvaccinated population). 
Treatment conditions:
Previously unvaccinated population
!
2 doses of AZD1222 given on Day 1 and on Day 29 (4-week interval)
!
2 doses of AZD2816 given on Day 1 and on Day 29 (4-week dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 85 (12-week dosing interval)

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Previously vaccinated population
!
1 dose of AZD1222 given on Day 1. 
!
1 dose of AZD2816 given on Day 1. 
Intercurrent events: the following intercurrent events could impact the antibody levels 
achieved:  
!
missing the second vaccination (for the unvaccinated population)  
!
receiving of immune-modifying drugs or vaccines 
!
subsequent infection with SARS-CoV-2. 
All immunogenicity descriptions and comparisons will use the principal stratum strategy, 
ie, all analyses will exclude participants who experience any of the intercurrent events above
Population-level summary: 
Descriptive Analyses (see Table 19 and Table 20)
!
geometric means of the antibody titres 
!
seroresponse proportions
Comparative Analyses (see Table 21 and Table 22)
!
ratio of geometric means of the antibody titres.
!
difference in seroresponse proportion 
Planned Descriptive Analyses: 
Table 19 and Table 20 present planned descriptive immunogenicity analyses for the 
unvaccinated and previously vaccinated populations respectively (each one exploring an 
individual treatment arm at a specific timepoint against a particular strain). 
The tables show that without introduction of further variants, there are 24 planned descriptive 
analyses for the unvaccinated population and 16 planned descriptive analyses for the 
previously immunised population (index).  Within each table there is an analysis key which 
describes the population (see Table 18). The descriptive analyses presented in Tables 19 and 
20 will be repeated for the subset of participants who are seropositive at screening.

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Table 18
Description of the Analysis Keys for Tables 19 and 20
Population
Analysis Key
Example
Previously 
unvaccinated
Primary series dosing interval: 
    P4 (4-week dosing interval) or
    P12 (12-week dosing interval)
Treatment received: 
    1222 (2 doses of AZD1222) or 
    2816 (2 doses of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
Analysis Timepoint:
   1 (28 days post-dose 1)
   2 (28 days post-dose 2)
[P4:1222:W:1] = Immunogenicity 
following primary vaccination 
with a 4-week dosing interval of 
2 doses of AZD1222 against 
Wuhan-Hu-1 28 days post-dose 1
Previously vaccinated
Pre-study primary vaccination: 
    P1222 (2 doses of AZD1222) or
    PmRNA (2 doses of an mRNA vaccine)
Treatment received: 
    B1222 (1 booster dose of AZD1222) or 
    B2816 (1 booster dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
[P1222:B1222:V] = 
Immunogenicity in participants 
who were previously vaccinated 
with 2 doses of AZD1222 as 
primary vaccination series and 
received a single boost dose of 
AZD1222 against the B.1.351 
variant 

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Table 19
Immunogenicity Descriptive Analysis for Previously Unvaccinated Treatment Groups (with Separate 
Seronegative and Seropositive Analyses)
Objective
Treatment
Dosing 
interval
Strain
Timepoint
Endpoint
Index
Analysis Key
To describe the humoral immune response 
against the B.1.351 and Wuhan-Hu-1 variant 
strains induced by a 2-dose primary vaccination 
with AZD1222 with a 4-week interval in 
unvaccinated participants
AZD1222
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
1
[P4:1222:W:1]
Seroresponse
2
28 days after 2nd dose
GMT
3
[P4:1222:W:2]
Seroresponse
4
B.1.351
28 days after 1st dose
GMT
5
[P4:1222:V:1]
Seroresponse
6
28 days after 2nd dose
GMT
7
[P4:1222:V:2]
Seroresponse
8
To assess the humoral immune response against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
a 2-dose primary vaccination with AZD2816 
with a 4-week dosing interval in unvaccinated 
participants
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
9
[P4:2816:W:1]
Seroresponse
10
28 days after 2nd dose
GMT
11
[P4:2816:W:2]
Seroresponse
12
B.1.351
28 days after 1st dose
GMT
13
[P4:2816:V:1]
Seroresponse
14
28 days after 2nd dose
GMT
15
[P4:2816:V:2]
Seroresponse
16
To describe the humoral immune response 
against the B.1.351 and Wuhan-Hu-1 variant 
strains induced by a 2-dose primary vaccination 
with AZD2816 with a 12-week interval in 
unvaccinated participants
AZD2816
12 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
17
[P12:2816:W:1]
Seroresponse
18
28 days after 2nd dose
GMT
19
[P12:2816:W:2]
Seroresponse
20
B.1.351
28 days after 1st dose
GMT
21
[P12:2816:V:1]
Seroresponse
22
28 days after 2nd dose
GMT
23
[P12:2816:V:2]
Seroresponse
24
GMT: Geometric mean titre

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Table 20
Immunogenicity Descriptive Analysis for Previously Vaccinated Treatment Groups (with Separate 
Seronegative and Seropositive Analyses)
Objective
Primary 
vaccination
Booster 
Treatment
Strain
Timepoint
Endpoint
Index
Analysis Key
To assess the humoral immune response 
against the B.1.351 and Wuhan-Hu-1 strains 
induced by 1 dose of AZD1222 in 
participants previously vaccinated with 2 
doses of AZD1222
AZD1222
AZD1222
Wuhan-Hu-1
28 days after booster dose
GMT
1
[P1222:B1222:W]
Seroresponse
2
B.1.351
28 days after booster dose
GMT
3
[P1222:B1222:V]
Seroresponse
4
To assess the humoral immune response 
against the B.1.351 and Wuhan-Hu-1 
strains induced by 1 dose of AZD2816 in 
participants previously vaccinated with 
2-doses of AZD1222
AZD2816
Wuhan-Hu-1
28 days after booster dose
GMT
5
[P1222:B2816:W]
Seroresponse
6
B.1.351
28 days after booster dose
GMT
7
[P1222:B2816:V]
Seroresponse
8
To assess the humoral immune response 
against the B.1.351 and Wuhan-Hu-1 strains 
induced by 1 dose of AZD2816 in 
participants previously vaccinated with 2-
doses of a SARS-CoV-2 mRNA vaccine
mRNA
AZD2816
Wuhan-Hu-1
28 days after booster dose
GMT
9
[PmRNA:B2816:W]
Seroresponse
10
B.1.351
28 days after booster dose
GMT
11
[PmRNA:B2816:V]
Seroresponse
12
GMT: Geometric mean titre

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In addition to descriptive immunogenicity assessments for all treatment arms, geometric mean 
titre ratios and differences in seroresponse will be evaluated for the pairs of groups as detailed 
in Table 21 and Table 22.  For each pair, the two-sided 95% confidence intervals for the ratio 
of the geometric mean titre and difference in seroresponse will be calculated.  The geometric 
mean titre ratio assume a normal distribution for the natural log of the concentration.  All 
confidence intervals will be unadjusted for multiple analyses and are provided solely as a 
guide to clinical and scientific judgment.  It is acknowledged that the chance of falsely 
concluding that one or more differences in immunogenicity outcomes exist will be greater 
than the nominal two-sided 0.05 level used for each individual comparison.
Table 21
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
To evaluate the immune response 
against the B.1.351 and Wuhan-Hu-1 
variant strain elicited by a primary 
2-dose vaccination with AZD2816 with 
a 4-week dosing interval relative to the 
response elicited by a primary 2-dose 
vaccination with AZD1222 with a 
4-week interval in previously 
unvaccinated seronegative participants
[P4:2816: V: 2]
[P4:1222: W:2]
[P4:2816: V: 2] −[P4:1222: W:2]
[!4: 2816: V: 1]
[!4: 1222: W:1]
[P4:2816: V: 1] −[P4:1222: W:1]
[P4:2816: W:2]
[P4:1222: W:2]
[P4:2816: W:2] −[P4:1222: W:2]
[P4:2816: W:1]
[!4: 1222: W:1]
[P4:2816: W:1] −[P4:1222: W:1]
[P4:2816: V: 2]
[P4:1222: V: 2]
[P4: 2816: V: 2] −[P4:1222: V: 2]
[!4: 2816: V: 1]
[!4: 1222: V: 1]
[P4: 2816: V: 1] −[P4:1222: V: 1]
To evaluate the immune responses 
against the B.1.351 variant strain and 
the Wuhan-Hu-1 strain elicited by a 
2-dose primary vaccination with 
AZD2816 with a 12-week dosing 
interval relative to the response elicited 
by a 2-dose primary vaccination with 
AZD2816 with a 4-week interval in 
previously unvaccinated seronegative 
participants
[P12:2816: W:2]
[P4:2816: W:2]
[P12:2816: W:2] −[P4:2816: W: 2]
[!12:2816: W:1]
[!4: 2816: W:1]
[P12:2816: W:1] −[P4:2816: W: 1]
[!12:2816: V: 2]
[!4: 2816: V: 2]
[P12:2816: V: 2] −[P4:2816: V: 2]
[!4: 2816: V: 2]
[!4: 2816: V: 2]
[P12:2816: V: 1] −[P4:2816: V: 1]
[!12:2816: V: 1]
[!4: 1222: V: 1]
[P12:2816: V: 1] −[P4:1222: V: 1]

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Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
To evaluate the immune responses against 
the B.1.3.51 variant strain and Wuhan-Hu-
1 strain elicited by 1 dose of AZD2816 in 
seronegative participants previously 
vaccinated with 2 doses of AZD1222 
relative to the response elicited by a 
2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in
seronegative unvaccinated participants
[P1222:B2816: V]
[P4:1222: W]
[P1222: B2816:V] −[P4:1222: W]
[P1222:B2816: W]
[P4: 1222: W]
[P1222:B2816: W] −[P4: 1222: W]
To evaluate the immune responses 
against the B.1.351 variant strain and 
Wuhan-Hu-1 strain elicited by 1 dose of 
AZD2816 in seronegative participants 
previously vaccinated with 2 doses of a 
SARS-CoV-2 mRNA vaccine relative to 
the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-
week dosing interval in seronegative
unvaccinated participants
[PmRNA:B2816: V]
[P4:1222:W]
[PmRNA:B2816: V] −[P4:1222:W]
[PmRNA:B2816: W]
[P4:1222: W]
[PmRNA:B2816: W] −[P4:1222: W]
To evaluate the immune response against 
the B.1.351 and Wuhan-Hu-1 variant 
strain elicited by 1 dose of AZD2816 in 
seronegative participants previously 
vaccinated with a mRNA vaccine 
relative to the response with 1 dose of 
AZD1222 in seronegative participants 
previously vaccinated with 2 doses of 
AZD1222
[PmRNA:B2816: V]
[P1222:B1222: W]
[PmRNA:B2816:V] −[P1222:B1222: W]
[PmRNA:B2816: W]
[P1222: B1222:W]
[PmRNA:B2816: W] −[P1222: B1222:W]
[PmRNA:B2816: V]
[P1222: B1222:V]
[PmRNA:B2816: V] −[P1222: B1222:V]
To evaluate the  immune responses 
against the B.1.351 variant strain and the 
Wuhan-Hu-1 strain elicited by 
1 dose of AZD2816 relative to the 
response with 1 dose of AZD1222 in 
seronegative participants previously 
vaccinated with 2 doses of AZD1222
[P1222:B2816: V]
[P1222:B1222: W]
[P1222:B2816: V] −[P1222: B1222:W]
[P1222:B2816: W]
[P1222:B1222: W]
[P1222: B2816:W] −[P1222:B1222: W]
[P1222:B2816: V]
[P1222:B1222: V]
[P1222: B2816: V] −[P1222:B1222: V]

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9.4.4
Data Safety Monitoring Board
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, to 
ensure safe and ethical conduct of the study.  During the study, the benefit/risk assessment 
will be continuously monitored by the Board to ensure that the balance remains favourable.  
Further details, composition, and operation of the COVID-19 Vaccine Data Safety Monitoring 
Board will be described in a separate charter. For further details, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Not applicable.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
∀
Applicable ICH/GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigators Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority.  This responsibility may be delegated to 
a contract research organization but the accountability remains with the Sponsor.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH/GCP guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all Food and 
Drug Administration (FDA) Regulations, as applicable and all other applicable local 
regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study.  Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH/GCP guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
!
The study medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples.  The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use.  Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

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!
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law.  The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committee Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A COVID-19 Vaccine Data Safety Monitoring Board comprised of independent experts will 
be convened to provide oversight and to ensure safe and ethical conduct of the study.  The 
COVID 19 Vaccine Data Safety Monitoring Board will have the responsibility of evaluating 
cumulative safety and other clinical study data at regular intervals and making appropriate 
recommendations based on the available data.  During the study, the benefit/risk assessment 
will be continuously monitored by the COVID-19 Vaccine Data Safety Monitoring Board to 
ensure that the balance remains favourable.  Full details of the COVID-19 Vaccine Data 
Safety Monitoring Board composition and operations can be found in the COVID-19 Vaccine 
Data Safety Monitoring Board Charter.
An independent Neurological AESI Expert Committee will be available to review and provide 
on request about the diagnosis and causality assessment of selected neurological AEs of 
special interest occurring in the study.  Details on the composition and operation of this 
committee are described in the Neurological AESI Expert Committee Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available.  The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

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!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
!
Study monitors will perform ongoing source data review to confirm that data entered into 
the eCRF by authorized site personnel are accurate and complete, that the safety and 
rights of participants are being protected, and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH/GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or ICH/GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both SAEs and non-SAEs and can include a deterioration of a 
pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs.  
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used.  
In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a non-
SAE.  For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur.  Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as non-serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  
Examples of important medical events include such events as listed below:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Intensity Rating Scale
A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events with 
an assigned severity grading including Grade 5.  
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 

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intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the investigational product.
!
Time Course.  Exposure to suspect drug.  Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect investigational product?
!
Consistency with known investigational product profile.  Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or drugs of the same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational medicinal product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.

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Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the investigational product, but rather a human or 
process related failure while the investigational product is in control of the study site staff or 
participant.
Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the investigational product
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Investigational product name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration
!
Investigational product not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Investigational product not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong participant received the medication (excluding IRT errors)
!
Wrong investigational product administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from 
the participants while in storage at the study site until shipment or disposal (where 
appropriate) and records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
The Sponsor or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
The Sponsor ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented.  If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and the Sponsor are informed about the sample disposal.

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The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus.  Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814.  Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
!
Table 23: Clinical Abnormalities, Local Reactions to Injectable Product
!
Table 24: Clinical Abnormalities, Vital Signs
!
Table 25: Clinical Abnormalities, Systemic (General or Illness)
Table 23
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalization
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded.
b
Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE e-Diary.
ER: emergency room.

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Table 24
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)a
Fever (°C/°F)
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
Emergency room visit 
or hospitalization for 
arrhythmia
Bradycardia 
(beats/minute)
50-54
45-49
< 45
Emergency room visit 
or hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
Emergency room visit 
or hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes.

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Table 25
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic 
(General)
Systemic Gradea
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/
vomiting
No interference with 
activity or 
1-2 episodes/24 hours
Some interference 
with activity or 
> 2 episodes/24 hours
Prevents daily activity, 
required outpatient 
intravenous hydration
Emergency room 
visit or 
hospitalization for 
hypotensive shock
Chills
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
Emergency room 
visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Systemic Illness
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations)
No interference with 
activity
Some interference 
with activity not 
requiring intervention
Prevents daily activity 
and required medical 
intervention
Emergency room 
visit or 
hospitalization

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Appendix E
Adverse Events of Special Interest
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 26
Adverse Events of Special Interest
Category
Medical Concept
Neurologic
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment or 
loss of consciousness.  
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis.
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population.
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (eg, weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, or other 
sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate.
Hematologic
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL.
Immunologic
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention.
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non-neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: a group of autoimmune inflammatory disorders 
characterized by an alteration in cellular homeostasis, which may or may not have an 
autoimmune aetiology.  A list of events is provided in Table 27. 

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune haemolytic anaemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anaemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Actions Required in Cases of any Thrombotic Events With 
Thrombocytopenia and/or Bleeding
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombotic events with thrombocytopenia and/or bleeding.  It is not intended to 
be a comprehensive guide to the management of all venous thromboembolic events.  
During the course of the study, the investigator will remain vigilant for occurrence of 
thrombotic events with thrombocytopenia and/or bleeding.  Appropriate investigations (eg, 
imaging) to diagnose these events should be made on a case-by-case basis.  The investigator is 
responsible for determining whether a participant meets criteria for thrombotic events with 
thrombocytopenia and/or bleeding at any point during the study.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombotic events with thrombocytopenia 
and/or bleeding.  The Study Physician contacts the investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data.  
Guidance from the International Society of Thrombosis and Haemostasis for management of 
thrombocytopenic thromboembolism occurring after vaccination can be found at 
www.isth.org.  Notably, participants should only be treated with heparin if a test for heparin-
induced thrombocytopenia antibodies is negative.  An alternative explanation for 
thrombocytopenia should be considered (eg, alcohol use, liver cirrhosis, concomitant 
medications, exposure to toxic chemicals, viral infections).
The investigator is responsible for recording data pertaining to thrombotic events with 
thrombocytopenia and/or bleeding and for reporting AEs and SAEs according to the outcome 
of the review and assessment in line with standard safety reporting processes.
F 2
Tests that Should Be Considered if Thrombotic Events With 
Thrombocytopenia and/or Bleeding Are Suspected
The following tests should be considered, but not limited to:
1. Measurement of platelet levels, prothrombin time, activated partial thromboplastin time, 
D-dimer levels, and fibrinogen levels
2. Complete blood count, reticulocyte count, blood film, haptoglobins
3. Anti-platelet factor 4 antibodies

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4. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, human 
leucocyte antigen B27, ADAMTS13 activity, anti-cardiolipin antibodies IgG + IgM, and 
anti-B2GPI antibodies IgG + IgM
5. Complement (eg, C3, C4, complement complex C5b-9, C5a), autoantibodies (eg, 
antinuclear IgG, anti-double stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG)
6. Factor V Leiden, Factor II (prothrombin) variant 
7. Platelet activation markers and functional assays (eg: sCD40L, soluble glycoproteins, 
degranulation markers [PF4, vWF, P-selectin, annexin V]), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 ELISA positive)
8. Inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13
9. Cell adhesion molecules: VCAM, ICAM, E-selectin
10. Adenovirus serology
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Ebstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19
12. COVID-19 testing, including PCR and serology
13. Calculation of an International Society of Thrombosis and Haemostatis score for 
Disseminated Intravascular Coagulation (derived from platelet levels, fibrinogen, and D-
Dimer)

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ChAdOx1 MERS
Chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
AZD1222 when initially developed by the University of Oxford
COVID-19
Coronavirus disease 2019
eCRF
electronic case report form
e-Diary
electronic diary
GMT
Geometric mean titre
ICF
Informed consent form
ICH/GCP
International Council for Harmonisation/Good Clinical Practice
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
MAAEs
Medically attended adverse events
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
S
Spike
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome-coronavirus-2

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Appendix H
Protocol Amendment History
Not applicable.

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11
REFERENCES
Dejnirattisai et al 2021
Dejnirattisai W, Zhou D, Supasa P, Liu C, Mentzer AJ, et al. Antibody evasion by the 
Brazilian P.1 strain of SARS-CoV-2. Cell 2021;184:1-16.
EMA 2021
European Medicines Agency. Reflection paper on the regulatory requirements for vaccines 
intended to provide protection against variant strain(s) of SARS-CoV-2 (EMA/117973/2021), 
February 2021. Available at: https://www.ema.europa.eu/en/regulatory-requirements-
vaccines-intended-provide-protection-against-variant-strains-sars-cov-2.
FDA 2007
US Food and Drug Administration. Guidance for Industry. Toxicity grading scale for healthy 
adult and adolescent volunteers enrolled in preventive vaccine clinical trials, Sept 2007.
Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-
preventive-vaccine-clinical.
FDA 2021
US Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent 
COVID-19: Guidance for Industry, February 2021. Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-
authorization-vaccines-prevent-covid-19.
Folegatti et al 2020
Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A et al. Safety and 
immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored 
vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, Phase 1 trial. Lancet 
Infect Dis 2020;20:816-26.
Lu et al 2020
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology 
of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 
2020;395(10224):565-74. 
Madhi et al 2021
Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AK, Fairlie L, et al. Efficacy of the 
ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Eng J Med 2021.
Ramasamy et al 2020
Ramasamy MN, Voysey M, Aley PK, Bibi S, Clutterbuck EA, et al. Safety and 
immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in 

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young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. 
Lancet 2020; 396(10267):1979-93.
Rovira et al 2015
Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP et al. MAGNIMS 
consensus guidelines on the use of MRI  multiple sclerosis—clinical implementation in the 
diagnostic process. Nature Rev Neurolog 2015;11(8):471-82.
SPEAC 2020
Safety Platform for Emergency Vaccines. D2.3 Priority list of adverse events of special 
interest: COVID-19. Work Package: WP2 Standards and Tools. v1.1. Available from: 
https://media.tghn.org/articles/COVID-19_AESIs_SPEAC_V1.1_5Mar2020.pdf.
Voysey et al 2021a
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al. Safety and efficacy of 
the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four 
randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397:99-111.
Voysey et al 2021b
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al.  Single-dose 
administration and the influence of the timing of the booster dose on immunogenicity and 
efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised 
trials. Lancet 2021;397:881-91.
Wang et al 2021
Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
B.1.1.7. Nature 2021;593:130-5.
Zhou et al 2020
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus 
of probable bat origin. Nature 2020;579:270-3.
Zhou et al 2021
Zhou D, Dejnirattisai W, Supasa P, Liu C, Mentzer AJ, Ginn HM, et al. Evidence of escape of 
SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 2021;189:1-14.

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Clinical Study Protocol
Study Intervention
AZD2816
Study Code
D7220C00001
Version
Amendment 1
Date
2 June 2021
TITLE PAGE
A Phase II/III Partially Double-Blinded, Randomised, Multinational, 
Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults to 
Determine the Safety and Immunogenicity of AZD2816, a Vaccine for the Prevention 
of COVID-19 Caused by Variant Strains of SARS-CoV-2
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
EudraCT: 2021-002530-17
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Number: D7220C00001
Amendment Number: 1
Study Intervention: AZD2816
Study Phase: II/III
Short Title: Phase II/III Study of AZD2816, a Vaccine for the Prevention of COVID-19 in 
Adults
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator:  Andrew J Pollard, FRCPCH PhD FMedSci
           University of Oxford
            Oxford, United Kingdom

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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment 1: 2 June 2021
Version 1 of the protocol was amended prior to the commencement of the study (ie, prior to 
approval of the protocol by an ethics committee) based on feedback from internal and 
regulatory authority reviews.  The most substantial changes were as follows:
!
addition of 2 treatment arms:  1) AZD1222 as a single booster vaccination in participants 
previously vaccinated with an mRNA COVID-19 vaccine and 2) heterologous 
vaccination with AZD1222 plus AZD2816 in previously unvaccinated participants
!
further definition of analysis sets
!
addition of thrombotic events with thrombocytopenia as a discontinuation criteria
In addition, corrections and revisions to text to improve readability were made.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................. 3
TABLE OF CONTENTS...................................................................................................... 4
1
PROTOCOL SUMMARY................................................................................ 10
1.1
Synopsis ........................................................................................................... 10
1.2
Schema............................................................................................................. 16
1.3
Schedule of Activities....................................................................................... 17
2
INTRODUCTION............................................................................................ 23
2.1
Study Rationale ................................................................................................ 23
2.2
Background ...................................................................................................... 23
2.3
Benefit/Risk Assessment................................................................................... 26
2.3.1
Risk Assessment............................................................................................... 26
2.3.2
Benefit Assessment........................................................................................... 27
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 27
3
OBJECTIVES AND ENDPOINTS................................................................... 28
4
DESIGN........................................................................................................... 34
4.1
Overall Design.................................................................................................. 34
4.1.1
COVID-19 Assessments ................................................................................... 35
4.1.2
Screening.......................................................................................................... 35
4.1.3
Vaccination Visit .............................................................................................. 36
4.1.4
Follow-up visits................................................................................................ 36
4.2
Scientific Rationale for Study Design ............................................................... 37
4.2.1
Rationale for Study Design and Participant Population ..................................... 37
4.2.2
Rationale for Study Endpoints .......................................................................... 37
4.3
Justification for Dose........................................................................................ 39
4.4
End of Study Definition.................................................................................... 39
5
STUDY POPULATION ................................................................................... 40
5.1
Inclusion Criteria .............................................................................................. 40
5.1.1
All Participants:................................................................................................ 40
5.1.2
Previously COVID-19 Vaccinated Participants................................................. 42
5.2
Exclusion Criteria ............................................................................................. 42
5.3
Lifestyle Considerations ................................................................................... 44
5.4
Screen Failures ................................................................................................. 44
6
STUDY INTERVENTION............................................................................... 44
6.1
Study Interventions Administered..................................................................... 45
6.1.1
Investigational Products.................................................................................... 45
6.1.2
Dosing Instructions........................................................................................... 46

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6.2
Preparation/Handling/Storage/Accountability ................................................... 46
6.2.1
Dose Preparation and Administration................................................................ 47
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 47
6.3.1
Randomization.................................................................................................. 47
6.3.2
Blinding............................................................................................................ 48
6.3.3
Procedures for Unblinding ................................................................................ 49
6.4
Study Intervention Compliance......................................................................... 49
6.5
Concomitant Therapy........................................................................................ 49
6.5.1
Permitted Concomitant Medications ................................................................. 49
6.5.2
Prohibited Concomitant Medications ................................................................ 50
6.6
Dose Modification ............................................................................................ 51
6.7
Intervention After the End of the Study............................................................. 51
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 51
7.1
Discontinuation of Study Intervention............................................................... 51
7.2
Participant Withdrawal from the Study ............................................................. 52
7.3
Lost to Follow-up ............................................................................................. 52
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 53
8.1
Efficacy Assessments........................................................................................ 53
8.2
Safety Assessments........................................................................................... 53
8.2.1
Physical Examinations...................................................................................... 53
8.2.2
Vital Signs........................................................................................................ 54
8.2.3
Clinical Laboratory Assessments ...................................................................... 54
8.3
Adverse Events and Serious Adverse Events..................................................... 55
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse
Event Information............................................................................................. 55
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 56
8.3.3
Causality Collection.......................................................................................... 57
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 57
8.3.5
Adverse Events Based on Examinations and Tests............................................ 57
8.3.6
Hy’s Law.......................................................................................................... 57
8.3.7
Solicited Adverse Events .................................................................................. 58
8.3.8
COVID-19 Assessment..................................................................................... 59
8.3.9
Medically-Attended Adverse Events................................................................. 59
8.3.10
Adverse Events of Special Interest.................................................................... 59
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest ................................ 60
8.3.10.2
Potential Neurological Adverse Events of Special Interest ................................ 60
8.3.11
Reporting of Serious Adverse Events................................................................ 62
8.3.12
Pregnancy......................................................................................................... 62
8.3.12.1
Maternal Exposure............................................................................................ 62
8.3.13
Medication Error............................................................................................... 63
8.4
Overdose .......................................................................................................... 63
8.5
Human Biological Samples............................................................................... 64

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8.5.1
Pharmacokinetics.............................................................................................. 64
8.5.2
Immunogenicity Assessments ........................................................................... 64
8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 65
8.5.2.2
8.5.2.3
8.5.2.4
8.5.3
Pharmacodynamics........................................................................................... 66
8.6
Human Biological Sample Biomarkers ............................................................. 66
8.7
Optional Genomics Initiative Sample................................................................ 66
8.8
Medical Resource Utilization and Health Economics ........................................ 66
9
STATISTICAL CONSIDERATIONS............................................................... 66
9.1
Statistical Hypotheses....................................................................................... 66
9.2
Sample Size Determination............................................................................... 66
9.3
Populations for Analyses .................................................................................. 71
9.4
Statistical Analyses........................................................................................... 72
9.4.1
General Considerations..................................................................................... 72
9.4.2
Safety ............................................................................................................... 73
9.4.2.1
Primary Endpoints ............................................................................................ 73
9.4.2.2
Other Safety Endpoints..................................................................................... 74
9.4.3
Immunogenicity................................................................................................ 74
9.4.3.1
Immunogenicity Endpoints ............................................................................... 74
9.4.4
Data Safety Monitoring Board .......................................................................... 81
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 81
11
REFERENCES............................................................................................... 104
CCI
CCI
CCI

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LIST OF TABLES
Table 1
Schedule of Activities: Screening ............................................................ 17
Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine . 18
Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 4-Week Dosing 
Interval.................................................................................................... 19
Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 12-Week 
Dosing Interval........................................................................................ 21
Table 5
Study Objectives and Endpoints............................................................... 28
Table 6
Highly Effective Methods of Contraception............................................. 41
Table 7
Investigational Products........................................................................... 45
Table 8
Laboratory Safety Variables..................................................................... 54
Table 9
Predefined Solicited Adverse Events for Reactogenicity Assessment....... 58
Table 10
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)...... 67
Table 11
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set) .......................... 67
Table 12
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes........... 68
Table 13
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroconversion Rates and 
Proposed Sample Sizes ............................................................................ 68
Table 14
Probability of detecting 1 or more safety events (N = 300)....................... 69
Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the
Geometric Mean Titre Ratio .................................................................... 70
Table 16
Power for Non-inferiority Using -10% as the Upper Bound of the 
Difference in Seroresponse Rate .............................................................. 71
Table 17
Populations for Analysis .......................................................................... 71
Table 18 
Description of the Analysis Keys for Tables 19 and 20 ............................ 76
Table 19
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 77

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Table 20
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 78
Table 21
Immunogenicity Comparisons for Previously Unvaccinated Groups........ 79
Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups............ 80
Table 23
Tables for Clinical Abnormalities: Local Reactions to Injectable Product 93
Table 24
Tables for Clinical Abnormalities: Vital Signs......................................... 94
Table 25
Tables for Clinical Abnormalities: Systemic (General or Illness) ............. 95
Table 26
Adverse Events of Special Interest........................................................... 96
Table 27
List of Potential Immune-mediated Medical Conditions........................... 97
LIST OF FIGURES
Figure 1
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants.............................................................................................. 16
Figure 2
Study Design for Unvaccinated Seronegative/Seropositive Participants ... 17
Figure 3
Neurology Testing Algorithm .................................................................. 61

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 82
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 87
Appendix C
Handling of Human Biological Samples .................................................. 91
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ............................. 93
Appendix E
Adverse Events of Special Interest........................................................... 96
Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding ....................................................... 100
Appendix G
Abbreviations ........................................................................................ 102
Appendix H
Protocol Amendment History................................................................. 103

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A phase II/III partially double-blinded, randomised, multinational, active-
controlled study in both previously vaccinated and unvaccinated adults to determine the safety 
and immunogenicity of AZD2816, a vaccine for the prevention of COVID-19 caused by 
variant strains of SARS-CoV-2.
Short Title: Phase II/III study of AZD2816, a vaccine for the prevention of COVID-19 in 
adults.
Rationale: Recently, several variants of the SARS-CoV-2 virus with increased
transmissibility have emerged, including B.1.1.7, first identified in the UK, P.1, first identified 
in Brazil, and B.1.351, first identified in South Africa.  In an ongoing clinical trial of 
AZD1222 in South Africa, interim results failed to show protection against mild to moderate 
disease caused by the B.1.351 variant; protection against severe disease could not be 
determined as no severe cases were identified (Madhi et al 2021). 
Based on available evidence about vaccine effectiveness and molecular epidemiology of 
emerging variants, B.1.351 is estimated to have a potential to escape vaccine-induced 
immunity. B.1.351 carries sequence mutations in common with other variants of concerns; 
immunity to B.1.351 therefore has the potential to provide some cross-immunity against other 
emerging strains. Development of candidate vaccines that include the B.1.351 S-protein 
variant is underway.  AstraZeneca is developing AZD2816, a vaccine against the B.1.351 
SARS-CoV-2 variant using the same ChAdOx1 platform and manufacturing processes used 
for AstraZeneca’s currently available COVD-19 vaccine, AZD1222.
Objectives and Endpoints:
The purpose of this study is to demonstrate the safety and characterize the immunogenicity of 
AZD2816, AstraZeneca’s candidate ChAdOx1 vector vaccine against SARS-CoV-2 variant 
strain B.1.351, when administered:
!
As a single dose to SARS-CoV-2 seronegative individuals who previously received 
a 2-dose primary vaccination against SARS-CoV-2 with AZD1222 or an mRNA 
COVID-19 vaccine
!
As a 2-dose primary homologous vaccination to SARS-CoV-2 seronegative 
individuals who are unvaccinated
!
As the second dose of 2-dose primary heterologous vaccination (with AZD1222 
as first dose) to SARS-CoV-2 seronegative individuals who are unvaccinated.
The following table lists the primary and secondary endpoints:

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Objectives
Endpoints
Safety Objectives
- Primary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination

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To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD1222 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a heterologous 2-dose primary vaccination with 
1 dose of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD1222 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary heterologous vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
- Primary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)

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1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres 
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD1222 with a 
4-week interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
heterologous 2-dose primary vaccination with 1 dose 
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
12-week interval in unvaccinated seronegative
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (comparative)
Previously vaccinated seronegative participants receiving 1 dose versus unvaccinated seronegative participants 
receiving 2 doses
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres

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AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week dosing 
interval in unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week dosing 
interval in unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Previously vaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 relative to the response with 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with an mRNA vaccine relative to the 
response with 1 dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 relative to 1 dose of AZD2816 in 
seronegative participants previously vaccinated with 
a SARS-CoV-2 mRNA vaccine
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Unvaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 variant strain elicited by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval relative to the response 
elicited by a 2-dose primary vaccination with
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres

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AZD1222 with a 4-week interval in previously 
unvaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 variant strain elicited by a 
2-dose primary heterologous vaccination with 
AZD1222/AZD2816 with a 4-week dosing interval 
relative to the response elicited by a 2-dose primary 
homologous vaccination with AZD1222 with a 
4-week interval in previously unvaccinated 
seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 variant strain and the Wuhan-Hu-1 strain 
elicited by a 2-dose primary vaccination with 
AZD2816 with a 12-week dosing interval relative to 
the response elicited by a 2-dose primary vaccination 
with AZD2816 with a 4-week interval in previously 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
SAEs: serious adverse events; MAAEs: medically attended adverse events; AESIs: adverse events of special 
interest.
a
At least a 4-fold increase in geometric mean titre from baseline
Overall Design: This is a phase II/III, multinational, randomised, partially double-blind, 
controlled study in both previously vaccinated and unvaccinated participants. 
Disclosure Statement: This is a parallel-group preventive study with 8 treatment arms.
Number of Participants: Approximately 2250 SARS-CoV-2 nucleocapsid seronegative 
participants will be assigned to study intervention to support the primary and secondary 
objectives of this study. In addition, participants that are SARS-Cov-2 nucleocapsid 
seropositive at screening will be enrolled and assigned to study intervention for an exploratory 
analysis, with a cap of 10% of the seronegative population (ie, approximately 225 total 
participants).
Intervention Groups and Duration: Previously vaccinated individuals will receive 1 dose of 
AZD1222 or AZD2816 on Day 1.  Previously unvaccinated participants will receive one of 
the following 2-dose vaccinations:
!
1 dose of AZD2816 on Day 1 and on Day 29
!
1 dose of AZD1222 on Day1 and on Day 29
!
1 dose of AZD1222 on Day 1 and 1 dose of AZD2816 on Day 29
!
1 dose of AZD2816 on Day 1 and on Day 85. 
Participants will be followed up for safety for 180 days after last study vaccine administration.
Data Monitoring Committee: A Data Safety Monitoring Board will provide oversight to 
ensure safe and ethical conduct of the study.

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Statistical Methods:
Sample sizes of 300 seronegative participants per group (or 150 for the AZD2816 primary 
vaccination with a 12-week dosing interval group) are deemed appropriate based upon 
available immunogenicity data from previous clinical studies with AZD1222 for the primary 
and secondary objectives of this study.  
The safety analysis set for adverse events consists of all participants who have received at 
least one dose of study intervention.  The immunogenicity analysis set includes all participants 
in the safety analysis set who have no protocol deviations or intercurrent events judged to 
have the potential to interfere with the generation or interpretation of an immune response.
An interim analysis will be performed when all previously vaccinated participants have 
completed their Day 29 visit. A primary analysis will be performed on data from 28 days after 
the second dose of the 4-week dosing intervals to support assessment of these 2-dose primary 
vaccinations.  A secondary analysis will be performed on data from 28 days after the second 
dose of the 12-week dosing interval to support assessment of this 2-dose primary vaccination.  
The final analysis will be performed on data from 6 months follow-up after participant's 
vaccination.  
1.2
Schema
Figure 1
Study Design for Previously Vaccinated Seronegative/Seropositive
Participants

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Figure 2
Study Design for Unvaccinated Seronegative/Seropositive Participants
Note:  In addition to the approximately 2250 seronegative participants enrolled to support the primary/secondary objectives, 
seropositive participants will also be enrolled in the study to support exploratory objectives in this population, with a cap of 
10% of the planned seronegative participants (ie, a maximum of 225 seropositive participants, bringing total enrollment to 
2475).
1.3
Schedule of Activities
Table 1
Schedule of Activities: Screening 
Procedure
Day -14 to Day 1
See Section
Informed consent
X
5.1, Appendix A 3
Demography
X
-
Medical and surgical history
X
-
Prior and concomitant medications
X
6.5
Complete physical examination, including height and weight
X
8.2.1
Vital signs
X
8.2.2
Urine pregnancy test (for women of childbearing potential only) 
X
8.2.3
Clinical safety laboratory assessments
X
8.2.3
Assessment of serious adverse events
X
8.3, Appendix B
Blood sample for SARS-CoV-2 antibody testing (lateral flow test)
X
8.5.2
Verify eligibility criteria
X
5.1, 5.2
Note:  Screening activities can occur at same visit as initial vaccination with investigational product (ie, Visit 1 in 
Table 2, Table 3, and Table 4).

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Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine
Procedure
Treatment and Follow-up Period
Section
Day
1
8
15
29
180
Window (days)
-
±2
±2
±3
±14
Medical and surgical history
X
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
-
-
6.1.1
Immunological assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
-
8.3.7
e-Diary collected
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: 
serious adverse event

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
Urine pregnancy test
(women of childbearing potential)
X 
-
-
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
X 
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample for SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample for additional immunogenicity
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
X
-
-
-
8.3.7

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
X
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
-
X
X
X
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X
-
-
-
X
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X
-
-
-
X
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
X
-
-
-
8.3.7

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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2
INTRODUCTION
AZD2816 is being developed for the prevention of COVID-19.  It is a modified version of the 
current AstraZeneca SARS-CoV-2 vaccine (referred to as AZD1222 in clinical 
documentation) that has been modified to also provide immunity against the newly emerging
SARS-CoV-2 variant strain B.1.351.  Like AZD1222, AZD2816 is a recombinant replication-
defective chimpanzee adenovirus vector (ChAdOx1) expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tissue plasminogen activator leader sequence at the 
N terminus.  AZD2816 differs from AZD1222 in that the S glycoprotein gene sequence used 
is from the B.1.351 variant strain instead of the original Wuhan-Hu-1 variant.
2.1
Study Rationale
The aim of the study is to assess the safety and immunogenicity of AZD2816 for prevention 
of COVID-19 as both a 2-dose primary vaccination in previously unvaccinated participants 
and a 1-dose booster vaccination in participants previously vaccinated against the original 
Wuhan-Hu-1 strain of SARS-CoV-2.  A safe and effective vaccine for COVID-19 prevention, 
including against the B.1.351 variant, would have significant global public health impact. 
The study will also investigate the safety and immunogenicity of 1) a heterologous 2-dose 
vaccination with AZD1222 as first dose and AZD2816 as the second dose and 2) a single dose 
of AZD1222 as a booster vaccination in participants that have been previously vaccinated 
with an mRNA COVID-19 vaccine.  
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (Zhou et al 2020).  The disease these patients contracted was subsequently 
named Coronavirus Disease 2019 (COVID-19).  The World Health Organization declared the 
novel coronavirus a pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the 
novel coronavirus SARS-CoV-2, has resulted in significant global morbidity and mortality as 
well as major disruption to healthcare systems.  Measures to change the course of the 
pandemic have included the accelerated development vaccines against the original Wuhan-
Hu-1 strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes.  SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus,
and it is the seventh corona virus known to cause human infections and the third known to 
cause severe disease after SARS-CoV and MERS-CoV. One fourth of the viral genome is 
responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 

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and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 spike (S) glycoprotein is a type I trimeric, transmembrane protein that is 
located at the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s 
subunits are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the 
receptor binding domain and subsequent fusion of virus and cell membranes, thereby
mediating the entry of SARS-CoV-2 into the target cells.  The S protein has an essential role 
in virus entry and determines tissue and cell tropism, as well as host range.  The roles of the 
S-protein in receptor binding and membrane fusion have made it a desirable target for vaccine 
and antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947 
(ie, the Wuhan-Hu-1 isolate).
To date, 5 vaccines that rely upon the expression of the SARS CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 
NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b).  Immunogenicity data indicate that a 
single dose of AZD1222 elicits both humoral and cellular immunogenicity responses and that 
antibody responses are boosted after a second dose.  In a pooled analysis of the 4 studies 
conducted in the United Kingdom, Brazil, and South Africa (DCO2 database lock 07 
December 2020), the vaccine was highly immunogenic; seroresponse of S binding antibody 
was > 98% after a single dose of AZD1222.  Seroresponse of live neutralising antibody was 
82.4% after 1 dose, which rose to 99.4% after a second dose.  Efficacy analyses of the pooled 
DCO2 data demonstrated effective protection of AZD1222 against COVID-19 with a vaccine 
efficacy of 66.73% (95.84% CI: 57.41%, 74.01%) (p < 0.001) from 15 days after the second
dose in seronegative participants receiving 2 doses.  The DCO2 data also demonstrated that 
the standard dose of AZD1222 (5 x 1010 viral particles) provides complete protection against 
COVID-19 hospital admission ≥ 22 days after the first dose in the seronegative analysis set 
(0 versus 14 cases in the control group, 2 of which were severe, including one with a fatal
outcome).  Vaccine efficacy was similar in participants with pre-existing comorbidities, being 
those at greatest risk of severe outcomes of COVID-19, compared to that in the general 

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population.  Recently available primary analysis data from a Phase III study performed in the 
United States and Latin America showed primary endpoint vaccine efficacy of 76% (95% CI: 
67.60%, 82.22%; p-value < 0.001). 
A sharp rise in COVID-19 cases was reported in late 2020, which was attributed to the 
emergence of new SARS-CoV-2 variant strains: B.1.1.7 in the United Kingdom, B.1.351 
in South Africa, and P.1 in Brazil.  These variant strains carry a number mutations in the 
S protein sequence: 9 amino acids in B.1.1.7, 10 amino acids in B.1.351, and 12 amino acids 
in P.1 compared with the Wuhan-Hu-1 sequence.  These mutations may result in an increase 
of transmissibility and/or reduced vaccine effectiveness.  Variant B.1.351 was first identified 
in South Africa in October 2020.  Its attributes include approximately 50% increased
transmission and moderate impact of neutralization by monoclonal antibody therapeutics, 
convalescent plasma and vaccine sera.  In vitro neutralization assays suggest that the B.1.351 
lineage viruses may be the most antigenically distinct from the original Wuhan-like strains 
(Zhou et al 2021).  In addition, evidence suggests that AZD1222 may afford diminished 
protection against mild-moderate COVID-19 disease arising from the B.1.351 variant which 
is also antigenically the most different from the Wuhan-Hu-1 virus (Madhi et al 2021).  
The development of candidate vaccines that would be effective against the B.1.351 variant 
strain is underway.  AZD2816 is being developed as an updated ChADOx-nCOv19 vaccine 
designed to provide protective immunity against the newly arising B.1.351 variant strain, 
using the same ChAdOx1 platform and manufacturing processes used for AstraZeneca’s 
currently approved COVID-19 vaccine, AZD1222.  The purpose of this Phase II/III, 
multinational, randomised, partially double-blind, active-controlled study is to demonstrate 
the safety and characterize the immunogenicity of AZD2816, AstraZeneca’s candidate 
ChAdOx1 vector vaccine against B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative individuals who have previously 
received a 2-dose primary vaccination series (AZD1222 or an mRNA vaccine) against 
SARS-CoV-2
!
As a 2-dose homologous primary vaccination to SARS-CoV-2 seronegative individuals 
who have not been vaccinated previously. 
The immunogenicity of a 2-dose primary heterologous vaccination (with AZD1222 as first 
dose and AZD2816 as second dose) to SARS-CoV-2 seronegative individuals who are 
unvaccinated and a single booster dose of AZD1222 to SARS-CoV-2 seronegative individuals 
who have previously received a 2-dose primary mRNA vaccination series will also be 
investigated.
SARS-CoV-2 seropositive participants will be enrolled in separate cohorts to support a 
parallel exploratory analysis in these participants.

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A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD1222 and 
AZD2816 is provided in the respective Investigator’s Brochures.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD2816 and AZD1222 can be found in the respective Investigator’s Brochures.
2.3.1
Risk Assessment
AZD2816 has been developed using the same vaccine vector, ChAdOx1, as AZD1222 and 
only differs in the sequence for SARS-CoV-2 S glycoprotein that is inserted in the vector.  
The anticipated safety profile of AZD2816 is the same as the observed safety profile of 
AZD1222.  Risks associated with AZD2816 are thus the same as the risks associated with 
AZD1222, and no additional risks are anticipated due to the change in the targeted sequence.
A number of essentially mild and moderate adverse reactions to AZD1222 have been 
identified and resemble reactions frequently observed after many vaccines.  Based on pooled 
clinical data from studies with AZD1222, the most commonly expected local solicited AEs for 
participants in this study are vaccination site pain and tenderness.  The most commonly 
expected systemic solicited AEs are fatigue, headache, and malaise.  The majority of reported 
events have been mild or moderate in severity and resolved within 1 to 7 days.  Following the 
second dose, a general attenuation in the incidence and severity of local and systemic solicited 
AEs was observed. 
Post-authorisation hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk.
A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, 
has been observed very rarely following vaccination with COVID-19 Vaccine (ie, AZD1222) 
during post-authorisation use. No events have been observed in the AZD1222 clinical 
development programme.  Thrombosis in combination with thrombocytopenia is thus 
considered to be an important identified risk.  This includes cases presenting as venous 
thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein 
thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia.  Considering 
the frequency of this rare event and the size of this study, the risk for participants in this trial 
is considered to be low.  The protocol includes exclusion criteria and instructions for 
heightened vigilance and thorough investigations for suspected cases to mitigate against 
further the risk for these rare event. 
Important potential risks are 1) neurologic events and potential immune-mediated neurologic 
conditions and 2) vaccine-associated enhanced disease, including vaccine-associated enhanced 
respiratory disease. 

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2.3.2 Benefit Assessment
All participants will receive active treatment: either AZD1222, which has been shown to be 
effective in providing protection against SARS-CoV-2, or AZD2816, which as a modified 
form of AZD1222 designed to be effective against the emergent B.1.351 variant strain and 
may also provide participants with protection.  The information gained from this study will 
inform development decisions with regard to the efficacy of AZD2816 as both a primary 
2-dose vaccination in participants that have not been previously vaccinated and a 1-dose 
booster vaccination in participants previously vaccinated against SARS-CoV-2.
2.3.3 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria and close monitoring of participants to 
minimize known and potential risks. 
An independent Data Safety Monitoring Board will provide study oversight, evaluating 
cumulative safety and other clinical data at regular intervals. 
Taking these measures into account, the potential risks identified in association with the 
administration of AZD2816 and AZD1222 are justified by the anticipated benefit that may 
be afforded to participants for the prevention of COVID-19.

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3
OBJECTIVES AND ENDPOINTS
Table 5 describes the objectives and endpoints of this study.  Co-primary objectives were 
chosen to characterise the safety and humoral immune response of AZD2816 and AZD1222 
against selected strains when administered as a primary 2-dose homologous vaccination series
or a primary 2-dose heterologous vaccination series in previously unvaccinated participants or 
as a single booster vaccination to participants who have been previously vaccinated with 
2 doses of AZD1222 or an approved mRNA COVID-19 vaccine.  All primary and secondary 
objectives/endpoints are descriptive; there will be no hypothesis testing in this study. 
Estimates of neutralizing antibody geometric mean titre ratio and difference in seroresponse 
rates (and 95% confidence interval) will be generated as secondary analyses to support the 
assessment of relative immune responses between selected study groups.
Table 5
Study Objectives and Endpoints 
Objectives
Endpoints
Safety Objectives
- Primary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose

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To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD1222 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered  with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD1222 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety and tolerability of 
a heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination

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To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
- Primary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres 
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD1222 with a 
4-week interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres

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To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
heterologous dose primary vaccination with 1 dose 
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
12-week interval in unvaccinated seronegative
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (comparative)
Previously vaccinated seronegative participants receiving 1 dose versus unvaccinated seronegative participants 
receiving 2 doses
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week dosing 
interval in unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-
dose primary vaccination with AZD1222 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Previously vaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 relative to the response with 1 dose of 
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)

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AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with an mRNA vaccine relative to the 
response with 1 dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 relative to 1 dose of AZD2816 in 
seronegative participants previously vaccinated with 
a SARS-CoV-2 mRNA vaccine
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Unvaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by a 
primary 2-dose vaccination with AZD2816 with a
4-week dosing interval relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week interval in previously 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by a 
heterologous dose primary vaccination with 1 dose 
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval relative 
to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week interval in 
previously unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval relative to the response elicited by a 
2-dose primary vaccination with AZD2816 with a 
4-week interval in previously unvaccinated 
seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
Exploratory
Previously vaccinated and unvaccinated participants (seronegative and seropositive at screening)
To explore antibody response to selected SARS-
CoV-2 variants of interest/variants of concern 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or AZD1222 
in a sub-group of seronegative participants
! Magnitude of SARS-CoV-2 specific antibody 
binding titres (geometric mean titre) for selected 
variants of concern/variants of interest
! Seroresponsea rate of SARS-CoV-2 specific  
antibody binding titres for selected variants of 
concern/variants of interest

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To explore B-cell and T-cell responses following a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in a 
sub-group of seronegative participants
! Intracellular cytokine staining and flow cytometry 
for T-cell responses over time
! Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 B.1.351 or Wuhan-Hu-1 S protein 
from day of dosing baseline over time
! Breadth and depth of peripheral blood B-cell and T-
cell repertoire over time through immunosequencing
To monitor the incidence of SARS-CoV-2 infection 
following 1 dose of AZD2816 or 1 dose of AZD1222
in previously vaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by 
the presence of nucleocapsid antibodies occurring
post-dose of study intervention 
To monitor the incidence of COVID-19 following 
1 dose of AZD2816 or AZD1222 in previously 
vaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To monitor the incidence of SARS-CoV-2 infection 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or 
AZD1222 in unvaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by 
the presence of nucleocapsid antibodies occurring 
post-second dose of study intervention 
To monitor the incidence of COVID-19 following a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in 
unvaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Magnitude of SARS-CoV-2 neutralization titres 
(geometric mean titre) as determined by a live virus 
neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres as determined by a 
live virus neutralization assay
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a 2-dose homologous or 
heterologous primary vaccination with AZD2816 
and/or AZD1222 in sub-groups of seronegative and 
seropositive participants
! Magnitude of ChAdOx1 nAb titres (geometric mean 
titre)
! Seroresponse rate of ChAdOx1 neutralizing antibody 
titres
! Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody 
titres, 1 month after both Dose 1 and Dose 2
To explore additional immune responses following 
a 2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity data
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.

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4
DESIGN
4.1
Overall Design
This is a multi-country Phase II/III study to evaluate the safety and immunogenicity of 
AZD2816 as single-dose vaccination in previously vaccinated adult participants and as a 
2-dose primary vaccination in previously unvaccinated adult participants. 
A total of approximately 2250 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled across these 2 
populations with the goal of 1200 previously vaccinated participants receiving single-dose 
vaccination and 1050 unvaccinated participants receiving 2-dose primary vaccination. In 
addition, seropositive participants will be enrolled (with a cap of 10% of the seronegative 
population or 225 participants) to support exploratory analysis is these participants. 
The enrollment and randomization strategy is intended to minimize group differences in terms 
of age, gender and the presence of comorbidities.
In both the single-dose booster treatment regimen and the 2-dose primary vaccination 
treatment regimen, participants will receive study intervention consisting of intramuscular 
administration of either AZD1222 (5 ×1010 viral particles) or AZD2816 (5 ×1010 viral 
particles).
Approximately 600 seronegative participants previously vaccinated with AZD1222 will be 
randomised 1:1 to receive a single intramuscular dose of either AZD1222 or AZD2816 in a 
double-blinded fashion.  
Approximately 600 seronegative participants previously vaccinated with an approved mRNA 
based vaccination will be randomised 1:1 to receive a single intramuscular dose of AZD2816
or AZD1222 in a double-blinded fashion.
Approximately 1050 seronegative, previously unvaccinated participants will be randomised 
2:2:2:1 to receive a 2-dose primary vaccination of the following:
!
2 doses of AZD1222 with a 4-week dosing interval
!
2 doses of AZD2816 with a 4-week dosing interval
!
1 dose of AZD1222 followed by 1 dose of AZD2816 with a 4-week dosing interval
!
2 doses of AZD2816 with a 12-week dosing interval.
The 3 treatments with a 4-week dosing interval will be double-blinded while the treatment 
with the 12-week interval will be open-label due to the difference in dosing interval.

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In addition, a smaller population seropositive participants (approximately 10% of the 
seronegative population), will be randomised to treatment in a similar manner as above.
Immunogenicity (ie, anti-Wuhan-Hu-1 and anti-B.1.351 immune responses including 
S-binding antibody titres and neutralizing antibody levels [pseudo-neutralization]) will be 
assessed in serum samples collected pre-dose on the day of each vaccination (baseline levels 
before vaccination), 14 and 28 days after each vaccination, and 180 days after the last 
vaccination.
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1-8 for all participants and Days 29-36 for the 4-week dosing interval and Days 85-92 
for the 12-week dosing interval).  An e-diary will be used to collect information on the timing 
and severity of the solicited signs and symptoms.
Follow-up visits will take place as per the schedule of assessment within respective windows.  
All participants will be assessed for local and systemic AE, physical examination, review of 
e-diaries at these time points as detailed in the schedule of assessment.  Blood will also be 
taken for safety assessments and immunology purposes.
All study participants will be followed for safety for 180 days after administration of their last 
vaccination dose.  In every participant, solicited local and systemic events will be reported for 
up to 7 days after each dose, all unsolicited AEs will be reported for up to 28 days after each 
dose, and SAEs and AEs of special interest will be evaluated through study completion 
(up to 180 days after the last study vaccination).  
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, 
to ensure safe and ethical conduct of the study.
4.1.1
COVID-19 Assessments
Occurrence of COVID-19 in the trial will be reported as safety events, including monitoring 
of the potential risk of vaccine-induced enhanced disease as an AE of special interest (see 
Appendix E).  COVID-19 will be diagnosed and treated as per standard medical practice.  
In addition, experimental treatments are permitted.  Detailed information will be collected in 
a standard way and reported on a specific case report form. 
4.1.2
Screening 
All potential participants will be screened, which may take place at a visit up to 14 days prior 
to Day 1 or on Day 1 itself.  

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Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the screening procedures specified in the Schedule of Activities (Section 1.3) will be 
undertaken including a medical history, physical examination, height and weight, a 
SARS-CoV-2 screening test and clinical safety laboratory assessments.  Baseline information 
collected in the previously vaccinated participants will include which vaccine was received, 
immunization dose interval, and time since last vaccination.
For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled.  (Note: Women with urine test results that are positive or undetermined will not be 
enrolled and should be advised to seek medical attendance outside the context of the trial if 
pregnancy is suspected.) 
The eligibility of the participants will be reviewed at the end of the screening visit and again 
when all results from the screening visit have been considered.  Decisions to exclude the 
participant from enrollment or to withdraw a participant from the study will be at the 
discretion of the Investigator.
4.1.3
Vaccination Visit
Participants will be considered enrolled at the point of vaccination.  Before vaccination, the 
eligibility of the participant will be reviewed.  Body temperature will be observed and a 
medical history and physical examination will be undertaken before the first vaccination to 
determine need to postpone vaccination or screen fail the participant.  A negative pregnancy 
test (urine test) will need to be obtained from women of childbearing potential before 
vaccination.  Baseline blood samples will be obtained before the first vaccination.
Participants will receive 1 dose of AZD2816 or AZD1222 at vaccination visits, administered 
by intramuscular injection.  Previously immunized participants will have a single vaccination 
visit, Day 1.  Participants that have not been previously vaccinated at baseline will have a 
second vaccination visit on Day 29 (4-week interval) or Day 85 (12-week interval).  
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1 to 8 and Days 29 to 36 or Days 85 to 92 when applicable).
4.1.4
Follow-up visits
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3).  All 
participants will be assessed for local and systemic AE, physical examination, review of the 

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e-diary and blood tests at these time points as detailed in the Schedule of Activities.  Blood 
will also be taken for safety and immunogenicity assessments.
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate way until the last 
study visit in order to collect information on any SAEs/AE of special interest.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population includes adults ≥18 years of age.  Persons who are healthy or have 
medically stable underlying conditions will be eligible.  Adults with medically-stable chronic 
diseases may participate if, according to the judgement of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Some seropositive participants 
(capped at 10% of the seronegative participant population) will be enrolled to support an 
exploratory analysis.  
Those enrolled in the single-dose vaccination part of the study must have received 2 doses of 
AZD1222 (with a dosing interval of 4-12 weeks) or 2 doses of an mRNA COVID-19 vaccine 
(with a dosing interval of 3-12 weeks for the BNT162b2 mRNA vaccine [Pfizer-BioNTech] 
and 4-12 weeks for the mRNA-1273 vaccine [Moderna]) with the second doses administered 
at least 3 months prior to first study intervention administration. 
Pregnant/breastfeeding women, persons with severe immunodeficiency or severe underlying 
disease will be excluded from participation in the study.  Persons previously vaccinated with 
AZD1222 in the context of an AZD1222 vaccine trial are eligible for enrollment as previously 
vaccinated participants in the trial.  Persons who have previously received any other 
investigational product for the prevention of COVID-19 will be excluded from participation in 
this study.
Participants with known risk factors for thrombosis and thrombocytopenia (excluding 
contraceptive hormonal therapy or replacement hormonal therapy) are excluded.
4.2.2
Rationale for Study Endpoints
There is no statistical hypothesis testing planned for this study.  Descriptive statistics will 
support evaluation of safety, reactogenicity, and immunogenicity.

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An interim analysis will occur when all previously vaccinated participants have completed 
their Day 29 visit. A second interim analysis may be conducted when previously unvaccinated 
participants have completed their Day 29 visit.
The primary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants randomised to a 4-week dosing interval have 
completed their Day 57 visit (ie, 28 days after their second dose).
A secondary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants (including those randomised to either a 4-week or a 
12-week dosing interval) have completed their Day 57/Day 113 visit (ie, 28 days after their
second dose). 
The final analysis will occur when data from all vaccinated participants are available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants/180 days after the second dose for unvaccinated participants).
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination 
will be summarized by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be 
summarized by system organ class and preferred term, and by relationship to 
vaccination as assessed by the investigator.
!
SAEs and AEs of special interest following the first vaccination and throughout the 
study duration will be summarized by system organ class and preferred term and by 
relationship to vaccination as assessed by the investigator.
Solicited AEs will be collected for 7 days after each dose of study intervention, a period that 
has proven adequate to describe reactogenicity events in previous vaccine studies.  For all 
participants, AEs will be collected through 28 days after each dose of study intervention.  
SAEs, medically-attended AEs, and AEs of special interest and will be collected from Day 1 
through end of the study.  AEs of special interest include terms identified by the Brighton 
Collaboration involving events associated with vaccination in general .
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean titre
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean titre from baseline

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Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of 
interest.
Immunogenicity against SARS-CoV-2 Wuhan-Hu-1 and B.1.351 strains will be characterized 
through the quantification of Spike-binding antibodies, pseudo-neutralization and, in a subset 
of participants, live neutralization.  Exploratory analysis of immunogenicity against other 
strains and induction of other immune effectors including cell-mediated immunity will be 
conducted. 
4.3
Justification for Dose
The AZD2816 nominal dose of 5 × 1010 viral particles is the same dose as the approved dose 
for AZD1222, which was based on the accumulated non-clinical data and clinical data from 
the AZD1222 clinical studies, as well as from other SARS-CoV-2 vaccines in development. 
Safety and immunogenicity data from an additional clinical study, MERS001(NCT03399578), 
using the same ChAdOx1 vector, also helped inform dose selection. MERS001 was the first 
clinical study of a ChAdOx1-vectored vaccine expressing the full-length S protein from a 
separate, but related, beta-coronavirus.  ChAdOx1 MERS has been given to 31 participants to 
date at doses ranging from 5 × 109 viral particles to 5 × 1010 viral particles.  Despite higher 
reactogenicity observed at the 5 × 1010 viral particles, this dose was safe, with self-limiting 
AEs and no serious adverse reactions recorded.  The 5 × 1010 viral particles was the most 
immunogenic, in terms of inducing neutralizing antibodies against MERS-CoV using a live 
virus assay (Folegatti et al 2020).  Given the immunogenicity findings and safety profile 
observed with the ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 viral particles 
dose was chosen for AZD1222.  
Based on accumulating nonclinical and clinical data gathered for AZD1222, a 2-dose regimen 
was selected for vaccination of unvaccinated participants with AZD2816 (AZD1222 
Investigators Brochure).  A single dose vaccination has been selected for participants 
previously vaccinated in line with both FDA and EMA guidance (FDA 2021, EMA 2021).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities (Section
1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally.

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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as a protocol waiver or exemption, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1
All Participants: 
Age
1
Adult, ≥ 18 years of age at the time of consent
COVID-19
For inclusion in the SARS-CoV-2 seronegative population supporting the primary and 
secondary objectives: 
2
No history of laboratory-confirmed SARS-CoV-2 infection (ie, no positive nucleic acid 
amplification test and no positive antibody test).
3
Seronegative for SARS-CoV-2 at screening (lateral flow test to detect reactivity to the 
nucleoprotein).
Note, patients failing to meet criteria 2 and/or 3 may be included in the separate seropositive 
population supporting the seropositive exploratory objectives. 
Type of Participant 
4
Medically stable such that, according to the judgment of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up
∀
- A stable medical condition is defined as disease not requiring significant change in 
therapy or hospitalization for worsening disease during the 3 months prior to enrollment
5
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator
6
Signed informed consent obtained before conducting any study-related procedures
Reproduction
7
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants:
(a) Women of childbearing potential must:

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!
Have a negative pregnancy test on the day of screening and on days of 
vaccination
!
Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
30 days following administration of the last dose of study intervention.  A highly 
effective method of contraception is defined as one that can achieve a failure rate 
of less than 1% per year when used consistently and correctly (see Table 6).  
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy) or 
!
Post-menopausal:
!
For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥ 12 months amenorrhea prior to randomization, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and
o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal 
range, the participant is to be considered of childbearing potential
!
For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomization, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.
Table 6
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing systema
Bilateral tubal occlusion
Vasectomized partner b
Sexual abstinence c
Combined (oestrogen- and progestogen-containing 
hormonal contraception
      Oral (combined pill)
      Intravaginal
     Transdermal (patch)
Progestogen-only hormonal contraception
#
     Oral 
#
     Injectable
#
     Implantable
a
This is also considered a hormonal method 
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse from 28 days prior to Day 1 through 30 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant

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5.1.2
Previously COVID-19 Vaccinated Participants
8
Prior completion of a 2-dose primary homologous vaccination regimen against SARS-
CoV-2 with either AZD1222 (2 standard doses as authorized vaccine or as investigational 
product in a clinical trial with a 4- to 12-week dosing interval) or with an mRNA vaccine 
approved for emergency or conditional use (eg, BNT162b2 vaccine [Pfizer-BioNTech] 
with a 3- to 12-week dosing interval or mRNA-1273 vaccine [Moderna] with a 4- to 12-
week dosing interval).  The second dose in all cases should have been administered at 
least 3 months prior to first administration of study intervention.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of allergy to any component of AZD1222/AZD2816.
2
History of Guillain-Barré syndrome, any demyelinating disease, or any other 
neuroimmunologic condition
3
Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) on the 
day prior to or day of randomization 
4
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia or HIV/AIDS.
5
Recurrent severe infections and use of immunosuppressant medication within the past 
6 months (≥ 20 mg per day of prednisone or its equivalent, given daily or on alternate 
days for ≥ 15 days within 30 days prior to administration of study intervention)
The following exceptions are permitted:  
∀
Topical/inhaled steroids or short-term oral steroids (course lasting ≤14 days)
6
History of primary malignancy except for:
(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or for metastasis (for example, indolent 
prostate cancer) in the opinion of the site investigator.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
(c) Adequately treated uterine cervical carcinoma in situ without evidence of disease
(d) Localized prostate cancer
7
History of thrombocytopenia and/or thrombosis, including participants who have 
experienced major venous and/or arterial thrombosis in combination with 
thrombocytopenia following vaccination with any COVID-19 vaccine
8
History of heparin-induced thrombocytopenia, congenital thrombophilia (ie, factor V 
Leiden, prothrombin G20210A, antithrombin III deficiency, protein C deficiency and 

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protein S deficiency, factor XIII mutation, familial dysfibrinogenemia), auto-immune 
thrombophilia (antiphospholipid syndrome, anti-cardiolipin antibodies, anti-β2-
glycoprotein 1 antibodies), or paroxysmal nocturnal haemoglobinuria.
9
Clinically significant bleeding (eg, factor deficiency, coagulopathy, or platelet disorder), 
or prior history of significant bleeding or bruising following intramuscular injections or 
venepuncture
10 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, or neurological illness, as judged 
by the Investigator (note, mild/moderate well-controlled comorbidities are allowed)
11 Any other significant disease, disorder, or finding that may significantly increase the risk 
to the participant because of participation in the study, affect the ability of the participant 
to participate in the study, or impair interpretation of the study data
12 Any autoimmune conditions, except mild psoriasis and vitiligo
Note: The AEs of special interest as outlined in Appendix E (including Table 27) should be 
considered when evaluating a participant for exclusion criteria as the presence of these AEs of 
special interest, especially if untreated or uncontrolled, may be a safety risk to the participant, 
affect the ability of the participant to participate in the study, and/or impair interpretation of 
the study data.  Investigators should review and consider the list of conditions in Appendix E.  
If any of these conditions are present in a participant, the Investigator is asked to utilize 
his/her clinical judgment in determining the participant’s eligibility for the study.  Should the 
participant have conditions as outlined in Appendix E and the participant is enrolled, the 
Investigator is asked to document notes on site regarding the final rationale for enrollment.
Prior/Concomitant Therapy
13 Receipt of or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 with the exception of prior vaccination with 
AZD1222 or an mRNA COVID-10 vaccine (2 doses of the same vaccine within an 
approved dosing interval, see Section 5.1.2), which is allowed for participants in the 
previously vaccinated cohort 
Note: For participants who develop COVID-19, receipt of licensed treatment options 
and/or participation in investigational treatment studies is permitted
14 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to or after administration of study intervention
15 Receipt of any influenza vaccine (licensed or investigational) within 7 days prior to and 
after administration of AZD1222/AZD2816.
16 Receipt of immunoglobulins and/or any blood products within 3 months prior to 
administration of study intervention or expected receipt during the period of study 
follow-up

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Other Exclusions
17 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)
18 Women who are currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, having given birth less than 3 months before or planning pregnancy during 
the study. 
19 Has donated ≥ 450 mL of blood products within 30 days prior to randomization or 
expects to donate blood within 90 days of administration of second dose of study 
intervention
20 Participants with a history of chronic alcohol or drug abuse or any condition associated 
with poor compliance.
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements or 
if vaccination would interfere with the participant’s ongoing treatment.
22 Previous enrollment in the present study.
5.3
Lifestyle Considerations
1
Participants must follow the contraception requirements outlined in Section 5.1
2
Restrictions relating to concomitant medications are described in Section 6.5
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Only a single rescreening is allowed in the study.  Rescreened participants are 
required to sign a new ICF (Appendix A 3), and will be assigned a new participant number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical device utilized by a study participant according to 
the study protocol.  Study intervention is defined as AZD2816 or AZD1222 (Table 7).

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6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 7
Investigational Products
Intervention 
Name
AZD2816
AZD1222
Type 
Vaccine
Vaccine
Dose Formulation
Unit Dose Strength
1 × 1011 viral particles/mL
1 × 1011 viral particles/mL
≥5 × 108 infectious units/mL
≥5 × 108 infectious units/mL
Dosage Level
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
≥ 2.5 × 108 infectious units
≥ 2.5 × 108 infectious units
Route
Intramuscular
Intramuscular
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labelling
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Current/Former 
Name
-
Previous clinical documentation:
ChAdOx1 nCoV-19
Current tradename: Vaxzevria
IMP: investigational medicinal product; NIMP: non-investigational medical product; w/v: weight/volume.
AZD2816
AZD2816 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD2816 has 
a label-claim volume of 5 mL and can provide up to ten 0.5 mL doses.
AZD1222
AZD1222 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD1222 has 
a label-claim volume of 4 mL and can provide up to eight 0.5 mL doses.
CCI
CCI

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Unopened vials of AZD2816 and AZD1222 must be stored at 2-8 oC (36-46 oF) for the 
duration of the assigned shelf-life and must not be frozen.  Both investigational products must 
be kept in original packaging until use to prevent prolonged light exposure. 
6.1.2
Dosing Instructions
Previously unvaccinated participants will receive 2 doses of either AZD1222, AZD2816, or 
AZD1222 plus AZD2816, with the first dose administered on Day 1 and the second dose on 
Day 29 (for a 4-week dosing interval) (Table 3) or Day 85 (for a 12-week dosing interval) 
(Table 4). 
Previously vaccinated participants will receive 1 dose of either AZD1222 or AZD2816
(Table 2).  
It is recommended that the study interventions be administered as an intramuscular injection 
into the deltoid of the non-dominant arm. Other injection sites may be used if necessary.
All study participants will be observed in the clinic for at least 15 minutes after vaccination. 
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.
6.2
Preparation/Handling/Storage/Accountability
The procedures for preparation, handling, storage, and accountability are identical for 
AZD2816 and AZD1222.
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual or specified handling instructions.

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6.2.1
Dose Preparation and Administration
Doses of AZD2816 and AZD1222 must be prepared by the unblinded pharmacist (or designee 
in accordance with local and institutional regulations) using aseptic technique. Each dose is 
prepared by withdrawing 0.5 mL from a vial of AZD2816 or AZD1222 in a sterile syringe.
AZD2816 and AZD1222 do not contain preservatives. Each vial must be assigned a beyond-
use-date of 6 hours at 2-30 °C (36-86 °F) from first needle puncture of the vial, after which 
any unused portion must be discarded.
Once an AZD2816 or AZD1222 dose is drawn into a syringe for administration, the dose must 
be administered within the beyond-use-date of the vial. If dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
The study contains 3 cohorts that are randomised to a total of 8 treatments: 
!
Participants that have previously been vaccinated with 2 doses of AZD1222 will be 
randomised 1:1 to 1 dose of AZD2816 or 1 dose of AZD1222.
!
Participants that have been previously vaccinated with an mRNA COVID-19 vaccine will 
be randomised 1:1 to 1 dose of AZD2816 or AZD2816.  
!
Vaccination naïve participants that will be randomised 2:2:2:1 to 2 doses of AZD2816 
with a 4-week dosing interval, 2 doses of AZD1222 with a 4-week dosing interval, 1 dose 
of AZD1222 followed by 1 dose of AZD216 with a 4-week dosing interval, or 2 doses of 
AZD2816 with a 12-week dosing interval.
Separate populations of SARS-CoV-2 seronegative participants (supporting the primary and 
secondary objectives) and SARS-CoV-2 seropositive participants (supporting exploratory 
objectives) will be randomised/included in the above cohorts.
Randomization will be stratified based on age (less than 65, 65 and above), gender, and 
presence of at least one of the following comorbidities that are known risk factors for severe 
illness from COVID-19 (based on the participant’s past and current medical history):
!
Obesity (BMI ≥ 30 kg/m2 at baseline)
!
Significant cardiovascular disease (eg, heart failure, coronary artery disease, congenital 
heart disease, cardiomyopathies, or pulmonary hypertension)
!
Chronic lung disease (eg, chronic obstructive pulmonary disease, idiopathic pulmonary 
disease, cystic fibrosis, or moderate to severe asthma)
!
Diabetes (Type 1 or Type 2).  

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The randomised participants will be centrally assigned to randomised study intervention using 
an Interactive Response Technology (IRT)/Randomisation and Trial Supply Management.  
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 
the log in information & directions for the Randomisation and Trial Supply Management will 
be provided to each site.
Where a participant does not meet all the eligibility criteria but incorrectly received study 
intervention, the investigator should inform the Study Physician immediately, and a discussion 
should occur between the Study Physician and the investigator regarding whether to continue 
or discontinue the participant.
6.3.2
Blinding
Treatment will be double-blinded for previously vaccinated participants randomised to a 
single dose of either AZD2816 or AZD1222. Treatment will also be double-blind for 
previously unvaccinated participants randomised to 2 dose vaccinations with a 4-week dosing 
interval (ie, homologous AZD2816 or AZD1222 vaccination or heterologous 
AZD1222/AZD2816 vaccination).  Previously unvaccinated participants randomised to a  
homologous AZD2816 vaccination with a 12-week dosing interval will receive treatment in 
an open-label fashion due to the different dosing interval.
For the double-blinded treatments, neither the participant nor any of the investigators or 
Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
participants will be aware of the study intervention received.  Since AZD2816 and AZD1222 
are visually distinct prior to dose preparation (due to differences in container closure), all 
investigational product will be handled by an unblinded pharmacist (or designee in accordance 
with local and institutional regulations) at the study site. Once drawn into syringes for 
administration, AZD2816 and AZD1222 are not visually distinct from each other.
The IRT will provide the investigators with a dose tracking number to be allocated to the 
participant at the dispensing visit.  Routines for this will be described in the IRT user manual 
that will be provided to each study site.
For participants receiving double-blinded treatments, the randomization code should not be 
broken except in medical emergencies when the appropriate management of the participant 
requires knowledge of the treatment randomization.  The investigator documents and reports 
the action to the Sponsor, without revealing the treatment given to participant to the Sponsor 
staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities.  Randomization codes will not be broken 

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for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.
6.3.3
Procedures for Unblinding
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
in which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment 
is warranted.  Participant safety must always be the first consideration in making such a 
determination.  If a participant’s intervention assignment is unblinded for safety, the Sponsor 
must be notified within 24 hours after breaking the blind. 
In the event that a study participant is contacted about receiving a licensed and/or authorized 
COVID-19 vaccine outside of this clinical study, unblinding instructions are being provided to 
the sites.  If the participant is unblinded, the Sponsor needs to be notified within 24 hours, and 
this should be documented in the site source documents.
6.4
Study Intervention Compliance
Participants are dosed at the study site, receiving study intervention directly from the 
investigator or designee, under medical supervision.  The date, and time if applicable, of dose 
administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the period specified in the 
Schedule of Activities (Section 1.3), must be recorded in the eCRF along with the information 
listed below.  Vitamins and/or herbal supplements are not to be recorded.
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
!
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance.

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!
Primary care providers, or where appropriate investigators, should prescribe appropriate 
concomitant medications or treatments deemed necessary to provide full supportive care 
and comfort during the study.
!
Participants who develop COVID-19 after receiving study intervention should be treated 
with licensed medications and interventions according to standard of care.  All routine 
vaccinations other than influenza are permitted beginning > 30 days after last dose of 
study intervention.  Licensed influenza vaccines are permitted 7 days before and 7 days 
after administration of study intervention.
!
Topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 days) are 
permitted
6.5.2
Prohibited Concomitant Medications
The following medications are prohibited and the Sponsor must be notified if a participant 
receives any of these prohibited medications.  The use of the following concomitant 
medications and/or vaccines, however, will not definitively require withdrawal of the 
participant from the study, but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis set.
!
Primary or booster vaccinations, other than AZD2816 or AZD1222, for prevention of 
SARS-CoV-2 or COVID-19.
Note: Participants choosing to receive a licenced and/or authorized COVID-19 vaccine 
should inform the Investigator so it can be properly documented.  Participants, who 
receive a licenced and/or authorized COVID-19 vaccine outside the study, should be 
encouraged to continue study conduct to be followed for safety reporting and all 
assessments.
!
Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention.  Thirty days after 
the second vaccination, other routine vaccinations are permitted as clinically indicated.
!
Glucocorticoids at a dose ≥ 20 mg/day of prednisone or equivalent given daily or on
alternate days for ≥ 14 consecutive days between randomization and the participant’s
scheduled final visit
!
Other systemically administered drugs with significant immunosuppressive activity,
such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy
between randomization and the participant’s scheduled final visit
!
Immunoglobulins and/or any blood product.
If a participant receives a prohibited concomitant medication, the investigator in consultation 
with the Sponsor will evaluate any potential impact on receipt of study intervention based on 
time the medication was administered, the medication’s pharmacology and pharmacokinetics, 
and whether the medication will compromise the participant’s safety or interpretation of the 
data (see Section 7.1). 

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6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.  Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive the first or second dose (if applicable) of study 
intervention if any of the following occur in the participant in question:
1
Withdrawal of consent after signing informed consent
2
Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 
3
Participant is pregnant or nursing
4
Any grade 3 or greater allergic reaction including anaphylaxis that is assessed as related 
to study intervention 
5
Occurrence of any thrombosis with concurrent thrombocytopenia 
6
Any SAE assessed as related to study intervention
7
Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardize the safety of the study participant 
8
Receipt of a prohibited concomitant medication that may jeopardize the safety of the 
study participant or interpretation of the data
Each participant who has received at least 1 dose of study intervention will be followed for the 
full study period unless consent is withdrawn specifically from further study participation, or 
the participant is lost to follow-up.  Participants who have not received study intervention, 
regardless of reason, will not be followed.
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine 
during the study, AstraZeneca needs to be notified within 24 hours and this should be 
documented in the site source documents. Participants who have received study intervention, 
regardless of reason, will be followed for the full study period.

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7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent.  If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken should be 
carried out in line with what was stated in the informed consent and local regulation.  
The investigator must document the decision on use of existing samples in the site study 
records and inform the Sponsor Study Team.  If the participant does not specifically 
request withdrawal of consent for use of samples, then the samples collected prior to the 
consent withdrawal will be destroyed once per protocol analysis is complete.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the Schedule of Activities (Section
1.3).  Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities.
8.1
Efficacy Assessments
Not applicable.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.  Each clinically significant 
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history, 
clinical signs, and symptoms and will include signs of thrombosis and/or 
thrombocytopenia.  Each clinically significant abnormal finding following vaccination 
will be recorded as an AE.
!
All physical examinations will be performed by a licensed healthcare provider 
(eg, physician, physician assistant, or licensed nurse practitioner). 

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8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3).  The participant should be 
resting prior to the collection of vital signs.  On vaccination days, vital signs should be 
assessed prior to vaccine administration.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3).  Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the investigator, with the 
date and time of collection recorded in the appropriate eCRF.
The standard clinical chemistry and haematology analysis will be performed at a local 
laboratory at or near to the investigator site.  Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.  
The following laboratory variables will be measured:
Table 8
Laboratory Safety Variables
Blood
Serum/Plasma
Haemoglobin
Activated partial thromboplastin time
Leukocyte count
Prothrombin time
Leukocyte differential count (absolute count)
Fibrinogen
Platelet count
D-dimer
-
Creatinine
-
Bilirubin, total
-
Alkaline phosphatase
-
Aspartate aminotransferase 
-
Alanine aminotransferase
In case a participant shows an aspartate aminotransferase or alanine aminotransferase 
≥3 × upper limit of normal together with total bilirubin ≥2 × the upper limit of normal, please 
refer to Section 8.3.6
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the Schedule of Activities (Section 1.3).  Urine pregnancy tests for 
∃-human chorionic gonadotropin may be performed at the site using a licensed dipstick test.  

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8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a e-diary (Section 8.3.7), and will be assessed separately 
from the (unsolicited) AEs collected during the study.  General information for AEs in this 
protocol excludes the reporting of solicited AEs via e-diary unless otherwise noted.. 
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
AEs will be recorded for 28 days after each dose of study intervention. 
Solicited AEs will be recorded for 7 days after each dose of study intervention (ie, Day 1 
through Day 8). If a solicited AE is not resolved within the e-diary reporting period, the event 
will be reported as a non-solicited adverse event in the eCRF, with a start date of when started 
and the actual stop date. 
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact. 
See the Schedule of Activities for the scheduled timepoints (Section 1.3). 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the Sponsor.

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8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Severity grade/maximum severity grade/changes in severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA 2007) will be utilized for all unsolicited events with an 
assigned severity grading including Grade 5. 

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8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol-mandated vital signs and laboratory safety 
assessments will be summarized in the Clinical Study Report. 
Deterioration as compared to baseline in protocol-mandated vital signs and laboratory safety 
assessment should therefore only be reported as AEs if they fulfil any of the SAE or 
medically-attended AE criteria or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or 
non-planned visits were required).
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an SAE or medically-attended AE, and the associated vital sign 
will be considered as additional information. 
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation.  Any occurrences of aspartate aminotransferase or alanine aminotransferase 
≥3 × the upper limit of normal together with total bilirubin ≥2 × upper limit of normal at any 
point during the study following the administration of study medication should be reported to 
the Sponsor as a potential Hy's Law SAE within 1 day with a serious criteria of ‘Important 
medical event’ and causality assessment ‘yes/related’.

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The study physician will contact the investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 9) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention via e-diary collection. If a solicited AE is not resolved within the e-diary 
reporting period, the event will be also reported as a non-solicited adverse event in the eCRF,
with a start date of when started and the actual stop date.
Solicited AEs should not be reported as unsolicited AEs unless they fulfil the criteria for SAEs 
or medically-attended AEs(see Sections 8.3 and 8.3.8, respectively).
Table 9
Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic 
Pain at the site of the injection 
Fever (> 100 °F/37.8 °C)
Redness/erythema at the site of the injection
Chills
Tenderness at the site of the injection
Muscle pains
Induration/swelling at the site of the injection 
Fatigue (physical or mental tiredness/exhaustion)
-
Headache
-
Malaise (general feeling of discomfort or uneasiness)
-
Nausea
-
Vomiting
Solicited AE e-Diary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given a thermometer, tape measure or ruler, and access to the Solicited 
AE e-Diary, with instructions on use, along with the emergency 24-hour telephone number to 
contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms. 
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorized representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix D.  Because 

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solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention. 
8.3.8 COVID-19 Assessment
This study will describe the incidence of COVID-19 adverse events reported from Day 1 to 
180 days after the participant’s last/only dose of vaccine.
COVID-19 is defined as SARS-CoV 2-RT-PCR positive symptomatic illness.  At all clinic 
visits following the initial vaccination, participants will be asked if they have had a diagnosis 
of COVID-19 since their last clinic visit (see Schedule of Activities in Section 1.3). Medical 
records will be obtained for confirmation of a participant-reported diagnoses of COVID-19.  
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea.  Events will be reported as AEs/SAEs.
If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed 
using RT-PCR.
8.3.9 Medically-Attended Adverse Events
Medically-attended AEs will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3).
Medically-attended AEs are defined as AEs leading to medically-attended visits that were not 
routine visits for physical examination or vaccination, such as an emergency room visit, or an 
otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. 
AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
illness visits will not be considered medically-attended AEs.
8.3.10
Adverse Events of Special Interest
AEs of special interest will be collected according to the timepoints specified in the Schedule 
of Activities (Section 1.3). 
AEs of special interest are events of scientific and medical interest specific to the further 
understanding of study intervention safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor.  AEs of special interest are based on 
Brighton Collaboration case definitions (SPEAC 2020), clinical experience, and scientific 
interest.  A list of events is provided in Appendix E.
An AE of special interest can be serious or non-serious.  All AEs of special interest will be 
recorded in the eCRF.  If any AE of special interest occurs in the course of the study, 
investigators or other site personnel will inform the appropriate Sponsor representatives within 

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1 day ie, immediately but no later than 24 hours of when he or she becomes aware of it.  
Serious AEs of special interest will be recorded and reported as per Section 8.3.11.
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest
Both thrombotic, thromboembolic, and neurovascular events and thrombocytopenia events are 
considered to be adverse events of special interest.  The investigator should remain vigilant for 
the occurrence of thrombotic events with thrombocytopenia and/or bleeding.  If a participant 
experiences new onset thromboembolic events with thrombocytopenia, there should be 
prompt evaluation with a thorough haematological investigation.  COVID-19 testing, 
including PCR and serology (nucleoprotein antibodies), should also be performed.  See 
Appendix F for further guidance on investigation and management of suspected events.
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and whole genome 
sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events.
8.3.10.2
Potential Neurological Adverse Events of Special Interest
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation, including referral to a neurology specialist for further 
evaluation and testing, as clinically indicated.  Testing can include evaluation for peripheral 
demyelinating conditions (eg, electromyography).  In cases of concern for spinal cord disease, 
see Figure 3 for a recommended testing algorithm. 
An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AEs of special interest occurring 
in the AZD1222 clinical development program (see Appendix A 5).  

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Figure 3
Neurology Testing Algorithm
a
Adapted from Rovira et al 2015
Ab: antibody; ACE: angiotensin converting enzyme; ADC: apparent diffusion coefficient; ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibodies; AQP4: 
aquaporin 4; CMV: cytomegalovirus; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebral spinal fluid; CT: computed tomography; DWI: diffusion-weighted 
image; EBV: Epstein-Barr virus; ED: emergency department; ENA: extractable nuclear antigen antibodies; ESR: erythrocyte sedimentation rate; FLAIR: fluid-attenuated inversion 
recovery; GRE: gradient echo; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IgG: immunoglobulin G; MOG: myelin oligodendrocyte glycoprotein; MRI: 
magnetic resonance image; PCR: polymerase chain reaction; RF: rheumatoid factor; RPR: rapid plasma reagin; STIR: short T1 inversion recovery; SWI: susceptibility-weighted 
imaging; TSH: thyroid stimulating hormone; TM: transverse myelitis; VDRL: Venereal Disease Research Laboratories; VZV: varicella-zoster virus. 

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8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedures.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Sponsor representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available.
The Sponsor representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness is the AZD1222 Investigators 
Brochure, Section 5.6. 
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor, except if the pregnancy is discovered 
before the participant has received any study intervention.
8.3.12.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2).  Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the study intervention may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 

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spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the participant was discontinued 
from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.11) and within 30 days for all other pregnancies 
that are not associated with an SAEs.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module may be used to report the outcome of the pregnancy.
8.3.13
Medication Error
If a medication error occurs, then the investigator or other site personnel informs the 
appropriate Sponsor representatives within 1 day, ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 3. 
8.4
Overdose
For this study, any dose of study intervention exceeding that specified in the protocol will be 
considered an overdose.
There is no specific treatment for an overdose with AZD2816 or AZD1222.  If overdose 
occurs, the participant should be treated supportively with appropriate monitoring as 
necessary.

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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose occurs in the course of the study, the investigator or other site personnel inform 
appropriate Sponsor representatives immediately, but no later than 24 hours after when he or 
she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual.  Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality.  Further details on Handling of Human 
Biological Samples are provided in Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a 
maximum of 15 years following issue of the Clinical Study Report.  Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses, eg, exploratory immunology, such 
as systems serology and profiling of B- and T-cell repertoire.  The results from further 
analysis will not be reported in the Clinical Study Report.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).  Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual.  Results for exploratory immunogenicity analyses may 
be reported separately from the CSR.

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8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the Schedule of Activities (Section 1.3).  Authorized laboratories 
will assess serologic responses to AZD1222 and AZD2816 using validated (or qualified, 
where appropriate) assays.  Serologic assessment to the S protein from different SARS-CoV-2 
variants (which include Wuhan-Hu-1, B.1.351, B.1.1.7, and P.1) will be assessed 
quantitatively using a validated multiplexed ECL based immunoassay.  Additionally, 
seroresponse will be assessed for each antigen over time.  The rate of SARS-CoV-2 infection 
in participants receiving AZD2816 versus AZD1222 will be determined by seroconversion in 
a SARS-CoV-2 nucleocapsid antigen in a multiplexed electrochemiluminescence-based assay 
performed at an authorized laboratory. Additional exploratory assessments may be performed 
to measure binding antibodies to SARS-CoV-2 variants of interest (which may include 
B.1.429, B.1.525, B.1.526, P.2, P.3, B.1.617, and the Q677H mutation observed in multiple 
variants).
8.5.2.2
 
 
 
 
 
 
 
 
 
8.5.2.3
 
 
 
 
 
CCI
CCI
CCI
CCI

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8.5.2.4
 
 
 
 
 
 
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Already collected samples may be analysed for biomarkers thought to play a role in 
COVID-19 severity or outcomes based upon emerging immunogenicity and 
pharmacodynamic analysis from this or other studies involving the study interventions. These 
analyses include but are not limited to serum or plasma cytokines, quantification of RNA, 
micro-RNA, and/or non-coding RNA using quantitative reverse transcriptase polymerase 
chain reaction (RT-PCR), microarray, sequencing, or other technologies in blood, or 
peripheral blood mononuclear cells to evaluate their association with AZD1222/2816 and 
observed clinical responses to these study interventions.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
There is no statistical hypothesis testing planned for this study.  Descriptive analyses will 
support evaluation of safety, reactogenicity and immunogenicity.
9.2
Sample Size Determination
Primary Objective: Characterise Immunogenicity (Precision)
Historical data were available for the immunogenicity responses to AZD1222 from the pooled 
COV001/002/003/005 studies.  Table 10 presents the log transformed immunogenicity 
responses (ie, geometric mean titres) by assay for participants that received 2 standard doses 
CCI
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of AZD1222.  These results indicate that the pseudo-neutralising antibodies exhibited the 
largest variation (standard deviation of 1.20 and 1.10 for the 4-week and 12-week dosing 
intervals respectively), while live-neutralising antibodies had the lowest (standard deviation of 
0.72 for the 4-week dosing interval).
Table 10
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-week dosing intervalb
Assay
N
Mean
Std Dev
N
Mean
Std Dev
N
Mean
Std Dev
Pseudo
476
4.3
1.34
166
5.3
1.20
113
5.4
1.10
Live
51
4.9
1.15
42
6.2
0.72
0
-
-
Spike protein
1139
9.1
1.14
293
10.1
0.96
302
10.7
0.83
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval
Table 11 presents the seroresponse (ie, > 4 fold increase from baseline) by assay.  These 
results indicate that the pseudo-neutralising antibodies exhibited the lowest proportion of 
seroresponse (59.7% and 85.5% for the 4-week and 12-week dosing intervals respectively), 
while both live-neutralising and spike-binding seroresponse rates exceeded 95%.
Table 11
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-dose week intervalb
Assay
N
Proportion
N
Proportion
N
Proportion
Pseudo
499
32%
382
59.7%
117
85.5%
Live
96
75%
95
96.8%
-
-
Spike protein
940
96.6%
636
95.9%
304
99.3%
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval 
Under the assumption that the immunogenicity responses (ie, geometric mean antibody titres) 
associated with AZD2816 will be similar to the responses associated with AZD1222 in 
participants that received 2 standard doses in the pooled COV001/002/003/005 studies, in 
which standard deviations ranged from 0.72 to 1.2 (Table 10), 150 participants will provide a 
95% confidence interval half-width between 0.115 and 0.192 (see Table 12).  Similarly, 300 
participants will provide a 95% confidence interval half-width between 0.081 and 0.136.

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Table 12
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes
Standard Deviation
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
0.72
150
0.115
300
0.081
0.83
150
0.133
300
0.094
0.96
150
0.154
300
0.109
1.1
150
0.176
300
0.124
1.2
150
0.192
300
0.136
Under the assumption that the seroresponse rates associated with AZD2816 will be similar to 
the response rates in adults that received 2 standard doses of AZD1222 in the pooled 
COV001/002/003/005 studies (Table 11), 150 participants will provide a 95% confidence 
interval half-width between 1.33% and 7.85%, and 300 participants will provide a 95% 
confidence interval half-width between 0.94% and 5.55% (Table 13). 
Table 13
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroconversion Rates and 
Proposed Sample Sizes
Observed 
seroconversion rate
Number of participants
Estimated half-width of the 95% confidence interval 
59.7%
150
7.85%
300
5.55%
85.5%
150
5.63%
300
3.98%
95.9%
150
3.17%
300
2.24%
96.8%
150
2.82%
300
1.99%
99.3%
150
1.33%
300
0.94%

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For a fixed sample size, the precision with which the 95% confidence interval of the binary 
seroresponse rate can be estimated is a function of the response rate.  Table 13 provides the 
lower bounds of the 95% confidence interval for selected response proportions for alternate 
sample sizes.  For a given response rate, we can be 95% confident that the true seroresponse 
rate is at least as large as the lower bound of the confidence interval.
Primary Objective: Safety
Table 14 indicates the probability of observing 1 or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 
particular type for participants in each treatment arm.  With the sample size of 300 
participants, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 95%.
Table 14
Probability of detecting 1 or more safety events (N = 300)
Event Frequency
Probability (> 1 event)
≥ 10% (Very Common)
> 99%
≥ 1% (Common)
95%
≥ 0.1% (Uncommon)
26%
≥ 0.01% (Rare)
3%
Secondary Objective: Compare Immunogenicity
Although this study will describe and compare the immune responses between AZD2816 and 
AZD1222 for selected group pairs, no-formal non-inferiority margin for either the geometric 
mean titre ratio or the difference in seroresponse is prospectively defined. 
Under the assumption that there is no difference between treatment arms of interest (ie, a ratio 
of 1, difference on the log scale of 0), the power conferred by 150 and 300 participants 
respectively for the comparison of geometric mean titre ratio using a noninferiority margin of 
1.5 (equivalent to a difference on the log scale of 0.405) is presented in Table 15.

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Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
Sides
Null 
difference
Assumed 
mean 
treatment 
difference
Assumed 
standard 
deviation
N of 
participants in 
comparator 
group
N of 
participants 
in reference 
group
Alpha
Power
Upper
ln1.5 = 0.405
0
0.72
150
300
0.025
> 0.999
300
300
> 0.999
0.83
150
300
0.998
300
300
> 0.999
0.96
150
300
0.988
300
300
> 0.999
1.10
150
300
0.957
300
300
0.994
1.20
150
300
0.920
300
300
0.985
Similarly, if there is no difference between treatment arms of interest (ie, a ratio of 1) in the 
proportion of seroresponders, 300 participants provides 80% power for to establish non-
inferiority to within margin of -10% if the seroresponse rate is > 75%.  The observed pseudo-
neutralising response rates (> 4 fold increase from baseline) from the COV001/002/003/005 
studies for AZD1222 were 59.7% and 85.5% for the 4-week and 12-week dosing interval 
respectively (Table 11).  A population of 300 participants provides 70% power to detect non-
inferiority (using a non-inferiority margin of -10%) if the observed response rate is 59.7% 
(Table 16).

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Table 16
Power for Non-inferiority Using -10% as the Upper Bound of the 
Difference in Seroresponse Rate
Sides
Null 
proportion 
difference
Assumed 
proportion of 
seroresponders 
in both groups
Assumed 
difference in 
proportion of 
seroresponders 
N in 
comparator 
group
N in 
reference 
group
Alpha
Power
Lower
-0.1
0.597
0
150
300
0.025
0.546
300
300
0.707
0.855
150
300
0.844
300
300
0.929
0.959
150
300
0.998
300
300
> 0.999
0.968
150
300
> 0.999
300
300
> 0.999
0.993
150
300
> 0.999
300
300
> 0.999
9.3
Populations for Analyses
The following populations are defined:
Table 17
Populations for Analysis
Population
Description
All participants analysis set 
All participants screened for the study, to be used for reporting disposition and 
screening failures.
Full analysis set
All randomised participants who received study treatment, irrespective of their 
protocol adherence and continued participation in the study. Participants will be
analysed according to their randomised treatment, irrespective of whether or not 
they have prematurely discontinued, according to the intent-
to-treat principle. Participants who withdraw consent or assent to participate in the
study will be included up to the date of their study termination.
Safety analysis set
The safety analysis set consists of all participants who have received study 
treatment. Erroneously-treated participants (eg, those randomised to AZD2816, but 
were actually given treatment AZD12222) are accounted for in this analysis set by 
assigning them to the treatment they actually received.

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Table 17
Populations for Analysis
Population
Description
Immunogenicity analysis set
The vaccine immunogenicity analysis set will include all randomised participants, 
received at least 1 dose of planned study treatment (ie, 1 dose of either AZD2816 or 
1 dose of AZD1222), had baseline and post-dose antibody measurements, have at 
least 1 post-dose quantifiable serum titre, and had no protocol deviations judged to 
have the potential to interfere with the generation or interpretation of an antibody 
response. The analyses conducted using this analysis set will be based on the actual 
treatment received.
Seronegative 
immunogenicity analysis set 
The subset of the immunogenicity analysis set who were seronegative at baseline.
Seropositive 
immunogenicity analysis set
The subset of the immunogenicity analysis set who were seropositive at baseline.
Participants that are SARS-CoV-2 seropositive at screening will be included in seropositive 
analysis sets analogous to the above seronegative analysis sets. Further definition is provided 
in the Statistical Analysis Plan.
9.4
Statistical Analyses
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints.  A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to the interim analyses.
9.4.1 General Considerations
An interim analysis will occur when all previously vaccinated participants have completed 
their Day 29 visit (ie, 28 days after booster dose).  It is estimated that this early analysis has 
the potential to provide clear signals about whether AZD2816 provides a strong neutralizing 
response against the B.1.351 strain while retaining immunogenicity against the Wuhan strain, 
and thereby influence programmatic decisions early.  
A second interim analysis may be performed when previously unvaccinated participants have 
completed their Day 29 visit (ie, 28 days after fist dose).  This analysis is intended to assess 
immunogenicity variability. The number of previously unvaccinated participants per treatment 
arm may be increased based upon the results of this analysis.  The details of this interim 
analysis, including the trigger and methods, will be specified in the Statistical Analysis Plan to 
be finalized prior to any interim analysis.
The primary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants randomised to a 4-week 

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dosing interval are available through completion of their visit 28 days after the second priming 
dose.
A secondary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants (including those 
randomised to a 12-week dosing interval) are available through completion of the visit 28 
days after the second dose. 
The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).
To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.
9.4.2 Safety
9.4.2.1
Primary Endpoints
Overview
Descriptive analyses will support evaluation of safety, reactogenicity and immunogenicity. 
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination will 
be summarised by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be summarised 
by system organ class and preferred term, and by relationship to vaccination as assessed 
by the investigator.
!
MAAEs, SAEs, and AESIs following the first vaccination and throughout the study 
duration will be summarised by system organ class and preferred term and by relationship 
to vaccination as assessed by the investigator. 
!
The change from baseline for safety laboratory measures at 7 and 28 days after 
vaccination.
AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities.  AEs will be presented for each treatment group by system organ class 
and preferred term.  Summaries will include the number and percentage of participants 
reporting at least one event, number of events and exposure adjusted rates, where appropriate.

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An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs.  Summaries will present the relationship to 
study intervention as assessed by the investigator, maximum intensity, seriousness, and death.
A listing will cover details for each individual AE.  Full details of all AE analyses will be 
provided in the Statistical Analysis Plan, including intercurrent events for safety due to 
potential unblinding of participants for administration of licensed and/or approved SARS-
CoV-2 or COVID-19 vaccine.
At the time of the interim analyses, group assignment will not be presented when safety event 
data has the potential to unblind participant’s study group attribution.
9.4.2.2
Other Safety Endpoints
Vital Signs
Vital sign measurements will be performed as specified in the Schedule of Activities (Section 
1.3).  The set of assessments will include pulse oximetry, blood pressure, and body
temperature.  
Details of all vital sign analyses will be provided in the Statistical Analysis Plan, which will 
include descriptive statistics presented for observed values for all vital sign parameters. 
COVID-19
This study will describe the incidence of COVID-19 adverse events from the first dose of the 
vaccine to study end (180 days post-vaccination). Descriptive statistics will be produced 
based on the safety analysis set. Full details will be documented in the statistical analysis plan.
9.4.3
Immunogenicity
9.4.3.1
Immunogenicity Endpoints
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean antibody titre.
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean antibody titre from 
baseline
Both the geometric mean antibody titre and seroresponse of participants will be summarized 
descriptively by strain, treatment arm, and timepoint for the immunogenicity population.
9.4.3.1.1
Estimand framework for immunogenicity descriptions and comparisons
Target populations: 
1) Previously unvaccinated participants 

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a.
Seronegative Analysis Set: and with no evidence of prior or current infection  
2) Participants who previously received SARS-CoV-2 vaccination with either AZD1222 
or a licensed mRNA vaccine according to the authorized dose and dosing regimen at 
least 3 months prior to first study intervention (see Section 5.1.2).
Outcome variable: neutralizing antibody and binding titres to SARS-CoV-2 at 28 days after 
each treatment administration (1 treatment administration for the previously vaccinated 
population and 2 planned treatment administrations for the unvaccinated population). 
Treatment conditions:
Previously unvaccinated population
!
2 doses of AZD1222 given on Day 1 and on Day 29 (4-week interval)
!
2 doses of AZD2816 given on Day 1 and on Day 29 (4-week dosing interval)
!
1 dose of AZD1222 given on Day 1 and 1 dose of AZD2816 on Day 29 (4-week 
dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 85 (12-week dosing interval)
Previously vaccinated population
!
1 dose of AZD1222 given on Day 1. 
!
1 dose of AZD2816 given on Day 1. 
Intercurrent events: the following intercurrent events could impact the antibody levels 
achieved:  
!
missing the second vaccination (for the unvaccinated population)  
!
receiving of immune-modifying drugs or vaccines 
!
subsequent infection with SARS-CoV-2. 
All immunogenicity descriptions and comparisons will use the principal stratum strategy, 
ie, all analyses will exclude participants who experience any of the intercurrent events above
Population-level summary: 
Descriptive Analyses (see Table 19 and Table 20)
!
geometric means of the antibody titres 

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!
seroresponse proportions
Comparative Analyses (see Table 21 and Table 22)
!
ratio of geometric means of the antibody titres.
!
difference in seroresponse proportion 
Planned Descriptive Analyses: 
Table 19 and Table 20 present planned descriptive immunogenicity analyses for the 
unvaccinated and previously vaccinated populations respectively (each one exploring an 
individual treatment arm at a specific timepoint against a particular strain). 
The tables show that without introduction of further variants, there are 24 planned descriptive 
analyses for the unvaccinated population and 16 planned descriptive analyses for the 
previously immunised population (index).  Within each table there is an analysis key which 
describes the population (see Table 18). The descriptive analyses presented in Tables 19 and 
20 will be repeated for the subset of participants who are seropositive at screening.
Table 18
Description of the Analysis Keys for Tables 19 and 20
Population
Analysis Key
Example
Previously 
unvaccinated
Primary series dosing interval: 
    P4 (4-week dosing interval) or
    P12 (12-week dosing interval)
Treatment received: 
    1222 (2 doses of AZD1222) or 
    2816 (2 doses of AZD2816) or
1222/2816 (1 dose of AZD1222  
followed by 1 dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
Analysis Timepoint:
   1 (28 days post-dose 1)
   2 (28 days post-dose 2)
[P4:1222:W:1] = Immunogenicity 
following primary vaccination 
with a 4-week dosing interval of 
2 doses of AZD1222 against 
Wuhan-Hu-1 28 days post-dose 1
Previously vaccinated
Pre-study primary vaccination: 
  P1222 (2 doses of AZD1222) or
    PmRNA (2 doses of an mRNA vaccine)
Treatment received: 
    B1222 (1 booster dose of AZD1222) or 
B2816 (1 booster dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
[P1222:B1222:V] = 
Immunogenicity in participants 
who were previously vaccinated 
with 2 doses of AZD1222 as 
primary vaccination series and 
received a single boost dose of 
AZD1222 against the B.1.351 
variant 

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Table 19
Immunogenicity Descriptive Analysis for Previously Unvaccinated Treatment Groups (with Separate Seronegative 
and Seropositive Analyses)
Objective
Treatment
Dosing 
interval
Strain
Timepoint
Endpoint
Index
Analysis Key
To describe the humoral immune responses induced 
by a 2-dose primary vaccination with AZD1222 with 
a 4-week interval in unvaccinated participants
AZD1222
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
1
[P4:1222:W:1]†
Seroresponse
2
28 days after 2nd dose
GMT
3
[P4:1222:W:2]
Seroresponse
4
B.1.351
28 days after 1st dose
GMT
5
[P4:1222:V:1] †
Seroresponse
6
28 days after 2nd dose
GMT
7
[P4:1222:V:2]
Seroresponse
8
To describe the humoral immune responses induced 
by a 2-dose primary vaccination with AZD2816 with 
a 4-week dosing interval in unvaccinated participants
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
9
[P4:2816:W:1] ‡
Seroresponse
10
28 days after 2nd dose
GMT
11
[P4:2816:W:2]
Seroresponse
12
B.1.351
28 days after 1st dose
GMT
13
[P4:2816:V:1] ‡
Seroresponse
14
28 days after 2nd dose
GMT
15
[P4:2816:V:2]
Seroresponse
16
To describe the humoral immune responses against 
induced by a 2-dose primary heterologous 
vaccination with AZD1222/AZD2816 with a 4-week 
dosing interval in unvaccinated participants
AZD1222/2816
4 weeks
Wuhan-Hu-1
28 days after 2nd dose
GMT
17
[P4:1222/2816:W:2]
Seroresponse
18
B.1.351
28 days after 2nd dose
GMT
19
[P4:1222/2816:V:2]
Seroresponse
20
To describe the humoral immune responses induced 
by a 2-dose primary vaccination with AZD2816 with 
a 12-week interval in unvaccinated participants
AZD2816
12 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
21
[P12:2816:W:2]
Seroresponse
22
B.1.351
28 days after 2nd dose
GMT
23
[P12:2816:V:2]
Seroresponse
24
† descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD1222 as their first dose (ie, homologous and heterologous series).
‡ descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD2816 as their first dose (4-week interval and 12-week interval treatment arms).
GMT: Geometric mean titre

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Table 20
Immunogenicity Descriptive Analysis for Previously Vaccinated Treatment Groups (with Separate 
Seronegative and Seropositive Analyses)
Objective
Primary 
vaccination
Booster 
Treatment
Strain
Timepoint
Endpoint
Index
Analysis Key
To assess the humoral immune response 
induced by 1 dose of AZD1222 in 
participants previously vaccinated with 
AZD1222
AZD1222
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
1
[P1222:B1222:W]
Seroresponse
2
B.1.351
28 days after 
booster dose
GMT
3
[P1222:B1222:V]
Seroresponse
4
To assess the humoral immune response 
induced by 1 dose of AZD2816 in 
participants previously vaccinated with 
AZD1222
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
5
[P1222:B2816:W]
Seroresponse
6
B.1.351
28 days after 
booster dose
GMT
7
[P1222:B2816:V]
Seroresponse
8
To assess the humoral immune response 
induced by 1 dose of AZD2816 in 
participants previously vaccinated with a 
SARS-CoV-2 mRNA vaccine
mRNA
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
9
[PmRNA:B2816:W]
Seroresponse
10
B.1.351
28 days after 
booster dose
GMT
11
[PmRNA:B2816:V]
Seroresponse
12
To assess the humoral immune response 
induced by 1 dose of AZD1222 in 
participants previously vaccinated with a 
SARS-CoV-2 mRNA vaccine
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
13
[PmRNA:B1222:W]
Seroresponse
14
B.1.351
28 days after 
booster dose
GMT
15
[PmRNA:B1222:V]
Seroresponse
16
GMT: Geometric mean titre

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In addition to descriptive immunogenicity assessments for all treatment arms, geometric mean 
titre ratios and differences in seroresponse will be evaluated for the pairs of groups as detailed 
in Table 21 and Table 22.  For each pair, the two-sided 95% confidence intervals for the ratio 
of the geometric mean titre and difference in seroresponse will be calculated.  The geometric 
mean titre ratio assume a normal distribution for the natural log of the concentration.  All 
confidence intervals will be unadjusted for multiple analyses and are provided solely as a 
guide to clinical and scientific judgment.  It is acknowledged that the chance of falsely 
concluding that one or more differences in immunogenicity outcomes exist will be greater 
than the nominal two-sided 0.05 level used for each individual comparison.
Table 21
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
To evaluate the immune responses 
elicited by a 2-dose primary 
vaccination with AZD2816 with a 
4-week dosing interval relative to the 
response elicited by a 2-dose primary
vaccination with AZD1222 with a 
4-week interval in previously 
unvaccinated participants
[P4:2816: V:2]
[P4: 1222: W:2]
[P4:2816: V: 2] −[P4: 1222: W:2]
[P4:2816: V:1]
[P4: 1222: W:1]
[P4:2816: V: 1] −[P4: 1222: W:1]
[P4: 2816: W:2]
[P4: 1222: W:2]
[P4:2816:W: 2] −[P4:1222: W:2]
[P4: 2816: W:1]
[!4: 1222: W:1]
[P4:2816:W: 1] −[P4:1222: W:1]
[P4:2816: V:2]
[P4:1222: V:2]
[P4:2816: V: 2] −[P4:1222: V: 2]
[!4:2816:V: 1]
[!4:1222:V: 1]
[P4:2816: V: 1] −[P4:1222: V: 1]
To evaluate the immune responses 
elicited by a 2-dose primary 
heterologous vaccination with 
AZD1222/AZD2816 with a 4-week 
dosing interval relative to the 
response elicited by a 2-dose primary 
homologous vaccination with 
AZD1222 with a 4-week interval in 
previously unvaccinated participants
[P4:1222/2816: V: 2]
[P4:1222: W:2]
[P4:1222/2816:V: 2] −[P4:1222: W: 2]
[P4:1222/2816: W:2]
[P4: 1222: W:2]
[P4:1222/2816: W:2] −[P4: 1222: W:2]
[P4:1222/2816: V: 2]
[P4:1222: V:2]
[P4:1222/2816: V: 2] −[P4: 1222: V: 2]
To evaluate the immune responses 
elicited by a 2-dose primary 
vaccination with AZD2816 with a 
12-week dosing interval relative to 
the response elicited by a 2-dose 
primary vaccination with AZD2816 
with a 4-week interval in previously 
unvaccinated participants
[P12:2816: W: 2]
[P4:2816: W:2]
[P12: 2816: W:2] −[P4:2816: W:2]
[P12: 2816: V: 2]
[P4:2816: V:2]
[P12:2816: V: 2] −[P4:2816: V: 2]

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Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 in 
participants previously vaccinated with 
AZD1222 relative to the response 
elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing 
interval in unvaccinated participants
[P1222:B2816: V]
[P4:1222: W: 2]
[P1222:B2816: V] −[P4:1222: W:2]
[P1222:B2816: W]
[P4:1222: W: 2]
[P1222:B2816: W] −[P4:1222: W: 2]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 in 
participants previously vaccinated with a
mRNA vaccine relative to the response 
elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing 
interval in unvaccinated participants
[PmRNA:B2816: V]
[P4:1222: W:2]
[PmRNA:B2816: V] −[P4: 1222: W:2]
[PmRNA:B2816: W]
[P4:1222: W:2]
[PmRNA:B2816:W] −[P4:1222: W:2]
To evaluate the immune responses
elicited by 1 dose of AZD2816 in 
participants previously vaccinated with
an mRNA vaccine relative to the 
response with 1 dose of AZD1222 in 
participants previously vaccinated with 
AZD1222
[PmRNA:B2816: V]
[P1222:B1222: W]
[PmRNA:B2816:V] −[P1222:B1222: W]
[PmRNA:B2816: W]
[P1222: B1222:W]
[PmRNA:B2816: W] −[P1222: B1222:W]
[PmRNA:B2816: V]
[P1222: B1222:V]
[PmRNA:B2816: V] −[P1222: B1222:V]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 relative 
to the response with 1 dose of AZD1222 
in participants previously vaccinated 
with AZD1222
[P1222:B2816: V]
[P1222:B1222: W]
[P1222:B2816: V] −[P1222: B1222:W]
[P1222:B2816: W]
[P1222:B1222: W]
[P1222: B2816:W] −[P1222:B1222: W]
[P1222:B2816: V]
[P1222:B1222: V]
[P1222: B2816: V] −[P1222:B1222: V]
To evaluate the immune responses 
elicited by 1 dose of AZD1222 in 
participants previously vaccinated with 
AZD1222 relative to the response 
elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing 
interval in unvaccinated participants
[P1222:B1222: V]
[P4:1222: W: 2]
[P1222:B1222: V] −[P4:1222: W:2]
[P1222:B1222: W]
[P4:1222: W: 2]
[P1222:B1222: W] −[P4:1222: W: 2]
To evaluate the immune responses 
elicited by 1 dose of AZD1222 in 
[PmRNA:B1222: V]
[P4:1222: W:2]
[PmRNA:B1222: V] −[P4: 1222: W:2]

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Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
participants previously vaccinated with 
an mRNA vaccine relative to the 
response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-
week dosing interval in unvaccinated 
participants
[PmRNA:B1222: W]
[P4:1222: W:2]
[PmRNA:B1222:W] −[P4:1222: W:2]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 versus 
1 dose of AZD1222 in participants 
previously vaccinated with a SARS-
CoV-2 mRNA vaccine 
[PmRNA:B2816:V]
[PmRNA:B1222: W]
[PmRNA:B2816: V]
−[PmRNA:B1222:W]
[PmRNA:B2816: W]
[PmRNA:B1222: W]
[PmRNA:B2816: W]
−[PmRNA:B1222:W]
[PmRNA:B2816: V]
[PmRNA:B1222: V]
[PmRNA:B2816: V] −[PmRNA:B1222: V]
9.4.4
Data Safety Monitoring Board
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, to 
ensure safe and ethical conduct of the study.  During the study, the benefit/risk assessment 
will be continuously monitored by the Board to ensure that the balance remains favourable.  
Further details, composition, and operation of the COVID-19 Vaccine Data Safety Monitoring 
Board will be described in a separate charter. For further details, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Not applicable.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
∀
Applicable ICH/GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigators Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority.  This responsibility may be delegated to 
a contract research organization but the accountability remains with the Sponsor.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH/GCP guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all Food and 
Drug Administration (FDA) Regulations, as applicable and all other applicable local 
regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study.  Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH/GCP guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
!
The study medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples.  The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use.  Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

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!
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law.  The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committee Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A COVID-19 Vaccine Data Safety Monitoring Board comprised of independent experts will 
be convened to provide oversight and to ensure safe and ethical conduct of the study.  The 
COVID 19 Vaccine Data Safety Monitoring Board will have the responsibility of evaluating 
cumulative safety and other clinical study data at regular intervals and making appropriate 
recommendations based on the available data.  During the study, the benefit/risk assessment 
will be continuously monitored by the COVID-19 Vaccine Data Safety Monitoring Board to 
ensure that the balance remains favourable.  Full details of the COVID-19 Vaccine Data 
Safety Monitoring Board composition and operations can be found in the COVID-19 Vaccine 
Data Safety Monitoring Board Charter.
An independent Neurological AESI Expert Committee will be available to review and provide 
on request about the diagnosis and causality assessment of selected neurological AEs of 
special interest occurring in the study.  Details on the composition and operation of this 
committee are described in the Neurological AESI Expert Committee Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available.  The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

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!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
!
Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected, and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH/GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or ICH/GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both SAEs and non-SAEs and can include a deterioration of a 
pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout,
follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs.  
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used.  
In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a non-
SAE.  For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur.  Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as non-serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  Examples of important medical events include such events as listed 
below:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Intensity Rating Scale
A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events with 
an assigned severity grading including Grade 5.  
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 

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intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the investigational product.
!
Time Course.  Exposure to suspect drug.  Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect investigational product?
!
Consistency with known investigational product profile.  Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or drugs of the same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational medicinal product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the investigational product, but rather a human or 
process related failure while the investigational product is in control of the study site staff or 
participant.
Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the investigational product
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Investigational product name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration
!
Investigational product not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Investigational product not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong participant received the medication (excluding IRT errors)
!
Wrong investigational product administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from 
the participants while in storage at the study site until shipment or disposal (where 
appropriate) and records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
The Sponsor or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
The Sponsor ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented.  If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and the Sponsor are informed about the sample disposal.

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The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus.  Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814.  Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
!
Table 23: Clinical Abnormalities, Local Reactions to Injectable Product
!
Table 24: Clinical Abnormalities, Vital Signs
!
Table 25: Clinical Abnormalities, Systemic (General or Illness)
Table 23
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily
activity
ER visit or 
hospitalization
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalization
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded.
b
Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE e-Diary.
ER: emergency room.

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Table 24
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)a
Fever (°C/°F)
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
Emergency room visit 
or hospitalization for 
arrhythmia
Bradycardia 
(beats/minute)
50-54
45-49
< 45
Emergency room visit 
or hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
Emergency room visit 
or hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes.

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Table 25
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic 
(General)
Systemic Gradea
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/
vomiting
No interference with 
activity or 
1-2 episodes/24 hours
Some interference 
with activity or 
> 2 episodes/24 hours
Prevents daily activity, 
required outpatient 
intravenous hydration
Emergency room 
visit or 
hospitalization for 
hypotensive shock
Chills
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
Emergency room 
visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Systemic Illness
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations)
No interference with 
activity
Some interference 
with activity not 
requiring intervention
Prevents daily activity 
and required medical 
intervention
Emergency room 
visit or 
hospitalization

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Appendix E
Adverse Events of Special Interest
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 26
Adverse Events of Special Interest
Category
Medical Concept
Neurologic
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment or 
loss of consciousness.  
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis.
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population.
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (eg, weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, or other 
sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate.
Hematologic
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL.
Immunologic
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention.
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non-neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: a group of autoimmune inflammatory disorders 
characterized by an alteration in cellular homeostasis, which may or may not have an 
autoimmune aetiology.  A list of events is provided in Table 27. 

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune haemolytic anaemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anaemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombotic events with thrombocytopenia and/or bleeding.  It is not intended to 
be a comprehensive guide to the management of all venous thromboembolic events.  
During the course of the study, the investigator will remain vigilant for occurrence of 
thrombotic events with thrombocytopenia and/or bleeding.  Appropriate investigations (eg, 
imaging) to diagnose these events should be made on a case-by-case basis.  The investigator is 
responsible for determining whether a participant meets criteria for thrombotic events with 
thrombocytopenia and/or bleeding at any point during the study.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombotic events with thrombocytopenia 
and/or bleeding.  The Study Physician contacts the investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data.  
Guidance from the International Society of Thrombosis and Haemostasis for management of 
thrombocytopenic thromboembolism occurring after vaccination can be found at 
www.isth.org.  Notably, participants should only be treated with heparin if a test for heparin-
induced thrombocytopenia antibodies is negative.  An alternative explanation for 
thrombocytopenia should be considered (eg, alcohol use, liver cirrhosis, concomitant 
medications, exposure to toxic chemicals, viral infections).
The investigator is responsible for recording data pertaining to thrombotic events with 
thrombocytopenia and/or bleeding and for reporting AEs and SAEs according to the outcome 
of the review and assessment in line with standard safety reporting processes.
F 2
Tests that Should Be Considered if Thrombotic Events With 
Thrombocytopenia and/or Bleeding Are Suspected
The following tests should be considered, but not limited to:
1. Measurement of platelet levels, prothrombin time, activated partial thromboplastin time, 
D-dimer levels, and fibrinogen levels
2. Complete blood count, reticulocyte count, blood film, haptoglobins
3. Anti-platelet factor 4 antibodies

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4. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, human 
leucocyte antigen B27, ADAMTS13 activity, anti-cardiolipin antibodies IgG + IgM, and 
anti-B2GPI antibodies IgG + IgM
5. Complement (eg, C3, C4, complement complex C5b-9, C5a), autoantibodies (eg, 
antinuclear IgG, anti-double stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG)
6. Factor V Leiden, Factor II (prothrombin) variant 
7. Platelet activation markers and functional assays (eg: sCD40L, soluble glycoproteins, 
degranulation markers [PF4, vWF, P-selectin, annexin V]), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 ELISA positive)
8. Inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13
9. Cell adhesion molecules: VCAM, ICAM, E-selectin
10. Adenovirus serology
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Ebstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19
12. COVID-19 testing, including PCR and serology
13. Calculation of an International Society of Thrombosis and Haemostatis score for 
Disseminated Intravascular Coagulation (derived from platelet levels, fibrinogen, and D-
Dimer)

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ChAdOx1 MERS
Chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
AZD1222 when initially developed by the University of Oxford
COVID-19
Coronavirus disease 2019
eCRF
Electronic case report form
e-Diary
Electronic diary
GMT
Geometric mean titre
ICF
Informed consent form
ICH/GCP
International Council for Harmonisation/Good Clinical Practice
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
MAAEs
Medically attended adverse events
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
S
Spike
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome-coronavirus-2

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Appendix H
Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment 1: 2 June 2021
Version 1 of the protocol was amended prior to the commencement of the study (ie, prior to 
approval of the protocol by an ethics committee) based on feedback from internal and 
regulatory authority reviews.  The most substantial changes were as follows:
!
addition of 2 treatment arms:  1) AZD1222 as a single booster vaccination in participants 
previously vaccinated with an mRNA COVID-19 vaccine and 2) heterologous 
vaccination with AZD1222 plus AZD2816 in previously unvaccinated participants
!
further definition of analysis sets
!
addition of thrombotic events with thrombocytopenia as a discontinuation criteria
In addition, corrections and revisions to text to improve readability were made.

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11
REFERENCES
Dejnirattisai et al 2021
Dejnirattisai W, Zhou D, Supasa P, Liu C, Mentzer AJ, et al. Antibody evasion by the 
Brazilian P.1 strain of SARS-CoV-2. Cell 2021;184:1-16.
EMA 2021
European Medicines Agency. Reflection paper on the regulatory requirements for vaccines 
intended to provide protection against variant strain(s) of SARS-CoV-2 (EMA/117973/2021), 
February 2021. Available at: https://www.ema.europa.eu/en/regulatory-requirements-
vaccines-intended-provide-protection-against-variant-strains-sars-cov-2.
FDA 2007
US Food and Drug Administration. Guidance for Industry. Toxicity grading scale for healthy 
adult and adolescent volunteers enrolled in preventive vaccine clinical trials, Sept 2007.
Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-
preventive-vaccine-clinical.
FDA 2021
US Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent 
COVID-19: Guidance for Industry, February 2021. Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-
authorization-vaccines-prevent-covid-19.
Folegatti et al 2020
Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A et al. Safety and 
immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored 
vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, Phase 1 trial. Lancet 
Infect Dis 2020;20:816-26.
Lu et al 2020
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology 
of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 
2020;395(10224):565-74. 
Madhi et al 2021
Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AK, Fairlie L, et al. Efficacy of the 
ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Eng J Med 2021.
Ramasamy et al 2020
Ramasamy MN, Voysey M, Aley PK, Bibi S, Clutterbuck EA, et al. Safety and 
immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in 

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young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. 
Lancet 2020; 396(10267):1979-93.
Rovira et al 2015
Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP et al. MAGNIMS 
consensus guidelines on the use of MRI multiple sclerosis—clinical implementation in the 
diagnostic process. Nature Rev Neurolog 2015;11(8):471-82.
SPEAC 2020
Safety Platform for Emergency Vaccines. D2.3 Priority list of adverse events of special 
interest: COVID-19. Work Package: WP2 Standards and Tools. v1.1. Available from: 
https://media.tghn.org/articles/COVID-19_AESIs_SPEAC_V1.1_5Mar2020.pdf.
Voysey et al 2021a
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al. Safety and efficacy of 
the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four 
randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397:99-111.
Voysey et al 2021b
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al.  Single-dose 
administration and the influence of the timing of the booster dose on immunogenicity and 
efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised 
trials. Lancet 2021;397:881-91.
Wang et al 2021
Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
B.1.1.7. Nature 2021;593:130-5.
Zhou et al 2020
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus 
of probable bat origin. Nature 2020;579:270-3.
Zhou et al 2021
Zhou D, Dejnirattisai W, Supasa P, Liu C, Mentzer AJ, Ginn HM, et al. Evidence of escape of 
SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 2021;189:1-14.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7220c00001-csp-v2
Document Title:
D7220C00001 Clinical Study Protocol Version 2 01Jun2021
Document ID:
Doc ID-004538576
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
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Content Approval
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Content Approval
02-Jun-2021 13:42 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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Clinical Study Protocol
Study Intervention
AZD2816
Study Code
D7220C00001
Version
Amendment 2
Date
29 July 2021
TITLE PAGE
A Phase II/III Partially Double-Blinded, Randomised, Multinational, 
Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults to 
Determine the Safety and Immunogenicity of AZD2816, a Vaccine for the Prevention 
of COVID-19 Caused by Variant Strains of SARS-CoV-2
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
EudraCT: 2021-002530-17
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Number: D7220C00001
Amendment Number: 2
Study Intervention: AZD2816
Study Phase: II/III
Short Title: Phase II/III Study of AZD2816, a Vaccine for the Prevention of COVID-19 in 
Adults
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator:  Andrew J Pollard, FRCPCH PhD FMedSci
            University of Oxford
            Oxford, United Kingdom

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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Amendment 2
29 July 2021
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment 2: 29 July 2021
The principal reason for this amendment was to
1) add an additional interim analysis to evaluate immunogenicity in a subset of 
AZD1222 previously vaccinated subjects boosted with AZD1222 or AZD2816
2) revise Objectives/Endpoints from descriptive to comparative, with ranking of primary, 
key secondary, other secondary, and exploratory objectives
3) add non-inferiority margins to primary analysis and add additional participants to 
maintain power 
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis 
(Objectives and 
Endpoints)
Revised this section from 
primarily descriptive to 
primarily comparative.  
Comparative immunogenicity 
objectives created and ranked as 
primary, key secondary, other 
secondary.
Objectives of study 
changed from descriptive 
to comparative, testing for 
non-inferiority across 
treatment comparisons
Substantial
1.1 Synopsis 
(Number of 
Participants; Statistical 
Methods)
Overall size increased to 2590
participants
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.1 Synopsis (Statistical 
Methods)
An additional interim analysis 
added. Second interim analysis 
changed to include only the 
previously vaccinated with 
AZD1222 cohort.
Interim analysis plan was 
reviewed and revised.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.2 Schema
Figures updated with increased 
participant numbers
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.3 Schedule of 
Activities
Table 2: footnote clarification 
added
Table 3: minor corrections
Clarification/Correction
Non-substantial
2.1 Study Rationale 
(and elsewhere in 
protocol)
Clarification on previous 
vaccination criteria
Clarification
Non-substantial
3 Objectives
Section completely rewritten.  
Divided into 2 sections: 
Previously unvaccinated and 
previously vaccinated.  
Immunogenicity objectives 
created for comparisons.  
Objectives ranked as primary, 
key secondary, other secondary, 
or exploratory.
Objectives of study 
changed to show non-
inferiority across 
treatments.  
Substantial
4.1 Overall design
Participant numbers increased
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
4.1 Overall design
Cap on age added
To ensure good 
representation across age 
groups
Substantial
8.3.2
Removal of severity grade 5
Correction
Non-substantial
8.5.2.3
 
 
Addition of information on 
number of patients sampled for 
Clarification
Non-substantial
9.1 Statistical 
Hypotheses
Addition of statistical 
hypotheses
Include hypothesis being 
tested.
Substantial
9.2 Sample size 
determination
Confidence intervals for 
populations of 350 and 380 
added to Table 14 and Table 15
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
9.2 Sample size 
determination
Power estimates for populations 
of 350 and 380 added to Table 
17 and Table 18
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
CCI
CCI

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
9.4.1 General 
considerations
Details on the initial interim, 
second interim, and third interim 
analysis added
Include revised 
information on the 
analysis plan, including 
interim analyses
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Objectives removed from 
descriptive analysis Table 23 
and Table 24
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Section of  Immunogenicity 
Comparisons added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for
immunogenicity 
descriptions and 
comparisons
Table 25 and Table 26 on 
immunogenicity comparisons 
revised, aligned with the revised 
objectives/endpoints.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.4 Multiple 
Comparisons
Section added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
In addition, the protocol has been revised with minor corrections and clarifications.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................. 3
TABLE OF CONTENTS...................................................................................................... 6
1
PROTOCOL SUMMARY................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 21
1.3
Schedule of Activities....................................................................................... 22
2
INTRODUCTION............................................................................................ 28
2.1
Study Rationale ................................................................................................ 28
2.2
Background ...................................................................................................... 28
2.3
Benefit/Risk Assessment................................................................................... 31
2.3.1
Risk Assessment............................................................................................... 31
2.3.2
Benefit Assessment........................................................................................... 32
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 32
3
OBJECTIVES AND ENDPOINTS................................................................... 33
3.1
Naïve unvaccinated cohort receiving a 2-dose primary vaccination................... 33
3.2
Previously vaccinated cohort receiving a 1-dose booster vaccination ................ 38
4
DESIGN........................................................................................................... 44
4.1
Overall Design.................................................................................................. 44
4.1.1
COVID-19 Assessments ................................................................................... 45
4.1.2
Screening.......................................................................................................... 46
4.1.3
Vaccination Visit .............................................................................................. 46
4.1.4
Follow-up visits................................................................................................ 47
4.2
Scientific Rationale for Study Design ............................................................... 47
4.2.1
Rationale for Study Design and Participant Population ..................................... 47
4.2.2
Rationale for Study Endpoints .......................................................................... 48
4.3
Justification for Dose........................................................................................ 48
4.4
End of Study Definition.................................................................................... 49
5
STUDY POPULATION ................................................................................... 49
5.1
Inclusion Criteria .............................................................................................. 49
5.1.1
All Participants:................................................................................................ 49
5.1.2
Previously COVID-19 Vaccinated Participants................................................. 51
5.2
Exclusion Criteria ............................................................................................. 51
5.3
Lifestyle Considerations ................................................................................... 54
5.4
Screen Failures ................................................................................................. 54
6
STUDY INTERVENTION............................................................................... 54
6.1
Study Interventions Administered..................................................................... 54

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6.1.1
Investigational Products.................................................................................... 54
6.1.2
Dosing Instructions........................................................................................... 55
6.2
Preparation/Handling/Storage/Accountability ................................................... 56
6.2.1
Dose Preparation and Administration................................................................ 56
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 56
6.3.1
Randomization.................................................................................................. 56
6.3.2
Blinding............................................................................................................ 57
6.3.3
Procedures for Unblinding ................................................................................ 58
6.4
Study Intervention Compliance......................................................................... 58
6.5
Concomitant Therapy........................................................................................ 59
6.5.1
Permitted Concomitant Medications ................................................................. 59
6.5.2
Prohibited Concomitant Medications ................................................................ 59
6.6
Dose Modification ............................................................................................ 60
6.7
Intervention After the End of the Study............................................................. 60
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 60
7.1
Discontinuation of Study Intervention............................................................... 60
7.2
Participant Withdrawal from the Study ............................................................. 61
7.3
Lost to Follow-up ............................................................................................. 62
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 62
8.1
Efficacy Assessments........................................................................................ 63
8.2
Safety Assessments........................................................................................... 63
8.2.1
Physical Examinations...................................................................................... 63
8.2.2
Vital Signs........................................................................................................ 63
8.2.3
Clinical Laboratory Assessments ...................................................................... 63
8.3
Adverse Events and Serious Adverse Events..................................................... 64
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 65
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 65
8.3.3
Causality Collection.......................................................................................... 66
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 66
8.3.5
Adverse Events Based on Examinations and Tests............................................ 66
8.3.6
Hy’s Law.......................................................................................................... 67
8.3.7
Solicited Adverse Events .................................................................................. 67
8.3.8
COVID-19 Assessment..................................................................................... 68
8.3.9
Medically-Attended Adverse Events................................................................. 69
8.3.10
Adverse Events of Special Interest.................................................................... 69
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest ................................ 69
8.3.10.2
Potential Neurological Adverse Events of Special Interest ................................ 70
8.3.11
Reporting of Serious Adverse Events................................................................ 72
8.3.12
Pregnancy......................................................................................................... 72
8.3.12.1
Maternal Exposure............................................................................................ 72
8.3.13
Medication Error............................................................................................... 73

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8.4
Overdose .......................................................................................................... 73
8.5
Human Biological Samples............................................................................... 74
8.5.1
Pharmacokinetics.............................................................................................. 74
8.5.2
Immunogenicity Assessments ........................................................................... 74
8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 75
8.5.2.2
8.5.2.3
8.5.2.4
8.5.3
Pharmacodynamics........................................................................................... 76
8.6
Human Biological Sample Biomarkers ............................................................. 76
8.7
Optional Genomics Initiative Sample................................................................ 76
8.8
Medical Resource Utilization and Health Economics ........................................ 76
9
STATISTICAL CONSIDERATIONS............................................................... 76
9.1
Statistical Hypotheses....................................................................................... 76
9.2
Sample Size Determination............................................................................... 77
9.3
Populations for Analyses .................................................................................. 83
9.4
Statistical Analyses........................................................................................... 83
9.4.1
General Considerations..................................................................................... 84
9.4.2
Safety ............................................................................................................... 85
9.4.2.1
Primary Endpoints ............................................................................................ 85
9.4.2.2
Other Safety Endpoints..................................................................................... 86
9.4.3
Immunogenicity................................................................................................ 86
9.4.3.1
Immunogenicity Endpoints ............................................................................... 86
9.4.4
Multiple Comparisons....................................................................................... 97
9.4.5
Data Safety Monitoring Board .......................................................................... 97
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 97
11
REFERENCES............................................................................................... 122
CCI
CCI
CCI

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LIST OF TABLES
Table 1
Schedule of Activities: Screening ............................................................ 22
Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine . 23
Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 4-Week Dosing 
Interval.................................................................................................... 24
Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 12-Week 
Dosing Interval........................................................................................ 26
Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination.............................. 34
Table 6
Study Objectives and Endpoints for Previously Vaccinated Participants 
Receiving a 1-Dose Booster Vaccination ................................................. 39
Table 7
Highly Effective Methods of Contraception............................................. 51
Table 8
Investigational Products........................................................................... 54
Table 9
Laboratory Safety Variables..................................................................... 64
Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment....... 68
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)...... 77
Table 12
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set) .......................... 77
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes........... 78
Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroresponse Rates and Proposed 
Sample Sizes ........................................................................................... 79
Table 15
Probability of detecting 1 or more safety events (N = 300)....................... 80
Table 16
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio .................................................................... 81
Table 17
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate .............................................................. 82
Table 18
Populations for Analysis .......................................................................... 83
Table 19 
Description of the Analysis Keys for Tables 19 and 20 ............................ 88

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 89
Table 21
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 90
Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups........ 93
Table 23
Immunogenicity Comparisons for Previously Vaccinated Group.............. 95
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable Product109
Table 25
Tables for Clinical Abnormalities: Vital Signs....................................... 110
Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness) ........... 111
Table 27
Adverse Events of Special Interest......................................................... 112
Table 28
List of Potential Immune-mediated Medical Conditions......................... 113
LIST OF FIGURES
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination................................................. 21
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster.................................................. 21
Figure 3
Neurology Testing Algorithm .................................................................. 71

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 98
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 103
Appendix C
Handling of Human Biological Samples ................................................ 107
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ........................... 109
Appendix E
Adverse Events of Special Interest......................................................... 112
Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding ....................................................... 116
Appendix G
Abbreviations ........................................................................................ 118
Appendix H
Protocol Amendment History................................................................. 119

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A phase II/III partially double-blinded, randomised, multinational, active-
controlled study in both previously vaccinated and unvaccinated adults to determine the safety 
and immunogenicity of AZD2816, a vaccine for the prevention of COVID-19 caused by 
variant strains of SARS-CoV-2.
Short Title: Phase II/III study of AZD2816, a vaccine for the prevention of COVID-19 in 
adults.
Rationale: Recently, several variants of the SARS-CoV-2 virus with increased 
transmissibility have emerged, including B.1.1.7, first identified in the UK, P.1, first identified 
in Brazil, and B.1.351, first identified in South Africa.  In an ongoing clinical trial of 
AZD1222 in South Africa, interim results failed to show protection against mild to moderate 
disease caused by the B.1.351 variant; protection against severe disease could not be 
determined as no severe cases were identified (Madhi et al 2021). 
Based on available evidence about vaccine effectiveness and molecular epidemiology of 
emerging variants, B.1.351 is estimated to have a potential to escape vaccine-elicited 
immunity. B.1.351 carries sequence mutations in common with other variants of concerns; 
immunity to B.1.351 therefore has the potential to provide some cross-immunity against other 
emerging strains. Development of candidate vaccines that include the B.1.351 S-protein 
variant is underway.  AstraZeneca is developing AZD2816, a vaccine against the B.1.351 
SARS-CoV-2 variant using the same ChAdOx1 platform and manufacturing processes used 
for AstraZeneca’s currently available COVD-19 vaccine, AZD1222.
Objectives and Endpoints:
The purpose of this study is to characterize the safety and immunogenicity of AZD2816, 
AstraZeneca’s candidate ChAdOx1 vector vaccine against SARS-CoV-2 variant strain 
B.1.351, when administered:
!
As a single dose to SARS-CoV-2 seronegative participants who previously received a 
2-dose primary vaccination against SARS-CoV-2 with AZD1222 or an mRNA 
COVID-19 vaccine
!
As a 2-dose primary homologous vaccination to SARS-CoV-2 seronegative 
participants who are unvaccinated
!
As the second dose of 2-dose primary heterologous vaccination (with AZD1222 
as first dose) to SARS-CoV-2 seronegative participants who are unvaccinated. 
The following table lists the primary and secondary endpoints:

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Objectives
Endpoints
Safety Objectives: Previously unvaccinated participants
- Primary
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 4-
week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of a 2-dose 
primary heterologous vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 4-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety and tolerability of a 
heterologous primary vaccination with 1 dose
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 12-week dosing 
interval in unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
Immunogenicity objectives: Previously unvaccinated participants
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-hu-1
Wuhan-hu-1

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Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 
heterologous primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 

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Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original
Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
Safety Objectives: Previously vaccinated participants
- Primary
To characterize the safety and tolerability of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 
days post dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose

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- Secondary
!
To characterize the safety and tolerability of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 
days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 7 
days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 booster dose of 
AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
To characterize the extended safety of 1 booster dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
To characterize the extended safety of 1 booster dose of 
AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
To characterize the extended safety of 1 booster dose of 
AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
Immunogenicity objectives: previously vaccinated participants
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-hu-1
Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 
vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-hu-1
Wuhan-hu-1

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Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in participants
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.4
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 
vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination

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Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus  AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster

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Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster version
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
SAEs: serious adverse events; MAAEs: medically attended adverse events; AESIs: adverse events of special 
interest.
a
At least a 4-fold increase in geometric mean titre from baseline
Overall Design: This is a phase II/III, multinational, randomised, partially double-blind, 
controlled study in two distinct cohorts: previously vaccinated and previously unvaccinated 
participants. 
Disclosure Statement: This is a parallel-group preventive study with 8 treatment arms.

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Number of Participants: Approximately 2590 SARS-CoV-2 nucleocapsid seronegative 
participants will be assigned to study intervention to support the primary and secondary 
objectives of this study. In addition, participants that are SARS-Cov-2 nucleocapsid 
seropositive at screening will be enrolled and assigned to study intervention for an exploratory 
analysis, with a cap of 10% of the seronegative population (ie, approximately 259 total 
participants).
Intervention Groups and Duration: Previously vaccinated participants will receive 1 dose 
of AZD1222 or AZD2816 on Day 1.  Previously unvaccinated participants will receive one of 
the following 2-dose vaccinations:
!
1 dose of AZD2816 on Day 1 and on Day 29
!
1 dose of AZD1222 on Day1 and on Day 29
!
1 dose of AZD1222 on Day 1 and 1 dose of AZD2816 on Day 29
!
1 dose of AZD2816 on Day 1 and on Day 85. 
Participants will be followed up for safety for 180 days after last study vaccine administration.
Data Monitoring Committee: A Data Safety Monitoring Board will provide oversight to 
ensure safe and ethical conduct of the study.
Statistical Methods:
Sample sizes of 300-380 seronegative participants per group  are deemed appropriate based 
upon available immunogenicity data from previous clinical studies with AZD1222 for the 
primary and secondary objectives of this study.  
The safety analysis set for adverse events consists of all participants who have received at 
least one dose of study intervention.  The immunogenicity analysis set includes all participants 
in the safety analysis set who have no protocol deviations or intercurrent events judged to 
have the potential to interfere with the generation or interpretation of an immune response.
An initial interim analysis will be performed on a subset of previously AZD1222 vaccinated 
participants that have received a booster dose to consider unblinded sample size adjustment. A 
second interim analysis will be performed when all previously AZD1222 vaccinated 
participants have completed their Day 29 visit to support registration of a booster dose. A 
third interim analysis will be performed on a subset of naïve previously unvaccinated 
participants that have received their second dose to consider blinded sample size adjustment in 
this population. The primary analysis will be performed when there are data from all naïve 
participants, 28 days after the second dose of the 4-week dosing intervals to support 
assessment of these 2-dose primary vaccinations to support registration of the booster dose 
and a 2-dose primary vaccination.  A secondary analysis will be performed on data from 28 
days after the second dose of the 12-week dosing interval to support assessment of this 2-dose 

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primary vaccination.  The final analysis will be performed on data from 6 months follow-up 
after participant's vaccination.  
1.2
Schema
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster 
Note:  In addition to the planned 2590 seronegative participants enrolled to support the primary/secondary objectives, 
seropositive participants will also be enrolled in the study to support exploratory objectives in this population, with a cap of 

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10% of the planned seronegative participants (ie, a maximum of 259 seropositive participants, bringing total planned 
enrollment to 2849).
1.3
Schedule of Activities
Table 1
Schedule of Activities: Screening 
Procedure
Day -14 to Day 1
See Section
Informed consent
X
5.1, Appendix A 3
Demography
X
-
Medical and surgical history
X
-
Prior and concomitant medications
X
6.5
Complete physical examination, including height and weight
X
8.2.1
Vital signs
X
8.2.2
Urine pregnancy test (for women of childbearing potential only) 
X
8.2.3
Clinical safety laboratory assessments
X
8.2.3
Assessment of serious adverse events
X
8.3, Appendix B
Blood sample for SARS-CoV-2 antibody testing (lateral flow test)
X
8.5.2
Verify eligibility criteria
X
5.1, 5.2
Note:  Screening activities can occur at same visit as initial vaccination with investigational product (ie, Visit 1 in 
Table 2, Table 3, and Table 4).

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Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine
Procedure
Treatment and Follow-up Period
Section
Day
1
8
15
29
180
Window (days)
-
±2
±2
±3
±14
Medical and surgical history
X
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
-
-
6.1.1
Immunological assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
-
8.3.7
e-Diary collected
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)b
X
-
X
X
8.2.3
a
Only SAEs pre-dose
a
Not required to be repeated if performed on screening day prior to Day 1.
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: 
serious adverse event

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
Urine pregnancy test
(women of childbearing potential)
X 
-
-
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
X 
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample for SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample for additional immunogenicity
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
X
-
-
-
8.3.7

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
X
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X (pre-dose)
X
-
X
X
8.2.3
b
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X
-
-
-
X
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X
-
-
-
X
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
X
-
-
-
8.3.7

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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2
INTRODUCTION
AZD2816 is being developed for the prevention of COVID-19.  It is a modified version of the 
current AstraZeneca SARS-CoV-2 vaccine (referred to as AZD1222 in clinical 
documentation) that has been modified to also provide immunity against the newly emerging 
SARS-CoV-2 variant strain B.1.351.  Like AZD1222, AZD2816 is a recombinant replication-
defective chimpanzee adenovirus vector (ChAdOx1) expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tissue plasminogen activator leader sequence at the 
N terminus.  AZD2816 differs from AZD1222 in that the S glycoprotein gene sequence used 
is from the B.1.351 variant strain instead of the original Wuhan-Hu-1 variant.
2.1
Study Rationale
The aim of the study is to assess the safety and immunogenicity of AZD2816 for prevention 
of COVID-19 as both a 2-dose primary vaccination in previously unvaccinated participants 
and a 1-dose booster vaccination in participants previously vaccinated against the original 
Wuhan-Hu-1 strain of SARS-CoV-2 by either AZD1222 or an mRNA-based vaccine.  A safe 
and effective vaccine for COVID-19 prevention, including against the B.1.351 variant, would 
have significant global public health impact. 
The study will also investigate the safety and immunogenicity of 1) a heterologous 2-dose 
vaccination with AZD1222 as first dose and AZD2816 as the second dose and 2) a single dose 
of AZD1222 as a booster vaccination in participants that have been previously vaccinated 
with an mRNA COVID-19 vaccine targeting the original Wuhan-Hu-1 strain.  
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (Zhou et al 2020). The disease these patients contracted was subsequently 
named Coronavirus Disease 2019 (COVID-19).  The World Health Organization declared the 
novel coronavirus a pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the 
novel coronavirus SARS-CoV-2, has resulted in significant global morbidity and mortality as 
well as major disruption to healthcare systems.  Measures to change the course of the 
pandemic have included the accelerated development vaccines against the original Wuhan-
Hu-1 strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes.  SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus,
and it is the seventh corona virus known to cause human infections and the third known to 
cause severe disease after SARS-CoV and MERS-CoV.  One fourth of the viral genome is 

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responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 
and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 spike (S) glycoprotein is a type I trimeric, transmembrane protein that is 
located at the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s 
subunits are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the 
receptor binding domain and subsequent fusion of virus and cell membranes, thereby 
mediating the entry of SARS-CoV-2 into the target cells.  The S protein has an essential role 
in virus entry and determines tissue and cell tropism, as well as host range.  The roles of the 
S-protein in receptor binding and membrane fusion have made it a desirable target for vaccine 
and antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947 
(ie, the Wuhan-Hu-1 isolate).
To date, 5 vaccines that rely upon the expression of the SARS CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 
NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b).  Immunogenicity data indicate that a 
single dose of AZD1222 elicits both humoral and cellular immunogenicity responses and that 
antibody responses are boosted after a second dose.  In a pooled analysis of the 4 studies 
conducted in the United Kingdom, Brazil, and South Africa (database lock 7 December 2020), 
the vaccine was highly immunogenic; seroresponse of S binding antibody was > 98% after a 
single dose of AZD1222.  Seroresponse of live neutralising antibody was 82.4% after 1 dose, 
which rose to 99.4% after a second dose.  Efficacy analyses of the pooled DCO2 data 
demonstrated effective protection of AZD1222 against COVID-19 with a vaccine efficacy of 
66.73% (95.84% CI: 57.41%, 74.01%) (p < 0.001) from 15 days after the second dose in 
seronegative participants receiving 2 doses.  The DCO2 data also demonstrated that the 
standard dose of AZD1222 (5 x 1010 viral particles) provides complete protection against 
COVID-19 hospital admission ≥ 22 days after the first dose in the seronegative analysis set 
(0 versus 14 cases in the control group, 2 of which were severe, including one with a fatal 
outcome).  Vaccine efficacy was similar in participants with pre-existing comorbidities, being 

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those at greatest risk of severe outcomes of COVID-19, compared to that in the general 
population.  Recently available primary analysis data from a Phase III study performed in the 
United States and Latin America showed primary endpoint vaccine efficacy of 76% (95% CI: 
67.60%, 82.22%; p-value < 0.001). 
A sharp rise in COVID-19 cases was reported in late 2020, which was attributed to the 
emergence of new SARS-CoV-2 variant strains: B.1.1.7 in the United Kingdom, B.1.351 
in South Africa, and P.1 in Brazil.  These variant strains carry a number mutations in the 
S protein sequence: 9 amino acids in B.1.1.7, 10 amino acids in B.1.351, and 12 amino acids 
in P.1 compared with the Wuhan-Hu-1 sequence.  These mutations may result in an increase 
of transmissibility and/or reduced vaccine effectiveness.  Variant B.1.351 was first identified 
in South Africa in October 2020.  Its attributes include approximately 50% increased 
transmission and moderate impact of neutralization by monoclonal antibody therapeutics, 
convalescent plasma and vaccine sera.  In vitro neutralization assays suggest that the B.1.351 
lineage viruses may be the most antigenically distinct from the original Wuhan-like strains 
(Zhou et al 2021).  In addition, evidence suggests that AZD1222 may afford diminished 
protection against mild-moderate COVID-19 disease arising from the B.1.351 variant (Madhi 
et al 2021).  
The development of candidate vaccines that would be effective against the B.1.351 variant 
strain is underway.  AZD2816 is being developed as an updated ChAdOx-nCov19 (AZD1222) 
vaccine designed to provide protective immunity against the newly arising B.1.351 variant 
strain, using the same ChAdOx1 platform and manufacturing processes used for 
AstraZeneca’s currently approved COVID-19 vaccine, AZD1222.  The purpose of this Phase 
II/III, multinational, randomised, partially double-blind, active-controlled study is to 
demonstrate the safety and characterize the immunogenicity of AZD2816, AstraZeneca’s 
candidate ChAdOx1 vector vaccine against B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative participants who have previously 
received a 2-dose primary vaccination series against the original SARS-CoV-2 Wuhan-
hu-1 strain (AZD1222 or an mRNA vaccine).
!
As a 2-dose homologous primary vaccination to SARS-CoV-2 seronegative participants 
who have not been vaccinated previously. 
The immunogenicity of a 2-dose primary heterologous vaccination (with AZD1222 as first 
dose and AZD2816 as second dose) to SARS-CoV-2 seronegative participants who are 
unvaccinated and a single booster dose of AZD1222 to SARS-CoV-2 seronegative 
participants who have previously received a 2-dose primary mRNA vaccination series against 
the original Wuhan-hu-1 strain will also be investigated.
SARS-CoV-2 seropositive participants will also be enrolled to support a parallel exploratory 
analysis in these participants. 

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A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD1222 and 
AZD2816 is provided in the respective Investigator’s Brochures.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD2816 and AZD1222 can be found in the respective Investigator’s Brochures.
2.3.1
Risk Assessment
AZD2816 has been developed using the same vaccine vector, ChAdOx1, as AZD1222 and 
only differs in the sequence for SARS-CoV-2 S glycoprotein that is inserted in the vector.  
The anticipated safety profile of AZD2816 is the same as the observed safety profile of 
AZD1222.  Risks associated with AZD2816 are thus the same as the risks associated with 
AZD1222, and no additional risks are anticipated due to the change in the targeted sequence.
A number of essentially mild and moderate adverse reactions to AZD1222 have been 
identified and resemble reactions frequently observed after many vaccines.  Based on pooled 
clinical data from studies with AZD1222, the most commonly expected local solicited AEs for 
participants in this study are vaccination site pain and tenderness.  The most commonly 
expected systemic solicited AEs are fatigue, headache, and malaise.  The majority of reported 
events have been mild or moderate in severity and resolved within 1 to 7 days.  Following the 
second dose, a general attenuation in the incidence and severity of local and systemic solicited 
AEs was observed. 
Post-authorisation hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk.
A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, 
has been observed very rarely following vaccination with COVID-19 Vaccine (ie, AZD1222) 
during post-authorisation use.  No events have been observed in the AZD1222 clinical 
development programme.  Thrombosis in combination with thrombocytopenia is thus 
considered to be an important identified risk.  This includes cases presenting as venous 
thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein 
thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia.  Considering 
the frequency of this rare event and the size of this study, the risk for participants in this trial 
is considered to be low.  The protocol includes exclusion criteria and instructions for 
heightened vigilance and thorough investigations for suspected cases to mitigate against 
further the risk for these rare event. 
Important potential risks are 1) neurologic events and potential immune-mediated neurologic 
conditions and 2) vaccine-associated enhanced disease, including vaccine-associated enhanced 
respiratory disease. 

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2.3.2 Benefit Assessment
All participants will receive active treatment: either AZD1222, which has been shown to be 
effective in providing protection against SARS-CoV-2, or AZD2816, which as a modified 
form of AZD1222 designed to be effective against the emergent B.1.351 variant strain and 
may also provide participants with protection.  The information gained from this study will 
inform development decisions with regard to the efficacy of AZD2816 as both a primary 
2-dose vaccination in participants that have not been previously vaccinated and a 1-dose 
booster vaccination in participants previously vaccinated against SARS-CoV-2. 
2.3.3 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria and close monitoring of participants to 
minimize known and potential risks. 
An independent Data Safety Monitoring Board will provide study oversight, evaluating 
cumulative safety and other clinical data at regular intervals. 
Taking these measures into account, the potential risks identified in association with the 
administration of AZD2816 and AZD1222 are justified by the anticipated benefit that may 
be afforded to participants for the prevention of COVID-19.

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3
OBJECTIVES AND ENDPOINTS
3.1
Naïve unvaccinated cohort receiving a 2-dose primary vaccination
The primary safety objective for the cohort of previously unvaccinated participants receiving a 
2-dose dose primary vaccination is to characterize the safety and tolerability of a 2-dose 
primary vaccination with AZD2816 with a 4-week dosing interval in previously unvaccinated 
seronegative participants.
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary: 
1: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response against the original 
Wuhan-hu-1 strain elicited by a 2-dose AZD1222 vaccination.
Key secondary:
2.1: To determine if seroresponse against the B.1.351 variant elicited by a 2-dose AZD2816 
vaccination is non-inferior to seroresponse against the original Wuhan-hu-1 strain elicited by a 
2-dose AZD1222 vaccination.
2.2: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 2-dose 
AZD1222 vaccination.
2.3: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose heterologous AZD1222 + AZD2816 vaccination is non-inferior to the 
response against the original Wuhan-hu-1 strain elicited by a 2-dose AZD1222 vaccination
2.4: To determine if the neutralizing antibody GMT response against the original Wuhan-hu-1 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 2-dose 
AZD1222 vaccination
The above primary and the key secondary immunogenicity objectives will be supported by 
other secondary immunogenicity objectives (see below) for which there will be no formal 
hypothesis testing.
Table 5 further describes the objectives and endpoints for this cohort of participants, including 
estimands for the immunogenicity objectives.

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Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination
Safety Objectives
Endpoints
- Primary
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 4-
week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of a 
heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 4-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety and tolerability of a 
heterologous primary vaccination with 1 dose
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 12-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
Immunogenicity Objectives
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:

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Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 
heterologous primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:

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Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original
Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a 2-dose homologous or 
heterologous primary vaccination with AZD2816 
and/or AZD1222 in sub-groups of seronegative and 
seropositive participants
! GMT of ChAdOx1 neutralizing antibody titres
! Seroresponse rate of ChAdOx1 neutralizing 
antibody titres
Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody 
titres, 1 month after both Dose 1 and Dose 2
Exploratory Objectives
Objective
Endpoints
To explore the immune response elicited by a 2-dose 
AZD2816 primary vaccination with a 12-week dosing 
interval compared to the response elicited by a 2-dose 
AZD2814 primary vaccination with a 4-week dosing 
interval
! GMT ratio of pseudoneutralizing antibodies
! Seroresponse

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To explore antibody response to selected SARS-CoV-2 
variants of interest/variants of concern following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! GMT of SARS-CoV-2 anti-S binding antibodies 
for selected variants of concern/variants of interest
! Seroresponse rate of SARS-CoV-2 specific   
binding antibody titres for selected variants of 
concern/variants of interest
! GMT of SARS-CoV-2 pseudoneutralizing 
antibody responses against the B.1.617.2 (delta) 
variant
! Seroresponse rate of SARS-CoV-2 
pseudoneutralizing antibody responses against the 
B.1.617.2 (delta) variant
To explore B-cell and T-cell responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! Intracellular cytokine staining and flow cytometry 
for T-cell responses over time
! Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 B.1.351 or Wuhan-Hu-1 S protein 
from day of dosing baseline over time
! Breadth and depth of peripheral blood B-cell and 
T-cell repertoire over time through 
immunosequencing
To monitor the incidence of SARS-CoV-2 infection 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or AZD1222 
in previously unvaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined 
by the seroresponse to nucleocapsid antibodies 
occurring post-second dose of study intervention 
To monitor the incidence of COVID-19 following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in previously 
unvaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses against the 
B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Magnitude of SARS-CoV-2 neutralization titres 
(geometric mean titre) as determined by a live 
virus neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific 
antibody binding and neutralization titres as 
determined by a live virus neutralization assay
To explore additional immune responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in sub-groups of 
seronegative and seropositive participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity 
data
!
To explore the immunogenicity objectives in 
seropositive participants
!
GMT of pseudoneutralizing antibodies
!
Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.

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3.2
Previously vaccinated cohort receiving a 1-dose booster 
vaccination
The primary safety objective for the cohort of seronegative previously vaccinated participants 
receiving a booster dose is to characterize the safety and tolerability of 1 booster dose of 
AZD2816 in participants previously vaccinated with AZD1222. 
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary:
1: To determine if the humoral immune response against the B.1.351 variant elicited by an 
AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior to 
the response against the original Wuhan-hu-1 strain elicited by 2-dose AZD1222 vaccination 
administered to vaccination naïve participants.
Key secondary:
2.1: To determine if the humoral immune response against the B.1.351 variant elicited by an 
AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior to 
the response elicited by 2-dose AZD1222 vaccination administered to vaccination naïve 
participants.
2.2:  To determine if the humoral immune response elicited against the B.1.351 variant by an 
AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 booster dose  
in participants previously vaccinated with AZD1222.
2.3: To determine if the humoral immune response against the original Wuhan-hu-1 strain 
elicited by an AZD2816 booster dose in participants previously vaccinated with AZD1222 is 
non-inferior to the response elicited by 2-dose AZD1222 vaccination administered to 
vaccination naïve participants.
2.4: To determine if the humoral immune response against the original Wuhan-hu-1 strain 
elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222 is 
non-inferior to the response elicited by a 2-dose AZD1222 vaccination
2.5: To determine if the humoral immune response against the original Wuhan-hu-1 strain 
elicited by an AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 
booster dose in participants previously vaccinated with AZD1222.
The primary and key secondary immunogenicity objectives will be supported by other 
secondary objectives for which there will be no formal hypothesis testing. Table 6 further 
describes the objectives and endpoints for this cohort of participants, including estimands for 
the primary and secondary immunogenicity objectives.

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Table 6
Study Objectives and Endpoints for Previously Vaccinated Participants 
Receiving a 1-Dose Booster Vaccination
Safety Objectives
Endpoints
- Primary
To characterize the safety and tolerability of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days 
post dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory measures 
for 28 days post-dose
- Secondary
To characterize the safety and tolerability of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the extended safety of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-hu-1
Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-hu-1
Wuhan-hu-1

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Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 
vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary (2.4)
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 
vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated with 
AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster

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To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated with 
AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated with 
an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1

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Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus  AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster vaccination
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:

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Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a booster dose of 
AZD2816 in sub-groups of seronegative and 
seropositive participants
! Magnitude of ChAdOx1 nAb titres (geometric mean 
titre)
! Seroresponse rate of ChAdOx1 neutralizing antibody 
titres
Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody titres, 1 
month after both Dose 1 and Dose 2
Exploratory objectives
Objective
Endpoints
To explore antibody response to selected SARS-
CoV-2 variants of interest/variants of concern 
following a booster dose of AZD2816 and in a 
sub-group of seronegative participants
! Magnitude of SARS-CoV-2 specific antibody binding 
titres (geometric mean titre) for selected variants of 
concern/variants of interest
! Seroresponse rate of SARS-CoV-2 specific   antibody 
binding titres for selected variants of concern/variants of 
interest
! GMT of SARS-CoV-2 pseudoneutralizing antibody 
responses against the B.1.617.2 (delta) variant
! Seroresponse rate of SARS-CoV-2 pseudoneutralizing 
antibody responses against the B.1.617.2 (delta) variant
To explore B-cell and T-cell responses following 
a booster dose of AZD2816 in a sub-group of 
seronegative participants
! Intracellular cytokine staining and flow cytometry for T-
cell responses over time
! Quantification of (IFN-γ) ELISpot responses to SARS-
CoV-2 B.1.351 or Wuhan-Hu-1 S protein from day of 
dosing baseline over time
! Breadth and depth of peripheral blood B-cell and T-cell 
repertoire over time through immunosequencing
To monitor the incidence of SARS-CoV-2 
infection following a booster dose of AZD2816 in 
previously vaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by the 
presence of nucleocapsid antibodies occurring post-dose 
of study intervention 
To monitor the incidence of COVID-19 following 
a booster dose of AZD2816 in previously 
vaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the immunogenicity objectives in 
seropositive participants
! GMT of pseudoneutralizing antibodies
! Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest.
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.

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4
DESIGN
4.1
Overall Design
This is a multi-country Phase II/III study to evaluate the safety and immunogenicity of 
AZD2816 as single-dose vaccination in previously vaccinated adult participants and as a 
2-dose primary vaccination in previously unvaccinated adult participants. 
A total of approximately 2590 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled across these 2 
populations with the goal of 1300 previously vaccinated participants receiving single-dose 
vaccination and 1290 unvaccinated participants receiving 2-dose primary vaccination. In 
addition, seropositive participants will be enrolled (with a cap of 10% of the seronegative 
population or 259 participants) to support exploratory analysis is these participants. 
The enrollment and randomization strategy is intended to minimize group differences in terms 
of age, gender and the presence of comorbidities, to support this strategy the study 
randomisation will include caps to ensure that at least 25% of enrolled participants within 
each treatment arm will be ≥ 65 years of age.
In both the single-dose booster treatment regimen and the 2-dose primary vaccination 
treatment regimen, participants will receive study intervention consisting of intramuscular 
administration of either AZD1222 (5 ×1010 viral particles) or AZD2816 (5 ×1010 viral 
particles).
Approximately 700 seronegative participants previously vaccinated with AZD1222 will be 
randomised 1:1 to receive a single intramuscular dose of either AZD1222 or AZD2816 in a 
double-blinded fashion.  
Approximately 600 seronegative participants previously vaccinated with an approved mRNA 
based vaccination against the original Wuhan-hu-1 strain will be randomised 1:1 to receive a 
single intramuscular dose of AZD2816 or AZD1222 in a double-blinded fashion.
Approximately 1290 seronegative, previously unvaccinated participants will be randomised 
approximately 5:5:5:2 to receive a 2-dose primary vaccination of the following:
!
2 doses of AZD1222 with a 4-week dosing interval
!
2 doses of AZD2816 with a 4-week dosing interval
!
1 dose of AZD1222 followed by 1 dose of AZD2816 with a 4-week dosing interval 
!
2 doses of AZD2816 with a 12-week dosing interval.
The 3 treatments with a 4-week dosing interval will be double-blinded while the treatment 
with the 12-week interval will be open-label due to the difference in dosing interval.

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In addition, a smaller population seropositive participants (approximately 10% of the
seronegative population), will be randomised to treatment in a similar manner as above.
Immunogenicity (ie, anti-Wuhan-Hu-1 and anti-B.1.351 immune responses including 
S-binding antibody titres and neutralizing antibody levels [pseudo-neutralization]) will be 
assessed in serum samples collected pre-dose on the day of each vaccination (baseline levels 
before vaccination), 14 and 28 days after each vaccination, and 180 days after the last 
vaccination.
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1-8 for all participants and Days 29-36 for the 4-week dosing interval and Days 85-92 
for the 12-week dosing interval).  An e-diary will be used to collect information on the timing 
and severity of the solicited signs and symptoms.
Follow-up visits will take place as per the schedule of assessment within respective windows.  
All participants will be assessed for local and systemic AE, physical examination, review of 
e-diaries at these time points as detailed in the schedule of assessment.  Blood will also be 
taken for safety assessments and immunology purposes.
All study participants will be followed for safety for 180 days after administration of their last 
vaccination dose.  In every participant, solicited local and systemic events will be reported for 
up to 7 days after each dose, all unsolicited AEs will be reported for up to 28 days after each 
dose, and SAEs and AEs of special interest will be evaluated through study completion 
(up to 180 days after the last study vaccination).  
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, 
to ensure safe and ethical conduct of the study.
4.1.1
COVID-19 Assessments
Occurrence of COVID-19 in the trial will be reported as safety events, including monitoring 
of the potential risk of vaccine-elicited enhanced disease as an AE of special interest (see 
Appendix E).  COVID-19 will be diagnosed and treated as per standard medical practice.  
In addition, experimental treatments are permitted.  Detailed information will be collected in 
a standard way and reported on a specific case report form. 

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4.1.2
Screening 
All potential participants will be screened, which may take place at a visit up to 14 days prior 
to Day 1 or on Day 1 itself.  
Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the screening procedures specified in the Schedule of Activities (Section 1.3) will be 
undertaken including a medical history, physical examination, height and weight, a 
SARS-CoV-2 screening test and clinical safety laboratory assessments.  Baseline information 
collected in the previously vaccinated participants will include which vaccine was received, 
immunization dose interval, and time since last vaccination.
For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled.  (Note: Women with urine test results that are positive or undetermined will not be 
enrolled and should be advised to seek medical attendance outside the context of the trial if 
pregnancy is suspected.) 
The eligibility of the participants will be reviewed at the end of the screening visit and again 
when all results from the screening visit have been considered.  Decisions to exclude the 
participant from enrollment or to withdraw a participant from the study will be at the 
discretion of the Investigator.
4.1.3
Vaccination Visit
Participants will be considered enrolled at the point of vaccination.  Before vaccination, the 
eligibility of the participant will be reviewed.  Body temperature will be observed and a 
medical history and physical examination will be undertaken before the first vaccination to 
determine need to postpone vaccination or screen fail the participant.  A negative pregnancy 
test (urine test) will need to be obtained from women of childbearing potential before 
vaccination.  Baseline blood samples will be obtained before the first vaccination.
Participants will receive 1 dose of AZD2816 or AZD1222 at vaccination visits, administered 
by intramuscular injection.  Previously immunized participants will have a single vaccination 
visit, Day 1.  Participants that have not been previously vaccinated at baseline will have a 
second vaccination visit on Day 29 (4-week interval) or Day 85 (12-week interval).  
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1 to 8 and Days 29 to 36 or Days 85 to 92 when applicable).

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4.1.4
Follow-up visits
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3).  All 
participants will be assessed for local and systemic AE, physical examination, review of the 
e-diary and blood tests at these time points as detailed in the Schedule of Activities.  Blood 
will also be taken for safety and immunogenicity assessments.
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate way until the last 
study visit in order to collect information on any SAEs/AE of special interest.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population includes adults ≥ 18 years of age.  Persons who are healthy or have 
medically stable underlying conditions will be eligible.  Adults with medically-stable chronic 
diseases may participate if, according to the judgement of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Some seropositive participants 
(capped at 10% of the seronegative participant population) will be enrolled to support an 
exploratory analysis.  
Those enrolled in the single-dose vaccination part of the study must have received 2 doses of 
AZD1222 (with a dosing interval of 4-12 weeks) or 2 doses of an approved mRNA-based 
COVID-19 vaccine (with a dosing interval of 3-12 weeks for the BNT162b2 mRNA vaccine 
[Pfizer-BioNTech] and 4-12 weeks for the mRNA-1273 vaccine [Moderna]) with the second 
doses administered at least 3 months prior to first study intervention administration. 
Pregnant/breastfeeding women, persons with severe immunodeficiency or severe underlying 
disease will be excluded from participation in the study.  Persons previously vaccinated with 
AZD1222 in the context of an AZD1222 vaccine trial are eligible for enrollment as previously 
vaccinated participants in the trial.  Persons who have previously received any other
investigational product for the prevention of COVID-19 will be excluded from participation in 
this study.
Participants with known risk factors for thrombosis and thrombocytopenia (excluding 
contraceptive hormonal therapy or replacement hormonal therapy) are excluded.

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4.2.2
Rationale for Study Endpoints
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination 
will be summarized by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be 
summarized by system organ class and preferred term, and by relationship to 
vaccination as assessed by the investigator.
!
SAEs and AEs of special interest following the first vaccination and throughout the 
study duration will be summarized by system organ class and preferred term and by 
relationship to vaccination as assessed by the investigator.
Solicited AEs will be collected for 7 days after each dose of study intervention, a period that 
has proven adequate to describe reactogenicity events in previous vaccine studies.  For all 
participants, AEs will be collected through 28 days after each dose of study intervention.  
SAEs, medically-attended AEs, and AEs of special interest and will be collected from Day 1 
through end of the study.  AEs of special interest include terms identified by the Brighton 
Collaboration involving events associated with vaccination in general .
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean titre
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean titre from baseline
Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of 
interest.
Immunogenicity against SARS-CoV-2 Wuhan-Hu-1 and B.1.351 strains will be characterized 
through the quantification of Spike-binding antibodies, pseudo-neutralization and, in a subset 
of participants, live neutralization.  Exploratory analysis of immunogenicity against other 
strains and induction of other immune effectors including cell-mediated immunity will be 
conducted. 
4.3
Justification for Dose
The AZD2816 nominal dose of 5 × 1010 viral particles is the same dose as the approved dose 
for AZD1222, which was based on the accumulated non-clinical data and clinical data from 
the AZD1222 clinical studies, as well as from other SARS-CoV-2 vaccines in development. 
Safety and immunogenicity data from an additional clinical study, MERS001(NCT03399578), 
using the same ChAdOx1 vector, also helped inform dose selection. MERS001 was the first 
clinical study of a ChAdOx1-vectored vaccine expressing the full-length S protein from a 

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separate, but related, beta-coronavirus.  ChAdOx1 MERS has been given to 31 participants to 
date at doses ranging from 5 × 109 viral particles to 5 × 1010 viral particles.  Despite higher 
reactogenicity observed at the 5 × 1010 viral particles, this dose was safe, with self-limiting 
AEs and no serious adverse reactions recorded.  The 5 × 1010 viral particles was the most 
immunogenic, in terms of inducing neutralizing antibodies against MERS-CoV using a live 
virus assay (Folegatti et al 2020).  Given the immunogenicity findings and safety profile 
observed with the ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 viral particles 
dose was chosen for AZD1222.  
Based on accumulating nonclinical and clinical data gathered for AZD1222, a 2-dose regimen 
was selected for vaccination of unvaccinated participants with AZD2816 (AZD1222 
Investigators Brochure).  A single dose vaccination has been selected for participants 
previously vaccinated in line with both FDA and EMA guidance (FDA 2021, EMA 2021).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities (Section 
1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as a protocol waiver or exemption, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1
All Participants: 
Age
1
Adult, ≥ 18 years of age at the time of consent
COVID-19
For inclusion in the SARS-CoV-2 seronegative population supporting the primary and 
secondary objectives: 
2
No history of laboratory-confirmed SARS-CoV-2 infection (ie, no positive nucleic acid 
amplification test and no positive antibody test).

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3
Seronegative for SARS-CoV-2 at screening (lateral flow test to detect reactivity to the 
nucleoprotein).
Note, patients failing to meet criteria 2 and/or 3 may be included in the separate seropositive 
population supporting the seropositive exploratory objectives. 
Type of Participant 
4
Medically stable such that, according to the judgment of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up
∀
- A stable medical condition is defined as disease not requiring significant change in 
therapy or hospitalization for worsening disease during the 3 months prior to enrollment
5
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator
6
Signed informed consent obtained before conducting any study-related procedures
Reproduction
7
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants:
(a) Women of childbearing potential must:
!
Have a negative pregnancy test on the day of screening and on days of 
vaccination
!
Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
30 days following administration of the last dose of study intervention.  A highly 
effective method of contraception is defined as one that can achieve a failure rate 
of less than 1% per year when used consistently and correctly (see Table 7).  
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy) or 
!
Post-menopausal:
!
For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥ 12 months amenorrhea prior to randomization, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and

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o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal 
range, the participant is to be considered of childbearing potential
!
For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomization, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.
Table 7
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing systema
Bilateral tubal occlusion
Vasectomized partner b
Sexual abstinence c
Combined (oestrogen- and progestogen-containing 
hormonal contraception
      Oral (combined pill)
      Intravaginal
     Transdermal (patch)
Progestogen-only hormonal contraception
#
     Oral 
#
     Injectable
#
     Implantable
a
This is also considered a hormonal method 
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse from 28 days prior to Day 1 through 30 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant
5.1.2
Previously COVID-19 Vaccinated Participants
8
Prior completion of a 2-dose primary homologous vaccination regimen against the 
original SARS-CoV-2 Wuhan-hu-1 strain with either AZD1222 (2 standard doses as 
authorized vaccine or as investigational product in a clinical trial with a 4- to 12-week 
dosing interval) or with an mRNA vaccine approved for emergency or conditional use 
(eg, BNT162b2 vaccine [Pfizer-BioNTech] with a 3- to 12-week dosing interval or 
mRNA-1273 vaccine [Moderna] with a 4- to 12-week dosing interval).  The second dose 
in all cases should have been administered at least 3 months prior to first administration 
of study intervention.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of allergy to any component of AZD1222/AZD2816.
2
History of Guillain-Barré syndrome, any demyelinating disease, or any other 
neuroimmunologic condition

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3
Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) on the 
day prior to or day of randomization 
4
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia or HIV/AIDS. 
5
Recurrent severe infections and use of immunosuppressant medication within the past 
6 months (≥ 20 mg per day of prednisone or its equivalent, given daily or on alternate 
days for ≥ 15 days within 30 days prior to administration of study intervention)
The following exceptions are permitted:  
∀
Topical/inhaled steroids or short-term oral steroids (course lasting ≤14 days)
6
History of primary malignancy except for:
(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or for metastasis (for example, indolent 
prostate cancer) in the opinion of the site investigator.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
(c) Adequately treated uterine cervical carcinoma in situ without evidence of disease
(d) Localized prostate cancer
7
History of thrombocytopenia and/or thrombosis, including participants who have 
experienced major venous and/or arterial thrombosis in combination with 
thrombocytopenia following vaccination with any COVID-19 vaccine
8
History of heparin-elicited thrombocytopenia, congenital thrombophilia (ie, factor V 
Leiden, prothrombin G20210A, antithrombin III deficiency, protein C deficiency and 
protein S deficiency, factor XIII mutation, familial dysfibrinogenemia), auto-immune 
thrombophilia (antiphospholipid syndrome, anti-cardiolipin antibodies, anti-β2-
glycoprotein 1 antibodies), or paroxysmal nocturnal haemoglobinuria.
9
Clinically significant bleeding (eg, factor deficiency, coagulopathy, or platelet disorder), 
or prior history of significant bleeding or bruising following intramuscular injections or 
venepuncture
10 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, or neurological illness, as judged 
by the Investigator (note, mild/moderate well-controlled comorbidities are allowed)
11 Any other significant disease, disorder, or finding that may significantly increase the risk 
to the participant because of participation in the study, affect the ability of the participant 
to participate in the study, or impair interpretation of the study data
12 Any autoimmune conditions, except mild psoriasis and vitiligo
Note: The AEs of special interest as outlined in Appendix E (including Table 28) should be 
considered when evaluating a participant for exclusion criteria as the presence of these AEs of 
special interest, especially if untreated or uncontrolled, may be a safety risk to the participant, 

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affect the ability of the participant to participate in the study, and/or impair interpretation of 
the study data.  Investigators should review and consider the list of conditions in Appendix E.  
If any of these conditions are present in a participant, the Investigator is asked to utilize 
his/her clinical judgment in determining the participant’s eligibility for the study.  Should the 
participant have conditions as outlined in Appendix E and the participant is enrolled, the 
Investigator is asked to document notes on site regarding the final rationale for enrollment.
Prior/Concomitant Therapy
13 Receipt of or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 with the exception of prior vaccination with 
AZD1222 or an mRNA COVID-10 vaccine (2 doses of the same vaccine within an 
approved dosing interval, see Section 5.1.2), which is allowed for participants in the 
previously vaccinated cohort 
Note: For participants who develop COVID-19, receipt of licensed treatment options 
and/or participation in investigational treatment studies is permitted
14 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to or after administration of study intervention
15 Receipt of any influenza vaccine (licensed or investigational) within 7 days prior to and 
after administration of AZD1222/AZD2816.
16 Receipt of immunoglobulins and/or any blood products within 3 months prior to 
administration of study intervention or expected receipt during the period of study 
follow-up
Other Exclusions
17 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)
18 Women who are currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, having given birth less than 3 months before or planning pregnancy during 
the study. 
19 Has donated ≥ 450 mL of blood products within 30 days prior to randomization or 
expects to donate blood within 90 days of administration of second dose of study 
intervention
20 Participants with a history of chronic alcohol or drug abuse or any condition associated 
with poor compliance.
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements or 
if vaccination would interfere with the participant’s ongoing treatment.
22 Previous enrollment in the present study.

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5.3
Lifestyle Considerations
1
Participants must follow the contraception requirements outlined in Section 5.1
2
Restrictions relating to concomitant medications are described in Section 6.5
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Only a single rescreening is allowed in the study.  Rescreened participants are 
required to sign a new ICF (Appendix A 3), and will be assigned a new participant number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical device utilized by a study participant according to 
the study protocol.  Study intervention is defined as AZD2816 or AZD1222 (Table 8).
6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 8
Investigational Products
Intervention 
Name
AZD2816
AZD1222
Type 
Vaccine
Vaccine
Dose Formulation
Unit Dose Strength
1 × 1011 viral particles/mL
1 × 1011 viral particles/mL
≥ 5 × 108 infectious units/mL
≥ 5 × 108 infectious units/mL
Dosage Level
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
≥ 2.5 × 108 infectious units
≥ 2.5 × 108 infectious units
Route
Intramuscular
Intramuscular
CCI
CCI

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Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labelling
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Current/Former 
Name
-
Previous clinical documentation:
ChAdOx1 nCoV-19
Current tradename: Vaxzevria
IMP: investigational medicinal product; NIMP: non-investigational medical product; w/v: weight/volume.
AZD2816 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD2816 has 
a label-claim volume of 5 mL and can provide up to ten 0.5 mL doses.
AZD1222 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD1222 has 
a label-claim volume of 4 mL and can provide up to eight 0.5 mL doses.
Unopened vials of AZD2816 and AZD1222 must be stored at 2-8 oC (36-46 oF) for the 
duration of the assigned shelf-life and must not be frozen.  Both investigational products must 
be kept in original packaging until use to prevent prolonged light exposure. 
6.1.2
Dosing Instructions
Previously unvaccinated participants will receive 2 doses of either AZD1222, AZD2816, or 
AZD1222 plus AZD2816, with the first dose administered on Day 1 and the second dose on 
Day 29 (for a 4-week dosing interval) (Table 3) or Day 85 (for a 12-week dosing interval) 
(Table 4). 
Previously vaccinated participants will receive 1 dose of either AZD1222 or AZD2816 
(Table 2).  
It is recommended that the study interventions be administered as an intramuscular injection 
into the deltoid of the non-dominant arm. Other injection sites may be used if necessary.
All study participants will be observed in the clinic for at least 15 minutes after vaccination. 
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.

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6.2
Preparation/Handling/Storage/Accountability
The procedures for preparation, handling, storage, and accountability are identical for 
AZD2816 and AZD1222.
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual or specified handling instructions.
6.2.1
Dose Preparation and Administration
Doses of AZD2816 and AZD1222 must be prepared by the unblinded pharmacist (or designee 
in accordance with local and institutional regulations) using aseptic technique.  Each dose is 
prepared by withdrawing 0.5 mL from a vial of AZD2816 or AZD1222 in a sterile syringe. 
AZD2816 and AZD1222 do not contain preservatives. Each vial must be assigned a beyond-
use-date of 6 hours at 2-30 °C (36-86 °F) from first needle puncture of the vial, after which 
any unused portion must be discarded.
Once an AZD2816 or AZD1222 dose is drawn into a syringe for administration, the dose must 
be administered within the beyond-use-date of the vial. If dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
The study contains 3 cohorts that are randomised to a total of 8 treatments: 
!
Participants that have previously been vaccinated with 2 doses of AZD1222 will be 
randomised 1:1 to 1 dose of AZD2816 or 1 dose of AZD1222.

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!
Participants that have been previously vaccinated with an mRNA COVID-19 vaccine will 
be randomised 1:1 to 1 dose of AZD2816 or AZD1222.  
!
Vaccination naïve participants that will be randomised 5:5:5:2 to 2 doses of AZD2816 
with a 4-week dosing interval, 2 doses of AZD1222 with a 4-week dosing interval, 1 dose 
of AZD1222 followed by 1 dose of AZD216 with a 4-week dosing interval, or 2 doses of 
AZD2816 with a 12-week dosing interval.
Separate populations of SARS-CoV-2 seronegative participants (supporting the primary and 
secondary objectives) and SARS-CoV-2 seropositive participants (supporting exploratory 
objectives) will be randomised/included in the above cohorts.
Randomization will be stratified based on age (less than 65, 65 and above), gender, and 
presence of at least one of the following comorbidities that are known risk factors for severe 
illness from COVID-19 (based on the participant’s past and current medical history):
!
Obesity (BMI ≥ 30 kg/m2 at baseline)
!
Significant cardiovascular disease (eg, heart failure, coronary artery disease, congenital 
heart disease, cardiomyopathies, or pulmonary hypertension)
!
Chronic lung disease (eg, chronic obstructive pulmonary disease, idiopathic pulmonary 
disease, cystic fibrosis, or moderate to severe asthma)
!
Diabetes.  
The randomised participants will be centrally assigned to randomised study intervention using 
an Interactive Response Technology (IRT)/Randomisation and Trial Supply Management.  
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 
the log in information & directions for the Randomisation and Trial Supply Management will 
be provided to each site.
Where a participant does not meet all the eligibility criteria but incorrectly received study 
intervention, the investigator should inform the Study Physician immediately, and a discussion 
should occur between the Study Physician and the investigator regarding whether to continue 
or discontinue the participant.
6.3.2
Blinding
Treatment will be double-blinded for previously vaccinated participants randomised to a 
single dose of either AZD2816 or AZD1222. Treatment will also be double-blind for 
previously unvaccinated participants randomised to 2 dose vaccinations with a 4-week dosing 
interval (ie, homologous AZD2816 or AZD1222 vaccination or heterologous 
AZD1222/AZD2816 vaccination).  Previously unvaccinated participants randomised to a  
homologous AZD2816 vaccination with a 12-week dosing interval will receive treatment in 
an open-label fashion due to the different dosing interval.

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For the double-blinded treatments, neither the participant nor any of the investigators or 
Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
participants will be aware of the study intervention received.  Since AZD2816 and AZD1222 
are visually distinct prior to dose preparation (due to differences in container closure), all 
investigational product will be handled by an unblinded pharmacist (or designee in accordance 
with local and institutional regulations) at the study site. Once drawn into syringes for 
administration, AZD2816 and AZD1222 are not visually distinct from each other.
The IRT will provide the investigators with a dose tracking number to be allocated to the 
participant at the dispensing visit.  Routines for this will be described in the IRT user manual 
that will be provided to each study site.
For participants receiving double-blinded treatments, the randomization code should not be 
broken except in medical emergencies when the appropriate management of the participant 
requires knowledge of the treatment randomization.  The investigator documents and reports 
the action to the Sponsor, without revealing the treatment given to participant to the Sponsor 
staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities.  Randomization codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.
6.3.3
Procedures for Unblinding
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
in which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment 
is warranted.  Participant safety must always be the first consideration in making such a 
determination.  If a participant’s intervention assignment is unblinded for safety, the Sponsor 
must be notified within 24 hours after breaking the blind. 
In the event that a study participant is contacted about receiving a licensed and/or authorized 
COVID-19 vaccine outside of this clinical study, unblinding instructions are being provided to 
the sites.  If the participant is unblinded, the Sponsor needs to be notified within 24 hours, and 
this should be documented in the site source documents.
6.4
Study Intervention Compliance
Participants are dosed at the study site, receiving study intervention directly from the 
investigator or designee, under medical supervision.  The date, and time if applicable, of dose 

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administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the period specified in the 
Schedule of Activities (Section 1.3), must be recorded in the eCRF along with the information 
listed below.  Vitamins and/or herbal supplements are not to be recorded.
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
!
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance.
!
Primary care providers, or where appropriate investigators, should prescribe appropriate 
concomitant medications or treatments deemed necessary to provide full supportive care 
and comfort during the study.
!
Participants who develop COVID-19 after receiving study intervention should be treated 
with licensed medications and interventions according to standard of care.  All routine 
vaccinations other than influenza are permitted beginning > 30 days after last dose of 
study intervention.  Licensed influenza vaccines are permitted 7 days before and 7 days 
after administration of study intervention. 
!
Topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 days) are 
permitted
6.5.2
Prohibited Concomitant Medications
The following medications are prohibited and the Sponsor must be notified if a participant 
receives any of these prohibited medications.  The use of the following concomitant 
medications and/or vaccines, however, will not definitively require withdrawal of the 
participant from the study, but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis set.
!
Primary or booster vaccinations, other than AZD2816 or AZD1222, for prevention of 
SARS-CoV-2 or COVID-19.

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Note: Participants choosing to receive a licenced and/or authorized COVID-19 vaccine 
should inform the Investigator so it can be properly documented.  Participants, who 
receive a licenced and/or authorized COVID-19 vaccine outside the study, should be 
encouraged to continue study conduct to be followed for safety reporting and all 
assessments.
!
Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention.  Thirty days after 
the second vaccination, other routine vaccinations are permitted as clinically indicated.
!
Glucocorticoids at a dose ≥ 20 mg/day of prednisone or equivalent given daily or on
alternate days for ≥ 14 consecutive days between randomization and the participant’s
scheduled final visit
!
Other systemically administered drugs with significant immunosuppressive activity,
such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy
between randomization and the participant’s scheduled final visit
!
Immunoglobulins and/or any blood product.
If a participant receives a prohibited concomitant medication, the investigator in consultation 
with the Sponsor will evaluate any potential impact on receipt of study intervention based on 
time the medication was administered, the medication’s pharmacology and pharmacokinetics, 
and whether the medication will compromise the participant’s safety or interpretation of the 
data (see Section 7.1). 
6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.  Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive the first or second dose (if applicable) of study 
intervention if any of the following occur in the participant in question:
1
Withdrawal of consent after signing informed consent
2
Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 
3
Participant is pregnant or nursing

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4
Any grade 3 or greater allergic reaction including anaphylaxis that is assessed as related 
to study intervention 
5
Occurrence of any thrombosis with concurrent thrombocytopenia 
6
Any SAE assessed as related to study intervention
7
Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardize the safety of the study participant 
8
Receipt of a prohibited concomitant medication that may jeopardize the safety of the 
study participant or interpretation of the data
Each participant who has received at least 1 dose of study intervention will be followed for the 
full study period unless consent is withdrawn specifically from further study participation, or 
the participant is lost to follow-up.  Participants who have not received study intervention, 
regardless of reason, will not be followed.
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine 
during the study, AstraZeneca needs to be notified within 24 hours and this should be 
documented in the site source documents.  Participants who have received study intervention, 
regardless of reason, will be followed for the full study period.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent.  If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken should be 
carried out in line with what was stated in the informed consent and local regulation.  
The investigator must document the decision on use of existing samples in the site study 
records and inform the Sponsor Study Team.  If the participant does not specifically 
request withdrawal of consent for use of samples, then the samples collected prior to the 
consent withdrawal will be destroyed once per protocol analysis is complete.

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7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the Schedule of Activities (Section 
1.3).  Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities.

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8.1
Efficacy Assessments
Not applicable.  
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.  Each clinically significant 
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history, 
clinical signs, and symptoms and will include signs of thrombosis and/or 
thrombocytopenia.  Each clinically significant abnormal finding following vaccination 
will be recorded as an AE.
!
All physical examinations will be performed by a licensed healthcare provider 
(eg, physician, physician assistant, or licensed nurse practitioner). 
8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3).  The participant should be 
resting prior to the collection of vital signs.  On vaccination days, vital signs should be 
assessed prior to vaccine administration.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3).  Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the investigator, with the 
date and time of collection recorded in the appropriate eCRF.
The standard clinical chemistry and haematology analysis will be performed at a local 
laboratory at or near to the investigator site.  Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.  
The following laboratory variables will be measured:

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Table 9
Laboratory Safety Variables
Blood
Serum/Plasma
Haemoglobin
Activated partial thromboplastin time
Leukocyte count
Prothrombin time
Leukocyte differential count (absolute count)
Fibrinogen
Platelet count
D-dimer
-
Creatinine
-
Bilirubin, total
-
Alkaline phosphatase
-
Aspartate aminotransferase 
-
Alanine aminotransferase
In case a participant shows an aspartate aminotransferase or alanine aminotransferase 
≥3 × upper limit of normal together with total bilirubin ≥2 × the upper limit of normal, please 
refer to Section 8.3.6
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the Schedule of Activities (Section 1.3).  Urine pregnancy tests for 
∃-human chorionic gonadotropin may be performed at the site using a licensed dipstick test.  
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a e-diary (Section 8.3.7), and will be assessed separately 
from the (unsolicited) AEs collected during the study.  General information for AEs in this 
protocol excludes the reporting of solicited AEs via e-diary unless otherwise noted.. 
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.

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8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
AEs will be recorded for 28 days after each dose of study intervention. 
Solicited AEs will be recorded for 7 days after each dose of study intervention (ie, Day 1 
through Day 8). If a solicited AE is not resolved within the e-diary reporting period, the event 
will be reported as a non-solicited adverse event in the eCRF, with a start date of when started 
and the actual stop date. 
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact. 
See the Schedule of Activities for the scheduled timepoints (Section 1.3). 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Severity grade/maximum severity grade/changes in severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome

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In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA 2007) will be utilized for all unsolicited events. 
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol-mandated vital signs and laboratory safety 
assessments will be summarized in the Clinical Study Report. 

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Deterioration as compared to baseline in protocol-mandated vital signs and laboratory safety 
assessment should therefore only be reported as AEs if they fulfil any of the SAE or 
medically-attended AE criteria or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or 
non-planned visits were required).
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an SAE or medically-attended AE, and the associated vital sign 
will be considered as additional information. 
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation.  Any occurrences of aspartate aminotransferase or alanine aminotransferase 
≥3 × the upper limit of normal together with total bilirubin ≥2 × upper limit of normal at any 
point during the study following the administration of study medication should be reported to 
the Sponsor as a potential Hy's Law SAE within 1 day with a serious criteria of ‘Important 
medical event’ and causality assessment ‘yes/related’.
The study physician will contact the investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 10) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention via e-diary collection. If a solicited AE is not resolved within the e-diary 
reporting period, the event will be also reported as a non-solicited adverse event in the eCRF, 
with a start date of when started and the actual stop date.
Solicited AEs should not be reported as unsolicited AEs unless they fulfil the criteria for SAEs 
or medically-attended AEs(see Sections 8.3 and 8.3.8, respectively).

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Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic 
Pain at the site of the injection 
Fever (> 100 °F/37.8 °C)
Redness/erythema at the site of the injection
Chills
Tenderness at the site of the injection
Muscle pains
Induration/swelling at the site of the injection 
Fatigue (physical or mental tiredness/exhaustion)
-
Headache
-
Malaise (general feeling of discomfort or uneasiness)
-
Nausea
-
Vomiting
Solicited AE e-Diary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given a thermometer, tape measure or ruler, and access to the Solicited 
AE e-Diary, with instructions on use, along with the emergency 24-hour telephone number to 
contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms. 
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorized representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix D.  Because 
solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention. 
8.3.8 COVID-19 Assessment
This study will describe the incidence of COVID-19 adverse events reported from Day 1 to 
180 days after the participant’s last/only dose of vaccine.  
COVID-19 is defined as SARS-CoV 2-RT-PCR positive symptomatic illness.  At all clinic 
visits following the initial vaccination, participants will be asked if they have had a diagnosis 
of COVID-19 since their last clinic visit (see Schedule of Activities in Section 1.3). Medical 
records will be obtained for confirmation of a participant-reported diagnoses of COVID-19.  
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea.  Events will be reported as AEs/SAEs.

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If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed 
using RT-PCR.
8.3.9 Medically-Attended Adverse Events
Medically-attended AEs will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3).
Medically-attended AEs are defined as AEs leading to medically-attended visits that were not 
routine visits for physical examination or vaccination, such as an emergency room visit, or an 
otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. 
AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
illness visits will not be considered medically-attended AEs.
8.3.10
Adverse Events of Special Interest
AEs of special interest will be collected according to the timepoints specified in the Schedule 
of Activities (Section 1.3). 
AEs of special interest are events of scientific and medical interest specific to the further 
understanding of study intervention safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor.  AEs of special interest are based on 
Brighton Collaboration case definitions (SPEAC 2020), clinical experience, and scientific 
interest.  A list of events is provided in Appendix E.
An AE of special interest can be serious or non-serious.  All AEs of special interest will be 
recorded in the eCRF.  If any AE of special interest occurs in the course of the study, 
investigators or other site personnel will inform the appropriate Sponsor representatives within 
1 day ie, immediately but no later than 24 hours of when he or she becomes aware of it.  
Serious AEs of special interest will be recorded and reported as per Section 8.3.11.
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest
Both thrombotic, thromboembolic, and neurovascular events and thrombocytopenia events are 
considered to be adverse events of special interest.  The investigator should remain vigilant for 
the occurrence of thrombotic events with thrombocytopenia and/or bleeding.  If a participant 
experiences new onset thromboembolic events with thrombocytopenia, there should be 
prompt evaluation with a thorough haematological investigation.  COVID-19 testing, 
including PCR and serology (nucleoprotein antibodies), should also be performed.  See 
Appendix F for further guidance on investigation and management of suspected events.
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and whole genome 

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sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events.
8.3.10.2
Potential Neurological Adverse Events of Special Interest
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation, including referral to a neurology specialist for further 
evaluation and testing, as clinically indicated.  Testing can include evaluation for peripheral 
demyelinating conditions (eg, electromyography).  In cases of concern for spinal cord disease, 
see Figure 3 for a recommended testing algorithm. 
An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AEs of special interest occurring 
in the AZD1222 clinical development program (see Appendix A 5).  

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Figure 3
Neurology Testing Algorithm
a
Adapted from Rovira et al 2015
Ab: antibody; ACE: angiotensin converting enzyme; ADC: apparent diffusion coefficient; ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibodies; AQP4: 
aquaporin 4; CMV: cytomegalovirus; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebral spinal fluid; CT: computed tomography; DWI: diffusion-weighted 
image; EBV: Epstein-Barr virus; ED: emergency department; ENA: extractable nuclear antigen antibodies; ESR: erythrocyte sedimentation rate; FLAIR: fluid-attenuated inversion 
recovery; GRE: gradient echo; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IgG: immunoglobulin G; MOG: myelin oligodendrocyte glycoprotein; MRI: 
magnetic resonance image; PCR: polymerase chain reaction; RF: rheumatoid factor; RPR: rapid plasma reagin; STIR: short T1 inversion recovery; SWI: susceptibility-weighted 
imaging; TSH: thyroid stimulating hormone; TM: transverse myelitis; VDRL: Venereal Disease Research Laboratories; VZV: varicella-zoster virus. 

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8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedures.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Sponsor representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available.
The Sponsor representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness is the AZD1222 Investigators 
Brochure, Section 5.6. 
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor, except if the pregnancy is discovered 
before the participant has received any study intervention.
8.3.12.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2).  Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the study intervention may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 

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spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the participant was discontinued 
from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.11) and within 30 days for all other pregnancies 
that are not associated with an SAEs.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module may be used to report the outcome of the pregnancy.
8.3.13
Medication Error
If a medication error occurs, then the investigator or other site personnel informs the 
appropriate Sponsor representatives within 1 day, ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 3. 
8.4
Overdose
For this study, any dose of study intervention exceeding that specified in the protocol will be 
considered an overdose.
There is no specific treatment for an overdose with AZD2816 or AZD1222.  If overdose 
occurs, the participant should be treated supportively with appropriate monitoring as 
necessary.

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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose occurs in the course of the study, the investigator or other site personnel inform 
appropriate Sponsor representatives immediately, but no later than 24 hours after when he or 
she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual.  Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality.  Further details on Handling of Human 
Biological Samples are provided in Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a 
maximum of 15 years following issue of the Clinical Study Report.  Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses, eg, exploratory immunology, such 
as systems serology and profiling of B- and T-cell repertoire.  The results from further 
analysis will not be reported in the Clinical Study Report.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).  Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual.  Results for exploratory immunogenicity analyses may 
be reported separately from the CSR.

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8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the Schedule of Activities (Section 1.3).  Authorized laboratories 
will assess serologic responses to AZD1222 and AZD2816 using validated (or qualified, 
where appropriate) assays.  Serologic assessment to the S protein from different SARS-CoV-2 
variants (which include Wuhan-Hu-1, B.1.351, B.1.1.7, and P.1) will be assessed 
quantitatively using a validated multiplexed ECL based immunoassay.  Additionally, 
seroresponse will be assessed for each antigen over time.  The rate of SARS-CoV-2 infection 
in participants receiving AZD2816 versus AZD1222 will be determined by seroresponse in a 
SARS-CoV-2 nucleocapsid antigen in a multiplexed electrochemiluminescence-based assay 
performed at an authorized laboratory.  Additional exploratory assessments may be performed 
to measure binding antibodies to SARS-CoV-2 variants of interest (which may include 
B.1.429, B.1.525, B.1.526, P.2, P.3, B.1.617, and the Q677H mutation observed in multiple 
variants).
8.5.2.2
 
 
 
  
 
 
 
 
 
8.5.2.3
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

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8.5.2.4
 
 
 
 
 
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Already collected samples may be analysed for biomarkers thought to play a role in 
COVID-19 severity or outcomes based upon emerging immunogenicity and 
pharmacodynamic analysis from this or other studies involving the study interventions. These 
analyses include but are not limited to serum or plasma cytokines, quantification of RNA, 
micro-RNA, and/or non-coding RNA using quantitative reverse transcriptase polymerase 
chain reaction (RT-PCR), microarray, sequencing, or other technologies in blood, or 
peripheral blood mononuclear cells to evaluate their association with AZD1222/2816 and 
observed clinical responses to these study interventions.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The overall hypothesis for this 8-armed study is that 28 days after vaccination (ie, following a 
single booster dose for the previously vaccinated participants or a second vaccination dose for 
previously unvaccinated participants), AZD2816 will be non-inferior to AZD1222 in terms of 
immunogenicity (ie, neutralising antibodies GMT ratio and difference in seroresponse rates).  
The specific null and alternative hypotheses for each objective are presented in Section 9.4.3.
CCI
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9.2
Sample Size Determination
Primary Objective: Characterise Immunogenicity (Precision)
Historical data were available for the immunogenicity responses (ie, pseudovirus neutralising 
antibodies, live virus neutralising antibodies, and spike protein binding antibodies) to 
AZD1222 from the pooled COV001/002/003/005 studies.  Table 11 presents the log 
transformed immunogenicity responses (ie, geometric mean titres) by assay for participants 
that received 2 standard doses of AZD1222.  These results indicate that the pseudo-
neutralising antibodies exhibited the largest variation (standard deviation of 1.20 and 1.10 for 
the 4-week and 12-week dosing intervals respectively), while live-neutralising antibodies had 
the lowest (standard deviation of 0.72 for the 4-week dosing interval).
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-week dosing intervalb
Assay
N
Mean
Std Dev
N
Mean
Std Dev
N
Mean
Std Dev
Pseudo
476
4.3
1.34
166
5.3
1.20
113
5.4
1.10
Live
51
4.9
1.15
42
6.2
0.72
0
-
-
Spike protein
1139
9.1
1.14
293
10.1
0.96
302
10.7
0.83
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval
Table 12 presents the seroresponse (ie, > 4 fold increase from baseline) by assay.  These 
results indicate that the pseudo-neutralising antibodies exhibited the lowest proportion of 
seroresponse (59.7% and 85.5% for the 4-week and 12-week dosing intervals respectively), 
while both live-neutralising and spike-binding seroresponse rates exceeded 95%.
Table 12
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-dose week intervalb
Assay
N
Proportion
N
Proportion
N
Proportion
Pseudo
499
32%
382
59.7%
117
85.5%
Live
96
75%
95
96.8%
-
-
Spike protein
940
96.6%
636
95.9%
304
99.3%
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval 

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Under the assumption that the immunogenicity responses (ie, geometric mean antibody titres) 
associated with AZD2816 will be similar to the responses associated with AZD1222 in 
participants that received 2 standard doses in the pooled COV001/002/003/005 studies, in 
which standard deviations ranged from 0.72 to 1.2 (Table 11), 150 participants will provide a 
95% confidence interval half-width between 0.115 and 0.192 (see Table 13).  Similarly, 380 
participants will provide a 95% confidence interval half-width between 0.072 and 0.120.
Under the assumption that the seroresponse rates associated with AZD2816 will be similar to 
the response rates in adults that received 2 standard doses of AZD1222 in the pooled 
COV001/002/003/005 studies (Table 12), 150 participants will provide a 95% confidence 
interval half-width between 1.33% and 7.85%, and 380 participants will provide a 95% 
confidence interval half-width between 0.84% and 4.93% (Table 14).
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes 
Standard Deviation
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
0.72
150
0.115
300
0.081
350
0.075
380
0.072
0.83
150
0.133
300
0.094
350
0.087
380
0.084
0.96
150
0.154
300
0.109
350
0.101
380
0.097
1.1
150
0.176
300
0.124
350
0.115
380
0.111
1.2
150
0.192
300
0.136
350
0.126
380
0.120

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Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroresponse Rates and Proposed 
Sample Sizes
Observed seroresponse rate
Participants (N)
Estimated half-width of the 95% confidence interval 
59.7%
150
7.85%
300
5.55%
350
5.14%
380
4.93%
85.5%
150
5.63%
300
3.98%
350
3.69%
380
3.54%
95.9%
150
3.17%
300
2.24%
350
2.08%
380
1.99%
96.8%
150
2.82%
300
1.99%
350
1.84%
380
1.77%
99.3%
150
1.33%
300
0.94%
350
0.87%
380
0.84%
For a fixed sample size, the precision with which the 95% confidence interval of the binary 
seroresponse rate can be estimated is a function of the response rate.  Table 14 provides the 
lower bounds of the 95% confidence interval for selected response proportions for alternate 
sample sizes.  For a given response rate, we can be 95% confident that the true seroresponse 
rate is at least as large as the lower bound of the confidence interval.
Primary Objective: Safety
Table 15 indicates the probability of observing 1 or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 

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particular type for participants in each treatment arm.  With the sample size of 300 
participants, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 95%.
Table 15
Probability of detecting 1 or more safety events (N = 300)
Event Frequency
Probability (> 1 event)
≥ 10% (Very Common)
> 99%
≥ 1% (Common)
95%
≥ 0.1% (Uncommon)
26%
≥ 0.01% (Rare)
3%
Secondary Objective: Compare Immunogenicity
Under the assumption that there is no difference between treatment arms of interest (ie, a ratio 
of 1, difference on the log scale of 0), the power conferred by 150 to 380 participants for the 
comparison of geometric mean titre ratio using a noninferiority margin of 1.5 (equivalent to a 
difference on the log scale of 0.405) is presented in .

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Table 16
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
and for the comparison of seroresponse rate using the non-inferiority margin of -15% as the 
upper bound of the difference is presented in Table 17.
If there is no difference between treatment arms of interest (ie, a ratio of 1) in the proportion 
of seroresponders, 380 participants provides 98% power to establish non-inferiority to within 
margin of -15% if the seroresponse rate is >50%.  The observed pseudo-neutralising response 
rates (> 4 fold increase from baseline) from the COV001/002/003/005 studies for AZD1222 
were 59.7% and 85.5% for the 4-week and 12-week dosing interval respectively (Table 12).  
A population of 380 participants provides 99% power to detect non-inferiority (using a non-
inferiority margin of -15%) if the observed response rate is 59.7%.

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Table 16
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
Sides
Null 
difference
Assumed mean 
treatment 
difference
Assumed 
standard 
deviation
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Upper
ln1.5 = 
0.405
0
0.72
150
300
0.025
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.83
150
300
0.998
150
350
0.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.96
150
300
0.988
150
350
0.991
150
380
0.992
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
1.10
150
300
0.957
150
350
0.965
150
380
0.968
300
300
0.994
300
350
0.997
300
380
0.997
350
380
0.999
350
350
0.998
380
380
>.999
1.20
150
300
0.920
150
350
0.932
150
380
0.937
300
300
0.985
300
350
0.990
300
380
0.992
350
380
0.995
350
350
0.994
380
380
0.996

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Table 17
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate
Sides
Null 
proportion 
difference
Assumed 
difference in 
proportion of 
seroresponders
Assumed 
proportion of 
seroresponders 
in both groups
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Lower
-0.15
0
0.597
150
300
0.025
0.878
150
350
0.894
150
380
0.902
300
300
0.964
300
350
0.975
300
380
0.979
350
380
0.986
350
350
0.982
380
380
0.989
0.855
150
300
0.993
150
350
0.995
150
380
0.996
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.959
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.968
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.993
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999

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9.3
Populations for Analyses
The following populations are defined:
Table 18
Populations for Analysis
Population
Description
All participants analysis set 
All participants screened for the study, to be used for reporting disposition and 
screening failures.
Full analysis set
All randomised participants who received study treatment, irrespective of their 
protocol adherence and continued participation in the study. Participants will be
analysed according to their randomised treatment, irrespective of whether or not 
they have prematurely discontinued, according to the intent-
to-treat principle. Participants who withdraw consent or assent to participate in the
study will be included up to the date of their study termination.
Safety analysis set
The safety analysis set consists of all participants who have received study 
treatment. Erroneously-treated participants (eg, those randomised to AZD2816, but 
were actually given treatment AZD12222) are accounted for in this analysis set by 
assigning them to the treatment they actually received.
Immunogenicity analysis set
The vaccine immunogenicity analysis set will include all randomised participants, 
received at least 1 dose of planned study treatment (ie, 1 dose of either AZD2816 or 
1 dose of AZD1222), had baseline and post-dose antibody measurements, have at 
least 1 post-dose quantifiable serum titre, and had no protocol deviations judged to 
have the potential to interfere with the generation or interpretation of an antibody 
response. The analyses conducted using this analysis set will be based on the actual 
treatment received.
Seronegative 
immunogenicity analysis set 
The subset of the immunogenicity analysis set who were seronegative at baseline.
Seropositive 
immunogenicity analysis set
The subset of the immunogenicity analysis set who were seropositive at baseline.
Participants that are SARS-CoV-2 seropositive at screening will be included in seropositive 
analysis sets analogous to the above seronegative analysis sets. Further definition is provided 
in the Statistical Analysis Plan. 
9.4
Statistical Analyses
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints.  A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to the interim analyses.

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9.4.1 General Considerations
An initial interim analysis will occur when a  subset of participants previously vaccinated 
with AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  This 
sample will include both participants randomised to receive a booster dose of AZD2816 as 
well as a those randomised to receive a booster dose of AZD1222.  Analyses presenting 
treatment arm summaries of both the raw and model adjusted immunogenicity will be 
reviewed by an unblinded team within AstraZeneca to make a decision regarding the potential 
need for sample size re-estimation.  Full details of this analyses are provided in the Interim 
Analysis Charter to be finalized prior to any interim analysis.
A second interim analysis will occur when all participants previously vaccinated with 
AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  It is estimated 
that this early analysis has the potential to provide clear signals about whether AZD2816 
provides a strong neutralizing response against the B.1.351 strain while retaining 
immunogenicity against the Wuhan strain, and thereby influence programmatic decisions 
early.  Analyses results will present treatment arm specific summaries of both the raw and 
model adjusted (baseline age and co-morbidities).  The raw data outputs will be stratified by 
age group (<65, ≥65) while the model adjusted summaries will pool data across age groups.  
Full details of this analyses are provided in the Interim Analysis Statistical analysis Plan to be 
finalized prior to any interim analysis.
A third interim analysis may be performed when a subset of previously unvaccinated 
participants have completed their Day 57 visit (ie, 56 days after fist dose).  The participant 
sample will include both participants randomised to AZD2816 as well as those randomised to 
AZD1222.  This analysis is intended to assess immunogenicity variability. The number of 
previously unvaccinated participants per treatment arm may be increased based upon the 
results of this analysis.  The details of this interim analysis, including the trigger and methods, 
will be specified in the Interim Analysis Charter.
The primary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants randomised to a 4-week 
dosing interval are available through completion of their visit 28 days after the second priming 
dose.
A secondary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants (including those 
randomised to a 12-week dosing interval) are available through completion of the visit 28 
days after the second dose. 

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The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).
Further details of the primary analysis, secondary analysis and final analysis are contained 
within the Statistical Analysis Plan
To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.
9.4.2 Safety
9.4.2.1
Primary Endpoints
Overview
Descriptive analyses will support evaluation of safety, reactogenicity and immunogenicity. 
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination will 
be summarised by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be summarised 
by system organ class and preferred term, and by relationship to vaccination as assessed 
by the investigator.
!
MAAEs, SAEs, and AESIs following the first vaccination and throughout the study 
duration will be summarised by system organ class and preferred term and by relationship 
to vaccination as assessed by the investigator. 
!
The change from baseline for safety laboratory measures at 7 and 28 days after 
vaccination.
AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities.  AEs will be presented for each treatment group by system organ class 
and preferred term.  Summaries will include the number and percentage of participants 
reporting at least one event, number of events and exposure adjusted rates, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs.  Summaries will present the relationship to 
study intervention as assessed by the investigator, maximum intensity, seriousness, and death.

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A listing will cover details for each individual AE.  Full details of all AE analyses will be 
provided in the Statistical Analysis Plan, including intercurrent events for safety due to 
potential unblinding of participants for administration of licensed and/or approved SARS-
CoV-2 or COVID-19 vaccine.
At the time of the interim analyses, group assignment will not be presented when safety event 
data has the potential to unblind participant’s study group attribution.
9.4.2.2
Other Safety Endpoints
Vital Signs
Vital sign measurements will be performed as specified in the Schedule of Activities (Section 
1.3).  The set of assessments will include pulse oximetry, blood pressure, and body 
temperature.  
Details of all vital sign analyses will be provided in the Statistical Analysis Plan, which will 
include descriptive statistics presented for observed values for all vital sign parameters. 
COVID-19
This study will describe the incidence of COVID-19 adverse events from the first dose of the 
vaccine to study end (180 days post-vaccination). Descriptive statistics will be produced 
based on the safety analysis set. Full details will be documented in the statistical analysis plan. 
9.4.3
Immunogenicity
9.4.3.1
Immunogenicity Endpoints
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean antibody titre.
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean antibody titre from 
baseline
Both the geometric mean antibody titre and seroresponse of participants will be summarized 
descriptively by strain, treatment arm, and timepoint for the immunogenicity population.
9.4.3.1.1
Estimand framework for immunogenicity descriptions and comparisons
Target populations: 
1) Previously unvaccinated participants 
a.
Seronegative Analysis Set: and with no evidence of prior or current infection  

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2) Participants who previously received SARS-CoV-2 vaccination with either AZD1222 
or a licensed mRNA vaccine according to the authorized dose and dosing regimen at 
least 3 months prior to first study intervention (see Section 5.1.2).
Outcome variable: neutralizing antibody and binding titres to SARS-CoV-2 at 28 days after 
each treatment administration (1 treatment administration for the previously vaccinated 
population and 2 planned treatment administrations for the unvaccinated population). 
Treatment conditions:
Previously unvaccinated population
!
2 doses of AZD1222 given on Day 1 and on Day 29 (4-week dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 29 (4-week dosing interval)
!
1 dose of AZD1222 given on Day 1 and 1 dose of AZD2816 on Day 29 (4-week 
dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 85 (12-week dosing interval)
Previously vaccinated population
!
1 dose of AZD1222 given on Day 1. 
!
1 dose of AZD2816 given on Day 1. 
Intercurrent events: the following intercurrent events could impact the antibody levels 
achieved:  
!
missing the second vaccination (for the unvaccinated population)  
!
receiving of immune-modifying drugs or vaccines 
!
subsequent infection with SARS-CoV-2. 
All immunogenicity descriptions and comparisons will use the principal stratum strategy, 
ie, all analyses will exclude participants who experience any of the above intercurrent events.
Population-level summary: 
Descriptive Analyses (see Table 20 and Table 21)
!
geometric means of the antibody titres 
!
seroresponse proportions

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Comparative Analyses (see Table 22 and Table 23Error! Reference source not found.)
!
ratio of geometric means of the antibody titres.
!
difference in seroresponse proportion 
Planned Descriptive Analyses: 
Table 20 and Table 21 present planned descriptive immunogenicity analyses for the 
unvaccinated and previously vaccinated populations respectively (each one exploring an 
individual treatment arm at a specific timepoint against a particular strain). 
The tables show that without introduction of further variants, there are 24 planned descriptive 
analyses for the unvaccinated population and 16 planned descriptive analyses for the 
previously immunised population (index).   Within each table there is an analysis key which 
describes the population (see Table 19). The descriptive analyses presented in Tables 19 and 
20 will be repeated for the subset of participants who are seropositive at screening.
Table 19
Description of the Analysis Keys for Tables 19 and 20
Population
Analysis Key
Example
Previously 
unvaccinated
Primary series dosing interval: 
    P4 (4-week dosing interval) or
    P12 (12-week dosing interval)
Treatment received: 
    1222 (2 doses of AZD1222) or 
    2816 (2 doses of AZD2816) or
1222/2816 (1 dose of AZD1222  
followed by 1 dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
Analysis Timepoint:
    1 (28 days post-dose 1)
    2 (28 days post-dose 2)
[P4:1222:W:1] = Immunogenicity 
following primary vaccination with a 4-
week dosing interval of 
2 doses of AZD1222 against Wuhan-
Hu-1 28 days post-dose 1
Previously 
vaccinated
Pre-study primary vaccination: 
    P1222 (2 doses of AZD1222) or
    PmRNA (2 doses of an mRNA vaccine)
Treatment received: 
    B1222 (1 booster dose of AZD1222) or 
B2816 (1 booster dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
[P1222:B1222:V] = Immunogenicity in 
participants who were previously 
vaccinated with 2 doses of AZD1222 as 
primary vaccination series and received 
a single boost dose of AZD1222 against 
the B.1.351 variant 

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)
Treatment
Interval
Strain
Timepoint
Endpoint
Index
Analysis Key
AZD1222
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
1
[P4:1222:W:1]†
Seroresponse
2
28 days after 2nd dose
GMT
3
[P4:1222:W:2]
Seroresponse
4
B.1.351
28 days after 1st dose
GMT
5
[P4:1222:V:1] †
Seroresponse
6
28 days after 2nd dose
GMT
7
[P4:1222:V:2]
Seroresponse
8
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
9
[P4:2816:W:1] ‡
Seroresponse
10
28 days after 2nd dose
GMT
11
[P4:2816:W:2]
Seroresponse
12
B.1.351
28 days after 1st dose
GMT
13
[P4:2816:V:1] ‡
Seroresponse
14
28 days after 2nd dose
GMT
15
[P4:2816:V:2]
Seroresponse
16
AZD1222/2816
4 weeks
Wuhan-Hu-1
28 days after 2nd dose
GMT
17
[P4:1222/2816:W:2]
Seroresponse
18
B.1.351
28 days after 2nd dose
GMT
19
[P4:1222/2816:V:2]
Seroresponse
20
AZD2816
12 weeks
Wuhan-Hu-1
28 days after 2nd dose
GMT
21
[P12:2816:W:2]
Seroresponse
22
B.1.351
28 days after 2nd dose
GMT
23
[P12:2816:V:2]
Seroresponse
24
† descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD1222 as their first dose 
(ie, homologous and heterologous series).
‡ descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD2816 as their first dose 
(4-week interval and 12-week interval treatment arms).
GMT: Geometric mean titre

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Table 21
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)
Primary 
vaccination
Booster 
Treatment
Strain
Timepoint
Endpoint
Index
Analysis Key
AZD1222
AZD1222
Wuhan-Hu-1
28 days after 
booster 
GMT
1
[P1222:B1222:W]
Seroresponse
2
B.1.351
28 days after 
booster 
GMT
3
[P1222:B1222:V]
Seroresponse
4
AZD2816
Wuhan-Hu-1
28 days after 
booster 
GMT
5
[P1222:B2816:W]
Seroresponse
6
B.1.351
28 days after 
booster 
GMT
7
[P1222:B2816:V]
Seroresponse
8
mRNA
AZD2816
Wuhan-Hu-1
28 days after 
booster 
GMT
9
[PmRNA:B2816:W]
Seroresponse
10
B.1.351
28 days after 
booster 
GMT
11
[PmRNA:B2816:V]
Seroresponse
12
AZD1222
Wuhan-Hu-1
28 days after 
booster 
GMT
13
[PmRNA:B1222:W]
Seroresponse
14
B.1.351
28 days after 
booster 
GMT
15
[PmRNA:B1222:V]
Seroresponse
16
GMT: Geometric mean titre
Immunogenicity comparisons:
Immunogenicity analysis
A number of comparisons of geometric mean titres and seroresponse rates between vaccine 
regimens and vaccine types are intended to be made. 
All non-inferiority comparisons of geometric mean titre ratios will be made utilizing the lower 
bound of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 
0.67
All non-inferiority comparisons of seroresponse rates will be made utilizing the lower bound 
of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 15%, and 
superiority comparisons of seroresponse rates will be made using one-sided Fisher’s exact test 
(α = 0.025). Comparisons of Ab titres between treatment groups will be conducted using 
geometric mean titre (GMT) ratios and seroresponse rates, facilitated by an analysis of 
covariance (ANCOVA) model of the log2 titre, which adjusts for the baseline level, time since 
previous vaccination (for previously vaccinated individuals), baseline co-morbidities and 
gender as fixed effects. All analyses of antibody titres (GMT ratios and differences in 
seroresponse) will be repeated using the unadjusted (raw observed) concentration values.
Geometric Mean Titres 

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The statistical methodology will be based on a 2-sided 95% CI of the ratio of the GMTs. Non-
inferiority will be demonstrated if the lower limit of the 2-sided 95% CI of the GMT ratio of 
the reference group and comparator group is >0.67 (see table xx). The 2-sided 95% CI for the 
ratio of GMTs will be calculated using normal approximation of log-transformed 
concentrations.
The 95% CI for the GMT ratio between 2 groups will be constructed as follows:
Logarithm transformation of the individual concentrations will be calculated.
The 95% CI for the difference in log(GMT) between 2 groups: GroupC and GroupR will 
be in the form:
 − ± 
1 − 2
 ,  +  −2 × 1 

+ 1 

Where  and  = log() are the means of the log-transformed concentration for 
 !"# and  !"#, respectively,
$ = [( −1)
$ + ( −1)
$]
( +  −2)
'
is the pooled sample variance,
 and  are the sample sizes for  !"# and  !"# , respectively,
 and  are the sample variances for  !"# and  !"# , respectively,

1 − 2
 ,  +  −2 is the 100 ,1 −
-
$. percentile of the t-distribution with degrees of 
freedom /0 =  +  −2
To test this hypothesis, a 2- sided 95% CI will be constructed around the ratio 
1234
1235, where 
 and  are the geometric mean of the antibody titres in the comparator and 
reference groups respectively, at the timepoints post vaccination for which the groups are 
being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 0.67. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.
:;:  

≤0.67
:>:  

> 0.67

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Or equivalently
:;: log() −log() ≤log(0.67)
:>: log() −log() > log(0.67)
For the separately considered GMT hypotheses, if the null hypothesis is rejected, then the 
alternative hypothesis of non-inferiority will be supported.
Seroresponse
The statistical methodology will be based on a 2-sided 95% CI of the difference in 
seroresponse rates. Non-inferiority will be demonstrated if the upper bound of the 2-sided 
95% CI rate difference in seroresponse between the reference group and comparator group is 
<15%.  The 95% CI of the difference in proportions ? −? will be computed using the 
Wilson score without continuity correction.
To test this hypothesis, a 2- sided 95% CI will be constructed around the difference ? −?, 
where? and ? are the proportions of participants in the comparator and reference groups 
respectively who are classified as seroresponders (> 4 fold increase from baseline) at the 
timepoints post vaccination for which the groups are being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 15%. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.
:;: ? −? < −15%
:>: ? −? ≥15%
If the null hypothesis is rejected, then the alternative hypothesis of non-inferiority will be 
supported.
Comparisons
The primary and secondary immunogenicity objectives and the GMT and seroresponse 
comparisons for the previously unvaccinated participants receiving a 2-dose primary 
vaccination are presented in Table 22
The immunogenicity objectives and the GMT and seroresponse comparisons for the 
previously vaccinated participants receiving a 1-dose booster vaccination are presented in 
Table 23.  

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −〖[TQNJNQULJSUQ〗NQRQNQSIQ]
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by a 2-dose AZD2816 
primary vaccination is non-inferior to 
the response elicited by a 2-dose 
AZD1222 primary vaccination 
[P4:2816: V: 2]/[P4:1222: W:2]
(Primary)
[P4:2816: V: 2] −[P4:1222: W:2]
(Key Secondary 2.1)
[P4:2816: V: 1]/[P4:1222: W:1]
[P4:2816: V: 1] −[P4:1222: W:1]
[P4: 2816: V: 2]/[P4:1222: V:2]
(Key Secondary 2.2)
[P4:2816: V: 2] −[P4:1222: V: 2]
(Other Secondary)
[?4: 2816: V: 1]/[?4:1222: V: 1]
[P4:2816: V: 1] −[P4:1222: V: 1]
[P4:2816:W: 2]/[P4:1222: W: 2]
(Key Secondary 2.4)
[P4:2816: W:2] −[P4:1222: W:2]
(Other Secondary)
[P4:2816: W: 1]/[?4:1222:W: 1]
[P4:2816: W:1] −[P4:1222: W:1]
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by a 2-dose AZD1222 + 
AZD2816 heterologous primary 
vaccination is non-inferior to the 
response elicited by a 
2-dose AZD1222 primary vaccination
[P4: 1222/2816:V: 2]/[P4:1222: W:2]
(Key Secondary 2.3)
[P4:1222/2816: V: 2] −[P4: 1222: W:2]
(Other Secondary)
[P4:1222/2816: W:2]/[P4:1222: W:2]
(Other Secondary)
[P4:1222/2816:W: 2] −[P4:1222:W: 2]
(Other Secondary)
[P4:1222/2816: V: 2])/([P4:1222: V: 2]
(Other Secondary)
[P4: 1222/2816: V: 2] −[P4:1222:V: 2]
(Other Secondary)

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −〖[TQNJNQULJSUQ〗NQRQNQSIQ]
To determine if the neutralizing 
antibody GMT response/seroresponse 
rate against the B.1.351 variant is 
non-inferior to the rate against the 
original Wuhan-hu-1 strain following 
a 2-dose AZD2816 primary 
vaccination
[P4:2816: V: 2]/[P4:2816: W:2]
(Other Secondary)
[P4:2816: V: 2] −[P4:2816: W:2]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
rate against the B.1.351 variant is 
non-inferior to the rate against the 
original Wuhan-hu-1 strain following 
a 2-dose AZD1222/AZD2816 
primary heterologous vaccination
[P4:1222/2816:V: 2]/[P4:1222/2816: W:2]
(Other Secondary)
[P4: 1222/2816: V: 2] −[P4:1222/2816:W: 2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −〖[TQNJNQULJSUQ〗NQRQNQSIQ]
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-
inferior to response elicited by a 2-dose 
AZD1222 vaccination
[P1222: B2816:V]/[P4:1222: W:2]
(Primary)
[P1222: B2816:V] −[P4:1222: W:2]
(Other Secondary)
[P1222:B2816: V]/[P4:1222:V: 2]
(Key Secondary 2.1)
[P1222:B2816: V] −[P4: 1222: V: 2]
(Other Secondary)
[P1222: B2816: W]/[P4:1222:W: 2]
(Key Secondary 2.3)
[P1222:B2816: W] −[P4: 1222: W:2]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster 
dose in participants previously vaccinated 
with AZD1222
[P1222:B2816: V]/[P1222: B1222:V]
(Key Secondary 2.2)
[P1222:B2816: V] −[P1222: B1222: V]
(Other Secondary)
[P1222:B2816: W]/[P1222: B1222:W]
(Key Secondary 2.5)
[P1222:B2816: W] −[P1222: B1222: W]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-
inferior to the response elicited by a 2-dose 
AZD1222 vaccination
[P1222: B1222: W]/[P4:1222:W: 2]
(Key Secondary 2.4)
[P1222:B1222: W] −[P4: 1222: W:2]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based 
vaccine is non-inferior to response elicited 
by a 2-dose AZD1222 vaccination
[PmRNA:B2816: V]/[P4:1222: W:2]
(Other Secondary)
[PmRNA:B2816: V] −[P4:1222:W: 2]
(Other Secondary)
[PmRNA:B2816: V]/[P4:1222: V: 2]
(Other Secondary)
[PmRNA:B2816:V] −[P4:1222: V: 2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −〖[TQNJNQULJSUQ〗NQRQNQSIQ]
[PmRNA:B2816: W]/[P4:1222: W:2]
(Other Secondary)
[PmRNA:B2816: W] −[P4:1222: W:2]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose is non-inferior to the 
response elicited by an AZD1222 booster 
dose in participants previously vaccinated 
with an mRNA-based vaccine
[PmRNA:B2816: W])/[PmRNA:B1222: W]
(Other Secondary)
[PmRNA:B2816: W] −[PmRNA:B1222:W]
(Other Secondary)
[PmRNA:B2816:V])/[PmRNA:B1222: V]
(Other Secondary)
[PmRNA:B2816: V] −[PmRNA:B1222:V]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse rate against the 
B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain 
following a 2816 booster dose
[P1222: B2816:V]/[P1222:B2816: W]
(Other Secondary)
[P1222:B2816: V] −[P1222: B2816: W]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse rate against the 
B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain 
following a 1222 booster dose
[P1222: B1222:V]/[P1222:B1222: W]
(Other Secondary)
[P1222: B1222:V] −[P1222:B1222: W]
(Other Secondary)

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9.4.4
Multiple Comparisons
A hierarchical approach will be used to control for multiplicity of the primary and key 
secondary efficacy endpoints. That is, the null hypotheses for the efficacy endpoints will be 
tested in a hierarchical order, and the subsequent null hypothesis will be tested only if the 
prior null hypothesis is rejected. Consequently, no adjustment to alpha for multiplicity will be 
made in the analysis of immune response. The primary statistical comparisons of safety data 
will not be adjusted for multiple comparisons.  Further details are provided in the statistical 
analysis plan.
9.4.5
Data Safety Monitoring Board
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, to 
ensure safe and ethical conduct of the study.  During the study, the benefit/risk assessment 
will be continuously monitored by the Board to ensure that the balance remains favourable.  
Further details, composition, and operation of the COVID-19 Vaccine Data Safety Monitoring 
Board will be described in a separate charter. For further details, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Not applicable.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
∀
Applicable ICH/GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigators Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority.  This responsibility may be delegated to 
a contract research organization but the accountability remains with the Sponsor.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH/GCP guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all Food and 
Drug Administration (FDA) Regulations, as applicable and all other applicable local 
regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study.  Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH/GCP guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
!
The study medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples.  The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use.  Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

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!
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law.  The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committee Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A COVID-19 Vaccine Data Safety Monitoring Board comprised of independent experts will 
be convened to provide oversight and to ensure safe and ethical conduct of the study.  The 
COVID 19 Vaccine Data Safety Monitoring Board will have the responsibility of evaluating 
cumulative safety and other clinical study data at regular intervals and making appropriate 
recommendations based on the available data.  During the study, the benefit/risk assessment 
will be continuously monitored by the COVID-19 Vaccine Data Safety Monitoring Board to 
ensure that the balance remains favourable.  Full details of the COVID-19 Vaccine Data 
Safety Monitoring Board composition and operations can be found in the COVID-19 Vaccine 
Data Safety Monitoring Board Charter.
An independent Neurological AESI Expert Committee will be available to review and provide 
on request about the diagnosis and causality assessment of selected neurological AEs of 
special interest occurring in the study.  Details on the composition and operation of this 
committee are described in the Neurological AESI Expert Committee Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available.  The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

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!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
!
Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected, and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH/GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or ICH/GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both SAEs and non-SAEs and can include a deterioration of a 
pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs.  
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used.  
In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a non-
SAE.  For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur.  Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as non-serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  Examples of important medical events include such events as listed 
below:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Intensity Rating Scale
A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 

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several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the investigational product.
!
Time Course.  Exposure to suspect drug.  Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect investigational product?
!
Consistency with known investigational product profile.  Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or drugs of the same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational medicinal product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the investigational product, but rather a human or 
process related failure while the investigational product is in control of the study site staff or 
participant.
Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the investigational product
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Investigational product name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration
!
Investigational product not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Investigational product not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong participant received the medication (excluding IRT errors)
!
Wrong investigational product administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from 
the participants while in storage at the study site until shipment or disposal (where 
appropriate) and records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
The Sponsor or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
The Sponsor ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented.  If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and the Sponsor are informed about the sample disposal.

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The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus.  Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814.  Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
!
Table 24: Clinical Abnormalities, Local Reactions to Injectable Product
!
Table 25: Clinical Abnormalities, Vital Signs
!
Table 26: Clinical Abnormalities, Systemic (General or Illness)
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalization
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded.
b
Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE e-Diary.
ER: emergency room.

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Table 25
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)a
Fever (°C/°F)
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
Emergency room visit 
or hospitalization for 
arrhythmia
Bradycardia 
(beats/minute)
50-54
45-49
< 45
Emergency room visit 
or hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
Emergency room visit 
or hospitalization for
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
Emergency room visit 
or hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes.

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Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic 
(General)
Systemic Gradea
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/
vomiting
No interference with 
activity or 
1-2 episodes/24 hours
Some interference 
with activity or 
> 2 episodes/24 hours
Prevents daily activity, 
required outpatient 
intravenous hydration
Emergency room 
visit or 
hospitalization for 
hypotensive shock
Chills
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room
visit or 
hospitalization
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
Emergency room 
visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Systemic Illness
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations)
No interference with 
activity
Some interference 
with activity not 
requiring intervention
Prevents daily activity 
and required medical 
intervention
Emergency room 
visit or 
hospitalization

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Appendix E
Adverse Events of Special Interest
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 27
Adverse Events of Special Interest
Category
Medical Concept
Neurologic
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment or 
loss of consciousness.  
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis.
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population.
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (eg, weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, or other 
sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate.
Hematologic
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL.
Immunologic
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention.
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non-neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: a group of autoimmune inflammatory disorders 
characterized by an alteration in cellular homeostasis, which may or may not have an 
autoimmune aetiology.  A list of events is provided in Table 28. 

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune haemolytic anaemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anaemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombotic events with thrombocytopenia and/or bleeding.  It is not intended to 
be a comprehensive guide to the management of all venous thromboembolic events.  
During the course of the study, the investigator will remain vigilant for occurrence of 
thrombotic events with thrombocytopenia and/or bleeding.  Appropriate investigations (eg, 
imaging) to diagnose these events should be made on a case-by-case basis.  The investigator is 
responsible for determining whether a participant meets criteria for thrombotic events with 
thrombocytopenia and/or bleeding at any point during the study.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombotic events with thrombocytopenia 
and/or bleeding.  The Study Physician contacts the investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data.  
Guidance from the International Society of Thrombosis and Haemostasis for management of 
thrombocytopenic thromboembolism occurring after vaccination can be found at 
www.isth.org.  Notably, participants should only be treated with heparin if a test for heparin-
elicited thrombocytopenia antibodies is negative.  An alternative explanation for 
thrombocytopenia should be considered (eg, alcohol use, liver cirrhosis, concomitant 
medications, exposure to toxic chemicals, viral infections).
The investigator is responsible for recording data pertaining to thrombotic events with 
thrombocytopenia and/or bleeding and for reporting AEs and SAEs according to the outcome 
of the review and assessment in line with standard safety reporting processes.
F 2
Tests that Should Be Considered if Thrombotic Events With 
Thrombocytopenia and/or Bleeding Are Suspected
The following tests should be considered, but not limited to:
1. Measurement of platelet levels, prothrombin time, activated partial thromboplastin time, 
D-dimer levels, and fibrinogen levels
2. Complete blood count, reticulocyte count, blood film, haptoglobins
3. Anti-platelet factor 4 antibodies

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4. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, human 
leucocyte antigen B27, ADAMTS13 activity, anti-cardiolipin antibodies IgG + IgM, and 
anti-B2GPI antibodies IgG + IgM
5. Complement (eg, C3, C4, complement complex C5b-9, C5a), autoantibodies (eg, 
antinuclear IgG, anti-double stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG)
6. Factor V Leiden, Factor II (prothrombin) variant 
7. Platelet activation markers and functional assays (eg: sCD40L, soluble glycoproteins, 
degranulation markers [PF4, vWF, P-selectin, annexin V]), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 ELISA positive)
8. Inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13
9. Cell adhesion molecules: VCAM, ICAM, E-selectin
10. Adenovirus serology
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Ebstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19
12. COVID-19 testing, including PCR and serology
13. Calculation of an International Society of Thrombosis and Haemostatis score for 
Disseminated Intravascular Coagulation (derived from platelet levels, fibrinogen, and D-
Dimer)

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ChAdOx1 MERS
Chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
AZD1222 when initially developed by the University of Oxford
COVID-19
Coronavirus disease 2019
eCRF
Electronic case report form
e-Diary
Electronic diary
GMT
Geometric mean titre
ICF
Informed consent form
ICH/GCP
International Council for Harmonisation/Good Clinical Practice
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
MAAEs
Medically attended adverse events
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
S
Spike
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome-coronavirus-2

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Appendix H
Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment 2
29 July 2021
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment 2: 15 July 2021
The principal reason for this amendment was to
1) add an additional interim analysis to evaluate immunogenicity in a subset of 
AZD1222 previously vaccinated subjects boosted with AZD1222 or AZD2816
2) revise Objectives/Endpoints from descriptive to comparative, with ranking of primary, 
key secondary, other secondary, and exploratory objectives
3) add non-inferiority margins to primary analysis and add additional participants to 
maintain power 
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis 
(Objectives and 
Endpoints)
Revised this section from 
primarily descriptive to 
primarily comparative.  
Comparative immunogenicity 
objectives created and ranked as 
primary, key secondary, other 
secondary.
Objectives of study 
changed from descriptive 
to comparative, testing for 
non-inferiority across 
treatment comparisons
Substantial
1.1 Synopsis 
(Number of 
Participants; Statistical 
Methods)
Overall size increased to 2590 
participants
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.1 Synopsis (Statistical 
Methods)
An additional interim analysis 
added. Second interim analysis 
changed to include only the 
previously vaccinated with 
AZD1222 cohort.
Interim analysis plan was 
reviewed and revised.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.2 Schema
Figures updated with increased 
participant numbers
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.3 Schedule of 
Activities
Table 2: footnote clarification 
added
Table 3: minor corrections
Clarification/Correction
Non-substantial
2.1 Study Rationale 
(and elsewhere in 
protocol)
Clarification on previous 
vaccination criteria
Clarification
Non-substantial
3 Objectives
Section completely rewritten.  
Divided into 2 sections: 
Previously unvaccinated and 
previously vaccinated.  
Immunogenicity objectives 
created for comparisons.  
Objectives ranked as primary, 
key secondary, other secondary, 
or exploratory.
Objectives of study 
changed to show non-
inferiority across 
treatments.  
Substantial
4.1 Overall design
Participant numbers increased
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
4.1 Overall design
Cap on age added
To ensure good 
representation across age 
groups
Substantial
8.3.2
Removal of severity grade 5
Correction
Non-substantial
8.5.2.3
 
 
Addition of information on 
number of patients sampled for 
Clarification
Non-substantial
9.1 Statistical 
Hypotheses
Addition of statistical 
hypotheses
Include hypothesis being 
tested.
Substantial
9.2 Sample size 
determination
Confidence intervals for 
populations of 350 and 380 
added to Table 14 and Table 15
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
9.2 Sample size 
determination
Power estimates for populations 
of 350 and 380 added to Table 
17 and Table 18
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
CCI
CCI

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
9.4.1 General 
considerations
Details on the initial interim, 
second interim, and third interim 
analysis added
Include revised 
information on the 
analysis plan, including 
interim analyses
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Objectives removed from 
descriptive analysis Table 23 
and Table 24
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Section of  Immunogenicity 
Comparisons added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for
immunogenicity 
descriptions and 
comparisons
Table 25 and Table 26 on 
immunogenicity comparisons 
revised, aligned with the revised 
objectives/endpoints.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.4 Multiple 
Comparisons
Section added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
In addition, the protocol has been revised with minor corrections and clarifications.
Amendment 1: 2 June 2021
Version 1 of the protocol was amended prior to the commencement of the study (ie, prior to 
approval of the protocol by an ethics committee) based on feedback from internal and 
regulatory authority reviews.  The most substantial changes were as follows:
!
addition of 2 treatment arms:  1) AZD1222 as a single booster vaccination in participants 
previously vaccinated with an mRNA COVID-19 vaccine and 2) heterologous 
vaccination with AZD1222 plus AZD2816 in previously unvaccinated participants
!
further definition of analysis sets
!
addition of thrombotic events with thrombocytopenia as a discontinuation criteria
In addition, corrections and revisions to text to improve readability were made.

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11
REFERENCES
Dejnirattisai et al 2021
Dejnirattisai W, Zhou D, Supasa P, Liu C, Mentzer AJ, et al. Antibody evasion by the 
Brazilian P.1 strain of SARS-CoV-2. Cell 2021;184:1-16.
EMA 2021
European Medicines Agency. Reflection paper on the regulatory requirements for vaccines 
intended to provide protection against variant strain(s) of SARS-CoV-2 (EMA/117973/2021), 
February 2021. Available at: https://www.ema.europa.eu/en/regulatory-requirements-
vaccines-intended-provide-protection-against-variant-strains-sars-cov-2.
FDA 2007
US Food and Drug Administration. Guidance for Industry. Toxicity grading scale for healthy 
adult and adolescent volunteers enrolled in preventive vaccine clinical trials, Sept 2007. 
Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-
preventive-vaccine-clinical.
FDA 2021
US Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent 
COVID-19: Guidance for Industry, February 2021. Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-
authorization-vaccines-prevent-covid-19.
Folegatti et al 2020
Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A et al. Safety and 
immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored 
vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, Phase 1 trial. Lancet 
Infect Dis 2020;20:816-26.
Lu et al 2020
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology 
of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 
2020;395(10224):565-74. 
Madhi et al 2021
Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AK, Fairlie L, et al. Efficacy of the 
ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Eng J Med 2021; 
384:1885-98.
Ramasamy et al 2020
Ramasamy MN, Voysey M, Aley PK, Bibi S, Clutterbuck EA, et al. Safety and 
immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in 

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young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. 
Lancet 2020; 396(10267):1979-93.
Rovira et al 2015
Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP et al. MAGNIMS 
consensus guidelines on the use of MRI multiple sclerosis—clinical implementation in the 
diagnostic process. Nature Rev Neurolog 2015;11(8):471-82.
SPEAC 2020
Safety Platform for Emergency Vaccines. D2.3 Priority list of adverse events of special 
interest: COVID-19. Work Package: WP2 Standards and Tools. v1.1. Available from: 
https://media.tghn.org/articles/COVID-19_AESIs_SPEAC_V1.1_5Mar2020.pdf.
Voysey et al 2021a
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al. Safety and efficacy of 
the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four 
randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397:99-111. 
Voysey et al 2021b
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al.  Single-dose 
administration and the influence of the timing of the booster dose on immunogenicity and 
efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised 
trials. Lancet 2021;397:881-91.
Wang et al 2021
Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
B.1.1.7. Nature 2021;593:130-5.
Zhou et al 2020
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus 
of probable bat origin. Nature 2020;579:270-3.
Zhou et al 2021
Zhou D, Dejnirattisai W, Supasa P, Liu C, Mentzer AJ, Ginn HM, et al. Evidence of escape of 
SARS-CoV-2 variant B.1.351 from natural and vaccine-elicited sera. Cell 2021;189:1-14.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7220c00001-csp-amendment-2
Document Title:
D7220C00001 Clinical Study Protocol Amendment Version 2
29Jun2021
Document ID:
Doc ID-004538576
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
02-Aug-2021 14:01 UTC
Content Approval
03-Aug-2021 08:01 UTC
Content Approval
03-Aug-2021 11:38 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
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Clinical Study Protocol
Study Intervention
AZD2816
Study Code
D7220C00001
Version
Amendment 3
Date
11 October 2021
TITLE PAGE
A Phase II/III Partially Double-Blinded, Randomised, Multinational, 
Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults to 
Determine the Safety and Immunogenicity of AZD2816, a Vaccine for the Prevention 
of COVID-19 Caused by Variant Strains of SARS-CoV-2
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
EudraCT: 2021-002530-17
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Number: D7220C00001
Amendment Number: 3
Study Intervention: AZD2816
Study Phase: II/III
Short Title: Phase II/III Study of AZD2816, a Vaccine for the Prevention of COVID-19 in 
Adults
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator:  Andrew J Pollard, FRCPCH PhD FMedSci
            University of Oxford
            Oxford, United Kingdom

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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Amendment 3
11 October 2021
Amendment 2
29 July 2021
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment 3: 11 October 2021
The principal reason for this amendment was to remove the age cap and revise the primary 
and key secondary non-inferiority analyses to included historical controls due to difficulties in 
recruiting the previously unvaccinated cohort
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Synopsis
Section 4.1
Section 9.4..3.1.1
Inserted information on use of 
historical controls
Required based on 
anticipated confounding 
between previously 
vaccinated and previously 
unvaccinated cohorts.
Substantial
Section 3.2, Table 6
Inserted exploratory objectives 
on exploration of humoral 
immune response with live virus 
neutralization assay and 
exploration of additional 
immune response based on 
emerging data
Omitted in error
Non-substantial
Section 4.1
Deleted age cap ensuring at least 
25% enrolled participants were 
>65 years of age.
Due to enrollment 
difficulties in finding
previously unvaccinated
elderly
Substantial
Section 7.1
Inserted laboratory-confirmed 
SARS-CoV-2 infection as 
discontinuation of study 
intervention
To explicitly state this 
criterion (which is 
implicitly included in 
criteria 2) as a 
discontinuation of 
treatment criterion.
Non-substantial
Section 9.2
Section on immunogenicity 
comparisons and previous Table 
16 and Table 17 were moved up 
Had been placed under 
Secondary Objective in 
error
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
under the Primary Objective 
sub-heading
Section 9.4.3.1.1
Table 19
Table 20
Table 21
Table 22
Table 23
Analysis key (abbreviations) 
revised
Improvements in 
abbreviations for clarity
Non-substantial
Section 9.4..3.1.1
Description of statistical 
approach to be used with 
historical control comparisons 
added. 
Inclusion of historical 
controls requires 
description of statistical 
methodology to be used.
Substantial
In addition, the protocol has been revised with minor rewordings, corrections, and 
clarifications which are all considered to be non-substantial.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................. 3
TABLE OF CONTENTS...................................................................................................... 5
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schema............................................................................................................. 20
1.3
Schedule of Activities....................................................................................... 21
2
INTRODUCTION............................................................................................ 27
2.1
Study Rationale ................................................................................................ 27
2.2
Background ...................................................................................................... 27
2.3
Benefit/Risk Assessment................................................................................... 30
2.3.1
Risk Assessment............................................................................................... 30
2.3.2
Benefit Assessment........................................................................................... 31
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 31
3
OBJECTIVES AND ENDPOINTS................................................................... 32
3.1
Naïve unvaccinated cohort receiving a 2-dose primary vaccination................... 32
3.2
Previously vaccinated cohort receiving a 1-dose booster vaccination ................ 37
4
DESIGN........................................................................................................... 43
4.1
Overall Design.................................................................................................. 43
4.1.1
COVID-19 Assessments ................................................................................... 45
4.1.2
Screening.......................................................................................................... 45
4.1.3
Vaccination Visit .............................................................................................. 45
4.1.4
Follow-up visits................................................................................................ 46
4.2
Scientific Rationale for Study Design ............................................................... 46
4.2.1
Rationale for Study Design and Participant Population ..................................... 46
4.2.2
Rationale for Study Endpoints .......................................................................... 47
4.3
Justification for Dose........................................................................................ 48
4.4
End of Study Definition.................................................................................... 48
5
STUDY POPULATION ................................................................................... 48
5.1
Inclusion Criteria .............................................................................................. 49
5.1.1
All Participants:................................................................................................ 49
5.1.2
Previously COVID-19 Vaccinated Participants................................................. 50
5.2
Exclusion Criteria ............................................................................................. 51
5.3
Lifestyle Considerations ................................................................................... 53
5.4
Screen Failures ................................................................................................. 53
6
STUDY INTERVENTION............................................................................... 53
6.1
Study Interventions Administered..................................................................... 54

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6.1.1
Investigational Products.................................................................................... 54
6.1.2
Dosing Instructions........................................................................................... 55
6.2
Preparation/Handling/Storage/Accountability ................................................... 55
6.2.1
Dose Preparation and Administration................................................................ 55
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 56
6.3.1
Randomization.................................................................................................. 56
6.3.2
Blinding............................................................................................................ 57
6.3.3
Procedures for Unblinding ................................................................................ 58
6.4
Study Intervention Compliance......................................................................... 58
6.5
Concomitant Therapy........................................................................................ 58
6.5.1
Permitted Concomitant Medications ................................................................. 58
6.5.2
Prohibited Concomitant Medications ................................................................ 59
6.6
Dose Modification ............................................................................................ 60
6.7
Intervention After the End of the Study............................................................. 60
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 60
7.1
Discontinuation of Study Intervention............................................................... 60
7.2
Participant Withdrawal from the Study ............................................................. 61
7.3
Lost to Follow-up ............................................................................................. 61
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 62
8.1
Efficacy Assessments........................................................................................ 62
8.2
Safety Assessments........................................................................................... 62
8.2.1
Physical Examinations...................................................................................... 62
8.2.2
Vital Signs........................................................................................................ 63
8.2.3
Clinical Laboratory Assessments ...................................................................... 63
8.3
Adverse Events and Serious Adverse Events..................................................... 64
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 64
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 65
8.3.3
Causality Collection.......................................................................................... 66
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 66
8.3.5
Adverse Events Based on Examinations and Tests............................................ 66
8.3.6
Hy’s Law.......................................................................................................... 66
8.3.7
Solicited Adverse Events .................................................................................. 67
8.3.8
COVID-19 Assessment..................................................................................... 68
8.3.9
Medically-Attended Adverse Events................................................................. 68
8.3.10
Adverse Events of Special Interest.................................................................... 68
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest ................................ 69
8.3.10.2
Potential Neurological Adverse Events of Special Interest ................................ 69
8.3.11
Reporting of Serious Adverse Events................................................................ 71
8.3.12
Pregnancy......................................................................................................... 71
8.3.12.1
Maternal Exposure............................................................................................ 71
8.3.13
Medication Error............................................................................................... 72

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8.4
Overdose .......................................................................................................... 72
8.5
Human Biological Samples............................................................................... 73
8.5.1
Pharmacokinetics.............................................................................................. 73
8.5.2
Immunogenicity Assessments ........................................................................... 73
8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 74
8.5.2.2
8.5.2.3
8.5.2.4
8.5.3
Pharmacodynamics........................................................................................... 75
8.6
Human Biological Sample Biomarkers ............................................................. 75
8.7
Optional Genomics Initiative Sample................................................................ 75
8.8
Medical Resource Utilization and Health Economics ........................................ 75
9
STATISTICAL CONSIDERATIONS............................................................... 75
9.1
Statistical Hypotheses....................................................................................... 75
9.2
Sample Size Determination............................................................................... 76
9.3
Populations for Analyses .................................................................................. 82
9.4
Statistical Analyses........................................................................................... 83
9.4.1
General Considerations..................................................................................... 83
9.4.2
Safety ............................................................................................................... 84
9.4.2.1
Primary Endpoints ............................................................................................ 84
9.4.2.2
Other Safety Endpoints..................................................................................... 85
9.4.3
Immunogenicity................................................................................................ 86
9.4.3.1
Immunogenicity Endpoints ............................................................................... 86
9.4.4
Multiple Comparisons....................................................................................... 98
9.4.5
Data Safety Monitoring Board .......................................................................... 98
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 98
11
REFERENCES............................................................................................... 125
CCI
CCI
CCI

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LIST OF TABLES
Table 1
Schedule of Activities: Screening ............................................................ 21
Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine . 22
Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 4-Week Dosing 
Interval.................................................................................................... 23
Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 12-Week 
Dosing Interval........................................................................................ 25
Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination.............................. 33
Table 6
Study Objectives and Endpoints for Previously Vaccinated Participants 
Receiving a 1-Dose Booster Vaccination ................................................. 38
Table 7
Highly Effective Methods of Contraception............................................. 50
Table 8
Investigational Products........................................................................... 54
Table 9
Laboratory Safety Variables..................................................................... 63
Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment....... 67
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)...... 76
Table 12
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set) .......................... 76
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes........... 77
Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroresponse Rates and Proposed 
Sample Sizes ........................................................................................... 78
Table 15
Probability of detecting 1 or more safety events (N = 300)....................... 82
Table 16
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio .................................................................... 80
Table 17
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate .............................................................. 81
Table 18
Populations for Analysis .......................................................................... 82
Table 19 
Description of the Analysis Keys for Tables 19 and 20 ............................ 88

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 89
Table 21
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 90
Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups........ 94
Table 23
Immunogenicity Comparisons for Previously Vaccinated Group.............. 96
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable Product110
Table 25
Tables for Clinical Abnormalities: Vital Signs....................................... 111
Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness) ........... 112
Table 27
Adverse Events of Special Interest......................................................... 113
Table 28
List of Potential Immune-mediated Medical Conditions......................... 114
LIST OF FIGURES
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination................................................. 20
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster.................................................. 20
Figure 3
Neurology Testing Algorithm .................................................................. 70

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 99
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 104
Appendix C
Handling of Human Biological Samples ................................................ 108
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ........................... 110
Appendix E
Adverse Events of Special Interest......................................................... 113
Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding ....................................................... 117
Appendix G
Abbreviations ........................................................................................ 119
Appendix H
Protocol Amendment History................................................................. 120

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A phase II/III partially double-blinded, randomised, multinational, active-
controlled study in both previously vaccinated and unvaccinated adults to determine the safety 
and immunogenicity of AZD2816, a vaccine for the prevention of COVID-19 caused by 
variant strains of SARS-CoV-2.
Short Title: Phase II/III study of AZD2816, a vaccine for the prevention of COVID-19 in 
adults.
Rationale: Recently, several variants of the SARS-CoV-2 virus with increased 
transmissibility have emerged, including B.1.1.7, first identified in the UK, P.1, first identified 
in Brazil, and B.1.351, first identified in South Africa.  In an ongoing clinical trial of 
AZD1222 in South Africa, interim results failed to show protection against mild to moderate 
disease caused by the B.1.351 variant; protection against severe disease could not be 
determined as no severe cases were identified (Madhi et al 2021). 
Based on available evidence about vaccine effectiveness and molecular epidemiology of 
emerging variants, B.1.351 is estimated to have a potential to escape vaccine-elicited 
immunity. B.1.351 carries sequence mutations in common with other variants of concerns; 
immunity to B.1.351 therefore has the potential to provide some cross-immunity against other 
emerging strains. Development of candidate vaccines that include the B.1.351 S-protein 
variant is underway.  AstraZeneca is developing AZD2816, a vaccine against the B.1.351
SARS-CoV-2 variant using the same ChAdOx1 platform and manufacturing processes used 
for AstraZeneca’s currently available COVD-19 vaccine, AZD1222.
Objectives and Endpoints:
The purpose of this study is to characterize the safety and immunogenicity of AZD2816, 
AstraZeneca’s candidate ChAdOx1 vector vaccine against SARS-CoV-2 variant strain 
B.1.351, when administered:
!
As a single dose to SARS-CoV-2 seronegative participants who previously received a 
2-dose primary vaccination against SARS-CoV-2 with AZD1222 or an mRNA 
COVID-19 vaccine
!
As a 2-dose primary homologous vaccination to SARS-CoV-2 seronegative 
participants who are unvaccinated
!
As the second dose of 2-dose primary heterologous vaccination (with AZD1222 
as first dose) to SARS-CoV-2 seronegative participants who are unvaccinated. 
The following table lists the primary and secondary endpoints:

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Objectives
Endpoints
Safety Objectives: Previously unvaccinated participants
- Primary
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 4-
week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of a 2-dose 
primary heterologous vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 4-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety and tolerability of a 
heterologous primary vaccination with 1 dose
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 12-week dosing 
interval in unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
Immunogenicity objectives: Previously unvaccinated participants
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-Hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-Hu-1
Wuhan-Hu-1

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Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 
heterologous primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥ 4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 

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Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versus Wuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versus Wuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
Safety Objectives: Previously vaccinated participants
- Primary
To characterize the safety and tolerability of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 
days post dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose

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- Secondary
!
To characterize the safety and tolerability of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 
days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 7 
days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 booster dose of 
AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
To characterize the extended safety of 1 booster dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
To characterize the extended safety of 1 booster dose of 
AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
To characterize the extended safety of 1 booster dose of 
AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from 
Day 1 through 6 months post-vaccination
Immunogenicity objectives: previously vaccinated participants
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-Hu-1
Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222
vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-Hu-1
Wuhan-Hu-1

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Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.4
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 
vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-Hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination

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Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (≥ 4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-Hu-1 strain following an AZD2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster

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Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster version
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-Hu-1 strain following an AZD1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following an AZD2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following an AZD1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
SAEs: serious adverse events; MAAEs: medically attended adverse events; AESIs: adverse events of special 
interest.
a
At least a 4-fold increase in geometric mean titre from baseline
Overall Design: This is a phase II/III, multinational, randomised, partially double-blind, 
controlled study in two distinct cohorts: previously vaccinated and previously unvaccinated 
participants. 
Disclosure Statement: This is a parallel-group preventive study with 8 treatment arms.

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Number of Participants: Approximately 2590 SARS-CoV-2 nucleocapsid seronegative 
participants will be assigned to study intervention to support the primary and secondary 
objectives of this study. In addition, participants that are SARS-Cov-2 nucleocapsid 
seropositive at screening will be enrolled and assigned to study intervention for an exploratory 
analysis, with a cap of 10% of the seronegative population (ie, approximately 259 total 
participants).
Intervention Groups and Duration: Previously vaccinated participants will receive 1 dose 
of AZD1222 or AZD2816 on Day 1.  Previously unvaccinated participants will receive one of 
the following 2-dose vaccinations:
!
1 dose of AZD2816 on Day 1 and on Day 29
!
1 dose of AZD1222 on Day1 and on Day 29
!
1 dose of AZD1222 on Day 1 and 1 dose of AZD2816 on Day 29
!
1 dose of AZD2816 on Day 1 and on Day 85. 
Participants will be followed up for safety for 180 days after last study vaccine administration.
Data Monitoring Committee: A Data Safety Monitoring Board will provide oversight to 
ensure safe and ethical conduct of the study.
Statistical Methods:
Sample sizes of 300-380 seronegative participants per group are deemed appropriate based 
upon available immunogenicity data from previous clinical studies with AZD1222 for the 
primary and secondary objectives of this study.  
Owing to national vaccine rollout in the recruitment countries, including the prioritization of 
elderly populations, it is anticipated that there will be critical differences between the 
previously vaccinated and previously unvaccinated cohorts that may confound the 
interpretation of the results.  Consequently, the primary and key secondary non-inferiority 
analyses across these two cohorts will compare the previously vaccinated participants that 
received a booster dose in this study with a subset of matched participants from the previously 
unvaccinated participants that received the 2-dose AZD1222 primary vaccine series in the 
AZD1222 Phase 3 trial, Study D8110C00001. 
The safety analysis set for adverse events consists of all participants who have received at 
least one dose of study intervention.  The immunogenicity analysis set includes all participants 
in the safety analysis set who have no protocol deviations or intercurrent events judged to 
have the potential to interfere with the generation or interpretation of an immune response.
An initial interim analysis will be performed on a subset of previously AZD1222 vaccinated 
participants that have received a booster dose to consider unblinded sample size adjustment. 

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A second interim analysis will be performed when all previously AZD1222 vaccinated 
participants have completed their Day 29 visit to support registration of a booster dose. 
A third interim analysis will be performed on a subset of previously unvaccinated participants 
that have received their second dose to consider blinded sample size adjustment in this 
population. The primary analysis will be performed when there are data from all previously 
unvaccinated participants, 28 days after the second dose of the 4-week dosing intervals to 
support assessment of these 2-dose primary vaccinations to support registration of the booster 
dose and a 2-dose primary vaccination.  A secondary analysis will be performed on data from 
28 days after the second dose of the 12-week dosing interval to support assessment of this 2-
dose primary vaccination.  The final analysis will be performed on data from 6 months follow-
up after participant's vaccination.  
1.2
Schema
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster 

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Note:  In addition to the planned 2590 seronegative participants enrolled to support the 
primary/secondary objectives, seropositive participants will also be enrolled in the study to 
support exploratory objectives in this population, with a cap of 10% of the planned 
seronegative participants (ie, a maximum of 259 seropositive participants, bringing total 
planned enrollment to 2849). 
1.3
Schedule of Activities
Table 1
Schedule of Activities: Screening 
Procedure
Day -14 to Day 1
See Section
Informed consent
X
5.1, Appendix A 3
Demography
X
-
Medical and surgical history
X
-
Prior and concomitant medications
X
6.5
Complete physical examination, including height and weight
X
8.2.1
Vital signs
X
8.2.2
Urine pregnancy test (for women of childbearing potential only) 
X
8.2.3
Clinical safety laboratory assessments
X
8.2.3
Assessment of serious adverse events
X
8.3, Appendix B
Blood sample for SARS-CoV-2 antibody testing (lateral flow test)
X
8.5.2
Verify eligibility criteria
X
5.1, 5.2
Note:  Screening activities can occur at same visit as initial vaccination with investigational product (ie, Visit 1 in 
Table 2, Table 3, and Table 4).

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Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
Day
1
8
15
29
180
Window (days)
-
±2
±2
±3
±14
Medical and surgical history
X
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
-
-
6.1.1
Immunological assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
-
8.3.7
e-Diary collected
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)b
X
-
X
X
8.2.3
a
Only SAEs pre-dose
a
Not required to be repeated if performed on screening day prior to Day 1.
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: 
serious adverse event

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
Urine pregnancy test
(women of childbearing potential)
X 
-
-
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
X 
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample for SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample for additional immunogenicity
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
X
-
-
-
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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
X
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X (pre-dose)
X
-
X
X
8.2.3
b
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X
-
-
-
X
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X
-
-
-
X
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
X
-
-
-
8.3.7

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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2
INTRODUCTION
AZD2816 is being developed for the prevention of COVID-19.  It is a modified version of the 
current AstraZeneca SARS-CoV-2 vaccine (referred to as AZD1222 in clinical 
documentation) that has been modified to also provide immunity against the newly emerging 
SARS-CoV-2 variant strain B.1.351.  Like AZD1222, AZD2816 is a recombinant replication-
defective chimpanzee adenovirus vector (ChAdOx1) expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tissue plasminogen activator leader sequence at the 
N terminus.  AZD2816 differs from AZD1222 in that the S glycoprotein gene sequence used 
is from the B.1.351 variant strain instead of the original Wuhan-Hu-1 variant.
2.1
Study Rationale
The aim of the study is to assess the safety and immunogenicity of AZD2816 for prevention 
of COVID-19 as both a 2-dose primary vaccination in previously unvaccinated participants 
and a 1-dose booster vaccination in participants previously vaccinated against the original 
Wuhan-Hu-1 strain of SARS-CoV-2 by either AZD1222 or an mRNA-based vaccine.  A safe 
and effective vaccine for COVID-19 prevention, including against the B.1.351 variant, would 
have significant global public health impact. 
The study will also investigate the safety and immunogenicity of 1) a heterologous 2-dose 
vaccination with AZD1222 as first dose and AZD2816 as the second dose and 2) a single dose 
of AZD1222 as a booster vaccination in participants that have been previously vaccinated 
with an mRNA COVID-19 vaccine targeting the original Wuhan-Hu-1 strain.  
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (Zhou et al 2020). The disease these patients contracted was subsequently 
named Coronavirus Disease 2019 (COVID-19).  The World Health Organization declared the 
novel coronavirus a pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the 
novel coronavirus SARS-CoV-2, has resulted in significant global morbidity and mortality as 
well as major disruption to healthcare systems.  Measures to change the course of the 
pandemic have included the accelerated development vaccines against the original Wuhan-
Hu-1 strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes.  SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus,
and it is the seventh corona virus known to cause human infections and the third known to 
cause severe disease after SARS-CoV and MERS-CoV.  One fourth of the viral genome is 

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responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 
and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 spike (S) glycoprotein is a type I trimeric, transmembrane protein that is 
located at the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s 
subunits are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the 
receptor binding domain and subsequent fusion of virus and cell membranes, thereby 
mediating the entry of SARS-CoV-2 into the target cells.  The S protein has an essential role 
in virus entry and determines tissue and cell tropism, as well as host range.  The roles of the 
S-protein in receptor binding and membrane fusion have made it a desirable target for vaccine 
and antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947 
(ie, the Wuhan-Hu-1 isolate).
To date, 5 vaccines that rely upon the expression of the SARS CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 
NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b).  Immunogenicity data indicate that a 
single dose of AZD1222 elicits both humoral and cellular immunogenicity responses and that 
antibody responses are boosted after a second dose.  In a pooled analysis of the 4 studies 
conducted in the United Kingdom, Brazil, and South Africa (database lock 7 December 2020), 
the vaccine was highly immunogenic; seroresponse of S binding antibody was > 98% after a 
single dose of AZD1222.  Seroresponse of live neutralising antibody was 82.4% after 1 dose, 
which rose to 99.4% after a second dose.  Efficacy analyses of the pooled DCO2 data 
demonstrated effective protection of AZD1222 against COVID-19 with a vaccine efficacy of 
66.73% (95.84% CI: 57.41%, 74.01%) (p < 0.001) from 15 days after the second dose in 
seronegative participants receiving 2 doses.  The DCO2 data also demonstrated that the 
standard dose of AZD1222 (5 x 1010 viral particles) provides complete protection against 
COVID-19 hospital admission ≥ 22 days after the first dose in the seronegative analysis set 
(0 versus 14 cases in the control group, 2 of which were severe, including one with a fatal 
outcome).  Vaccine efficacy was similar in participants with pre-existing comorbidities, being 

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those at greatest risk of severe outcomes of COVID-19, compared to that in the general 
population.  Recently available primary analysis data from a Phase III study performed in the 
United States and Latin America showed primary endpoint vaccine efficacy of 76% (95% CI: 
67.60%, 82.22%; p-value < 0.001). 
A sharp rise in COVID-19 cases was reported in late 2020, which was attributed to the 
emergence of new SARS-CoV-2 variant strains: B.1.1.7 in the United Kingdom, B.1.351 
in South Africa, and P.1 in Brazil.  These variant strains carry a number mutations in the 
S protein sequence: 9 amino acids in B.1.1.7, 10 amino acids in B.1.351, and 12 amino acids 
in P.1 compared with the Wuhan-Hu-1 sequence.  These mutations may result in an increase 
of transmissibility and/or reduced vaccine effectiveness.  Variant B.1.351 was first identified 
in South Africa in October 2020.  Its attributes include approximately 50% increased 
transmission and moderate impact of neutralization by monoclonal antibody therapeutics, 
convalescent plasma and vaccine sera.  In vitro neutralization assays suggest that the B.1.351 
lineage viruses may be the most antigenically distinct from the original Wuhan-like strains 
(Zhou et al 2021).  In addition, evidence suggests that AZD1222 may afford diminished 
protection against mild-moderate COVID-19 disease arising from the B.1.351 variant (Madhi 
et al 2021).  
The development of candidate vaccines that would be effective against the B.1.351 variant 
strain is underway.  AZD2816 is being developed as an updated ChAdOx-nCov19 (AZD1222) 
vaccine designed to provide protective immunity against the newly arising B.1.351 variant 
strain, using the same ChAdOx1 platform and manufacturing processes used for 
AstraZeneca’s currently approved COVID-19 vaccine, AZD1222.  The purpose of this Phase 
II/III, multinational, randomised, partially double-blind, active-controlled study is to 
demonstrate the safety and characterize the immunogenicity of AZD2816, AstraZeneca’s 
candidate ChAdOx1 vector vaccine against B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative participants who have previously 
received a 2-dose primary vaccination series against the original SARS-CoV-2 Wuhan-
Hu-1 strain (AZD1222 or an mRNA vaccine).
!
As a 2-dose homologous primary vaccination to SARS-CoV-2 seronegative participants 
who have not been vaccinated previously. 
The immunogenicity of a 2-dose primary heterologous vaccination (with AZD1222 as first 
dose and AZD2816 as second dose) to SARS-CoV-2 seronegative participants who are 
unvaccinated and a single booster dose of AZD1222 to SARS-CoV-2 seronegative 
participants who have previously received a 2-dose primary vaccination series against the 
original Wuhan-Hu-1 strain will also be investigated.
SARS-CoV-2 seropositive participants will also be enrolled to support a parallel exploratory 
analysis in these participants. 

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A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD1222 and 
AZD2816 is provided in the respective Investigator’s Brochures.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD2816 and AZD1222 can be found in the respective Investigator’s Brochures.
2.3.1
Risk Assessment
AZD2816 has been developed using the same vaccine vector, ChAdOx1, as AZD1222 and 
only differs in the sequence for SARS-CoV-2 S glycoprotein that is inserted in the vector.  
The anticipated safety profile of AZD2816 is the same as the observed safety profile of 
AZD1222.  Risks associated with AZD2816 are thus the same as the risks associated with 
AZD1222, and no additional risks are anticipated due to the change in the targeted sequence.
A number of essentially mild and moderate adverse reactions to AZD1222 have been 
identified and resemble reactions frequently observed after many vaccines.  Based on pooled 
clinical data from studies with AZD1222, the most commonly expected local solicited AEs for 
participants in this study are vaccination site pain and tenderness.  The most commonly 
expected systemic solicited AEs are fatigue, headache, and malaise.  The majority of reported 
events have been mild or moderate in severity and resolved within 1 to 7 days.  Following the 
second dose, a general attenuation in the incidence and severity of local and systemic solicited 
AEs was observed. 
Post-authorisation hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk.
A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, 
has been observed very rarely following vaccination with COVID-19 Vaccine (ie, AZD1222) 
during post-authorisation use.  No events have been observed in the AZD1222 clinical 
development programme.  Thrombosis in combination with thrombocytopenia is thus 
considered to be an important identified risk.  This includes cases presenting as venous 
thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein 
thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia.  Considering 
the frequency of this rare event and the size of this study, the risk for participants in this trial 
is considered to be low.  The protocol includes exclusion criteria and instructions for 
heightened vigilance and thorough investigations for suspected cases to mitigate against 
further the risk for these rare event. 
Important potential risks are 1) neurologic events and potential immune-mediated neurologic 
conditions and 2) vaccine-associated enhanced disease, including vaccine-associated enhanced 
respiratory disease. 

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2.3.2 Benefit Assessment
All participants will receive active treatment: either AZD1222, which has been shown to be 
effective in providing protection against SARS-CoV-2, or AZD2816, which as a modified 
form of AZD1222 designed to be effective against the emergent B.1.351 variant strain and 
may also provide participants with protection.  The information gained from this study will 
inform development decisions with regard to the efficacy of AZD2816 as both a primary 
2-dose vaccination in participants that have not been previously vaccinated and a 1-dose 
booster vaccination in participants previously vaccinated against SARS-CoV-2. 
2.3.3 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria and close monitoring of participants to 
minimize known and potential risks. 
An independent Data Safety Monitoring Board will provide study oversight, evaluating 
cumulative safety and other clinical data at regular intervals. 
Taking these measures into account, the potential risks identified in association with the 
administration of AZD2816 and AZD1222 are justified by the anticipated benefit that may 
be afforded to participants for the prevention of COVID-19.

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3
OBJECTIVES AND ENDPOINTS
3.1
Previously unvaccinated cohort receiving a 2-dose primary 
vaccination
The primary safety objective for the cohort of previously unvaccinated participants receiving 
a 2-dose dose primary vaccination is to characterize the safety and tolerability of a 2-dose 
primary vaccination with AZD2816 with a 4-week dosing interval in previously unvaccinated 
seronegative participants.
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary: 
1: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response against the original 
Wuhan-Hu-1 strain elicited by a 2-dose AZD1222 vaccination.
Key secondary:
2.1: To determine if seroresponse against the B.1.351 variant elicited by a 2-dose AZD2816 
vaccination is non-inferior to seroresponse against the original Wuhan-Hu-1 strain elicited 
by a 2-dose AZD1222 vaccination.
2.2: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 2-dose 
AZD1222 vaccination.
2.3: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose heterologous AZD1222 + AZD2816 vaccination is non-inferior to the 
response against the original Wuhan-Hu-1 strain elicited by a 2-dose AZD1222 vaccination
2.4: To determine if the neutralizing antibody GMT response against the original Wuhan-Hu-
1 elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 
2-dose AZD1222 vaccination
The above primary and the key secondary immunogenicity objectives will be supported by 
other secondary immunogenicity objectives (see below) for which there will be no formal 
hypothesis testing.
Table 5 further describes the objectives and endpoints for this cohort of participants, including 
estimands for the immunogenicity objectives.

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Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination
Safety Objectives
Endpoints
- Primary
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 4-
week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of a 
heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 4-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety and tolerability of a 
heterologous primary vaccination with 1 dose
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 12-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
Immunogenicity Objectives
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-Hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:

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Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 
heterologous primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:

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Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥ 4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versus Wuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥ 4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versus Wuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a 2-dose homologous or 
heterologous primary vaccination with AZD2816 
and/or AZD1222 in sub-groups of seronegative and 
seropositive participants
! GMT of ChAdOx1 neutralizing antibody titres
! Seroresponse rate of ChAdOx1 neutralizing 
antibody titres
! Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody 
titres, 28 days after both Dose 1 and Dose 2
Exploratory Objectives
Objective
Endpoints
To explore the immune response elicited by a 2-dose 
AZD2816 primary vaccination with a 12-week dosing 
interval compared to the response elicited by a 2-dose 
AZD2816 primary vaccination with a 4-week dosing 
interval
! GMT ratio of pseudoneutralizing antibodies
! Seroresponse

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To explore antibody response to selected SARS-CoV-2 
variants of interest/variants of concern following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! GMT of SARS-CoV-2 anti-S binding antibodies 
for selected variants of concern/variants of interest
! Seroresponse rate of SARS-CoV-2 specific 
binding antibody titres for selected variants of 
concern/variants of interest
! GMT of SARS-CoV-2 pseudoneutralizing 
antibody responses against the B.1.617.2 (delta) 
variant
! Seroresponse rate of SARS-CoV-2 
pseudoneutralizing antibody responses against the 
B.1.617.2 (delta) variant
To explore B-cell and T-cell responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! Intracellular cytokine staining and flow cytometry 
for T-cell responses over time
! Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 B.1.351 or Wuhan-Hu-1 S protein 
from day of dosing baseline over time
! Breadth and depth of peripheral blood B-cell and 
T-cell repertoire over time through 
immunosequencing
To monitor the incidence of SARS-CoV-2 infection 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or AZD1222 
in previously unvaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined 
by the seroresponse to nucleocapsid antibodies 
occurring post-second dose of study intervention 
To monitor the incidence of COVID-19 following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in previously 
unvaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses against the 
B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Geometric mean titre of SARS-CoV-2 
neutralization as determined by a live virus 
neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific 
antibody binding and neutralization titres as 
determined by a live virus neutralization assay
To explore additional immune responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in sub-groups of 
seronegative and seropositive participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity 
data
To explore the immunogenicity objectives in 
seropositive participants
!
GMT of pseudoneutralizing antibodies
!
Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.

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3.2
Previously vaccinated cohort receiving a 1-dose booster 
vaccination
The primary safety objective for the cohort of seronegative previously vaccinated participants 
receiving a booster dose is to characterize the safety and tolerability of 1 booster dose of 
AZD2816 in participants previously vaccinated with AZD1222. 
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary:
1: To determine if the humoral immune response against the B.1.351 variant elicited by an 
AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior to 
the response against the original Wuhan-Hu-1 strain elicited by 2-dose AZD1222 vaccination 
administered to previously unvaccinated participants.
Key secondary:
2.1: To determine if the humoral immune response against the B.1.351 variant elicited by 
an AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior 
to the response elicited by 2-dose AZD1222 vaccination administered to previously 
unvaccinated participants.
2.2:  To determine if the humoral immune response elicited against the B.1.351 variant by 
an AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 booster 
dose  in participants previously vaccinated with AZD1222.
2.3: To determine if the humoral immune response against the original Wuhan-Hu-1 strain 
elicited by an AZD2816 booster dose in participants previously vaccinated with AZD1222 
is non-inferior to the response elicited by 2-dose AZD1222 vaccination administered to 
previously unvaccinated participants.
2.4: To determine if the humoral immune response against the original Wuhan-Hu-1 strain 
elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222 
is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
2.5: To determine if the humoral immune response against the original Wuhan-Hu-1 strain 
elicited by an AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 
booster dose in participants previously vaccinated with AZD1222.
The primary and key secondary immunogenicity objectives will be supported by other 
secondary objectives for which there will be no formal hypothesis testing. Table 6 further 
describes the objectives and endpoints for this cohort of participants, including estimands 
for the primary and secondary immunogenicity objectives.

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Table 6
Study Objectives and Endpoints for Previously Vaccinated 
Participants Receiving a 1-Dose Booster Vaccination
Safety Objectives
Endpoints
- Primary
To characterize the safety and tolerability 
of 1 booster dose of AZD2816 in 
seronegative participants previously 
vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days post-
dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, and 
AESIs, for 28 days post-dose
! The change from baseline for safety laboratory measures for 28 
days post-dose
- Secondary
To characterize the safety and tolerability 
of 1 booster dose of AZD1222 in 
seronegative participants previously 
vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days post-
dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, and 
AESIs for 28 days post-dose
To characterize the safety and tolerability 
of 1 booster dose of AZD2816 in 
seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 7 days post-
dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, and 
AESIs for 28 days post-dose
To characterize the safety and tolerability 
of 1 booster dose of AZD1222 in 
seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 7 days post-
dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, and 
AESIs for 28 days post-dose
To characterize the extended safety of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with 
AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 through 6 
months post-vaccination
To characterize the extended safety of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with 
AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 through 6 
months post-vaccination
To characterize the extended safety of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with a 
SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 through 6 
months post-vaccination
To characterize the extended safety of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with a 
SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 through 6 
months post-vaccination
Immunogenicity objectives
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-Hu-1

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Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.4
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-Hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster

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To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 booster/
AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1

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Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-Hu-1 strain following an AZD2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster vaccination
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-Hu-1 strain following a AZD1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following an AZD2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a AZD1222 booster dose. 
Estimand:

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Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (≥4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
To explore anti-vector responses to the 
ChAdOx-1 adenovirus vector following a 
booster dose of AZD2816 in sub-groups of 
seronegative and seropositive participants
! Magnitude of ChAdOx1 nAb titres (geometric mean titre)
! Seroresponse rate of ChAdOx1 neutralizing antibody titres
! Pairwise correlations between anti-S, pseudo-neutralization, 
and ChAdOx1 neutralizing antibody titres, 28 days after both 
Dose 1 and Dose 2
Exploratory objectives
Objective
Endpoints
To explore antibody response to selected 
SARS-CoV-2 variants of interest/variants 
of concern following a booster dose of 
AZD2816 and in a sub-group of 
seronegative participants
! Magnitude of SARS-CoV-2 specific antibody binding titres 
(geometric mean titre) for selected variants of concern/variants 
of interest
! Seroresponse rate of SARS-CoV-2 specific antibody binding 
titres for selected variants of concern/variants of interest
! GMT of SARS-CoV-2 pseudoneutralizing antibody responses 
against the B.1.617.2 (delta) variant
! Seroresponse rate of SARS-CoV-2 pseudoneutralizing antibody 
responses against the B.1.617.2 (delta) variant
To explore B-cell and T-cell responses 
following a booster dose of AZD2816 in a 
sub-group of seronegative participants
! Intracellular cytokine staining and flow cytometry for T-cell
responses over time
! Quantification of (IFN-γ) ELISpot responses to SARS-CoV-2 
B.1.351 or Wuhan-Hu-1 S protein from day of dosing baseline 
over time
! Breadth and depth of peripheral blood B-cell and T-cell 
repertoire over time through immunosequencing
To monitor the incidence of SARS-CoV-2 
infection following a booster dose of 
AZD2816 in previously vaccinated 
seronegative participants
! The incidence of SARS-CoV-2 infection defined by the 
presence of nucleocapsid antibodies occurring post-dose of 
study intervention 
To monitor the incidence of COVID-19 
following a booster dose of AZD2816 in 
previously vaccinated seronegative 
participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses 
against the B.1.351 and Wuhan-Hu-1 
strains induced by a booster dose of  
AZD2816 or AZD1222 in sub-groups of 
seronegative and seropositive participants
! Geometric mean titre of SARS-CoV-2 neutralization as 
determined by a live virus neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific antibody binding 
and neutralization titres as determined by a live virus 
neutralization assay
To explore additional immune responses 
following a booster dose of  AZD2816 or 
AZD1222 in sub-groups of seronegative 
and seropositive participants
! Other exploratory assays for humoral and cellular immune 
responses may be performed based upon emerging safety, 
efficacy, and immunogenicity data

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To explore the immunogenicity objectives 
in seropositive participants
! GMT of pseudoneutralizing antibodies
! Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest.
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.
4
DESIGN
4.1
Overall Design
This is a multi-country Phase II/III study to evaluate the safety and immunogenicity of 
AZD2816 as single-dose vaccination in previously vaccinated adult participants and as a 
2-dose primary vaccination in previously unvaccinated adult participants. 
A total of approximately 2590 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled across these 2 
populations with the goal of 1300 previously vaccinated participants receiving single-dose 
vaccination and 1290 unvaccinated participants receiving 2-dose primary vaccination. In 
addition, seropositive participants will be enrolled (with a cap of 10% of the seronegative 
population or 259 participants) to support exploratory analysis is these participants. 
The enrollment and randomization strategy is intended to minimize group differences in terms 
of age, gender and the presence of comorbidities.
In both the single-dose booster treatment regimen and the 2-dose primary vaccination 
treatment regimen, participants will receive study intervention consisting of intramuscular 
administration of either AZD1222 (5 ×1010 viral particles) or AZD2816 (5 ×1010 viral 
particles).
Approximately 700 seronegative participants previously vaccinated with AZD1222 will be 
randomised 1:1 to receive a single intramuscular dose of either AZD1222 or AZD2816 in 
a double-blinded fashion.  
Approximately 600 seronegative participants previously vaccinated with an approved mRNA 
based vaccination against the original Wuhan-Hu-1 strain will be randomised 1:1 to receive 
a single intramuscular dose of AZD2816 or AZD1222 in a double-blinded fashion.
Approximately 1290 seronegative, previously unvaccinated participants will be randomised 
approximately 5:5:5:2 to receive a 2-dose primary vaccination of the following:
!
2 doses of AZD1222 with a 4-week dosing interval
!
2 doses of AZD2816 with a 4-week dosing interval
!
1 dose of AZD1222 followed by 1 dose of AZD2816 with a 4-week dosing interval 

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!
2 doses of AZD2816 with a 12-week dosing interval.
The 3 treatments with a 4-week dosing interval will be double-blinded while the treatment 
with the 12-week interval will be open-label due to the difference in dosing interval.
In addition, a smaller population seropositive participants (up to 10% of the seronegative 
population), will be randomised to treatment in a similar manner as above.
Owing to national vaccine rollout in the recruitment countries, including the prioritization 
of elderly populations, it is anticipated that there will be critical differences between the 
previously vaccinated and previously unvaccinated cohorts that may confound the 
interpretation of the results.  Consequently, the primary and key secondary non-inferiority 
analyses across these two cohorts will compare the previously vaccinated participants that 
received a booster dose in this study with a subset of matched participants from the previously 
unvaccinated participants that received the 2-dose AZD1222 primary vaccine series in the 
AZD1222 Phase 3 trial, Study D8110C00001. 
Immunogenicity (ie, anti-Wuhan-Hu-1 and anti-B.1.351 immune responses including 
S-binding antibody titres and neutralizing antibody levels [pseudo-neutralization]) will be 
assessed in serum samples collected pre-dose on the day of each vaccination (baseline levels 
before vaccination), 14 and 28 days after each vaccination, and 180 days after the last 
vaccination.
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1-8 for all participants and Days 29-36 for the 4-week dosing interval and Days 85-92 
for the 12-week dosing interval).  An e-diary will be used to collect information on the timing 
and severity of the solicited signs and symptoms.
Follow-up visits will take place as per the schedule of assessment within respective windows.  
All participants will be assessed for local and systemic AE, physical examination, review of 
e-diaries at these time points as detailed in the schedule of assessment.  Blood will also be 
taken for safety assessments and immunology purposes.
All study participants will be followed for safety for 180 days after administration of their last 
vaccination dose.  In every participant, solicited local and systemic events will be reported for 
up to 7 days after each dose, all unsolicited AEs will be reported for up to 28 days after each 
dose, and SAEs and AEs of special interest will be evaluated through study completion 
(up to 180 days after the last study vaccination).  

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An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, 
to ensure safe and ethical conduct of the study.
4.1.1
COVID-19 Assessments
Occurrence of COVID-19 in the trial will be reported as safety events, including monitoring 
of the potential risk of vaccine-elicited enhanced disease as an AE of special interest (see 
Appendix E).  COVID-19 will be diagnosed and treated as per standard medical practice.  
In addition, experimental treatments are permitted.  Detailed information will be collected 
in a standard way and reported on a specific case report form. 
4.1.2
Screening 
All potential participants will be screened, which may take place at a visit up to 14 days prior 
to Day 1 or on Day 1 itself.  
Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the screening procedures specified in the Schedule of Activities (Section 1.3) will be 
undertaken including a medical history, physical examination, height and weight, a 
SARS-CoV-2 screening test and clinical safety laboratory assessments.  Baseline information 
collected in the previously vaccinated participants will include which vaccine was received, 
immunization dose interval, and time since last vaccination.
For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled.  (Note: Women with urine test results that are positive or undetermined will not be 
enrolled and should be advised to seek medical attendance outside the context of the trial if 
pregnancy is suspected.) 
The eligibility of the participants will be reviewed at the end of the screening visit and again 
when all results from the screening visit have been considered.  Decisions to exclude the 
participant from enrollment or to withdraw a participant from the study will be at the 
discretion of the Investigator.
4.1.3
Vaccination Visit
Participants will be considered enrolled at the point of vaccination.  Before vaccination, the 
eligibility of the participant will be reviewed.  Body temperature will be observed and a 
medical history and physical examination will be undertaken before the first vaccination to 
determine need to postpone vaccination or screen fail the participant.  A negative pregnancy
test (urine test) will need to be obtained from women of childbearing potential before 
vaccination.  Baseline blood samples will be obtained before the first vaccination.

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Participants will receive 1 dose of AZD2816 or AZD1222 at vaccination visits, administered 
by intramuscular injection.  Previously immunized participants will have a single vaccination 
visit, Day 1.  Participants that have not been previously vaccinated at baseline will have a 
second vaccination visit on Day 29 (4-week interval) or Day 85 (12-week interval).  
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1 to 8 and Days 29 to 36 or Days 85 to 92 when applicable).
4.1.4
Follow-up visits
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3).  All 
participants will be assessed for local and systemic AE, physical examination, review of the 
e-diary and blood tests at these time points as detailed in the Schedule of Activities.  Blood 
will also be taken for safety and immunogenicity assessments.
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate way until the last 
study visit in order to collect information on any SAEs/AE of special interest.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population includes adults ≥ 18 years of age.  Persons who are healthy or have 
medically stable underlying conditions will be eligible.  Adults with medically-stable chronic 
diseases may participate if, according to the judgement of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Some seropositive participants 
(capped at 10% of the seronegative participant population) will be enrolled to support an 
exploratory analysis.  
Those enrolled in the single-dose vaccination part of the study must have received 2 doses of 
AZD1222 (with a dosing interval of 4-12 weeks) or 2 doses of an approved mRNA-based 
COVID-19 vaccine (with a dosing interval of 3-12 weeks for the BNT162b2 mRNA vaccine 
[Pfizer-BioNTech] and 4-12 weeks for the mRNA-1273 vaccine [Moderna]) with the second 
doses administered at least 90 days prior to first study intervention administration. 
Pregnant/breastfeeding women, persons with severe immunodeficiency or severe underlying 
disease will be excluded from participation in the study.  Persons previously vaccinated with 

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AZD1222 in the context of an AZD1222 vaccine trial are eligible for enrollment as previously 
vaccinated participants in the trial.  Persons who have previously received any other
investigational product for the prevention of COVID-19 will be excluded from participation 
in this study.
Participants with known risk factors for thrombosis and thrombocytopenia (excluding 
contraceptive hormonal therapy or replacement hormonal therapy) are excluded.
4.2.2
Rationale for Study Endpoints
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination 
will be summarized by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be 
summarized by system organ class and preferred term, and by relationship to 
vaccination as assessed by the investigator.
!
SAEs and AEs of special interest following the first vaccination and throughout the 
study duration will be summarized by system organ class and preferred term and by 
relationship to vaccination as assessed by the investigator.
Solicited AEs will be collected for 7 days after each dose of study intervention, a period that 
has proven adequate to describe reactogenicity events in previous vaccine studies.  For all 
participants, AEs will be collected through 28 days after each dose of study intervention.  
SAEs, medically-attended AEs, and AEs of special interest and will be collected from 
Day 1 through end of the study.  AEs of special interest include terms identified by the 
Brighton Collaboration involving events associated with vaccination in general.
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean titre
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean titre from baseline
Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of
interest.
Immunogenicity against SARS-CoV-2 Wuhan-Hu-1 and B.1.351 strains will be characterized 
through the quantification of Spike-binding antibodies, pseudo-neutralization and, in a subset 
of participants, live neutralization.  Exploratory analysis of immunogenicity against other 
strains and induction of other immune effectors including cell-mediated immunity will be 
conducted. 

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4.3
Justification for Dose
The AZD2816 nominal dose of 5 × 1010 viral particles is the same dose as the approved dose 
for AZD1222, which was based on the accumulated non-clinical data and clinical data from 
the AZD1222 clinical studies, as well as from other SARS-CoV-2 vaccines in development. 
Safety and immunogenicity data from an additional clinical study, MERS001(NCT03399578), 
using the same ChAdOx1 vector, also helped inform dose selection. MERS001 was the first 
clinical study of a ChAdOx1-vectored vaccine expressing the full-length S protein from a 
separate, but related, beta-coronavirus.  ChAdOx1 MERS has been given to 31 participants 
to date at doses ranging from 5 × 109 viral particles to 5 × 1010 viral particles.  Despite higher 
reactogenicity observed at the 5 × 1010 viral particles, this dose was safe, with self-limiting 
AEs and no serious adverse reactions recorded.  The 5 × 1010 viral particles was the most 
immunogenic, in terms of inducing neutralizing antibodies against MERS-CoV using a live 
virus assay (Folegatti et al 2020).  Given the immunogenicity findings and safety profile 
observed with the ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 viral particles 
dose was chosen for AZD1222.  
Based on accumulating nonclinical and clinical data gathered for AZD1222, a 2-dose regimen 
was selected for vaccination of unvaccinated participants with AZD2816 (AZD1222 
Investigators Brochure).  A single dose vaccination has been selected for participants 
previously vaccinated in line with both FDA and EMA guidance (FDA 2021, EMA 2021).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases 
of the study including the last scheduled procedure shown in the Schedule of Activities 
(Section 1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as a protocol waiver or exemption, is not permitted.

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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1
All Participants: 
Age
1
Adult, ≥ 18 years of age at the time of consent
COVID-19
For inclusion in the SARS-CoV-2 seronegative population supporting the primary and 
secondary objectives: 
2
No history of laboratory-confirmed SARS-CoV-2 infection (ie, no positive nucleic acid 
amplification test and no positive antibody test).
3
Seronegative for SARS-CoV-2 at screening (lateral flow test to detect reactivity to the 
nucleoprotein).
Note, patients failing to meet criteria 2 and/or 3 may be included in the separate seropositive 
population supporting the seropositive exploratory objectives. 
Type of Participant 
4
Medically stable such that, according to the judgment of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up
∀
- A stable medical condition is defined as disease not requiring significant change in 
therapy or hospitalization for worsening disease during the 90 days prior to enrollment
5
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator
6
Signed informed consent obtained before conducting any study-related procedures
Reproduction
7
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants:
(a) Women of childbearing potential must:
!
Have a negative pregnancy test on the day of screening and on days of 
vaccination
!
Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
30 days following administration of the last dose of study intervention.  A highly 

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effective method of contraception is defined as one that can achieve a failure rate 
of less than 1% per year when used consistently and correctly (see Table 7).  
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy) or 
!
Post-menopausal:
!
For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥ 12 months amenorrhea prior to randomization, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and
o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal 
range, the participant is to be considered of childbearing potential
!
For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomization, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.
Table 7
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing systema
Bilateral tubal occlusion
Vasectomized partner b
Sexual abstinence c
Combined (oestrogen- and progestogen-containing 
hormonal contraception
      Oral (combined pill)
      Intravaginal
     Transdermal (patch)
Progestogen-only hormonal contraception
#
     Oral 
#
     Injectable
#
     Implantable
a
This is also considered a hormonal method 
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse from 28 days prior to Day 1 through 30 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant
5.1.2
Previously COVID-19 Vaccinated Participants
8
Prior completion of a 2-dose primary homologous vaccination regimen against the 
original SARS-CoV-2 Wuhan-Hu-1 strain with either AZD1222 (2 standard doses as 
authorized vaccine or as investigational product in a clinical trial with a 4- to 12-week 

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dosing interval) or with an mRNA vaccine approved for emergency or conditional use 
(eg, BNT162b2 vaccine [Pfizer-BioNTech] with a 3- to 12-week dosing interval or 
mRNA-1273 vaccine [Moderna] with a 4- to 12-week dosing interval).  The second dose 
in all cases should have been administered at least 90 days prior to first administration of 
study intervention.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of allergy to any component of AZD1222/AZD2816.
2
History of Guillain-Barré syndrome, any demyelinating disease, or any other 
neuroimmunologic condition
3
Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) on the 
day prior to or day of randomization 
4
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia or HIV/AIDS. 
5
Recurrent severe infections and use of immunosuppressant medication within the past 
6 months (≥ 20 mg per day of prednisone or its equivalent, given daily or on alternate 
days for ≥ 15 days within 30 days prior to administration of study intervention)
The following exceptions are permitted:  
∀
Topical/inhaled steroids or short-term oral steroids (course lasting ≤14 days)
6
History of primary malignancy except for:
(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or for metastasis (for example, indolent 
prostate cancer) in the opinion of the site investigator.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease
(c) Adequately treated uterine cervical carcinoma in situ without evidence of disease
(d) Localized prostate cancer
7
History of thrombocytopenia and/or thrombosis, including participants who have 
experienced major venous and/or arterial thrombosis in combination with 
thrombocytopenia following vaccination with any COVID-19 vaccine
8
History of heparin-elicited thrombocytopenia, congenital thrombophilia (ie, factor V 
Leiden, prothrombin G20210A, antithrombin III deficiency, protein C deficiency and 
protein S deficiency, factor XIII mutation, familial dysfibrinogenemia), auto-immune 
thrombophilia (antiphospholipid syndrome, anti-cardiolipin antibodies, anti-β2-
glycoprotein 1 antibodies), or paroxysmal nocturnal haemoglobinuria.

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9
Clinically significant bleeding (eg, factor deficiency, coagulopathy, or platelet disorder), 
or prior history of significant bleeding or bruising following intramuscular injections or 
venepuncture
10 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, or neurological illness, as judged 
by the Investigator (note, mild/moderate well-controlled comorbidities are allowed)
11 Any other significant disease, disorder, or finding that may significantly increase the risk 
to the participant because of participation in the study, affect the ability of the participant 
to participate in the study, or impair interpretation of the study data
12 Any autoimmune conditions, except mild psoriasis and vitiligo
Note: The AEs of special interest as outlined in Appendix E (including Table 28) should be 
considered when evaluating a participant for exclusion criteria as the presence of these AEs of 
special interest, especially if untreated or uncontrolled, may be a safety risk to the participant, 
affect the ability of the participant to participate in the study, and/or impair interpretation of 
the study data.  Investigators should review and consider the list of conditions in Appendix E.  
If any of these conditions are present in a participant, the Investigator is asked to utilize 
his/her clinical judgment in determining the participant’s eligibility for the study.  Should the 
participant have conditions as outlined in Appendix E and the participant is enrolled, the 
Investigator is asked to document notes on site regarding the final rationale for enrollment.
Prior/Concomitant Therapy
13 Receipt of or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 with the exception of prior vaccination with 
AZD1222 or an mRNA COVID-10 vaccine (2 doses of the same vaccine within an 
approved dosing interval, see Section 5.1.2), which is allowed for participants in the 
previously vaccinated cohort 
Note: For participants who develop COVID-19, receipt of licensed treatment options 
and/or participation in investigational treatment studies is permitted
14 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to or after administration of study intervention
15 Receipt of any influenza vaccine (licensed or investigational) within 7 days prior to and 
after administration of AZD1222/AZD2816.
16 Receipt of immunoglobulins and/or any blood products within 90 days prior to 
administration of study intervention or expected receipt during the period of study 
follow-up
Other Exclusions
17 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)

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18 Women who are currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, having given birth less than 90 days before or planning pregnancy during 
the study. 
19 Has donated ≥ 450 mL of blood products within 30 days prior to randomization or 
expects to donate blood within 90 days of administration of second dose of study 
intervention
20 Participants with a history of chronic alcohol or drug abuse or any condition associated 
with poor compliance.
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements or 
if vaccination would interfere with the participant’s ongoing treatment.
22 Previous enrollment in the present study.
5.3
Lifestyle Considerations
1
Participants must follow the contraception requirements outlined in Section 5.1
2
Restrictions relating to concomitant medications are described in Section 6.5
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Only a single rescreening is allowed in the study.  Rescreened participants are 
required to sign a new ICF (Appendix A 3), and will be assigned a new participant number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical device utilized by a study participant according to 
the study protocol.  Study intervention is defined as AZD2816 or AZD1222 (Table 8).

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6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 8
Investigational Products
Intervention 
Name
AZD2816
AZD1222
Type 
Vaccine
Vaccine
Dose Formulation
Unit Dose Strength
1 × 1011 viral particles/mL
1 × 1011 viral particles/mL
≥ 5 × 108 infectious units/mL
≥ 5 × 108 infectious units/mL
Dosage Level
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
≥ 2.5 × 108 infectious units
≥ 2.5 × 108 infectious units
Route
Intramuscular
Intramuscular
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labelling
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Current/Former 
Name
-
Previous clinical documentation:
ChAdOx1 nCoV-19
Current tradename: Vaxzevria
IMP: investigational medicinal product; NIMP: non-investigational medical product; w/v: weight/volume.
AZD2816 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD2816 has 
a label-claim volume of 5 mL and can provide up to ten 0.5 mL doses.
AZD1222 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD1222 has 
a label-claim volume of 4 mL and can provide up to eight 0.5 mL doses.
Unopened vials of AZD2816 and AZD1222 must be stored at 2-8 oC (36-46 oF) for the 
duration of the assigned shelf-life and must not be frozen.  Both investigational products must 
be kept in original packaging until use to prevent prolonged light exposure. 
CCI
CCI

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6.1.2
Dosing Instructions
Previously unvaccinated participants will receive 2 doses of either AZD1222, AZD2816, 
or AZD1222 plus AZD2816, with the first dose administered on Day 1 and the second dose 
on Day 29 (for a 4-week dosing interval) (Table 3) or Day 85 (for a 12-week dosing interval) 
(Table 4). 
Previously vaccinated participants will receive 1 dose of either AZD1222 or AZD2816 
(Table 2).  
It is recommended that the study interventions be administered as an intramuscular injection 
into the deltoid of the non-dominant arm. Other injection sites may be used if necessary.
All study participants will be observed in the clinic for at least 15 minutes after vaccination. 
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.
6.2
Preparation/Handling/Storage/Accountability
The procedures for preparation, handling, storage, and accountability are identical for 
AZD2816 and AZD1222.
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual or specified handling instructions.
6.2.1
Dose Preparation and Administration
Doses of AZD2816 and AZD1222 must be prepared by the unblinded pharmacist (or designee 
in accordance with local and institutional regulations) using aseptic technique.  Each dose is 
prepared by withdrawing 0.5 mL from a vial of AZD2816 or AZD1222 in a sterile syringe. 

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AZD2816 and AZD1222 do not contain preservatives. Each vial must be assigned a beyond-
use-date of 6 hours at 2-30 °C (36-86 °F) from first needle puncture of the vial, after which 
any unused portion must be discarded.
Once an AZD2816 or AZD1222 dose is drawn into a syringe for administration, the dose must 
be administered within the beyond-use-date of the vial. If dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
The study contains 3 cohorts that are randomised to a total of 8 treatments: 
!
Participants that have previously been vaccinated with 2 doses of AZD1222 will be 
randomised 1:1 to 1 dose of AZD2816 or 1 dose of AZD1222.
!
Participants that have been previously vaccinated with an mRNA COVID-19 vaccine 
will be randomised 1:1 to 1 dose of AZD2816 or AZD1222.  
!
Previously unvaccinated participants that will be randomised 5:5:5:2 to 2 doses of 
AZD2816 with a 4-week dosing interval, 2 doses of AZD1222 with a 4-week dosing 
interval, 1 dose of AZD1222 followed by 1 dose of AZD216 with a 4-week dosing 
interval, or 2 doses of AZD2816 with a 12-week dosing interval.
Separate populations of SARS-CoV-2 seronegative participants (supporting the primary and 
secondary objectives) and SARS-CoV-2 seropositive participants (supporting exploratory 
objectives) will be randomised/included in the above cohorts.
Randomization will be stratified based on age (less than 65, 65 and above), gender, and 
presence of at least one of the following comorbidities that are known risk factors for severe 
illness from COVID-19 (based on the participant’s past and current medical history):
!
Obesity (BMI ≥ 30 kg/m2 at baseline)
!
Significant cardiovascular disease (eg, heart failure, coronary artery disease, congenital 
heart disease, cardiomyopathies, or pulmonary hypertension)
!
Chronic lung disease (eg, chronic obstructive pulmonary disease, idiopathic pulmonary 
disease, cystic fibrosis, or moderate to severe asthma)
!
Diabetes.  
The randomised participants will be centrally assigned to randomised study intervention using 
an Interactive Response Technology (IRT)/Randomisation and Trial Supply Management.  
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 

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the log in information & directions for the Randomisation and Trial Supply Management will 
be provided to each site.
Where a participant does not meet all the eligibility criteria but incorrectly received study 
intervention, the investigator should inform the Study Physician immediately, and a discussion 
should occur between the Study Physician and the investigator regarding whether to continue 
or discontinue the participant.
6.3.2
Blinding
Treatment will be double-blinded for previously vaccinated participants randomised to a 
single dose of either AZD2816 or AZD1222. Treatment will also be double-blind for 
previously unvaccinated participants randomised to 2 dose vaccinations with a 4-week 
dosing interval (ie, homologous AZD2816 or AZD1222 vaccination or heterologous 
AZD1222/AZD2816 vaccination).  Previously unvaccinated participants randomised to a 
homologous AZD2816 vaccination with a 12-week dosing interval will receive treatment in 
an open-label fashion due to the different dosing interval.
For the double-blinded treatments, neither the participant nor any of the investigators or 
Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
participants will be aware of the study intervention received.  Since AZD2816 and AZD1222 
are visually distinct prior to dose preparation (due to differences in container closure), all 
investigational product will be handled by an unblinded pharmacist (or designee in accordance 
with local and institutional regulations) at the study site. Once drawn into syringes for 
administration, AZD2816 and AZD1222 are not visually distinct from each other.
The IRT will provide the investigators with a dose tracking number to be allocated to the 
participant at the dispensing visit.  Routines for this will be described in the IRT user manual 
that will be provided to each study site.
For participants receiving double-blinded treatments, the randomization code should not be 
broken except in medical emergencies when the appropriate management of the participant 
requires knowledge of the treatment randomization.  The investigator documents and reports 
the action to the Sponsor, without revealing the treatment given to participant to the Sponsor
staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities.  Randomization codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.

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6.3.3
Procedures for Unblinding
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
in which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment 
is warranted.  Participant safety must always be the first consideration in making such a 
determination.  If a participant’s intervention assignment is unblinded for safety, the Sponsor 
must be notified within 24 hours after breaking the blind. 
In the event that a study participant is contacted about receiving a licensed and/or authorized 
COVID-19 vaccine outside of this clinical study, unblinding instructions are being provided to 
the sites.  If the participant is unblinded, the Sponsor needs to be notified within 24 hours, and 
this should be documented in the site source documents.
6.4
Study Intervention Compliance
Participants are dosed at the study site, receiving study intervention directly from the 
investigator or designee, under medical supervision.  The date, and time if applicable, of dose 
administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the period specified in the 
Schedule of Activities (Section 1.3), must be recorded in the eCRF along with the information 
listed below.  Vitamins and/or herbal supplements are not to be recorded.
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
!
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance.
!
Primary care providers, or where appropriate investigators, should prescribe appropriate 
concomitant medications or treatments deemed necessary to provide full supportive care 
and comfort during the study.

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!
Participants who develop COVID-19 after receiving study intervention should be treated 
with licensed medications and interventions according to standard of care.  All routine 
vaccinations other than influenza are permitted beginning > 30 days after last dose of 
study intervention.  Licensed influenza vaccines are permitted 7 days before and 7 days 
after administration of study intervention. 
!
Topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 days) are 
permitted
6.5.2
Prohibited Concomitant Medications
The following medications are prohibited and the Sponsor must be notified if a participant 
receives any of these prohibited medications.  The use of the following concomitant 
medications and/or vaccines, however, will not definitively require withdrawal of the 
participant from the study, but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis set.
!
Primary or booster vaccinations, other than AZD2816 or AZD1222, for prevention of 
SARS-CoV-2 or COVID-19.
Note: Participants choosing to receive a licenced and/or authorized COVID-19 vaccine 
should inform the Investigator so it can be properly documented.  Participants, who 
receive a licenced and/or authorized COVID-19 vaccine outside the study, should be 
encouraged to continue study conduct to be followed for safety reporting and all 
assessments.
!
Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention.  Thirty days after 
the second vaccination, other routine vaccinations are permitted as clinically indicated.
!
Glucocorticoids at a dose ≥ 20 mg/day of prednisone or equivalent given daily or on
alternate days for ≥ 14 consecutive days between randomization and the participant’s
scheduled final visit
!
Other systemically administered drugs with significant immunosuppressive activity,
such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy
between randomization and the participant’s scheduled final visit
!
Immunoglobulins and/or any blood product.
If a participant receives a prohibited concomitant medication, the investigator in consultation 
with the Sponsor will evaluate any potential impact on receipt of study intervention based on 
time the medication was administered, the medication’s pharmacology and pharmacokinetics, 
and whether the medication will compromise the participant’s safety or interpretation of the 
data (see Section 7.1). 

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6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.  Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive the first or second dose (if applicable) of study 
intervention if any of the following occur in the participant in question:
1
Withdrawal of consent after signing informed consent
2
Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 
3
Laboratory-confirmed SARS-CoV-2 infection
4
Participant is pregnant or nursing
5
Any grade 3 or greater allergic reaction including anaphylaxis that is assessed as related 
to study intervention 
6
Occurrence of any thrombosis with concurrent thrombocytopenia 
7
Any SAE assessed as related to study intervention
8
Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardize the safety of the study participant 
9
Receipt of a prohibited concomitant medication that may jeopardize the safety of the 
study participant or interpretation of the data
Each participant who has received at least 1 dose of study intervention will be followed for the 
full study period unless consent is withdrawn specifically from further study participation, or 
the participant is lost to follow-up.  Participants who have not received study intervention, 
regardless of reason, will not be followed.
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine 
during the study, AstraZeneca needs to be notified within 24 hours and this should be 
documented in the site source documents.  Participants who have received study intervention, 
regardless of reason, will be followed for the full study period.

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7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent.  If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken should be 
carried out in line with what was stated in the informed consent and local regulation.  
The investigator must document the decision on use of existing samples in the site study 
records and inform the Sponsor Study Team.  If the participant does not specifically 
request withdrawal of consent for use of samples, then the samples collected prior to the 
consent withdrawal will be destroyed once per protocol analysis is complete.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the Schedule of Activities (Section 
1.3).  Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities.
8.1
Efficacy Assessments
Not applicable.  
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.  Each clinically significant 
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history, 
clinical signs, and symptoms and will include signs of thrombosis and/or 
thrombocytopenia.  Each clinically significant abnormal finding following vaccination 
will be recorded as an AE.
!
All physical examinations will be performed by a licensed healthcare provider 
(eg, physician, physician assistant, or licensed nurse practitioner). 

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8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3).  The participant should be 
resting prior to the collection of vital signs.  On vaccination days, vital signs should be 
assessed prior to vaccine administration.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3).  Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the investigator, with the 
date and time of collection recorded in the appropriate eCRF.
The standard clinical chemistry and haematology analysis will be performed at a local 
laboratory at or near to the investigator site.  Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.  
The following laboratory variables will be measured:
Table 9
Laboratory Safety Variables
Blood
Serum/Plasma
Haemoglobin
Activated partial thromboplastin time
Leukocyte count
Prothrombin time
Leukocyte differential count (absolute count)
Fibrinogen
Platelet count
D-dimer
-
Creatinine
-
Bilirubin, total
-
Alkaline phosphatase
-
Aspartate aminotransferase 
-
Alanine aminotransferase
In case a participant shows an aspartate aminotransferase or alanine aminotransferase 
≥3 × upper limit of normal together with total bilirubin ≥2 × the upper limit of normal, please 
refer to Section 8.3.6
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the Schedule of Activities (Section 1.3).  Urine pregnancy tests for 
∃-human chorionic gonadotropin may be performed at the site using a licensed dipstick test.  

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8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a e-diary (Section 8.3.7), and will be assessed separately 
from the (unsolicited) AEs collected during the study.  General information for AEs in this 
protocol excludes the reporting of solicited AEs via e-diary unless otherwise noted.. 
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
AEs will be recorded for 28 days after each dose of study intervention. 
Solicited AEs will be recorded for 7 days after each dose of study intervention (ie, Day 1 
through Day 8). If a solicited AE is not resolved within the e-diary reporting period, the event 
will be reported as a non-solicited adverse event in the eCRF, with a start date of when started 
and the actual stop date. 
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact. 
See the Schedule of Activities for the scheduled timepoints (Section 1.3). 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the Sponsor.

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8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Severity grade/maximum severity grade/changes in severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA 2007) will be utilized for all unsolicited events. 

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8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol-mandated vital signs and laboratory safety 
assessments will be summarized in the Clinical Study Report. 
Deterioration as compared to baseline in protocol-mandated vital signs and laboratory safety 
assessment should therefore only be reported as AEs if they fulfil any of the SAE or 
medically-attended AE criteria or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or
non-planned visits were required).
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an SAE or medically-attended AE, and the associated vital sign 
will be considered as additional information. 
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation.  Any occurrences of aspartate aminotransferase or alanine aminotransferase 
≥3 × the upper limit of normal together with total bilirubin ≥2 × upper limit of normal at any 
point during the study following the administration of study medication should be reported to 
the Sponsor as a potential Hy's Law SAE within 1 day with a serious criteria of ‘Important 
medical event’ and causality assessment ‘yes/related’.

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The study physician will contact the investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 10) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention via e-diary collection. If a solicited AE is not resolved within the e-diary
reporting period, the event will be also reported as a non-solicited adverse event in the eCRF, 
with a start date of when started and the actual stop date.
Solicited AEs should not be reported as unsolicited AEs unless they fulfil the criteria for SAEs 
or medically-attended AEs(see Sections 8.3 and 8.3.8, respectively).
Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic 
Pain at the site of the injection 
Fever (> 100 °F/37.8 °C)
Redness/erythema at the site of the injection
Chills
Tenderness at the site of the injection
Muscle pains
Induration/swelling at the site of the injection 
Fatigue (physical or mental tiredness/exhaustion)
-
Headache
-
Malaise (general feeling of discomfort or uneasiness)
-
Nausea
-
Vomiting
Solicited AE e-Diary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given a thermometer, tape measure or ruler, and access to the Solicited 
AE e-Diary, with instructions on use, along with the emergency 24-hour telephone number to 
contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms. 
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorized representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix D.  Because 

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solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention. 
8.3.8 COVID-19 Assessment
This study will describe the incidence of COVID-19 adverse events reported from Day 1 to 
180 days after the participant’s last/only dose of vaccine.  
COVID-19 is defined as SARS-CoV 2-RT-PCR positive symptomatic illness.  At all clinic 
visits following the initial vaccination, participants will be asked if they have had a diagnosis 
of COVID-19 since their last clinic visit (see Schedule of Activities in Section 1.3). Medical 
records will be obtained for confirmation of a participant-reported diagnoses of COVID-19.  
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea.  Events will be reported as AEs/SAEs.
If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed 
using RT-PCR.
8.3.9 Medically-Attended Adverse Events
Medically-attended AEs will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3).
Medically-attended AEs are defined as AEs leading to medically-attended visits that were not 
routine visits for physical examination or vaccination, such as an emergency room visit, or an 
otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. 
AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
illness visits will not be considered medically-attended AEs.
8.3.10
Adverse Events of Special Interest
AEs of special interest will be collected according to the timepoints specified in the Schedule 
of Activities (Section 1.3). 
AEs of special interest are events of scientific and medical interest specific to the further 
understanding of study intervention safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor.  AEs of special interest are based on 
Brighton Collaboration case definitions (SPEAC 2020), clinical experience, and scientific 
interest.  A list of events is provided in Appendix E.
An AE of special interest can be serious or non-serious.  All AEs of special interest will be 
recorded in the eCRF.  If any AE of special interest occurs in the course of the study, 
investigators or other site personnel will inform the appropriate Sponsor representatives within 

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1 day ie, immediately but no later than 24 hours of when he or she becomes aware of it.  
Serious AEs of special interest will be recorded and reported as per Section 8.3.11.
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest
Both thrombotic, thromboembolic, and neurovascular events and thrombocytopenia events are 
considered to be adverse events of special interest.  The investigator should remain vigilant for 
the occurrence of thrombotic events with thrombocytopenia and/or bleeding.  If a participant 
experiences new onset thromboembolic events with thrombocytopenia, there should be 
prompt evaluation with a thorough haematological investigation.  COVID-19 testing, 
including PCR and serology (nucleoprotein antibodies), should also be performed.  See 
Appendix F for further guidance on investigation and management of suspected events.
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and whole genome 
sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events.
8.3.10.2
Potential Neurological Adverse Events of Special Interest
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation, including referral to a neurology specialist for further 
evaluation and testing, as clinically indicated.  Testing can include evaluation for peripheral 
demyelinating conditions (eg, electromyography).  In cases of concern for spinal cord disease, 
see Figure 3 for a recommended testing algorithm. 
An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AEs of special interest occurring 
in the AZD1222 clinical development program (see Appendix A 5).  

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Figure 3
Neurology Testing Algorithm
a
Adapted from Rovira et al 2015
Ab: antibody; ACE: angiotensin converting enzyme; ADC: apparent diffusion coefficient; ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibodies; AQP4: 
aquaporin 4; CMV: cytomegalovirus; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebral spinal fluid; CT: computed tomography; DWI: diffusion-weighted 
image; EBV: Epstein-Barr virus; ED: emergency department; ENA: extractable nuclear antigen antibodies; ESR: erythrocyte sedimentation rate; FLAIR: fluid-attenuated inversion 
recovery; GRE: gradient echo; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IgG: immunoglobulin G; MOG: myelin oligodendrocyte glycoprotein; MRI: 
magnetic resonance image; PCR: polymerase chain reaction; RF: rheumatoid factor; RPR: rapid plasma reagin; STIR: short T1 inversion recovery; SWI: susceptibility-weighted 
imaging; TSH: thyroid stimulating hormone; TM: transverse myelitis; VDRL: Venereal Disease Research Laboratories; VZV: varicella-zoster virus. 

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8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedures.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Sponsor representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available.
The Sponsor representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness is the AZD1222 Investigators 
Brochure, Section 5.6. 
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor, except if the pregnancy is discovered 
before the participant has received any study intervention.
8.3.12.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2).  Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the study intervention may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 

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spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the participant was discontinued 
from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.11) and within 30 days for all other pregnancies 
that are not associated with an SAEs.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module may be used to report the outcome of the pregnancy.
8.3.13
Medication Error
If a medication error occurs, then the investigator or other site personnel informs the 
appropriate Sponsor representatives within 1 day, ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 3. 
8.4
Overdose
For this study, any dose of study intervention exceeding that specified in the protocol will be 
considered an overdose.
There is no specific treatment for an overdose with AZD2816 or AZD1222.  If overdose 
occurs, the participant should be treated supportively with appropriate monitoring as 
necessary.

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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose occurs in the course of the study, the investigator or other site personnel inform 
appropriate Sponsor representatives immediately, but no later than 24 hours after when he or 
she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual.  Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality.  Further details on Handling of Human 
Biological Samples are provided in Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a 
maximum of 15 years following issue of the Clinical Study Report.  Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses, eg, exploratory immunology, such 
as systems serology and profiling of B- and T-cell repertoire.  The results from further 
analysis will not be reported in the Clinical Study Report.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).  Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual.  Results for exploratory immunogenicity analyses may 
be reported separately from the CSR.

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8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the Schedule of Activities (Section 1.3).  Authorized laboratories 
will assess serologic responses to AZD1222 and AZD2816 using validated (or qualified, 
where appropriate) assays.  Serologic assessment to the S protein from different SARS-CoV-2 
variants (which include Wuhan-Hu-1, B.1.351, B.1.1.7, and P.1) will be assessed 
quantitatively using a validated multiplexed ECL based immunoassay.  Additionally, 
seroresponse will be assessed for each antigen over time.  The rate of SARS-CoV-2 infection 
in participants receiving AZD2816 versus AZD1222 will be determined by seroresponse in a 
SARS-CoV-2 nucleocapsid antigen in a multiplexed electrochemiluminescence-based assay 
performed at an authorized laboratory.  Additional exploratory assessments may be performed 
to measure binding antibodies to SARS-CoV-2 variants of interest (which may include 
B.1.429, B.1.525, B.1.526, P.2, P.3, B.1.617, and the Q677H mutation observed in multiple 
variants).
8.5.2.2
 
 
 
  
 
 
 
 
 
8.5.2.3
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

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8.5.2.4
 
 
 
 
 
 
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Already collected samples may be analysed for biomarkers thought to play a role in 
COVID-19 severity or outcomes based upon emerging immunogenicity and 
pharmacodynamic analysis from this or other studies involving the study interventions. These 
analyses include but are not limited to serum or plasma cytokines, quantification of RNA, 
micro-RNA, and/or non-coding RNA using quantitative reverse transcriptase polymerase 
chain reaction (RT-PCR), microarray, sequencing, or other technologies in blood, or 
peripheral blood mononuclear cells to evaluate their association with AZD1222/2816 and 
observed clinical responses to these study interventions.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The overall hypothesis for this 8-armed study is that 28 days after vaccination (ie, following a 
single booster dose for the previously vaccinated participants or a second vaccination dose for 
previously unvaccinated participants), AZD2816 will be non-inferior to AZD1222 in terms of 
immunogenicity (ie, neutralising antibodies GMT ratio and difference in seroresponse rates).  
The specific null and alternative hypotheses for each objective are presented in Section 9.4.3.
CCI
CCI
CCI

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9.2
Sample Size Determination
Immunogenicity response
Historical data were available for the immunogenicity responses (ie, pseudovirus neutralising 
antibodies, live virus neutralising antibodies, and spike protein binding antibodies) to 
AZD1222 from the pooled COV001/002/003/005 studies.  Table 11 presents the log 
transformed immunogenicity responses (ie, geometric mean titres) by assay for participants 
that received 2 standard doses of AZD1222.  These results indicate that the pseudo-
neutralising antibodies exhibited the largest variation (standard deviation of 1.20 and 1.10 for 
the 4-week and 12-week dosing intervals respectively), while live-neutralising antibodies had 
the lowest (standard deviation of 0.72 for the 4-week dosing interval).
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-week dosing intervalb
Assay
N
Mean
Std Dev
N
Mean
Std Dev
N
Mean
Std Dev
Pseudo
476
4.3
1.34
166
5.3
1.20
113
5.4
1.10
Live
51
4.9
1.15
42
6.2
0.72
0
-
-
Spike protein
1139
9.1
1.14
293
10.1
0.96
302
10.7
0.83
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval
Table 12 presents the seroresponse (ie, ≥4 fold increase from baseline) by assay.  These 
results indicate that the pseudo-neutralising antibodies exhibited the lowest proportion of 
seroresponse (59.7% and 85.5% for the 4-week and 12-week dosing intervals respectively), 
while both live-neutralising and spike-binding seroresponse rates exceeded 95%.
Table 12
Historic Seroresponse Rates by Dosing Interval (≥4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-dose week intervalb
Assay
N
Proportion
N
Proportion
N
Proportion
Pseudo
499
32%
382
59.7%
117
85.5%
Live
96
75%
95
96.8%
-
-
Spike protein
940
96.6%
636
95.9%
304
99.3%
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval 

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Under the assumption that the immunogenicity responses (ie, geometric mean antibody titres) 
associated with AZD2816 will be similar to the responses associated with AZD1222 in 
participants that received 2 standard doses in the pooled COV001/002/003/005 studies, in 
which standard deviations ranged from 0.72 to 1.2 (Table 11), 150 participants will provide a 
95% confidence interval half-width between 0.115 and 0.192 (see Table 13).  Similarly, 380 
participants will provide a 95% confidence interval half-width between 0.072 and 0.120.
Under the assumption that the seroresponse rates associated with AZD2816 will be similar to 
the response rates in adults that received 2 standard doses of AZD1222 in the pooled 
COV001/002/003/005 studies (Table 12), 150 participants will provide a 95% confidence 
interval half-width between 1.33% and 7.85%, and 380 participants will provide a 95% 
confidence interval half-width between 0.84% and 4.93% (Table 14).
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes 
Standard Deviation
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
0.72
150
0.115
300
0.081
350
0.075
380
0.072
0.83
150
0.133
300
0.094
350
0.087
380
0.084
0.96
150
0.154
300
0.109
350
0.101
380
0.097
1.1
150
0.176
300
0.124
350
0.115
380
0.111
1.2
150
0.192
300
0.136
350
0.126
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0.120

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Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroresponse Rates and Proposed 
Sample Sizes
Observed seroresponse rate
Participants (N)
Estimated half-width of the 95% confidence interval 
59.7%
150
7.85%
300
5.55%
350
5.14%
380
4.93%
85.5%
150
5.63%
300
3.98%
350
3.69%
380
3.54%
95.9%
150
3.17%
300
2.24%
350
2.08%
380
1.99%
96.8%
150
2.82%
300
1.99%
350
1.84%
380
1.77%
99.3%
150
1.33%
300
0.94%
350
0.87%
380
0.84%
For a fixed sample size, the precision with which the 95% confidence interval of the binary 
seroresponse rate can be estimated is a function of the response rate.  Table 14 provides the 
lower bounds of the 95% confidence interval for selected response proportions for alternate 
sample sizes.  For a given response rate, we can be 95% confident that the true seroresponse 
rate is at least as large as the lower bound of the confidence interval.
Immunogenicity Comparisons: Non-inferiority
Under the assumption that there is no difference between treatment arms of interest (ie, a ratio 
of 1, difference on the log scale of 0), the power conferred by 150 to 380 participants for the 

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comparison of geometric mean titre ratio using a noninferiority margin of 1.5 (equivalent to a 
difference on the log scale of 0.405) is presented in .

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Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
and for the comparison of seroresponse rate using the non-inferiority margin of -15% as the 
upper bound of the difference is presented in Table 16.
If there is no difference between treatment arms of interest (ie, a ratio of 1) in the proportion 
of seroresponders, 380 participants provides 98% power to establish non-inferiority to within 
margin of -15% if the seroresponse rate is > 50%.  The observed pseudo-neutralising response 
rates (≥4 fold increase from baseline) from the COV001/002/003/005 studies for AZD1222 
were 59.7% and 85.5% for the 4-week and 12-week dosing interval respectively (Table 12).  
A population of 380 participants provides 99% power to detect non-inferiority (using a non-
inferiority margin of -15%) if the observed response rate is 59.7%.

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Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
Sides
Null 
difference
Assumed mean 
treatment 
difference
Assumed 
standard 
deviation
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Upper
ln1.5 = 
0.405
0
0.72
150
300
0.025
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.83
150
300
0.998
150
350
0.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.96
150
300
0.988
150
350
0.991
150
380
0.992
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
1.10
150
300
0.957
150
350
0.965
150
380
0.968
300
300
0.994
300
350
0.997
300
380
0.997
350
380
0.999
350
350
0.998
380
380
>.999
1.20
150
300
0.920
150
350
0.932
150
380
0.937
300
300
0.985
300
350
0.990
300
380
0.992
350
380
0.995
350
350
0.994
380
380
0.996

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Table 16
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate
Sides
Null 
proportion 
difference
Assumed 
difference in 
proportion of 
seroresponders
Assumed 
proportion of 
seroresponders 
in both groups
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Lower
-0.15
0
0.597
150
300
0.025
0.878
150
350
0.894
150
380
0.902
300
300
0.964
300
350
0.975
300
380
0.979
350
380
0.986
350
350
0.982
380
380
0.989
0.855
150
300
0.993
150
350
0.995
150
380
0.996
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.959
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.968
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.993
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999

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Safety
Table 17 indicates the probability of observing 1 or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 
particular type for participants in each treatment arm.  With the sample size of 300 
participants, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 95%.
Table 17
Probability of detecting 1 or more safety events (N = 300)
Event Frequency
Probability (> 1 event)
≥ 10% (Very Common)
> 99%
≥ 1% (Common)
95%
≥ 0.1% (Uncommon)
26%
≥ 0.01% (Rare)
3%
9.3
Populations for Analyses
The following populations are defined:
Table 18
Populations for Analysis
Population
Description
All participants analysis set 
All participants screened for the study, to be used for reporting disposition and 
screening failures.
Full analysis set
All randomised participants who received study treatment, irrespective of their 
protocol adherence and continued participation in the study. Participants will be
analysed according to their randomised treatment, irrespective of whether or not 
they have prematurely discontinued, according to the intent-
to-treat principle. Participants who withdraw consent or assent to participate in the
study will be included up to the date of their study termination.
Safety analysis set
The safety analysis set consists of all participants who have received study 
treatment. Erroneously-treated participants (eg, those randomised to AZD2816, but 
were actually given treatment AZD12222) are accounted for in this analysis set by 
assigning them to the treatment they actually received.
Immunogenicity analysis set
The vaccine immunogenicity analysis set will include all randomised participants, 
received at least 1 dose of planned study treatment (ie, 1 dose of either AZD2816 or 
1 dose of AZD1222), had baseline and post-dose antibody measurements, have at 
least 1 post-dose quantifiable serum titre, and had no protocol deviations judged to 
have the potential to interfere with the generation or interpretation of an antibody 
response. The analyses conducted using this analysis set will be based on the actual
treatment received.

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Table 18
Populations for Analysis
Population
Description
Seronegative 
immunogenicity analysis set 
The subset of the immunogenicity analysis set who were seronegative at baseline.
Seropositive 
immunogenicity analysis set
The subset of the immunogenicity analysis set who were seropositive at baseline.
Participants that are SARS-CoV-2 seropositive at screening will be included in seropositive 
analysis sets analogous to the above seronegative analysis sets. Further definition is provided 
in the Statistical Analysis Plan. 
9.4
Statistical Analyses
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints.  A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to the interim analyses.
9.4.1 General Considerations
An initial interim analysis will occur when a subset of participants previously vaccinated with 
AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  This sample will 
include both participants randomised to receive a booster dose of AZD2816 as well as a those 
randomised to receive a booster dose of AZD1222.  Analyses presenting treatment arm 
summaries of both the raw and model adjusted immunogenicity will be reviewed by an 
unblinded team within AstraZeneca to make a decision regarding the potential need for 
sample size re-estimation.  Full details of this analyses are provided in the Interim Analysis 
Charter to be finalized prior to any interim analysis.
A second interim analysis will occur when all participants previously vaccinated with 
AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  It is estimated 
that this early analysis has the potential to provide clear signals about whether AZD2816 
provides a strong neutralizing response against the B.1.351 strain while retaining 
immunogenicity against the Wuhan strain, and thereby influence programmatic decisions 
early.  Analyses results will present treatment arm specific summaries of both the raw and 
model adjusted (baseline age and co-morbidities).  The raw data outputs will be stratified by 
age group (<65, ≥65) while the model adjusted summaries will pool data across age groups.  
Full details of this analyses are provided in the Interim Analysis Statistical analysis Plan to be 
finalized prior to any interim analysis.
A third interim analysis may be performed when a subset of previously unvaccinated 
participants have completed their Day 57 visit (ie, 56 days after first dose).  The participant 

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sample will include both participants randomised to AZD2816 as well as those randomised to 
AZD1222.  This analysis is intended to assess immunogenicity variability. The number of 
previously unvaccinated participants per treatment arm may be increased based upon the 
results of this analysis.  The details of this interim analysis, including the trigger and methods, 
will be specified in the Interim Analysis Charter.
The primary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants randomised to a 4-week 
dosing interval are available through completion of their visit 28 days after the second priming 
dose.
A secondary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants (including those 
randomised to a 12-week dosing interval) are available through completion of the visit 28 
days after the second dose. 
The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).
Further details of the primary analysis, secondary analysis and final analysis are contained 
within the Statistical Analysis Plan
To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.
9.4.2 Safety
9.4.2.1
Primary Endpoints
Overview
Descriptive analyses will support evaluation of safety, reactogenicity and immunogenicity. 
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination will 
be summarised by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be summarised 
by system organ class and preferred term, and by relationship to vaccination as assessed 
by the investigator.

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!
MAAEs, SAEs, and AESIs following the first vaccination and throughout the study 
duration will be summarised by system organ class and preferred term and by relationship 
to vaccination as assessed by the investigator. 
!
The change from baseline for safety laboratory measures at 7 and 28 days after 
vaccination.
AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities.  AEs will be presented for each treatment group by system organ class 
and preferred term.  Summaries will include the number and percentage of participants 
reporting at least one event, number of events and exposure adjusted rates, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs.  Summaries will present the relationship to 
study intervention as assessed by the investigator, maximum intensity, seriousness, and death.
A listing will cover details for each individual AE.  Full details of all AE analyses will be 
provided in the Statistical Analysis Plan, including intercurrent events for safety due to 
potential unblinding of participants for administration of licensed and/or approved SARS-
CoV-2 or COVID-19 vaccine.
At the time of the interim analyses, group assignment will not be presented when safety event 
data has the potential to unblind participant’s study group attribution.
9.4.2.2
Other Safety Endpoints
Vital Signs
Vital sign measurements will be performed as specified in the Schedule of Activities (Section 
1.3).  The set of assessments will include pulse oximetry, blood pressure, and body 
temperature.  
Details of all vital sign analyses will be provided in the Statistical Analysis Plan, which will 
include descriptive statistics presented for observed values for all vital sign parameters. 
COVID-19
This study will describe the incidence of COVID-19 adverse events from the first dose of the 
vaccine to study end (180 days post-vaccination). Descriptive statistics will be produced based 
on the safety analysis set. Full details will be documented in the statistical analysis plan. 

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9.4.3
Immunogenicity
9.4.3.1
Immunogenicity Endpoints
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean antibody titre.
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean antibody titre from 
baseline
Both the geometric mean antibody titre and seroresponse of participants will be summarized 
descriptively by strain, treatment arm, and timepoint for the immunogenicity population.
9.4.3.1.1
Estimand framework for immunogenicity descriptions and comparisons
Target populations: 
1) Previously unvaccinated participants 
a.
Seronegative Analysis Set: and with no evidence of prior or current infection  
2) Participants who previously received SARS-CoV-2 vaccination with either AZD1222 
or a licensed mRNA vaccine according to the authorized dose and dosing regimen at 
least 90 days prior to first study intervention (see Section 5.1.2).
Outcome variable: neutralizing antibody and binding titres to SARS-CoV-2 at 28 days after 
each treatment administration (1 treatment administration for the previously vaccinated 
population and 2 planned treatment administrations for the unvaccinated population). 
Treatment conditions:
Previously unvaccinated population
!
2 doses of AZD1222 given on Day 1 and on Day 29 (4-week dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 29 (4-week dosing interval)
!
1 dose of AZD1222 given on Day 1 and 1 dose of AZD2816 on Day 29 (4-week 
dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 85 (12-week dosing interval)
Previously vaccinated population
!
1 dose of AZD1222 given on Day 1. 

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!
1 dose of AZD2816 given on Day 1. 
Intercurrent events: the following intercurrent events could impact the antibody levels 
achieved:  
!
missing the second vaccination (for the unvaccinated population)  
!
receiving of immune-modifying drugs or vaccines 
!
subsequent infection with SARS-CoV-2. 
All immunogenicity descriptions and comparisons will use the principal stratum strategy, 
ie, all analyses will exclude participants who experience any of the above intercurrent events.
Population-level summary: 
Descriptive Analyses (see Table 20 and Table 21)
!
geometric means of the antibody titres 
!
seroresponse proportions
Comparative Analyses (see Table 22 and Table 23Error! Reference source not found.)
!
ratio of geometric means of the antibody titres.
!
difference in seroresponse proportion 
Planned Descriptive Analyses: 
Table 20 and Table 21 present planned descriptive immunogenicity analyses for the 
unvaccinated and previously vaccinated populations respectively (each one exploring an 
individual treatment arm at a specific timepoint against a particular strain). 
The tables show that without introduction of further variants, there are 24 planned descriptive 
analyses for the unvaccinated population and 16 planned descriptive analyses for the 
previously immunised population (index).   Within each table there is an analysis key which 
describes the population (see Table 19). The descriptive analyses presented in Tables 19 and 
20 will be repeated for the subset of participants who are seropositive at screening.

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Table 19
Description of the Analysis Keys for Tables 19 and 20 
Population
Analysis Key
Example
Previously 
unvaccinated
Vaccination treatment received: 
   V1222: (2 doses of AZD1222) or 
   V2816: (2 doses of AZD2816) or
V1222/2816: (1 dose of AZD1222  
followed by 1 dose of AZD2816) or
HV1222: ([historical] 2 doses of AZD1222 from 
study D8110C00001) 
Dosing interval: 
   (4): 4-week dosing interval or
   (12): 12-week dosing interval
Strain: 
   Wuhan: Wuhan-Hu-1 or 
   Beta: Variant B.1.351
Analysis Timepoint:
   D1: 28 days post-dose 1
   D2: 28 days post-dose 2
[V1222 (4):Wuhan:D2] = 
Immunogenicity following primary 
vaccination with 2 doses of 
AZD1222 using a 4-week dosing 
interval against Wuhan-Hu-1 28 days 
post-dose 2
Previously 
vaccinated
Pre-study primary vaccination: 
   V1222: 2 doses of AZD1222 or
    VmRNA: 2 doses of an mRNA vaccine
Treatment received: 
    B1222: 1 booster dose of AZD1222 or 
B2816: 1 booster dose of AZD2816
Strain: 
    Wuhan: Wuhan-Hu-1 or 
    Beta: VarianteB.1.351
Note: analysis timepoint is 28 days post-booster dose
[V1222:B1222:Beta] = 
Immunogenicity in participants who 
were previously vaccinated with 2 
doses of AZD1222 as primary 
vaccination series and received a 
single boost dose of AZD1222 
against the B.1.351 variant 

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)
Treatment
Interval
Strain
Timepoint
Endpoint
Inde
x
Analysis Key
AZD1222
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
1
[V1222(4):Wuhan:D1]†
Seroresponse
2
28 days after 2nd dose
GMT
3
[V1222(4):Wuhan:D2]
Seroresponse
4
B.1.351
28 days after 1st dose
GMT
5
[V1222(4):Beta:D1] †
Seroresponse
6
28 days after 2nd dose
GMT
7
[V1222(4):Beta:D2]
Seroresponse
8
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
9
[V2816(4):Wuhan:D1] ‡
Seroresponse
10
28 days after 2nd dose
GMT
11
[V2816(4):Wuhan:D2]
Seroresponse
12
B.1.351
28 days after 1st dose
GMT
13
[V2816(4):Beta:D1] ‡
Seroresponse
14
28 days after 2nd dose
GMT
15
[V2816(4):Beta:D2]
Seroresponse
16
AZD1222/
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 2nd dose
GMT
17
[V1222/2816(4):Wuhan:D2]
Seroresponse
18
B.1.351
28 days after 2nd dose
GMT
19
[V1222/2816(4):Beta:D2]
Seroresponse
20
AZD2816
12 weeks
Wuhan-Hu-1
28 days after 2nd dose
GMT
21
[V2816(12):Wuhan:D2]
Seroresponse
22
B.1.351
28 days after 2nd dose
GMT
23
[V2816(12):Beta:D2]
Seroresponse
24
† descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD1222 as their first dose 
(ie, homologous and heterologous series).
‡ descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD2816 as their first dose 
(4-week interval and 12-week interval treatment arms).
GMT: Geometric mean titre

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Table 21
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)
Primary 
vaccination
Booster 
Treatment
Strain
Timepoint
Endpoint
Index
Analysis Key
AZD1222
AZD1222
Wuhan-Hu-1
28 days after 
booster dose 
GMT
1
[V1222:B1222:Wuhan]
Seroresponse
2
B.1.351
28 days after 
booster dose 
GMT
3
[V1222:B1222:Beta]
Seroresponse
4
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
5
[V1222:B2816:Wuhan]
Seroresponse
6
B.1.351
28 days after 
booster dose
GMT
7
[V1222:B2816:Beta]
Seroresponse
8
mRNA
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
9
[VmRNA:B2816:Wuhan]
Seroresponse
10
B.1.351
28 days after 
booster dose
GMT
11
[VmRNA:B2816:Beta]
Seroresponse
12
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
13
[VmRNA:B1222:Wuhan]
Seroresponse
14
B.1.351
28 days after 
booster dose
GMT
15
[VmRNA:B1222:Beta]
Seroresponse
16
GMT: Geometric mean titre
Immunogenicity comparisons:
Immunogenicity analysis
A number of comparisons of geometric mean titres and seroresponse rates between vaccine 
regimens and vaccine types are intended to be made. 
All non-inferiority comparisons of geometric mean titre ratios will be made utilizing the lower 
bound of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 
0.67
All non-inferiority comparisons of seroresponse rates will be made utilizing the lower bound 
of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 15%, and 
superiority comparisons of seroresponse rates will be made using one-sided Fisher’s exact test 
(α = 0.025). Comparisons of antibody titres between treatment groups will be conducted using 
geometric mean titre (GMT) ratios and seroresponse rates, facilitated by an analysis of 
covariance (ANCOVA) model of the log2 titre, which adjusts for the baseline level, time since 
previous vaccination (for previously vaccinated individuals), baseline co-morbidities and 
gender as fixed effects. All analyses of antibody titres (GMT ratios and differences in 
seroresponse) will be repeated using the unadjusted (raw observed) concentration values.

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Geometric Mean Titres 
The statistical methodology will be based on a 2-sided 95% CI of the ratio of the GMTs. Non-
inferiority will be demonstrated if the lower limit of the 2-sided 95% CI of the GMT ratio of 
the reference group and comparator group is > 0.67 (see Table 22 and Table 23). The 2-sided 
95% CI for the ratio of GMTs will be calculated using normal approximation of log-
transformed concentrations.
The 95% CI for the GMT ratio between 2 groups will be constructed as follows:
Logarithm transformation of the individual concentrations will be calculated.
The 95% CI for the difference in log(GMT) between 2 groups: GroupC and GroupR will 
be in the form:
 − ± 
1 − 2
 ,  +  −2 × 1 

+ 1 

Where  and  = log() are the means of the log-transformed concentration for 
 !"# and  !"#, respectively,
$ = [( −1)
$ + ( −1)
$]
( +  −2)
'
is the pooled sample variance,
 and  are the sample sizes for  !"# and  !"# , respectively,
 and  are the sample variances for  !"# and  !"# , respectively,

1 − 2
 ,  +  −2 is the 100 ,1 −
-
$. percentile of the t-distribution with degrees of 
freedom /0 =  +  −2
To test this hypothesis, a 2- sided 95% CI will be constructed around the ratio 
1234
1235, where 
 and  are the geometric mean of the antibody titres in the comparator and 
reference groups respectively, at the timepoints post vaccination for which the groups are 
being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 0.67. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.
:;:  

≤0.67

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:>:  

> 0.67
Or equivalently
:;: log() −log() ≤log(0.67)
:>: log() −log() > log(0.67)
For the separately considered GMT hypotheses, if the null hypothesis is rejected, then the 
alternative hypothesis of non-inferiority will be supported.
Seroresponse
The statistical methodology will be based on a 2-sided 95% CI of the difference in 
seroresponse rates. Non-inferiority will be demonstrated if the upper bound of the 2-sided 
95% CI rate difference in seroresponse between the reference group and comparator group is 
<15%.  The 95% CI of the difference in proportions ? −? will be computed using the 
Wilson score without continuity correction.
To test this hypothesis, a 2- sided 95% CI will be constructed around the difference ? −?, 
where? and ? are the proportions of participants in the comparator and reference groups 
respectively who are classified as seroresponders (≥4 fold increase from baseline) at the 
timepoints post vaccination for which the groups are being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 15%. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.
:;: ? −? < −15%
:>: ? −? ≥15%
If the null hypothesis is rejected, then the alternative hypothesis of non-inferiority will be 
supported.
Comparisons
The primary and secondary immunogenicity objectives and the GMT and seroresponse 
comparisons for the previously unvaccinated participants receiving a 2-dose primary 
vaccination are presented in Table 22

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The immunogenicity objectives and the GMT and seroresponse comparisons for the 
previously vaccinated participants receiving a 1-dose booster vaccination are presented in 
Table 23.  
Owing to national vaccine rollout in the recruitment countries, including the prioritization of 
elderly populations, it is anticipated that there will be critical differences between the 
previously vaccinated and previously unvaccinated cohorts with respect to age and presence 
of important underlying comorbidities that may confound the interpretation of the results.  
Consequently, the primary and key secondary non-inferiority analyses across these two 
cohorts will compare the previously vaccinated participants that received a booster dose in this 
study with a subset of matched participants from the previously unvaccinated participants that 
received the 2-dose AZD1222 primary vaccine series in the AZD1222 Phase 3 study 
D8110C00001, which was performed in the US, Chile, and Peru. 
This historical control group will be matched, at a minimum, to the previously vaccinated 
AZD1222 booster cohort in the D7220C00001 study based on age, gender, and presence of 
baseline comorbidities. These matched samples will then serve as the control arm for all 
planned non-inferiority analyses (both geometric mean titre [GMT] ratio and difference in 
seroresponse) of the previously vaccinated cohort treatment arms to the primary series 
vaccination. Comparisons of antibody titres between the previously vaccinated cohort in this 
study and the historical controls from Study D8110C00001 will be conducted using the 
immunogenicity analysis described above (ie, using an adjusted ANCOVA model to 
calculated adjusted means and standard errors for the historical comparators).
For immunogenicity data not already available, preserved sera samples from the matched 
controls will be used to generate immune response by the primary series parent vaccine 
against variant strains. AstraZeneca confirms that study D8110C00001 utilizes the same 
validated pseudovirus neutralising antibody assay for the Wuhan-Hu-1 strain and that residual 
sera are available from these study participants that will be tested in a pseudovirus neutralising 
antibody assay against the beta (B.1.351) variant (Monogram Biosciences, South San 
Francisco, USA).  
Further details on the matching procedures and reporting of historical samples are provided in 
the statistical analysis plan.

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −
〖[TQNJNQULJSUQ〗NQRQNQSIQ]
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by a 
2-dose AZD2816 primary vaccination is 
non-inferior to the response elicited by a 
2-dose AZD1222 primary vaccination 
[V2816(4): Beta:D2]/[V1222(4): Wuhan:D2]
(Primary)
[V2816(4):Beta: D2] −[V1222(4): Wuhan:D2]
(Key Secondary 2.1)
[V2816(4): Beta:D1]/[V1222(4): Wuhan: D1]
[V2816(4):Beta: D1] −[V1222(4): Wuhan:D1]
[V2816(4): Beta:D2]/[V1222(4): Beta:D2]
(Key Secondary 2.2)
[V2816(4): Beta: D2] −[V1222(4): Beta:D2]
(Other Secondary)
[V2816(4): Beta:D1]/[V1222(4): Beta:D1]
[V2816(4): Beta: D1] −[V1222(4): Beta:D1]
[V2816(4): Wuhan:D2]/[V1222(4): Wuhan: D2]
(Key Secondary 2.4)
[V2816(4): Wuhan: D2] −[V1222(4): Wuhan:D2]
(Other Secondary)
[V2816(4): Wuhan:D1]/[V1222(4): Wuhan: D1]
[V2816(4): Wuhan: D1] −[V1222(4): Wuhan:D1]
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by a 
2-dose AZD1222 + AZD2816 
heterologous primary vaccination is non-
inferior to the response elicited by a 
2-dose AZD1222 primary vaccination
[V1222/2816(4): Beta:D2]/[V1222(4): Wuhan:D2]
(Key Secondary 2.3)
[V1222/2816(4): Beta:D2] −[V1222(4):Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Wuhan:D2]
/[V1222(4): Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Wuhan:D2]
−[V1222(4): Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Wuhan:D2]
/[V1222(4): Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Wuhan:D2]
−[V1222(4): Wuhan:D2]
(Other Secondary)

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −
〖[TQNJNQULJSUQ〗NQRQNQSIQ]
To determine if the neutralizing antibody 
GMT response/seroresponse rate against 
the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-Hu-1 
strain following a 2-dose AZD2816 
primary vaccination
[V2816(4): Beta:D2]/[V2816(4): Wuhan:D2]
(Other Secondary)
[V2816(4):Beta: D2] −[V2816(4): Wuhan:D2]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse rate against 
the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-Hu-1 
strain following a 2-dose 
AZD1222/AZD2816 primary heterologous 
vaccination
[V1222/2816(4): Beta:D2]/[V1222
/2816(4): Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Beta:D2]
−[V1222/2816(4): Wuhan:D2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −
〖[TQNJNQULJSUQ〗NQRQNQSIQ]
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose 
in participants previously vaccinated 
with AZD1222 is non-inferior to 
response elicited by a 2-dose AZD1222 
vaccination
[V1222: B2816: Beta]/[HV1222(4):Wuhan:D2]
(Primary)
[V1222: B2816:Beta] −[HV1222(4): Wuhan:D2]
(Other Secondary)
[V1222: B2816: Beta]/[HV1222(4): Beta: D2]
(Key Secondary 2.1)
[V1222: B2816:Beta] −[HV1222(4): Beta:D2]
(Other Secondary)
[V1222: B2816: Wuhan]/[HV1222(4): Wuhan:D2]
(Key Secondary 2.3)
[V1222: B2816: Wuhan] −[HV1222(4): Wuhan:D2]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose is 
non-inferior to response elicited by an 
AZD1222 booster dose in participants 
previously vaccinated with AZD1222
[V1222: B2816:Beta]/[V1222: B1222:Beta]
(Key Secondary 2.2)
[V1222: B2816: Beta] −[V1222: B1222: Beta]
(Other Secondary)
[V1222: B2816: Wuhan]/[V1222: B1222:Wuhan]
(Key Secondary 2.5)
[V1222:B2816: Wuhan] −[V1222: B1222: Wuhan]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD1222 booster dose 
in patients previously vaccinated with 
AZD1222 is non-inferior to the 
response elicited by a 2-dose AZD1222 
vaccination
[V1222: B1222: Wuhan]/[HV1222(4): Wuhan:D2]
(Key Secondary 2.4)
[V1222: B1222: Wuhan] −[HV1222(4): Wuhan:D2]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose 
in participants previously vaccinated 
[VmRNA:B2816:Beta]/[HV1222(4): Wuhan: D2]
(Other Secondary)
[VmRNA:B2816: Beta] −[HV1222(4):Wuhan:D2]
(Other Secondary)
[VmRNA:B2816: Beta]/[HV1222(4): Beta:D2]
(Other Secondary)
[VmRNA:B2816: Beta] −[HV1222(4): Beta: D2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[EFG〗IJKLMNMOJNP
〖[EFG〗NQRQNQSIQ]
〖[TQNJNQULJSUQ〗IJKLMNMOJNP −
〖[TQNJNQULJSUQ〗NQRQNQSIQ]
with an mRNA-based vaccine is non-
inferior to response elicited by a 2-dose 
AZD1222 vaccination
[VmRNA:B2816:Wuhan]/[HV1222(4): Wuhan: D2]
(Other Secondary)
[VmRNA:B2816: Wuhan] −[HV1222(4): Wuhan:D2]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose is 
non-inferior to the response elicited by 
an AZD1222 booster dose in 
participants previously vaccinated with 
an mRNA-based vaccine
[VmRNA:B2816: Wuhan])/[VmRNA:B1222: Wuhan]
(Other Secondary)
[VmRNA:B2816: Wuhan] −[VmRNA:B1222: Wuhan]
(Other Secondary)
[VmRNA:B2816: Beta])/[VmRNA:B1222: Beta]
(Other Secondary)
[VmRNA:B2816: Beta] −[VmRNA:B1222: Beta]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
rate against the B.1.351 variant is non-
inferior to the rate against the original 
Wuhan-Hu-1 strain following an 
AZD2816 booster dose
[V1222: B2816: Beta]/[V1222: B2816:Wuhan]
(Other Secondary)
[V1222: B2816:Beta] −[V1222: B2816: Wuhan]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
rate against the B.1.351 variant is non-
inferior to the rate against the original 
Wuhan-Hu-1 strain following an 
AZD1222 booster dose
[V1222: B1222: Beta]/[V1222: B1222:Wuhan]
(Other Secondary)
[V1222: B1222: Beta] −[V1222:B1222: Wuhan]
(Other Secondary)

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9.4.4
Multiple Comparisons
A hierarchical approach will be used to control for multiplicity of the primary and key 
secondary immunogenicity endpoints. That is, the null hypotheses for the immunogenicity 
endpoints will be tested in a hierarchical order, and the subsequent null hypothesis will be 
tested only if the prior null hypothesis is rejected. Consequently, no adjustment to alpha for 
multiplicity will be made in the analysis of immune response. The primary statistical 
comparisons of safety data will not be adjusted for multiple comparisons.  Further details are 
provided in the statistical analysis plan.
9.4.5
Data Safety Monitoring Board
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, to 
ensure safe and ethical conduct of the study.  During the study, the benefit/risk assessment 
will be continuously monitored by the Board to ensure that the balance remains favourable.  
Further details, composition, and operation of the COVID-19 Vaccine Data Safety Monitoring 
Board will be described in a separate charter. For further details, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Not applicable.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
∀
Applicable ICH/GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigators Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority.  This responsibility may be delegated to 
a contract research organization but the accountability remains with the Sponsor.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH/GCP guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all Food and 
Drug Administration (FDA) Regulations, as applicable and all other applicable local 
regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study.  Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH/GCP guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
!
The study medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples.  The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use.  Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

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!
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law.  The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committee Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A COVID-19 Vaccine Data Safety Monitoring Board comprised of independent experts will 
be convened to provide oversight and to ensure safe and ethical conduct of the study.  The 
COVID 19 Vaccine Data Safety Monitoring Board will have the responsibility of evaluating 
cumulative safety and other clinical study data at regular intervals and making appropriate 
recommendations based on the available data.  During the study, the benefit/risk assessment 
will be continuously monitored by the COVID-19 Vaccine Data Safety Monitoring Board to 
ensure that the balance remains favourable.  Full details of the COVID-19 Vaccine Data 
Safety Monitoring Board composition and operations can be found in the COVID-19 Vaccine 
Data Safety Monitoring Board Charter.
An independent Neurological AESI Expert Committee will be available to review and provide 
on request about the diagnosis and causality assessment of selected neurological AEs of 
special interest occurring in the study.  Details on the composition and operation of this 
committee are described in the Neurological AESI Expert Committee Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available.  The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

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!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
!
Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected, and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH/GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or ICH/GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both SAEs and non-SAEs and can include a deterioration of a 
pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs.  
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used.  
In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a non-
SAE.  For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur.  Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as non-serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  Examples of important medical events include such events as listed 
below:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Intensity Rating Scale
A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 

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several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the investigational product.
!
Time Course.  Exposure to suspect drug.  Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect investigational product?
!
Consistency with known investigational product profile.  Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or drugs of the same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational medicinal product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the investigational product, but rather a human or 
process related failure while the investigational product is in control of the study site staff or 
participant.
Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the investigational product
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Investigational product name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration
!
Investigational product not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Investigational product not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong participant received the medication (excluding IRT errors)
!
Wrong investigational product administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from 
the participants while in storage at the study site until shipment or disposal (where 
appropriate) and records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
The Sponsor or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
The Sponsor ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented.  If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and the Sponsor are informed about the sample disposal.

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The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus.  Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814.  Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
!
Table 24: Clinical Abnormalities, Local Reactions to Injectable Product
!
Table 25: Clinical Abnormalities, Vital Signs
!
Table 26: Clinical Abnormalities, Systemic (General or Illness)
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalization
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded.
b
Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE e-Diary.
ER: emergency room.

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Table 25
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)a
Fever (°C/°F)
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
Emergency room visit 
or hospitalization for 
arrhythmia
Bradycardia 
(beats/minute)
50-54
45-49
< 45
Emergency room visit 
or hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
Emergency room visit 
or hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes.

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Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic 
(General)
Systemic Gradea
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/
vomiting
No interference with 
activity or 
1-2 episodes/24 hours
Some interference 
with activity or 
> 2 episodes/24 hours
Prevents daily activity, 
required outpatient 
intravenous hydration
Emergency room 
visit or 
hospitalization for 
hypotensive shock
Chills
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
Emergency room 
visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Systemic Illness
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations)
No interference with 
activity
Some interference 
with activity not 
requiring intervention
Prevents daily activity 
and required medical 
intervention
Emergency room 
visit or 
hospitalization

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Appendix E
Adverse Events of Special Interest
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 27
Adverse Events of Special Interest
Category
Medical Concept
Neurologic
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment or 
loss of consciousness.  
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis.
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population.
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (eg, weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, or other 
sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate.
Hematologic
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL.
Immunologic
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention.
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non-neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: a group of autoimmune inflammatory disorders 
characterized by an alteration in cellular homeostasis, which may or may not have an 
autoimmune aetiology.  A list of events is provided in Table 28. 

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune haemolytic anaemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anaemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombotic events with thrombocytopenia and/or bleeding.  It is not intended to 
be a comprehensive guide to the management of all venous thromboembolic events.  
During the course of the study, the investigator will remain vigilant for occurrence of 
thrombotic events with thrombocytopenia and/or bleeding.  Appropriate investigations (eg, 
imaging) to diagnose these events should be made on a case-by-case basis.  The investigator is 
responsible for determining whether a participant meets criteria for thrombotic events with 
thrombocytopenia and/or bleeding at any point during the study.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombotic events with thrombocytopenia 
and/or bleeding.  The Study Physician contacts the investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data.  
Guidance from the International Society of Thrombosis and Haemostasis for management of 
thrombocytopenic thromboembolism occurring after vaccination can be found at 
www.isth.org.  Notably, participants should only be treated with heparin if a test for heparin-
elicited thrombocytopenia antibodies is negative.  An alternative explanation for 
thrombocytopenia should be considered (eg, alcohol use, liver cirrhosis, concomitant 
medications, exposure to toxic chemicals, viral infections).
The investigator is responsible for recording data pertaining to thrombotic events with 
thrombocytopenia and/or bleeding and for reporting AEs and SAEs according to the outcome 
of the review and assessment in line with standard safety reporting processes.
F 2
Tests that Should Be Considered if Thrombotic Events With 
Thrombocytopenia and/or Bleeding Are Suspected
The following tests should be considered, but not limited to:
1. Measurement of platelet levels, prothrombin time, activated partial thromboplastin time, 
D-dimer levels, and fibrinogen levels
2. Complete blood count, reticulocyte count, blood film, haptoglobins
3. Anti-platelet factor 4 antibodies

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4. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, human 
leucocyte antigen B27, ADAMTS13 activity, anti-cardiolipin antibodies IgG + IgM, and 
anti-B2GPI antibodies IgG + IgM
5. Complement (eg, C3, C4, complement complex C5b-9, C5a), autoantibodies (eg, 
antinuclear IgG, anti-double stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG)
6. Factor V Leiden, Factor II (prothrombin) variant 
7. Platelet activation markers and functional assays (eg: sCD40L, soluble glycoproteins, 
degranulation markers [PF4, vWF, P-selectin, annexin V]), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 ELISA positive)
8. Inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13
9. Cell adhesion molecules: VCAM, ICAM, E-selectin
10. Adenovirus serology
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Ebstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19
12. COVID-19 testing, including PCR and serology
13. Calculation of an International Society of Thrombosis and Haemostatis score for 
Disseminated Intravascular Coagulation (derived from platelet levels, fibrinogen, and D-
Dimer)

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ChAdOx1 MERS
Chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
AZD1222 when initially developed by the University of Oxford
COVID-19
Coronavirus disease 2019
eCRF
Electronic case report form
e-Diary
Electronic diary
GMT
Geometric mean titre
ICF
Informed consent form
ICH/GCP
International Council for Harmonisation/Good Clinical Practice
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
MAAEs
Medically attended adverse events
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
S
Spike
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome-coronavirus-2

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Appendix H
Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment 3
11 October2021
Amendment 2
29 July 2021
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment 3: 11 October 2021
The principal reason for this amendment was to remove the age cap and revise the primary 
and key secondary non-inferiority analyses to included historical controls due to difficulties in 
recruiting the previously unvaccinated cohort
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Synopsis
Section 4.1
Section 9.4..3.1.1
Inserted information on use of 
historical controls
Required based on 
anticipated confounding 
between previously 
vaccinated and previously 
unvaccinated cohorts.
Substantial
Section 3.2, Table 6
Inserted exploratory objectives 
on exploration of humoral 
immune response with live virus 
neutralization assay and 
exploration of additional 
immune response based on 
emerging data
Omitted in error
Non-substantial
Section 4.1
Deleted age cap ensuring at least 
25% enrolled participants were 
>65 years of age.
Due to enrollment 
difficulties in finding 
previously unvaccinated 
elderly
Substantial
Section 7.1
Inserted laboratory-confirmed 
SARS-CoV-2 infection as 
discontinuation of study 
intervention
To explicitly state this 
criterion (which is 
implicitly included in 
criteria 2) as a 
discontinuation of 
treatment criterion.
Non-substantial
Section 9.2
Section on immunogenicity 
comparisons and previous Table 
Placed under Secondary 
Objective in error
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
16 and Table 17 were moved up 
under the Primary Objective
sub-heading
Section 9.4.3.1.1
Table 19
Table 20
Table 21
Table 22
Table 23
Analysis key (abbreviations) 
revised
Improvements in 
abbreviations for clarity
Non-substantial
Section 9.4..3.1.1
Description of statistical 
approach to be used with 
historical control comparisons 
added. 
Inclusion of historical 
controls requires 
description of statistical 
methodology to be used.
Substantial
In addition, the protocol has been revised with minor rewordings, corrections, and 
clarifications which are all considered to be non-substantial.
Amendment 2: 15 July 2021
The principal reason for this amendment was to
1) add an additional interim analysis to evaluate immunogenicity in a subset of 
AZD1222 previously vaccinated subjects boosted with AZD1222 or AZD2816
2) revise Objectives/Endpoints from descriptive to comparative, with ranking of primary, 
key secondary, other secondary, and exploratory objectives
3) add non-inferiority margins to primary analysis and add additional participants to 
maintain power 

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis 
(Objectives and 
Endpoints)
Revised this section from 
primarily descriptive to 
primarily comparative.  
Comparative immunogenicity 
objectives created and ranked as 
primary, key secondary, other 
secondary.
Objectives of study 
changed from descriptive 
to comparative, testing for 
non-inferiority across 
treatment comparisons
Substantial
1.1 Synopsis 
(Number of
Participants; Statistical 
Methods)
Overall size increased to 2590 
participants
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.1 Synopsis (Statistical 
Methods)
An additional interim analysis 
added. Second interim analysis 
changed to include only the 
previously vaccinated with 
AZD1222 cohort.
Interim analysis plan was 
reviewed and revised.
Substantial
1.2 Schema
Figures updated with increased 
participant numbers
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.3 Schedule of 
Activities
Table 2: footnote clarification 
added
Table 3: minor corrections
Clarification/Correction
Non-substantial
2.1 Study Rationale 
(and elsewhere in 
protocol)
Clarification on previous 
vaccination criteria
Clarification
Non-substantial
3 Objectives
Section completely rewritten.  
Divided into 2 sections: 
Previously unvaccinated and 
previously vaccinated.  
Immunogenicity objectives 
created for comparisons.  
Objectives ranked as primary, 
key secondary, other secondary, 
or exploratory.
Objectives of study 
changed to show non-
inferiority across 
treatments.  
Substantial
4.1 Overall design
Participant numbers increased
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
4.1 Overall design
Cap on age added
To ensure good 
representation across age 
groups
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
8.3.2
Removal of severity grade 5
Correction
Non-substantial
8.5.2.3
 
 
Addition of information on 
number of patients sampled for 
Clarification
Non-substantial
9.1 Statistical 
Hypotheses
Addition of statistical 
hypotheses
Include hypothesis being 
tested.
Substantial
9.2 Sample size 
determination
Confidence intervals for 
populations of 350 and 380 
added to Table 14 and Table 15
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
9.2 Sample size 
determination
Power estimates for populations 
of 350 and 380 added to Table 
17 and Table 18
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
9.4.1 General 
considerations
Details on the initial interim, 
second interim, and third interim 
analysis added
Include revised 
information on the 
analysis plan, including 
interim analyses
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Objectives removed from 
descriptive analysis Table 23 
and Table 24
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Section of  Immunogenicity 
Comparisons added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Table 25 and Table 26 on 
immunogenicity comparisons 
revised, aligned with the revised 
objectives/endpoints.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.4 Multiple 
Comparisons
Section added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
In addition, the protocol has been revised with minor corrections and clarifications.
Amendment 1: 2 June 2021
CCI
CCI

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Version 1 of the protocol was amended prior to the commencement of the study (ie, prior to 
approval of the protocol by an ethics committee) based on feedback from internal and 
regulatory authority reviews.  The most substantial changes were as follows:
!
addition of 2 treatment arms:  1) AZD1222 as a single booster vaccination in participants 
previously vaccinated with an mRNA COVID-19 vaccine and 2) heterologous 
vaccination with AZD1222 plus AZD2816 in previously unvaccinated participants
!
further definition of analysis sets
!
addition of thrombotic events with thrombocytopenia as a discontinuation criteria
In addition, corrections and revisions to text to improve readability were made.

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11
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Folegatti et al 2020
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Ramasamy MN, Voysey M, Aley PK, Bibi S, Clutterbuck EA, et al. Safety and 
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young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. 
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Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al. Safety and efficacy of 
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Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7220c00001-csp-amendment-3
Document Title:
D7220C00001 Clinical Study Protocol Amendment Version 3
11Oct2021
Document ID:
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Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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Clinical Study Protocol
Study Intervention
AZD2816
Study Code
D7220C00001
Version
Amendment GBR-1
Date
3 June 2021
TITLE PAGE
A Phase II/III Partially Double-Blinded, Randomised, Multinational, 
Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults Ages 
30 and Above to Determine the Safety and Immunogenicity of AZD2816, a Vaccine for 
the Prevention of COVID-19 Caused by Variant Strains of SARS-CoV-2
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
EudraCT: 2021-002530-17
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Number: D7220C00001
Amendment Number: GBR-1
Study Intervention: AZD2816
Study Phase: II/III
Short Title: Phase II/III Study of AZD2816, a Vaccine for the Prevention of COVID-19 in 
Adults
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator:  Andrew J Pollard, FRCPCH PhD FMedSci
           University of Oxford
            Oxford, United Kingdom

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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Amendment GBR-1
3 June 2021
Amendment 1
1 June 2021
Version 1
14 May 2021
Amendment GBR-1: 2 June 2021
Prior to the commencement of the study (ie, prior to approval of the protocol by an ethics 
committee), the Amendment 1 version of the protocol was amended based on feedback from 
the UK’s MHRA to restrict the study population to adults ages 30 and above and provide a 
risk:benefit statement for the inclusion of adults ages 30 to 39 (provided in Section 2.3.3)

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................. 3
TABLE OF CONTENTS...................................................................................................... 4
1
PROTOCOL SUMMARY................................................................................ 10
1.1
Synopsis ........................................................................................................... 10
1.2
Schema............................................................................................................. 16
1.3
Schedule of Activities....................................................................................... 17
2
INTRODUCTION............................................................................................ 23
2.1
Study Rationale ................................................................................................ 23
2.2
Background ...................................................................................................... 23
2.3
Benefit/Risk Assessment................................................................................... 26
2.3.1
Risk Assessment............................................................................................... 26
2.3.2
Benefit Assessment........................................................................................... 27
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 27
3
OBJECTIVES AND ENDPOINTS...ERROR! BOOKMARK NOT DEFINED.
4
DESIGN........................................................................................................... 35
4.1
Overall Design.................................................................................................. 35
4.1.1
COVID-19 Assessments ................................................................................... 36
4.1.2
Screening.......................................................................................................... 37
4.1.3
Vaccination Visit .............................................................................................. 37
4.1.4
Follow-up visits................................................................................................ 38
4.2
Scientific Rationale for Study Design ............................................................... 38
4.2.1
Rationale for Study Design and Participant Population ..................................... 38
4.2.2
Rationale for Study Endpoints .......................................................................... 39
4.3
Justification for Dose........................................................................................ 40
4.4
End of Study Definition.................................................................................... 40
5
STUDY POPULATION ................................................................................... 41
5.1
Inclusion Criteria .............................................................................................. 41
5.1.1
All Participants:................................................................................................ 41
5.1.2
Previously COVID-19 Vaccinated Participants................................................. 43
5.2
Exclusion Criteria ............................................................................................. 43
5.3
Lifestyle Considerations ................................................................................... 45
5.4
Screen Failures ................................................................................................. 45
6
STUDY INTERVENTION............................................................................... 45
6.1
Study Interventions Administered..................................................................... 46
6.1.1
Investigational Products.................................................................................... 46
6.1.2
Dosing Instructions........................................................................................... 47

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6.2
Preparation/Handling/Storage/Accountability ................................................... 47
6.2.1
Dose Preparation and Administration................................................................ 48
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 48
6.3.1
Randomization.................................................................................................. 48
6.3.2
Blinding............................................................................................................ 49
6.3.3
Procedures for Unblinding ................................................................................ 50
6.4
Study Intervention Compliance......................................................................... 50
6.5
Concomitant Therapy........................................................................................ 50
6.5.1
Permitted Concomitant Medications ................................................................. 50
6.5.2
Prohibited Concomitant Medications ................................................................ 51
6.6
Dose Modification ............................................................................................ 52
6.7
Intervention After the End of the Study............................................................. 52
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 52
7.1
Discontinuation of Study Intervention............................................................... 52
7.2
Participant Withdrawal from the Study ............................................................. 53
7.3
Lost to Follow-up ............................................................................................. 53
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 54
8.1
Efficacy Assessments........................................................................................ 54
8.2
Safety Assessments........................................................................................... 54
8.2.1
Physical Examinations...................................................................................... 54
8.2.2
Vital Signs........................................................................................................ 55
8.2.3
Clinical Laboratory Assessments ...................................................................... 55
8.3
Adverse Events and Serious Adverse Events..................................................... 56
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 56
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 57
8.3.3
Causality Collection.......................................................................................... 58
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 58
8.3.5
Adverse Events Based on Examinations and Tests............................................ 58
8.3.6
Hy’s Law.......................................................................................................... 58
8.3.7
Solicited Adverse Events .................................................................................. 59
8.3.8
COVID-19 Assessment..................................................................................... 60
8.3.9
Medically-Attended Adverse Events................................................................. 60
8.3.10
Adverse Events of Special Interest.................................................................... 60
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest ................................ 61
8.3.10.2
Potential Neurological Adverse Events of Special Interest ................................ 61
8.3.11
Reporting of Serious Adverse Events................................................................ 63
8.3.12
Pregnancy......................................................................................................... 63
8.3.12.1
Maternal Exposure............................................................................................ 63
8.3.13
Medication Error............................................................................................... 64
8.4
Overdose .......................................................................................................... 64
8.5
Human Biological Samples............................................................................... 65

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8.5.1
Pharmacokinetics.............................................................................................. 65
8.5.2
Immunogenicity Assessments ........................................................................... 65
8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 66
8.5.2.2
8.5.2.3
8.5.2.4
8.5.3
Pharmacodynamics........................................................................................... 67
8.6
Human Biological Sample Biomarkers ............................................................. 67
8.7
Optional Genomics Initiative Sample................................................................ 67
8.8
Medical Resource Utilization and Health Economics ........................................ 67
9
STATISTICAL CONSIDERATIONS............................................................... 67
9.1
Statistical Hypotheses....................................................................................... 67
9.2
Sample Size Determination............................................................................... 67
9.3
Populations for Analyses .................................................................................. 72
9.4
Statistical Analyses........................................................................................... 73
9.4.1
General Considerations..................................................................................... 73
9.4.2
Safety ............................................................................................................... 74
9.4.2.1
Primary Endpoints ............................................................................................ 74
9.4.2.2
Other Safety Endpoints..................................................................................... 75
9.4.3
Immunogenicity................................................................................................ 75
9.4.3.1
Immunogenicity Endpoints ............................................................................... 75
9.4.4
Data Safety Monitoring Board .......................................................................... 82
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 82
11
REFERENCES............................................................................................... 105
CCI
CCI
CCI

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LIST OF TABLES
Table 1
Schedule of Activities: Screening ............................................................ 17
Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine . 18
Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 4-Week Dosing 
Interval.................................................................................................... 19
Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 12-Week 
Dosing Interval........................................................................................ 21
Table 5
Study Objectives and Endpoints............................................................... 29
Table 6
Highly Effective Methods of Contraception............................................. 42
Table 7
Investigational Products........................................................................... 46
Table 8
Laboratory Safety Variables..................................................................... 55
Table 9
Predefined Solicited Adverse Events for Reactogenicity Assessment....... 59
Table 10
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)...... 68
Table 11
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set) .......................... 68
Table 12
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes........... 69
Table 13
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroconversion Rates and 
Proposed Sample Sizes ............................................................................ 69
Table 14
Probability of detecting 1 or more safety events (N = 300)....................... 70
Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio .................................................................... 71
Table 16
Power for Non-inferiority Using -10% as the Upper Bound of the 
Difference in Seroresponse Rate .............................................................. 72
Table 17
Populations for Analysis .......................................................................... 72
Table 18 
Description of the Analysis Keys for Tables 19 and 20 ............................ 77
Table 19
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 78

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Table 20
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 79
Table 21
Immunogenicity Comparisons for Previously Unvaccinated Groups........ 80
Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups............ 81
Table 23
Tables for Clinical Abnormalities: Local Reactions to Injectable Product 94
Table 24
Tables for Clinical Abnormalities: Vital Signs......................................... 95
Table 25
Tables for Clinical Abnormalities: Systemic (General or Illness) ............. 96
Table 26
Adverse Events of Special Interest........................................................... 97
Table 27
List of Potential Immune-mediated Medical Conditions........................... 98
LIST OF FIGURES
Figure 1
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants.............................................................................................. 16
Figure 2
Study Design for Unvaccinated Seronegative/Seropositive Participants ... 17
Figure 3
Neurology Testing Algorithm .................................................................. 62

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 83
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 88
Appendix C
Handling of Human Biological Samples .................................................. 92
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ............................. 94
Appendix E
Adverse Events of Special Interest........................................................... 97
Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding ....................................................... 101
Appendix G
Abbreviations ........................................................................................ 103
Appendix H
Protocol Amendment History................................................................. 104

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A phase II/III partially double-blinded, randomised, multinational, active-
controlled study in both previously vaccinated and unvaccinated adults to determine the safety 
and immunogenicity of AZD2816, a vaccine for the prevention of COVID-19 caused by 
variant strains of SARS-CoV-2.
Short Title: Phase II/III study of AZD2816, a vaccine for the prevention of COVID-19 in 
adults.
Rationale: Recently, several variants of the SARS-CoV-2 virus with increased
transmissibility have emerged, including B.1.1.7, first identified in the UK, P.1, first identified 
in Brazil, and B.1.351, first identified in South Africa.  In an ongoing clinical trial of 
AZD1222 in South Africa, interim results failed to show protection against mild to moderate 
disease caused by the B.1.351 variant; protection against severe disease could not be 
determined as no severe cases were identified (Madhi et al 2021). 
Based on available evidence about vaccine effectiveness and molecular epidemiology of 
emerging variants, B.1.351 is estimated to have a potential to escape vaccine-induced 
immunity. B.1.351 carries sequence mutations in common with other variants of concerns; 
immunity to B.1.351 therefore has the potential to provide some cross-immunity against other 
emerging strains. Development of candidate vaccines that include the B.1.351 S-protein 
variant is underway.  AstraZeneca is developing AZD2816, a vaccine against the B.1.351 
SARS-CoV-2 variant using the same ChAdOx1 platform and manufacturing processes used 
for AstraZeneca’s currently available COVD-19 vaccine, AZD1222.
Objectives and Endpoints:
The purpose of this study is to demonstrate the safety and characterize the immunogenicity of 
AZD2816, AstraZeneca’s candidate ChAdOx1 vector vaccine against SARS-CoV-2 variant 
strain B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative individuals who previously 
received a 2-dose primary vaccination against SARS-CoV-2 with AZD1222 or an 
mRNA COVID-19 vaccine
!
As a 2-dose primary homologous vaccination to SARS-CoV-2 seronegative 
individuals who are unvaccinated
!
As the second dose of 2-dose primary heterologous vaccination (with AZD1222 
as first dose) to SARS-CoV-2 seronegative individuals who are unvaccinated.

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It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to the previously-vaccinated cohort that will receive a single booster dose of AZD2816 or 
AZD1222.
The following table lists the primary and secondary endpoints:
Objectives
Endpoints
Safety Objectives
- Primary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination

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To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD1222 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a heterologous 2-dose primary vaccination with 
1 dose of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD1222 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary heterologous vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
- Primary (descriptive)
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To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Magnitude of SARS-CoV-2 specific antibody binding
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres 
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD1222 with a 
4-week interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
heterologous 2-dose primary vaccination with 1 dose 
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
12-week interval in unvaccinated seronegative
participants
! Magnitude of SARS-CoV-2 specific antibody binding 
and neutralization titres (geometric mean titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (comparative)
Previously vaccinated seronegative participants receiving 1 dose versus unvaccinated seronegative participants 
receiving 2 doses

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To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week dosing 
interval in unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week dosing 
interval in unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Previously vaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 relative to the response with 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with an mRNA vaccine relative to the 
response with 1 dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 relative to 1 dose of AZD2816 in 
seronegative participants previously vaccinated with 
a SARS-CoV-2 mRNA vaccine
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Unvaccinated seronegative participants

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To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 variant strain elicited by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval relative to the response 
elicited by a 2-dose primary vaccination with
AZD1222 with a 4-week interval in previously 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 variant strain elicited by a 
2-dose primary heterologous vaccination with 
AZD1222/AZD2816 with a 4-week dosing interval 
relative to the response elicited by a 2-dose primary 
homologous vaccination with AZD1222 with a 
4-week interval in previously unvaccinated 
seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 variant strain and the Wuhan-Hu-1 strain 
elicited by a 2-dose primary vaccination with 
AZD2816 with a 12-week dosing interval relative to 
the response elicited by a 2-dose primary vaccination 
with AZD2816 with a 4-week interval in previously 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
SAEs: serious adverse events; MAAEs: medically attended adverse events; AESIs: adverse events of special 
interest.
a
At least a 4-fold increase in geometric mean titre from baseline
Overall Design: This is a phase II/III, multinational, randomised, partially double-blind, 
controlled study in both previously vaccinated and unvaccinated participants. 
Disclosure Statement: This is a parallel-group preventive study with 8 treatment arms.
Number of Participants: Approximately 2250 SARS-CoV-2 nucleocapsid seronegative 
participants will be assigned to study intervention to support the primary and secondary 
objectives of this study. In addition, participants that are SARS-Cov-2 nucleocapsid 
seropositive at screening will be enrolled and assigned to study intervention for an exploratory 
analysis, with a cap of 10% of the seronegative population (ie, approximately 225 total 
participants).
Intervention Groups and Duration: Previously vaccinated individuals will receive 1 dose of 
AZD1222 or AZD2816 on Day 1.  Previously unvaccinated participants will receive one of 
the following 2-dose vaccinations:
!
1 dose of AZD2816 on Day 1 and on Day 29
!
1 dose of AZD1222 on Day1 and on Day 29
!
1 dose of AZD1222 on Day 1 and 1 dose of AZD2816 on Day 29
!
1 dose of AZD2816 on Day 1 and on Day 85. 

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Participants will be followed up for safety for 180 days after last study vaccine administration.
Data Monitoring Committee: A Data Safety Monitoring Board will provide oversight to 
ensure safe and ethical conduct of the study.
Statistical Methods:
Sample sizes of 300 seronegative participants per group (or 150 for the AZD2816 primary 
vaccination with a 12-week dosing interval group) are deemed appropriate based upon 
available immunogenicity data from previous clinical studies with AZD1222 for the primary 
and secondary objectives of this study.  
The safety analysis set for adverse events consists of all participants who have received at 
least one dose of study intervention.  The immunogenicity analysis set includes all participants 
in the safety analysis set who have no protocol deviations or intercurrent events judged to 
have the potential to interfere with the generation or interpretation of an immune response.
An interim analysis will be performed when all previously vaccinated participants have 
completed their Day 29 visit. A primary analysis will be performed on data from 28 days after 
the second dose of the 4-week dosing intervals to support assessment of these 2-dose primary 
vaccinations.  A secondary analysis will be performed on data from 28 days after the second 
dose of the 12-week dosing interval to support assessment of this 2-dose primary vaccination.  
The final analysis will be performed on data from 6 months follow-up after participant's 
vaccination.  
1.2
Schema
Figure 1
Study Design for Previously Vaccinated Seronegative/Seropositive
Participants

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Figure 2
Study Design for Unvaccinated Seronegative/Seropositive Participants
Note:  In addition to the approximately 2250 seronegative participants enrolled to support the primary/secondary objectives, 
seropositive participants will also be enrolled in the study to support exploratory objectives in this population, with a cap of 
10% of the planned seronegative participants (ie, a maximum of 225 seropositive participants, bringing total enrollment to 
2475).
1.3
Schedule of Activities
Table 1
Schedule of Activities: Screening 
Procedure
Day -14 to Day 1
See Section
Informed consent
X
5.1, Appendix A 3
Demography
X
-
Medical and surgical history
X
-
Prior and concomitant medications
X
6.5
Complete physical examination, including height and weight
X
8.2.1
Vital signs
X
8.2.2
Urine pregnancy test (for women of childbearing potential only) 
X
8.2.3
Clinical safety laboratory assessments
X
8.2.3
Assessment of serious adverse events
X
8.3, Appendix B
Blood sample for SARS-CoV-2 antibody testing (lateral flow test)
X
8.5.2
Verify eligibility criteria
X
5.1, 5.2
Note:  Screening activities can occur at same visit as initial vaccination with investigational product (ie, Visit 1 in 
Table 2, Table 3, and Table 4).

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Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine
Procedure
Treatment and Follow-up Period
Section
Day
1
8
15
29
180
Window (days)
-
±2
±2
±3
±14
Medical and surgical history
X
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
-
-
6.1.1
Immunological assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
-
8.3.7
e-Diary collected
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: 
serious adverse event

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
Urine pregnancy test
(women of childbearing potential)
X 
-
-
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
X 
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample for SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample for additional immunogenicity
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
X
-
-
-
8.3.7

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
X
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
-
X
X
X
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X
-
-
-
X
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X
-
-
-
X
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
X
-
-
-
8.3.7

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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2
INTRODUCTION
AZD2816 is being developed for the prevention of COVID-19.  It is a modified version of the 
current AstraZeneca SARS-CoV-2 vaccine (referred to as AZD1222 in clinical 
documentation) that has been modified to also provide immunity against the newly emerging
SARS-CoV-2 variant strain B.1.351.  Like AZD1222, AZD2816 is a recombinant replication-
defective chimpanzee adenovirus vector (ChAdOx1) expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tissue plasminogen activator leader sequence at the 
N terminus.  AZD2816 differs from AZD1222 in that the S glycoprotein gene sequence used 
is from the B.1.351 variant strain instead of the original Wuhan-Hu-1 variant.
2.1
Study Rationale
The aim of the study is to assess the safety and immunogenicity of AZD2816 for prevention 
of COVID-19 as both a 2-dose primary vaccination in previously unvaccinated participants 
and a 1-dose booster vaccination in participants previously vaccinated against the original 
Wuhan-Hu-1 strain of SARS-CoV-2.  A safe and effective vaccine for COVID-19 prevention, 
including against the B.1.351 variant, would have significant global public health impact. 
The study will also investigate the safety and immunogenicity of 1) a heterologous 2-dose 
vaccination with AZD1222 as first dose and AZD2816 as the second dose and 2) a single dose 
of AZD1222 as a booster vaccination in participants that have been previously vaccinated 
with an mRNA COVID-19 vaccine.  
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (Zhou et al 2020).  The disease these patients contracted was subsequently 
named Coronavirus Disease 2019 (COVID-19).  The World Health Organization declared the 
novel coronavirus a pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the 
novel coronavirus SARS-CoV-2, has resulted in significant global morbidity and mortality as 
well as major disruption to healthcare systems.  Measures to change the course of the 
pandemic have included the accelerated development vaccines against the original Wuhan-
Hu-1 strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes.  SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus,
and it is the seventh corona virus known to cause human infections and the third known to 
cause severe disease after SARS-CoV and MERS-CoV. One fourth of the viral genome is 
responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 

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and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 spike (S) glycoprotein is a type I trimeric, transmembrane protein that is 
located at the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s 
subunits are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the 
receptor binding domain and subsequent fusion of virus and cell membranes, thereby
mediating the entry of SARS-CoV-2 into the target cells.  The S protein has an essential role 
in virus entry and determines tissue and cell tropism, as well as host range.  The roles of the 
S-protein in receptor binding and membrane fusion have made it a desirable target for vaccine 
and antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947 
(ie, the Wuhan-Hu-1 isolate).
To date, 5 vaccines that rely upon the expression of the SARS CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 
NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b).  Immunogenicity data indicate that a 
single dose of AZD1222 elicits both humoral and cellular immunogenicity responses and that 
antibody responses are boosted after a second dose.  In a pooled analysis of the 4 studies 
conducted in the United Kingdom, Brazil, and South Africa (DCO2 database lock 07 
December 2020), the vaccine was highly immunogenic; seroresponse of S binding antibody 
was > 98% after a single dose of AZD1222.  Seroresponse of live neutralising antibody was 
82.4% after 1 dose, which rose to 99.4% after a second dose.  Efficacy analyses of the pooled 
DCO2 data demonstrated effective protection of AZD1222 against COVID-19 with a vaccine 
efficacy of 66.73% (95.84% CI: 57.41%, 74.01%) (p < 0.001) from 15 days after the second
dose in seronegative participants receiving 2 doses.  The DCO2 data also demonstrated that 
the standard dose of AZD1222 (5 x 1010 viral particles) provides complete protection against 
COVID-19 hospital admission ≥ 22 days after the first dose in the seronegative analysis set 
(0 versus 14 cases in the control group, 2 of which were severe, including one with a fatal
outcome).  Vaccine efficacy was similar in participants with pre-existing comorbidities, being 
those at greatest risk of severe outcomes of COVID-19, compared to that in the general 

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population.  Recently available primary analysis data from a Phase III study performed in the 
United States and Latin America showed primary endpoint vaccine efficacy of 76% (95% CI: 
67.60%, 82.22%; p-value < 0.001). 
A sharp rise in COVID-19 cases was reported in late 2020, which was attributed to the 
emergence of new SARS-CoV-2 variant strains: B.1.1.7 in the United Kingdom, B.1.351 
in South Africa, and P.1 in Brazil.  These variant strains carry a number mutations in the 
S protein sequence: 9 amino acids in B.1.1.7, 10 amino acids in B.1.351, and 12 amino acids 
in P.1 compared with the Wuhan-Hu-1 sequence.  These mutations may result in an increase 
of transmissibility and/or reduced vaccine effectiveness.  Variant B.1.351 was first identified 
in South Africa in October 2020.  Its attributes include approximately 50% increased
transmission and moderate impact of neutralization by monoclonal antibody therapeutics, 
convalescent plasma and vaccine sera.  In vitro neutralization assays suggest that the B.1.351 
lineage viruses may be the most antigenically distinct from the original Wuhan-like strains 
(Zhou et al 2021).  In addition, evidence suggests that AZD1222 may afford diminished 
protection against mild-moderate COVID-19 disease arising from the B.1.351 variant which 
is also antigenically the most different from the Wuhan-Hu-1 virus (Madhi et al 2021).  
The development of candidate vaccines that would be effective against the B.1.351 variant 
strain is underway.  AZD2816 is being developed as an updated ChADOx-nCOv19 vaccine 
designed to provide protective immunity against the newly arising B.1.351 variant strain, 
using the same ChAdOx1 platform and manufacturing processes used for AstraZeneca’s 
currently approved COVID-19 vaccine, AZD1222.  The purpose of this Phase II/III, 
multinational, randomised, partially double-blind, active-controlled study is to demonstrate 
the safety and characterize the immunogenicity of AZD2816, AstraZeneca’s candidate 
ChAdOx1 vector vaccine against B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative individuals who have previously 
received a 2-dose primary vaccination series (AZD1222 or an mRNA vaccine) against 
SARS-CoV-2
!
As a 2-dose homologous primary vaccination to SARS-CoV-2 seronegative individuals 
who have not been vaccinated previously. 
It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to the previously-vaccinated cohort that will receive a single booster dose.  
The immunogenicity of a 2-dose primary heterologous vaccination (with AZD1222 as first 
dose and AZD2816 as second dose) to SARS-CoV-2 seronegative individuals who are 
unvaccinated and a single booster dose of AZD1222 to SARS-CoV-2 seronegative individuals 
who have previously received a 2-dose primary mRNA vaccination series will also be 
investigated.

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SARS-CoV-2 seropositive participants will be enrolled in separate cohorts to support a 
parallel exploratory analysis in these participants.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD1222 and 
AZD2816 is provided in the respective Investigator’s Brochures.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD2816 and AZD1222 can be found in the respective Investigator’s Brochures.
2.3.1
Risk Assessment
AZD2816 has been developed using the same vaccine vector, ChAdOx1, as AZD1222 and 
only differs in the sequence for SARS-CoV-2 S glycoprotein that is inserted in the vector.  
The anticipated safety profile of AZD2816 is the same as the observed safety profile of 
AZD1222.  Risks associated with AZD2816 are thus the same as the risks associated with 
AZD1222, and no additional risks are anticipated due to the change in the targeted sequence.
A number of essentially mild and moderate adverse reactions to AZD1222 have been 
identified and resemble reactions frequently observed after many vaccines.  Based on pooled 
clinical data from studies with AZD1222, the most commonly expected local solicited AEs for 
participants in this study are vaccination site pain and tenderness.  The most commonly 
expected systemic solicited AEs are fatigue, headache, and malaise.  The majority of reported 
events have been mild or moderate in severity and resolved within 1 to 7 days.  Following the 
second dose, a general attenuation in the incidence and severity of local and systemic solicited 
AEs was observed. 
Post-authorisation hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk.
A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, 
has been observed very rarely following vaccination with COVID-19 Vaccine (ie, AZD1222) 
during post-authorisation use. No events have been observed in the AZD1222 clinical 
development programme.  Thrombosis in combination with thrombocytopenia is thus 
considered to be an important identified risk.  This includes cases presenting as venous 
thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein 
thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia.  Considering 
the frequency of this rare event and the size of this study, the risk for participants in this trial 
is considered to be low.  The protocol includes exclusion criteria and instructions for 
heightened vigilance and thorough investigations for suspected cases to mitigate against 
further the risk for these rare event. 

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Important potential risks are 1) neurologic events and potential immune-mediated neurologic 
conditions and 2) vaccine-associated enhanced disease, including vaccine-associated enhanced 
respiratory disease. 
2.3.2 Benefit Assessment
All participants will receive active treatment: either AZD1222, which has been shown to be 
effective in providing protection against SARS-CoV-2, or AZD2816, which as a modified 
form of AZD1222 designed to be effective against the emergent B.1.351 variant strain and 
may also provide participants with protection.  The information gained from this study will 
inform development decisions with regard to the efficacy of AZD2816 as both a primary 
2-dose vaccination in participants that have not been previously vaccinated and a 1-dose 
booster vaccination in participants previously vaccinated against SARS-CoV-2.
2.3.3 Benefit: Risk Assessment for Inclusion of Adults from 30 to 39 Years of 
Age
There have been reports of very rare adverse events of concurrent thrombosis and 
thrombocytopenia following vaccination with the first dose of AstraZeneca CoV-19 vaccine 
(AZD1222). There have been no safety concerns identified for thrombosis/thrombocytopenia 
associated with the second dose of the AstraZeneca (AZD1222) vaccine.  Up to 19 May 2021, 
the MHRA has received reports of 332 cases of major thromboembolic events with concurrent 
thrombocytopenia in the United Kingdom following vaccination with COVID-19 Vaccine 
AstraZeneca. The estimated number of first doses of COVID-19 Vaccine AstraZeneca 
administered was 24.2 million, and the estimated number of second doses was 10.7 million.
Any risk for serious thromboembolic events with thrombocytopenia is expected to be similar 
for AZD1222 and AZD2816 due to the similarity of the investigational products. 
In the context of this extremely rare adverse event, current advice from the United Kingdom’s 
Joint Committee on Vaccination and Immunization (JCVI) recommends that unvaccinated 
adults aged 30 to 39 years who are not in a clinical priority group at higher risk of severe 
COVID-19 disease should be preferentially offered an alternative to AZD1222 where possible 
and only where no substantial delay or barrier in access to vaccination would arise (JCVI 
2021).  The recommendations are not a contra-indication in this age group but a public 
vaccination policy recommendation in the context of a current low incidence of disease, the 
availability of alternative vaccines, and current speed and uptake of the vaccination 
programme overall in the UK.  The recommendations further advise that AZD1222 can be 
used in the age group 30-39 if these factors deteriorate, stating that if other vaccines are not 
available “the benefits of receiving the AstraZeneca (AZD1222) vaccine outweigh the risks”.  

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The participants of the proposed study differ from the general public in that they are carefully 
selected, with exclusion of individuals with a wide range of risk factors for 
thrombosis/thrombocytopenia, to minimize this risk.  The study also includes careful 
monitoring both pre-treatment and post-treatment to detect risk for thrombotic events with 
thrombocytopenia and promptly identify safety concerns at the individual participant level. 
The protocol and training for the investigators urges increased vigilance for these events of 
thrombosis with thrombocytopenia.  Furthermore, Appendix F provides guidance on 
identifying, treating, and assessing these very rare events. The risk of these events occurring 
is disclosed in the Participant Information Sheet and Informed Consent Form.  Furthermore, 
participants are advised to be alert for the following side effects in the 28 days after 
vaccination: severe/unusual headache, new or unexplained bruising/bleeding, shortness of 
breath, chest pain, leg swelling, persistent abdominal pain.  The exclusion of individuals with 
a wide range of risk factors for thrombosis with thrombocytopenia and measures included in 
the study to ensure early detection of these events mitigates the risk for these rare events.
With regard to benefit, all patients enrolled in the study will receive active treatment, either 
with the approved AZD1222, which has a good safety profile and high efficacy in adults ages 
18 and over, including protection against severe disease, or the experimental but closely 
related AZD2816, which is expected to have a similar safety profile with the potential to have 
broader efficacy than AZD1222, including against the emergent B.1.351 variant.  
Furthermore, the inclusion of these patients in the trial is important to investigate safety and 
immunogenicity of AZD2816, as both a primary vaccination and a booster vaccination, across 
the age groups for which it may be administered in clinical practice.
To summarise, the risk of serious harm due to vaccine-induced thrombotic thrombocytopenia 
is known to be small.  As of 19 May 2021, the MHRA’s estimate of the overall incidence after 
first or unknown doses is 1.3 per 100,000 doses.  Thus, the risk of one of these events 
occurring in the sub-group of participants 30 to 39 year of age from a study population of 
around 2000 patients is extremely low. This risk is appropriately mitigated in the study 
protocol to the extent that the risk-benefit of patients 30 to 39 years of age participating in this 
study is considered to be small, acceptable, and justified by the potential public health benefits 
of the study.
2.3.4 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria and close monitoring of participants to 
minimize known and potential risks. 
An independent Data Safety Monitoring Board will provide study oversight, evaluating 
cumulative safety and other clinical data at regular intervals. 

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Taking these measures into account, the potential risks identified in association with the 
administration of AZD2816 and AZD1222 are justified by the anticipated benefit that may 
be afforded to participants for the prevention of COVID-19.
3
OBJECTIVES AND ENDPOINTS
Table 5 describes the objectives and endpoints of this study.  Co-primary objectives were 
chosen to characterise the safety and humoral immune response of AZD2816 and AZD1222 
against selected strains when administered as a primary 2-dose homologous vaccination series
or a primary 2-dose heterologous vaccination series in previously unvaccinated participants or 
as a single booster vaccination to participants who have been previously vaccinated with 
2 doses of AZD1222 or an approved mRNA COVID-19 vaccine.  All primary and secondary 
objectives/endpoints are descriptive; there will be no hypothesis testing in this study. 
Estimates of neutralizing antibody geometric mean titre ratio and difference in seroresponse 
rates (and 95% confidence interval) will be generated as secondary analyses to support the 
assessment of relative immune responses between selected study groups.
Table 5
Study Objectives and Endpoints
Objectives
Endpoints
Safety Objectives
- Primary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
Previously vaccinated seronegative participants
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose

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To characterize the safety and tolerability of 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Unvaccinated seronegative participants
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD1222 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered  with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD1222 with a 4-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination

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To characterize the extended safety and tolerability of 
a heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
- Primary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (descriptive)
Previously vaccinated seronegative participants
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres 
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by 
1 dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
Unvaccinated seronegative participants

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To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD1222 with a 
4-week interval in unvaccinated seronegative 
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
heterologous dose primary vaccination with 1 dose
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
unvaccinated seronegative participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
To describe the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose primary vaccination with AZD2816 with a 
12-week interval in unvaccinated seronegative
participants
! Magnitude of SARS-CoV-2 specific antibody 
binding and neutralization titres (geometric mean 
titre)
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres
- Secondary (comparative)
Previously vaccinated seronegative participants receiving 1 dose versus unvaccinated seronegative participants 
receiving 2 doses
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week dosing 
interval in unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with AZD1222 relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week dosing interval in 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine 
relative to the response elicited by a 2-
dose primary vaccination with AZD1222 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres

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Previously vaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 relative to the response with 1 dose of 
AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD2816 in seronegative participants previously 
vaccinated with an mRNA vaccine relative to the 
response with 1 dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by 1 dose 
of AZD1222 relative to 1 dose of AZD2816 in 
seronegative participants previously vaccinated with 
a SARS-CoV-2 mRNA vaccine
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rates of SARS-CoV-2 
specific antibody binding titres and neutralization 
titres
Unvaccinated seronegative participants
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by a 
primary 2-dose vaccination with AZD2816 with a
4-week dosing interval relative to the response 
elicited by a 2-dose primary vaccination with 
AZD1222 with a 4-week interval in previously 
unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by a 
heterologous dose primary vaccination with 1 dose 
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval relative 
to the response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-week interval in 
previously unvaccinated seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
To evaluate the immune responses against the 
B.1.351 and Wuhan-Hu-1 strains elicited by a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval relative to the response elicited by a 
2-dose primary vaccination with AZD2816 with a 
4-week interval in previously unvaccinated 
seronegative participants
! Ratio of the magnitudes of SARS-CoV-2 specific 
antibody binding and neutralization titres (geometric 
mean titre ratio)
! Difference in seroresponsea rate of SARS-CoV-2 
specific antibody binding and neutralization titres
Exploratory
Previously vaccinated and unvaccinated participants (seronegative and seropositive at screening)

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To explore antibody response to selected SARS-
CoV-2 variants of interest/variants of concern 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or AZD1222 
in a sub-group of seronegative participants
! Magnitude of SARS-CoV-2 specific antibody 
binding titres (geometric mean titre) for selected 
variants of concern/variants of interest
! Seroresponsea rate of SARS-CoV-2 specific  
antibody binding titres for selected variants of 
concern/variants of interest
To explore B-cell and T-cell responses following a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in a 
sub-group of seronegative participants
! Intracellular cytokine staining and flow cytometry 
for T-cell responses over time
! Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 B.1.351 or Wuhan-Hu-1 S protein 
from day of dosing baseline over time
! Breadth and depth of peripheral blood B-cell and T-
cell repertoire over time through immunosequencing
To monitor the incidence of SARS-CoV-2 infection 
following 1 dose of AZD2816 or 1 dose of AZD1222
in previously vaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by 
the presence of nucleocapsid antibodies occurring
post-dose of study intervention 
To monitor the incidence of COVID-19 following 
1 dose of AZD2816 or AZD1222 in previously 
vaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To monitor the incidence of SARS-CoV-2 infection 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or 
AZD1222 in unvaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by 
the presence of nucleocapsid antibodies occurring 
post-second dose of study intervention 
To monitor the incidence of COVID-19 following a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in 
unvaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Magnitude of SARS-CoV-2 neutralization titres 
(geometric mean titre) as determined by a live virus 
neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres as determined by a 
live virus neutralization assay
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a 2-dose homologous or 
heterologous primary vaccination with AZD2816 
and/or AZD1222 in sub-groups of seronegative and 
seropositive participants
! Magnitude of ChAdOx1 nAb titres (geometric mean 
titre)
! Seroresponse rate of ChAdOx1 neutralizing antibody 
titres
! Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody 
titres, 1 month after both Dose 1 and Dose 2
To explore additional immune responses following 
a 2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity data
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.

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4
DESIGN
4.1
Overall Design
This is a multi-country Phase II/III study to evaluate the safety and immunogenicity of 
AZD2816 as single-dose vaccination in previously vaccinated adult participants and as a 
2-dose primary vaccination in previously unvaccinated adult participants. 
A total of approximately 2250 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled across these 2 
populations with the goal of 1200 previously vaccinated participants receiving single-dose 
vaccination and 1050 unvaccinated participants receiving 2-dose primary vaccination. In 
addition, seropositive participants will be enrolled (with a cap of 10% of the seronegative 
population or 225 participants) to support exploratory analysis is these participants. 
The enrollment and randomization strategy is intended to minimize group differences in terms 
of age, gender and the presence of comorbidities.
In both the single-dose booster treatment regimen and the 2-dose primary vaccination 
treatment regimen, participants will receive study intervention consisting of intramuscular 
administration of either AZD1222 (5 ×1010 viral particles) or AZD2816 (5 ×1010 viral 
particles).
Approximately 600 seronegative participants previously vaccinated with AZD1222 will be 
randomised 1:1 to receive a single intramuscular dose of either AZD1222 or AZD2816 in a 
double-blinded fashion.  
Approximately 600 seronegative participants previously vaccinated with an approved mRNA 
based vaccination will be randomised 1:1 to receive a single intramuscular dose of AZD2816
or AZD1222 in a double-blinded fashion.
It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to 1 of the 2 above previously-vaccinated groups.  
Approximately 1050 seronegative, previously unvaccinated participants will be randomised 
2:2:2:1 to receive a 2-dose primary vaccination of the following:
!
2 doses of AZD1222 with a 4-week dosing interval
!
2 doses of AZD2816 with a 4-week dosing interval
!
1 dose of AZD1222 followed by 1 dose of AZD2816 with a 4-week dosing interval
!
2 doses of AZD2816 with a 12-week dosing interval.

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The 3 treatments with a 4-week dosing interval will be double-blinded while the treatment 
with the 12-week interval will be open-label due to the difference in dosing interval.
In addition, a smaller population seropositive participants (approximately 10% of the 
seronegative population), will be randomised to treatment in a similar manner as above.
Immunogenicity (ie, anti-Wuhan-Hu-1 and anti-B.1.351 immune responses including 
S-binding antibody titres and neutralizing antibody levels [pseudo-neutralization]) will be 
assessed in serum samples collected pre-dose on the day of each vaccination (baseline levels 
before vaccination), 14 and 28 days after each vaccination, and 180 days after the last 
vaccination.
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1-8 for all participants and Days 29-36 for the 4-week dosing interval and Days 85-92 
for the 12-week dosing interval).  An e-diary will be used to collect information on the timing 
and severity of the solicited signs and symptoms.
Follow-up visits will take place as per the schedule of assessment within respective windows.  
All participants will be assessed for local and systemic AE, physical examination, review of 
e-diaries at these time points as detailed in the schedule of assessment.  Blood will also be 
taken for safety assessments and immunology purposes.
All study participants will be followed for safety for 180 days after administration of their last 
vaccination dose.  In every participant, solicited local and systemic events will be reported for 
up to 7 days after each dose, all unsolicited AEs will be reported for up to 28 days after each 
dose, and SAEs and AEs of special interest will be evaluated through study completion 
(up to 180 days after the last study vaccination).  
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, 
to ensure safe and ethical conduct of the study.
4.1.1
COVID-19 Assessments
Occurrence of COVID-19 in the trial will be reported as safety events, including monitoring 
of the potential risk of vaccine-induced enhanced disease as an AE of special interest (see 
Appendix E).  COVID-19 will be diagnosed and treated as per standard medical practice.  
In addition, experimental treatments are permitted.  Detailed information will be collected in 
a standard way and reported on a specific case report form. 

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4.1.2
Screening 
All potential participants will be screened, which may take place at a visit up to 14 days prior 
to Day 1 or on Day 1 itself.  
Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the screening procedures specified in the Schedule of Activities (Section 1.3) will be 
undertaken including a medical history, physical examination, height and weight, a 
SARS-CoV-2 screening test and clinical safety laboratory assessments.  Baseline information 
collected in the previously vaccinated participants will include which vaccine was received, 
immunization dose interval, and time since last vaccination.
For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled.  (Note: Women with urine test results that are positive or undetermined will not be 
enrolled and should be advised to seek medical attendance outside the context of the trial if 
pregnancy is suspected.) 
The eligibility of the participants will be reviewed at the end of the screening visit and again 
when all results from the screening visit have been considered.  Decisions to exclude the 
participant from enrollment or to withdraw a participant from the study will be at the 
discretion of the Investigator.
4.1.3
Vaccination Visit
Participants will be considered enrolled at the point of vaccination.  Before vaccination, the 
eligibility of the participant will be reviewed.  Body temperature will be observed and a 
medical history and physical examination will be undertaken before the first vaccination to 
determine need to postpone vaccination or screen fail the participant.  A negative pregnancy 
test (urine test) will need to be obtained from women of childbearing potential before 
vaccination.  Baseline blood samples will be obtained before the first vaccination.
Participants will receive 1 dose of AZD2816 or AZD1222 at vaccination visits, administered 
by intramuscular injection.  Previously immunized participants will have a single vaccination 
visit, Day 1.  Participants that have not been previously vaccinated at baseline will have a 
second vaccination visit on Day 29 (4-week interval) or Day 85 (12-week interval).  
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1 to 8 and Days 29 to 36 or Days 85 to 92 when applicable).

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4.1.4
Follow-up visits
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3).  All 
participants will be assessed for local and systemic AE, physical examination, review of the 
e-diary and blood tests at these time points as detailed in the Schedule of Activities.  Blood 
will also be taken for safety and immunogenicity assessments.
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate way until the last 
study visit in order to collect information on any SAEs/AE of special interest.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population includes adults ≥30 years of age.  Persons who are healthy or have 
medically stable underlying conditions will be eligible.  Adults with medically-stable chronic 
diseases may participate if, according to the judgement of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Some seropositive participants 
(capped at 10% of the seronegative participant population) will be enrolled to support an 
exploratory analysis.  
Those enrolled in the single-dose vaccination part of the study must have received 2 doses of 
AZD1222 (with a dosing interval of 4-12 weeks) or 2 doses of an mRNA COVID-19 vaccine 
(with a dosing interval of 3-12 weeks for the BNT162b2 mRNA vaccine [Pfizer-BioNTech] 
and 4-12 weeks for the mRNA-1273 vaccine [Moderna]) with the second doses administered 
at least 3 months prior to first study intervention administration. 
Pregnant/breastfeeding women, persons with severe immunodeficiency or severe underlying 
disease will be excluded from participation in the study.  Persons previously vaccinated with 
AZD1222 in the context of an AZD1222 vaccine trial are eligible for enrollment as previously 
vaccinated participants in the trial.  Persons who have previously received any other 
investigational product for the prevention of COVID-19 will be excluded from participation in 
this study.
Participants with known risk factors for thrombosis and thrombocytopenia (excluding 
contraceptive hormonal therapy or replacement hormonal therapy) are excluded.

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4.2.2
Rationale for Study Endpoints
There is no statistical hypothesis testing planned for this study.  Descriptive statistics will 
support evaluation of safety, reactogenicity, and immunogenicity.
An interim analysis will occur when all previously vaccinated participants have completed 
their Day 29 visit. A second interim analysis may be conducted when previously unvaccinated 
participants have completed their Day 29 visit.
The primary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants randomised to a 4-week dosing interval have 
completed their Day 57 visit (ie, 28 days after their second dose).
A secondary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants (including those randomised to either a 4-week or a 
12-week dosing interval) have completed their Day 57/Day 113 visit (ie, 28 days after their
second dose). 
The final analysis will occur when data from all vaccinated participants are available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants/180 days after the second dose for unvaccinated participants).
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination 
will be summarized by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be 
summarized by system organ class and preferred term, and by relationship to 
vaccination as assessed by the investigator.
!
SAEs and AEs of special interest following the first vaccination and throughout the 
study duration will be summarized by system organ class and preferred term and by 
relationship to vaccination as assessed by the investigator.
Solicited AEs will be collected for 7 days after each dose of study intervention, a period that 
has proven adequate to describe reactogenicity events in previous vaccine studies.  For all 
participants, AEs will be collected through 28 days after each dose of study intervention.  
SAEs, medically-attended AEs, and AEs of special interest and will be collected from Day 1 
through end of the study.  AEs of special interest include terms identified by the Brighton 
Collaboration involving events associated with vaccination in general .
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean titre

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!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean titre from baseline
Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of 
interest.
Immunogenicity against SARS-CoV-2 Wuhan-Hu-1 and B.1.351 strains will be characterized 
through the quantification of Spike-binding antibodies, pseudo-neutralization and, in a subset 
of participants, live neutralization.  Exploratory analysis of immunogenicity against other 
strains and induction of other immune effectors including cell-mediated immunity will be 
conducted. 
4.3
Justification for Dose
The AZD2816 nominal dose of 5 × 1010 viral particles is the same dose as the approved dose 
for AZD1222, which was based on the accumulated non-clinical data and clinical data from 
the AZD1222 clinical studies, as well as from other SARS-CoV-2 vaccines in development. 
Safety and immunogenicity data from an additional clinical study, MERS001(NCT03399578), 
using the same ChAdOx1 vector, also helped inform dose selection. MERS001 was the first 
clinical study of a ChAdOx1-vectored vaccine expressing the full-length S protein from a 
separate, but related, beta-coronavirus.  ChAdOx1 MERS has been given to 31 participants to 
date at doses ranging from 5 × 109 viral particles to 5 × 1010 viral particles.  Despite higher 
reactogenicity observed at the 5 × 1010 viral particles, this dose was safe, with self-limiting 
AEs and no serious adverse reactions recorded.  The 5 × 1010 viral particles was the most 
immunogenic, in terms of inducing neutralizing antibodies against MERS-CoV using a live 
virus assay (Folegatti et al 2020).  Given the immunogenicity findings and safety profile 
observed with the ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 viral particles 
dose was chosen for AZD1222.  
Based on accumulating nonclinical and clinical data gathered for AZD1222, a 2-dose regimen 
was selected for vaccination of unvaccinated participants with AZD2816 (AZD1222 
Investigators Brochure).  A single dose vaccination has been selected for participants 
previously vaccinated in line with both FDA and EMA guidance (FDA 2021, EMA 2021).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities (Section
1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally.

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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as a protocol waiver or exemption, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1
All Participants: 
Age
1
Adult, ≥ 30 years of age at the time of consent
COVID-19
For inclusion in the SARS-CoV-2 seronegative population supporting the primary and 
secondary objectives: 
2
No history of laboratory-confirmed SARS-CoV-2 infection (ie, no positive nucleic acid 
amplification test and no positive antibody test).
3
Seronegative for SARS-CoV-2 at screening (lateral flow test to detect reactivity to the 
nucleoprotein).
Note, patients failing to meet criteria 2 and/or 3 may be included in the separate seropositive 
population supporting the seropositive exploratory objectives. 
Type of Participant 
4
Medically stable such that, according to the judgment of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up
∀
- A stable medical condition is defined as disease not requiring significant change in 
therapy or hospitalization for worsening disease during the 3 months prior to enrollment
5
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator
6
Signed informed consent obtained before conducting any study-related procedures
Reproduction
7
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants:
(a) Women of childbearing potential must:

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!
Have a negative pregnancy test on the day of screening and on days of 
vaccination
!
Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
30 days following administration of the last dose of study intervention.  A highly 
effective method of contraception is defined as one that can achieve a failure rate 
of less than 1% per year when used consistently and correctly (see Table 6).  
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy) or 
!
Post-menopausal:
!
For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥ 12 months amenorrhea prior to randomization, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and
o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal 
range, the participant is to be considered of childbearing potential
!
For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomization, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.
Table 6
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing systema
Bilateral tubal occlusion
Vasectomized partner b
Sexual abstinence c
Combined (oestrogen- and progestogen-containing 
hormonal contraception
      Oral (combined pill)
      Intravaginal
     Transdermal (patch)
Progestogen-only hormonal contraception
#
     Oral 
#
     Injectable
#
     Implantable
a
This is also considered a hormonal method 
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse from 28 days prior to Day 1 through 30 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant

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5.1.2
Previously COVID-19 Vaccinated Participants
8
Prior completion of a 2-dose primary homologous vaccination regimen against SARS-
CoV-2 with either AZD1222 (2 standard doses as authorized vaccine or as investigational 
product in a clinical trial with a 4- to 12-week dosing interval) or with an mRNA vaccine 
approved for emergency or conditional use (eg, BNT162b2 vaccine [Pfizer-BioNTech] 
with a 3- to 12-week dosing interval or mRNA-1273 vaccine [Moderna] with a 4- to 12-
week dosing interval).  The second dose in all cases should have been administered at 
least 3 months prior to first administration of study intervention.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of allergy to any component of AZD1222/AZD2816.
2
History of Guillain-Barré syndrome, any demyelinating disease, or any other 
neuroimmunologic condition
3
Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) on the 
day prior to or day of randomization 
4
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia or HIV/AIDS.
5
Recurrent severe infections and use of immunosuppressant medication within the past 
6 months (≥ 20 mg per day of prednisone or its equivalent, given daily or on alternate 
days for ≥ 15 days within 30 days prior to administration of study intervention)
The following exceptions are permitted:  
∀
Topical/inhaled steroids or short-term oral steroids (course lasting ≤14 days)
6
History of primary malignancy except for:
(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or for metastasis (for example, indolent 
prostate cancer) in the opinion of the site investigator.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
(c) Adequately treated uterine cervical carcinoma in situ without evidence of disease
(d) Localized prostate cancer
7
History of thrombocytopenia and/or thrombosis, including participants who have 
experienced major venous and/or arterial thrombosis in combination with 
thrombocytopenia following vaccination with any COVID-19 vaccine
8
History of heparin-induced thrombocytopenia, congenital thrombophilia (ie, factor V 
Leiden, prothrombin G20210A, antithrombin III deficiency, protein C deficiency and 

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protein S deficiency, factor XIII mutation, familial dysfibrinogenemia), auto-immune 
thrombophilia (antiphospholipid syndrome, anti-cardiolipin antibodies, anti-β2-
glycoprotein 1 antibodies), or paroxysmal nocturnal haemoglobinuria.
9
Clinically significant bleeding (eg, factor deficiency, coagulopathy, or platelet disorder), 
or prior history of significant bleeding or bruising following intramuscular injections or 
venepuncture
10 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, or neurological illness, as judged 
by the Investigator (note, mild/moderate well-controlled comorbidities are allowed)
11 Any other significant disease, disorder, or finding that may significantly increase the risk 
to the participant because of participation in the study, affect the ability of the participant 
to participate in the study, or impair interpretation of the study data
12 Any autoimmune conditions, except mild psoriasis and vitiligo
Note: The AEs of special interest as outlined in Appendix E (including Table 27) should be 
considered when evaluating a participant for exclusion criteria as the presence of these AEs of 
special interest, especially if untreated or uncontrolled, may be a safety risk to the participant, 
affect the ability of the participant to participate in the study, and/or impair interpretation of 
the study data.  Investigators should review and consider the list of conditions in Appendix E.  
If any of these conditions are present in a participant, the Investigator is asked to utilize 
his/her clinical judgment in determining the participant’s eligibility for the study.  Should the 
participant have conditions as outlined in Appendix E and the participant is enrolled, the 
Investigator is asked to document notes on site regarding the final rationale for enrollment.
Prior/Concomitant Therapy
13 Receipt of or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 with the exception of prior vaccination with 
AZD1222 or an mRNA COVID-10 vaccine (2 doses of the same vaccine within an 
approved dosing interval, see Section 5.1.2), which is allowed for participants in the 
previously vaccinated cohort 
Note: For participants who develop COVID-19, receipt of licensed treatment options 
and/or participation in investigational treatment studies is permitted
14 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to or after administration of study intervention
15 Receipt of any influenza vaccine (licensed or investigational) within 7 days prior to and 
after administration of AZD1222/AZD2816.
16 Receipt of immunoglobulins and/or any blood products within 3 months prior to 
administration of study intervention or expected receipt during the period of study 
follow-up

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Other Exclusions
17 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)
18 Women who are currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, having given birth less than 3 months before or planning pregnancy during 
the study. 
19 Has donated ≥ 450 mL of blood products within 30 days prior to randomization or 
expects to donate blood within 90 days of administration of second dose of study 
intervention
20 Participants with a history of chronic alcohol or drug abuse or any condition associated 
with poor compliance.
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements or 
if vaccination would interfere with the participant’s ongoing treatment.
22 Previous enrollment in the present study.
5.3
Lifestyle Considerations
1
Participants must follow the contraception requirements outlined in Section 5.1
2
Restrictions relating to concomitant medications are described in Section 6.5
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Only a single rescreening is allowed in the study.  Rescreened participants are 
required to sign a new ICF (Appendix A 3), and will be assigned a new participant number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical device utilized by a study participant according to 
the study protocol.  Study intervention is defined as AZD2816 or AZD1222 (Table 7).

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6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 7
Investigational Products
Intervention 
Name
AZD2816
AZD1222
Type 
Vaccine
Vaccine
Dose Formulation
Unit Dose Strength
1 × 1011 viral particles/mL
1 × 1011 viral particles/mL
≥5 × 108 infectious units/mL
≥5 × 108 infectious units/mL
Dosage Level
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
≥ 2.5 × 108 infectious units
≥ 2.5 × 108 infectious units
Route
Intramuscular
Intramuscular
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labelling
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Current/Former 
Name
-
Previous clinical documentation:
ChAdOx1 nCoV-19
Current tradename: Vaxzevria
IMP: investigational medicinal product; NIMP: non-investigational medical product; w/v: weight/volume.
AZD2816
AZD2816 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD2816 has 
a label-claim volume of 5 mL and can provide up to ten 0.5 mL doses.
AZD1222
AZD1222 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD1222 has 
a label-claim volume of 4 mL and can provide up to eight 0.5 mL doses.
CCI
CCI

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Unopened vials of AZD2816 and AZD1222 must be stored at 2-8 oC (36-46 oF) for the 
duration of the assigned shelf-life and must not be frozen.  Both investigational products must 
be kept in original packaging until use to prevent prolonged light exposure. 
6.1.2
Dosing Instructions
Previously unvaccinated participants will receive 2 doses of either AZD1222, AZD2816, or 
AZD1222 plus AZD2816, with the first dose administered on Day 1 and the second dose on 
Day 29 (for a 4-week dosing interval) (Table 3) or Day 85 (for a 12-week dosing interval) 
(Table 4). 
Previously vaccinated participants will receive 1 dose of either AZD1222 or AZD2816
(Table 2).  
It is recommended that the study interventions be administered as an intramuscular injection 
into the deltoid of the non-dominant arm. Other injection sites may be used if necessary.
All study participants will be observed in the clinic for at least 15 minutes after vaccination. 
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.
6.2
Preparation/Handling/Storage/Accountability
The procedures for preparation, handling, storage, and accountability are identical for 
AZD2816 and AZD1222.
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual or specified handling instructions.

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6.2.1
Dose Preparation and Administration
Doses of AZD2816 and AZD1222 must be prepared by the unblinded pharmacist (or designee 
in accordance with local and institutional regulations) using aseptic technique. Each dose is 
prepared by withdrawing 0.5 mL from a vial of AZD2816 or AZD1222 in a sterile syringe.
AZD2816 and AZD1222 do not contain preservatives. Each vial must be assigned a beyond-
use-date of 6 hours at 2-30 °C (36-86 °F) from first needle puncture of the vial, after which 
any unused portion must be discarded.
Once an AZD2816 or AZD1222 dose is drawn into a syringe for administration, the dose must 
be administered within the beyond-use-date of the vial. If dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
The study contains 3 cohorts that are randomised to a total of 8 treatments: 
!
Participants that have previously been vaccinated with 2 doses of AZD1222 will be 
randomised 1:1 to 1 dose of AZD2816 or 1 dose of AZD1222.
!
Participants that have been previously vaccinated with an mRNA COVID-19 vaccine will 
be randomised 1:1 to 1 dose of AZD2816 or AZD2816.  
!
Vaccination naïve participants that will be randomised 2:2:2:1 to 2 doses of AZD2816 
with a 4-week dosing interval, 2 doses of AZD1222 with a 4-week dosing interval, 1 dose 
of AZD1222 followed by 1 dose of AZD216 with a 4-week dosing interval, or 2 doses of 
AZD2816 with a 12-week dosing interval.
Separate populations of SARS-CoV-2 seronegative participants (supporting the primary and 
secondary objectives) and SARS-CoV-2 seropositive participants (supporting exploratory 
objectives) will be randomised/included in the above cohorts.
Randomization will be stratified based on age (less than 65, 65 and above), gender, and 
presence of at least one of the following comorbidities that are known risk factors for severe 
illness from COVID-19 (based on the participant’s past and current medical history):
!
Obesity (BMI ≥ 30 kg/m2 at baseline)
!
Significant cardiovascular disease (eg, heart failure, coronary artery disease, congenital 
heart disease, cardiomyopathies, or pulmonary hypertension)
!
Chronic lung disease (eg, chronic obstructive pulmonary disease, idiopathic pulmonary 
disease, cystic fibrosis, or moderate to severe asthma)
!
Diabetes (Type 1 or Type 2).  

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The randomised participants will be centrally assigned to randomised study intervention using 
an Interactive Response Technology (IRT)/Randomisation and Trial Supply Management.  
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 
the log in information & directions for the Randomisation and Trial Supply Management will 
be provided to each site.
Where a participant does not meet all the eligibility criteria but incorrectly received study 
intervention, the investigator should inform the Study Physician immediately, and a discussion 
should occur between the Study Physician and the investigator regarding whether to continue 
or discontinue the participant.
6.3.2
Blinding
Treatment will be double-blinded for previously vaccinated participants randomised to a 
single dose of either AZD2816 or AZD1222. Treatment will also be double-blind for 
previously unvaccinated participants randomised to 2 dose vaccinations with a 4-week dosing 
interval (ie, homologous AZD2816 or AZD1222 vaccination or heterologous 
AZD1222/AZD2816 vaccination).  Previously unvaccinated participants randomised to a  
homologous AZD2816 vaccination with a 12-week dosing interval will receive treatment in 
an open-label fashion due to the different dosing interval.
For the double-blinded treatments, neither the participant nor any of the investigators or 
Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
participants will be aware of the study intervention received.  Since AZD2816 and AZD1222 
are visually distinct prior to dose preparation (due to differences in container closure), all 
investigational product will be handled by an unblinded pharmacist (or designee in accordance 
with local and institutional regulations) at the study site. Once drawn into syringes for 
administration, AZD2816 and AZD1222 are not visually distinct from each other.
The IRT will provide the investigators with a dose tracking number to be allocated to the 
participant at the dispensing visit.  Routines for this will be described in the IRT user manual 
that will be provided to each study site.
For participants receiving double-blinded treatments, the randomization code should not be 
broken except in medical emergencies when the appropriate management of the participant 
requires knowledge of the treatment randomization.  The investigator documents and reports 
the action to the Sponsor, without revealing the treatment given to participant to the Sponsor 
staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities.  Randomization codes will not be broken 

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for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.
6.3.3
Procedures for Unblinding
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
in which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment 
is warranted.  Participant safety must always be the first consideration in making such a 
determination.  If a participant’s intervention assignment is unblinded for safety, the Sponsor 
must be notified within 24 hours after breaking the blind. 
In the event that a study participant is contacted about receiving a licensed and/or authorized 
COVID-19 vaccine outside of this clinical study, unblinding instructions are being provided to 
the sites.  If the participant is unblinded, the Sponsor needs to be notified within 24 hours, and 
this should be documented in the site source documents.
6.4
Study Intervention Compliance
Participants are dosed at the study site, receiving study intervention directly from the 
investigator or designee, under medical supervision.  The date, and time if applicable, of dose 
administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the period specified in the 
Schedule of Activities (Section 1.3), must be recorded in the eCRF along with the information 
listed below.  Vitamins and/or herbal supplements are not to be recorded.
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
!
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance.

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!
Primary care providers, or where appropriate investigators, should prescribe appropriate 
concomitant medications or treatments deemed necessary to provide full supportive care 
and comfort during the study.
!
Participants who develop COVID-19 after receiving study intervention should be treated 
with licensed medications and interventions according to standard of care.  All routine 
vaccinations other than influenza are permitted beginning > 30 days after last dose of 
study intervention.  Licensed influenza vaccines are permitted 7 days before and 7 days 
after administration of study intervention.
!
Topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 days) are 
permitted
6.5.2
Prohibited Concomitant Medications
The following medications are prohibited and the Sponsor must be notified if a participant 
receives any of these prohibited medications.  The use of the following concomitant 
medications and/or vaccines, however, will not definitively require withdrawal of the 
participant from the study, but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis set.
!
Primary or booster vaccinations, other than AZD2816 or AZD1222, for prevention of 
SARS-CoV-2 or COVID-19.
Note: Participants choosing to receive a licenced and/or authorized COVID-19 vaccine 
should inform the Investigator so it can be properly documented.  Participants, who 
receive a licenced and/or authorized COVID-19 vaccine outside the study, should be 
encouraged to continue study conduct to be followed for safety reporting and all 
assessments.
!
Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention.  Thirty days after 
the second vaccination, other routine vaccinations are permitted as clinically indicated.
!
Glucocorticoids at a dose ≥ 20 mg/day of prednisone or equivalent given daily or on
alternate days for ≥ 14 consecutive days between randomization and the participant’s
scheduled final visit
!
Other systemically administered drugs with significant immunosuppressive activity,
such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy
between randomization and the participant’s scheduled final visit
!
Immunoglobulins and/or any blood product.
If a participant receives a prohibited concomitant medication, the investigator in consultation 
with the Sponsor will evaluate any potential impact on receipt of study intervention based on 
time the medication was administered, the medication’s pharmacology and pharmacokinetics, 
and whether the medication will compromise the participant’s safety or interpretation of the 
data (see Section 7.1). 

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6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.  Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive the first or second dose (if applicable) of study 
intervention if any of the following occur in the participant in question:
1
Withdrawal of consent after signing informed consent
2
Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 
3
Participant is pregnant or nursing
4
Any grade 3 or greater allergic reaction including anaphylaxis that is assessed as related 
to study intervention 
5
Occurrence of any thrombosis with concurrent thrombocytopenia 
6
Any SAE assessed as related to study intervention
7
Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardize the safety of the study participant 
8
Receipt of a prohibited concomitant medication that may jeopardize the safety of the 
study participant or interpretation of the data
Each participant who has received at least 1 dose of study intervention will be followed for the 
full study period unless consent is withdrawn specifically from further study participation, or 
the participant is lost to follow-up.  Participants who have not received study intervention, 
regardless of reason, will not be followed.
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine 
during the study, AstraZeneca needs to be notified within 24 hours and this should be 
documented in the site source documents. Participants who have received study intervention, 
regardless of reason, will be followed for the full study period.

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7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent.  If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken should be 
carried out in line with what was stated in the informed consent and local regulation.  
The investigator must document the decision on use of existing samples in the site study 
records and inform the Sponsor Study Team.  If the participant does not specifically 
request withdrawal of consent for use of samples, then the samples collected prior to the 
consent withdrawal will be destroyed once per protocol analysis is complete.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the Schedule of Activities (Section
1.3).  Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities.
8.1
Efficacy Assessments
Not applicable.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.  Each clinically significant
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history, 
clinical signs, and symptoms and will include signs of thrombosis and/or 
thrombocytopenia.  Each clinically significant abnormal finding following vaccination 
will be recorded as an AE.
!
All physical examinations will be performed by a licensed healthcare provider 
(eg, physician, physician assistant, or licensed nurse practitioner). 

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8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3).  The participant should be 
resting prior to the collection of vital signs.  On vaccination days, vital signs should be 
assessed prior to vaccine administration.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3).  Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the investigator, with the 
date and time of collection recorded in the appropriate eCRF.
The standard clinical chemistry and haematology analysis will be performed at a local 
laboratory at or near to the investigator site.  Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.  
The following laboratory variables will be measured:
Table 8
Laboratory Safety Variables
Blood
Serum/Plasma
Haemoglobin
Activated partial thromboplastin time
Leukocyte count
Prothrombin time
Leukocyte differential count (absolute count)
Fibrinogen
Platelet count
D-dimer
-
Creatinine
-
Bilirubin, total
-
Alkaline phosphatase
-
Aspartate aminotransferase 
-
Alanine aminotransferase
In case a participant shows an aspartate aminotransferase or alanine aminotransferase 
≥3 × upper limit of normal together with total bilirubin ≥2 × the upper limit of normal, please 
refer to Section 8.3.6
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the Schedule of Activities (Section 1.3).  Urine pregnancy tests for 
∃-human chorionic gonadotropin may be performed at the site using a licensed dipstick test.  

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8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a e-diary (Section 8.3.7), and will be assessed separately 
from the (unsolicited) AEs collected during the study.  General information for AEs in this 
protocol excludes the reporting of solicited AEs via e-diary unless otherwise noted.. 
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
AEs will be recorded for 28 days after each dose of study intervention. 
Solicited AEs will be recorded for 7 days after each dose of study intervention (ie, Day 1 
through Day 8). If a solicited AE is not resolved within the e-diary reporting period, the event 
will be reported as a non-solicited adverse event in the eCRF, with a start date of when started 
and the actual stop date. 
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact. 
See the Schedule of Activities for the scheduled timepoints (Section 1.3). 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the Sponsor.

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8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Severity grade/maximum severity grade/changes in severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA 2007) will be utilized for all unsolicited events with an 
assigned severity grading including Grade 5. 

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8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol-mandated vital signs and laboratory safety 
assessments will be summarized in the Clinical Study Report. 
Deterioration as compared to baseline in protocol-mandated vital signs and laboratory safety 
assessment should therefore only be reported as AEs if they fulfil any of the SAE or 
medically-attended AE criteria or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or 
non-planned visits were required).
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an SAE or medically-attended AE, and the associated vital sign 
will be considered as additional information. 
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation.  Any occurrences of aspartate aminotransferase or alanine aminotransferase 
≥3 × the upper limit of normal together with total bilirubin ≥2 × upper limit of normal at any 
point during the study following the administration of study medication should be reported to 
the Sponsor as a potential Hy's Law SAE within 1 day with a serious criteria of ‘Important 
medical event’ and causality assessment ‘yes/related’.

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The study physician will contact the investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 9) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention via e-diary collection. If a solicited AE is not resolved within the e-diary 
reporting period, the event will be also reported as a non-solicited adverse event in the eCRF,
with a start date of when started and the actual stop date.
Solicited AEs should not be reported as unsolicited AEs unless they fulfil the criteria for SAEs 
or medically-attended AEs(see Sections 8.3 and 8.3.8, respectively).
Table 9
Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic 
Pain at the site of the injection 
Fever (> 100 °F/37.8 °C)
Redness/erythema at the site of the injection
Chills
Tenderness at the site of the injection
Muscle pains
Induration/swelling at the site of the injection 
Fatigue (physical or mental tiredness/exhaustion)
-
Headache
-
Malaise (general feeling of discomfort or uneasiness)
-
Nausea
-
Vomiting
Solicited AE e-Diary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given a thermometer, tape measure or ruler, and access to the Solicited 
AE e-Diary, with instructions on use, along with the emergency 24-hour telephone number to 
contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms. 
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorized representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix D.  Because 

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solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention. 
8.3.8 COVID-19 Assessment
This study will describe the incidence of COVID-19 adverse events reported from Day 1 to 
180 days after the participant’s last/only dose of vaccine.
COVID-19 is defined as SARS-CoV 2-RT-PCR positive symptomatic illness.  At all clinic 
visits following the initial vaccination, participants will be asked if they have had a diagnosis 
of COVID-19 since their last clinic visit (see Schedule of Activities in Section 1.3). Medical 
records will be obtained for confirmation of a participant-reported diagnoses of COVID-19.  
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea.  Events will be reported as AEs/SAEs.
If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed 
using RT-PCR.
8.3.9 Medically-Attended Adverse Events
Medically-attended AEs will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3).
Medically-attended AEs are defined as AEs leading to medically-attended visits that were not 
routine visits for physical examination or vaccination, such as an emergency room visit, or an 
otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. 
AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
illness visits will not be considered medically-attended AEs.
8.3.10
Adverse Events of Special Interest
AEs of special interest will be collected according to the timepoints specified in the Schedule 
of Activities (Section 1.3). 
AEs of special interest are events of scientific and medical interest specific to the further 
understanding of study intervention safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor.  AEs of special interest are based on 
Brighton Collaboration case definitions (SPEAC 2020), clinical experience, and scientific 
interest.  A list of events is provided in Appendix E.
An AE of special interest can be serious or non-serious.  All AEs of special interest will be 
recorded in the eCRF.  If any AE of special interest occurs in the course of the study, 
investigators or other site personnel will inform the appropriate Sponsor representatives within 

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1 day ie, immediately but no later than 24 hours of when he or she becomes aware of it.  
Serious AEs of special interest will be recorded and reported as per Section 8.3.11.
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest
Both thrombotic, thromboembolic, and neurovascular events and thrombocytopenia events are 
considered to be adverse events of special interest.  The investigator should remain vigilant for 
the occurrence of thrombotic events with thrombocytopenia and/or bleeding.  If a participant 
experiences new onset thromboembolic events with thrombocytopenia, there should be 
prompt evaluation with a thorough haematological investigation.  COVID-19 testing, 
including PCR and serology (nucleoprotein antibodies), should also be performed.  See 
Appendix F for further guidance on investigation and management of suspected events.
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and whole genome 
sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events.
8.3.10.2
Potential Neurological Adverse Events of Special Interest
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation, including referral to a neurology specialist for further 
evaluation and testing, as clinically indicated.  Testing can include evaluation for peripheral 
demyelinating conditions (eg, electromyography).  In cases of concern for spinal cord disease, 
see Figure 3 for a recommended testing algorithm. 
An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AEs of special interest occurring 
in the AZD1222 clinical development program (see Appendix A 5).  

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Figure 3
Neurology Testing Algorithm
a
Adapted from Rovira et al 2015
Ab: antibody; ACE: angiotensin converting enzyme; ADC: apparent diffusion coefficient; ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibodies; AQP4: 
aquaporin 4; CMV: cytomegalovirus; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebral spinal fluid; CT: computed tomography; DWI: diffusion-weighted 
image; EBV: Epstein-Barr virus; ED: emergency department; ENA: extractable nuclear antigen antibodies; ESR: erythrocyte sedimentation rate; FLAIR: fluid-attenuated inversion 
recovery; GRE: gradient echo; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IgG: immunoglobulin G; MOG: myelin oligodendrocyte glycoprotein; MRI: 
magnetic resonance image; PCR: polymerase chain reaction; RF: rheumatoid factor; RPR: rapid plasma reagin; STIR: short T1 inversion recovery; SWI: susceptibility-weighted 
imaging; TSH: thyroid stimulating hormone; TM: transverse myelitis; VDRL: Venereal Disease Research Laboratories; VZV: varicella-zoster virus. 

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8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedures.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Sponsor representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available.
The Sponsor representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness is the AZD1222 Investigators 
Brochure, Section 5.6. 
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor, except if the pregnancy is discovered 
before the participant has received any study intervention.
8.3.12.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2).  Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the study intervention may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 

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spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the participant was discontinued 
from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.11) and within 30 days for all other pregnancies 
that are not associated with an SAEs.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module may be used to report the outcome of the pregnancy.
8.3.13
Medication Error
If a medication error occurs, then the investigator or other site personnel informs the 
appropriate Sponsor representatives within 1 day, ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 3. 
8.4
Overdose
For this study, any dose of study intervention exceeding that specified in the protocol will be 
considered an overdose.
There is no specific treatment for an overdose with AZD2816 or AZD1222.  If overdose 
occurs, the participant should be treated supportively with appropriate monitoring as 
necessary.

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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose occurs in the course of the study, the investigator or other site personnel inform 
appropriate Sponsor representatives immediately, but no later than 24 hours after when he or 
she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual.  Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality.  Further details on Handling of Human 
Biological Samples are provided in Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a 
maximum of 15 years following issue of the Clinical Study Report.  Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses, eg, exploratory immunology, such 
as systems serology and profiling of B- and T-cell repertoire.  The results from further 
analysis will not be reported in the Clinical Study Report.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).  Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual.  Results for exploratory immunogenicity analyses may 
be reported separately from the CSR.

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8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the Schedule of Activities (Section 1.3).  Authorized laboratories 
will assess serologic responses to AZD1222 and AZD2816 using validated (or qualified, 
where appropriate) assays.  Serologic assessment to the S protein from different SARS-CoV-2 
variants (which include Wuhan-Hu-1, B.1.351, B.1.1.7, and P.1) will be assessed 
quantitatively using a validated multiplexed ECL based immunoassay.  Additionally, 
seroresponse will be assessed for each antigen over time.  The rate of SARS-CoV-2 infection 
in participants receiving AZD2816 versus AZD1222 will be determined by seroconversion in 
a SARS-CoV-2 nucleocapsid antigen in a multiplexed electrochemiluminescence-based assay 
performed at an authorized laboratory. Additional exploratory assessments may be performed 
to measure binding antibodies to SARS-CoV-2 variants of interest (which may include 
B.1.429, B.1.525, B.1.526, P.2, P.3, B.1.617, and the Q677H mutation observed in multiple 
variants).
8.5.2.2
 
 
 
 
 
 
 
 
 
8.5.2.3
 
 
 
 
 
CCI
CCI
CCI
CCI

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8.5.2.4
 
 
 
 
 
 
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Already collected samples may be analysed for biomarkers thought to play a role in 
COVID-19 severity or outcomes based upon emerging immunogenicity and 
pharmacodynamic analysis from this or other studies involving the study interventions. These 
analyses include but are not limited to serum or plasma cytokines, quantification of RNA, 
micro-RNA, and/or non-coding RNA using quantitative reverse transcriptase polymerase 
chain reaction (RT-PCR), microarray, sequencing, or other technologies in blood, or 
peripheral blood mononuclear cells to evaluate their association with AZD1222/2816 and 
observed clinical responses to these study interventions.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
There is no statistical hypothesis testing planned for this study.  Descriptive analyses will 
support evaluation of safety, reactogenicity and immunogenicity.
9.2
Sample Size Determination
Primary Objective: Characterise Immunogenicity (Precision)
Historical data were available for the immunogenicity responses to AZD1222 from the pooled 
COV001/002/003/005 studies.  Table 10 presents the log transformed immunogenicity 
responses (ie, geometric mean titres) by assay for participants that received 2 standard doses 
CCI
CCI

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of AZD1222.  These results indicate that the pseudo-neutralising antibodies exhibited the 
largest variation (standard deviation of 1.20 and 1.10 for the 4-week and 12-week dosing 
intervals respectively), while live-neutralising antibodies had the lowest (standard deviation of 
0.72 for the 4-week dosing interval).
Table 10
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-week dosing intervalb
Assay
N
Mean
Std Dev
N
Mean
Std Dev
N
Mean
Std Dev
Pseudo
476
4.3
1.34
166
5.3
1.20
113
5.4
1.10
Live
51
4.9
1.15
42
6.2
0.72
0
-
-
Spike protein
1139
9.1
1.14
293
10.1
0.96
302
10.7
0.83
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval
Table 11 presents the seroresponse (ie, > 4 fold increase from baseline) by assay.  These 
results indicate that the pseudo-neutralising antibodies exhibited the lowest proportion of 
seroresponse (59.7% and 85.5% for the 4-week and 12-week dosing intervals respectively), 
while both live-neutralising and spike-binding seroresponse rates exceeded 95%.
Table 11
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-dose week intervalb
Assay
N
Proportion
N
Proportion
N
Proportion
Pseudo
499
32%
382
59.7%
117
85.5%
Live
96
75%
95
96.8%
-
-
Spike protein
940
96.6%
636
95.9%
304
99.3%
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval 
Under the assumption that the immunogenicity responses (ie, geometric mean antibody titres) 
associated with AZD2816 will be similar to the responses associated with AZD1222 in 
participants that received 2 standard doses in the pooled COV001/002/003/005 studies, in 
which standard deviations ranged from 0.72 to 1.2 (Table 10), 150 participants will provide a 
95% confidence interval half-width between 0.115 and 0.192 (see Table 12).  Similarly, 300 
participants will provide a 95% confidence interval half-width between 0.081 and 0.136.

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Table 12
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes
Standard Deviation
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
0.72
150
0.115
300
0.081
0.83
150
0.133
300
0.094
0.96
150
0.154
300
0.109
1.1
150
0.176
300
0.124
1.2
150
0.192
300
0.136
Under the assumption that the seroresponse rates associated with AZD2816 will be similar to 
the response rates in adults that received 2 standard doses of AZD1222 in the pooled 
COV001/002/003/005 studies (Table 11), 150 participants will provide a 95% confidence 
interval half-width between 1.33% and 7.85%, and 300 participants will provide a 95% 
confidence interval half-width between 0.94% and 5.55% (Table 13). 
Table 13
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroconversion Rates and 
Proposed Sample Sizes
Observed 
seroconversion rate
Number of participants
Estimated half-width of the 95% confidence interval 
59.7%
150
7.85%
300
5.55%
85.5%
150
5.63%
300
3.98%
95.9%
150
3.17%
300
2.24%
96.8%
150
2.82%
300
1.99%
99.3%
150
1.33%
300
0.94%

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For a fixed sample size, the precision with which the 95% confidence interval of the binary 
seroresponse rate can be estimated is a function of the response rate.  Table 13 provides the 
lower bounds of the 95% confidence interval for selected response proportions for alternate 
sample sizes.  For a given response rate, we can be 95% confident that the true seroresponse 
rate is at least as large as the lower bound of the confidence interval.
Primary Objective: Safety
Table 14 indicates the probability of observing 1 or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 
particular type for participants in each treatment arm.  With the sample size of 300 
participants, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 95%.
Table 14
Probability of detecting 1 or more safety events (N = 300)
Event Frequency
Probability (> 1 event)
≥ 10% (Very Common)
> 99%
≥ 1% (Common)
95%
≥ 0.1% (Uncommon)
26%
≥ 0.01% (Rare)
3%
Secondary Objective: Compare Immunogenicity
Although this study will describe and compare the immune responses between AZD2816 and 
AZD1222 for selected group pairs, no-formal non-inferiority margin for either the geometric 
mean titre ratio or the difference in seroresponse is prospectively defined. 
Under the assumption that there is no difference between treatment arms of interest (ie, a ratio 
of 1, difference on the log scale of 0), the power conferred by 150 and 300 participants 
respectively for the comparison of geometric mean titre ratio using anoninferiority margin of 
1.5 (equivalent to a difference on the log scale of 0.405) is presented in 
Table 15.

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Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
Sides
Null 
difference
Assumed 
mean 
treatment 
difference
Assumed 
standard 
deviation
N of 
participants in 
comparator 
group
N of 
participants 
in reference 
group
Alpha
Power
Upper
ln1.5 = 0.405
0
0.72
150
300
0.025
> 0.999
300
300
> 0.999
0.83
150
300
0.998
300
300
> 0.999
0.96
150
300
0.988
300
300
> 0.999
1.10
150
300
0.957
300
300
0.994
1.20
150
300
0.920
300
300
0.985
Similarly, if there is no difference between treatment arms of interest (ie, a ratio of 1) in the 
proportion of seroresponders, 300 participants provides 80% power for to establish non-
inferiority to within margin of -10% if the seroresponse rate is > 75%.  The observed pseudo-
neutralising response rates (> 4 fold increase from baseline) from the COV001/002/003/005 
studies for AZD1222 were 59.7% and 85.5% for the 4-week and 12-week dosing interval 
respectively (Table 11).  A population of 300 participants provides 70% power to detect non-
inferiority (using a non-inferiority margin of -10%) if the observed response rate is 59.7% 
(Table 16).

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Table 16
Power for Non-inferiority Using -10% as the Upper Bound of the 
Difference in Seroresponse Rate
Sides
Null 
proportion 
difference
Assumed 
proportion of 
seroresponders 
in both groups
Assumed 
difference in 
proportion of 
seroresponders 
N in 
comparator 
group
N in 
reference 
group
Alpha
Power
Lower
-0.1
0.597
0
150
300
0.025
0.546
300
300
0.707
0.855
150
300
0.844
300
300
0.929
0.959
150
300
0.998
300
300
> 0.999
0.968
150
300
> 0.999
300
300
> 0.999
0.993
150
300
> 0.999
300
300
> 0.999
9.3
Populations for Analyses
The following populations are defined:
Table 17
Populations for Analysis
Population
Description
All participants analysis set 
All participants screened for the study, to be used for reporting disposition and 
screening failures.
Full analysis set
All randomised participants who received study treatment, irrespective of their 
protocol adherence and continued participation in the study. Participants will be
analysed according to their randomised treatment, irrespective of whether or not 
they have prematurely discontinued, according to the intent-
to-treat principle. Participants who withdraw consent or assent to participate in the
study will be included up to the date of their study termination.
Safety analysis set
The safety analysis set consists of all participants who have received study 
treatment. Erroneously-treated participants (eg, those randomised to AZD2816, but 
were actually given treatment AZD12222) are accounted for in this analysis set by 
assigning them to the treatment they actually received.

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Table 17
Populations for Analysis
Population
Description
Immunogenicity analysis set
The vaccine immunogenicity analysis set will include all randomised participants, 
received at least 1 dose of planned study treatment (ie, 1 dose of either AZD2816 or 
1 dose of AZD1222), had baseline and post-dose antibody measurements, have at 
least 1 post-dose quantifiable serum titre, and had no protocol deviations judged to 
have the potential to interfere with the generation or interpretation of an antibody 
response. The analyses conducted using this analysis set will be based on the actual 
treatment received.
Seronegative 
immunogenicity analysis set 
The subset of the immunogenicity analysis set who were seronegative at baseline.
Seropositive 
immunogenicity analysis set
The subset of the immunogenicity analysis set who were seropositive at baseline.
Participants that are SARS-CoV-2 seropositive at screening will be included in seropositive 
analysis sets analogous to the above seronegative analysis sets. Further definition is provided 
in the Statistical Analysis Plan.
9.4
Statistical Analyses
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints.  A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to the interim analyses.
9.4.1 General Considerations
An interim analysis will occur when all previously vaccinated participants have completed 
their Day 29 visit (ie, 28 days after booster dose).  It is estimated that this early analysis has 
the potential to provide clear signals about whether AZD2816 provides a strong neutralizing 
response against the B.1.351 strain while retaining immunogenicity against the Wuhan strain, 
and thereby influence programmatic decisions early.  
A second interim analysis may be performed when previously unvaccinated participants have 
completed their Day 29 visit (ie, 28 days after fist dose).  This analysis is intended to assess 
immunogenicity variability. The number of previously unvaccinated participants per treatment 
arm may be increased based upon the results of this analysis.  The details of this interim 
analysis, including the trigger and methods, will be specified in the Statistical Analysis Plan to 
be finalized prior to any interim analysis.
The primary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants randomised to a 4-week 

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dosing interval are available through completion of their visit 28 days after the second priming 
dose.
A secondary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants (including those 
randomised to a 12-week dosing interval) are available through completion of the visit 28 
days after the second dose. 
The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).
To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.
9.4.2 Safety
9.4.2.1
Primary Endpoints
Overview
Descriptive analyses will support evaluation of safety, reactogenicity and immunogenicity. 
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination will 
be summarised by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be summarised 
by system organ class and preferred term, and by relationship to vaccination as assessed 
by the investigator.
!
MAAEs, SAEs, and AESIs following the first vaccination and throughout the study 
duration will be summarised by system organ class and preferred term and by relationship 
to vaccination as assessed by the investigator. 
!
The change from baseline for safety laboratory measures at 7 and 28 days after 
vaccination.
AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities.  AEs will be presented for each treatment group by system organ class 
and preferred term.  Summaries will include the number and percentage of participants 
reporting at least one event, number of events and exposure adjusted rates, where appropriate.

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An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs.  Summaries will present the relationship to 
study intervention as assessed by the investigator, maximum intensity, seriousness, and death.
A listing will cover details for each individual AE.  Full details of all AE analyses will be 
provided in the Statistical Analysis Plan, including intercurrent events for safety due to 
potential unblinding of participants for administration of licensed and/or approved SARS-
CoV-2 or COVID-19 vaccine.
At the time of the interim analyses, group assignment will not be presented when safety event 
data has the potential to unblind participant’s study group attribution.
9.4.2.2
Other Safety Endpoints
Vital Signs
Vital sign measurements will be performed as specified in the Schedule of Activities (Section 
1.3).  The set of assessments will include pulse oximetry, blood pressure, and body
temperature.  
Details of all vital sign analyses will be provided in the Statistical Analysis Plan, which will 
include descriptive statistics presented for observed values for all vital sign parameters. 
COVID-19
This study will describe the incidence of COVID-19 adverse events from the first dose of the 
vaccine to study end (180 days post-vaccination). Descriptive statistics will be produced 
based on the safety analysis set. Full details will be documented in the statistical analysis plan.
9.4.3
Immunogenicity
9.4.3.1
Immunogenicity Endpoints
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean antibody titre.
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean antibody titre from 
baseline
Both the geometric mean antibody titre and seroresponse of participants will be summarized 
descriptively by strain, treatment arm, and timepoint for the immunogenicity population.
9.4.3.1.1
Estimand framework for immunogenicity descriptions and comparisons
Target populations: 
1) Previously unvaccinated participants 

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a.
Seronegative Analysis Set: and with no evidence of prior or current infection  
2) Participants who previously received SARS-CoV-2 vaccination with either AZD1222 
or a licensed mRNA vaccine according to the authorized dose and dosing regimen at 
least 3 months prior to first study intervention (see Section 5.1.2).
Outcome variable: neutralizing antibody and binding titres to SARS-CoV-2 at 28 days after 
each treatment administration (1 treatment administration for the previously vaccinated 
population and 2 planned treatment administrations for the unvaccinated population). 
Treatment conditions:
Previously unvaccinated population
!
2 doses of AZD1222 given on Day 1 and on Day 29 (4-week interval)
!
2 doses of AZD2816 given on Day 1 and on Day 29 (4-week dosing interval)
!
1 dose of AZD1222 given on Day 1 and 1 dose of AZD2816 on Day 29 (4-week 
dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 85 (12-week dosing interval)
Previously vaccinated population
!
1 dose of AZD1222 given on Day 1. 
!
1 dose of AZD2816 given on Day 1. 
Intercurrent events: the following intercurrent events could impact the antibody levels 
achieved:  
!
missing the second vaccination (for the unvaccinated population)  
!
receiving of immune-modifying drugs or vaccines 
!
subsequent infection with SARS-CoV-2. 
All immunogenicity descriptions and comparisons will use the principal stratum strategy, 
ie, all analyses will exclude participants who experience any of the intercurrent events above
Population-level summary: 
Descriptive Analyses (see Table 19 and Table 20)
!
geometric means of the antibody titres 

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!
seroresponse proportions
Comparative Analyses (see Table 21 and Table 22)
!
ratio of geometric means of the antibody titres.
!
difference in seroresponse proportion 
Planned Descriptive Analyses: 
Table 19 and Table 20 present planned descriptive immunogenicity analyses for the 
unvaccinated and previously vaccinated populations respectively (each one exploring an 
individual treatment arm at a specific timepoint against a particular strain). 
The tables show that without introduction of further variants, there are 24 planned descriptive 
analyses for the unvaccinated population and 16 planned descriptive analyses for the 
previously immunised population (index).  Within each table there is an analysis key which 
describes the population (see Table 18). The descriptive analyses presented in Tables 19 and 
20 will be repeated for the subset of participants who are seropositive at screening.
Table 18
Description of the Analysis Keys for Tables 19 and 20
Population
Analysis Key
Example
Previously 
unvaccinated
Primary series dosing interval: 
    P4 (4-week dosing interval) or
    P12 (12-week dosing interval)
Treatment received: 
    1222 (2 doses of AZD1222) or 
    2816 (2 doses of AZD2816) or
1222/2816 (1 dose of AZD1222  
followed by 1 dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
Analysis Timepoint:
   1 (28 days post-dose 1)
   2 (28 days post-dose 2)
[P4:1222:W:1] = Immunogenicity 
following primary vaccination 
with a 4-week dosing interval of 
2 doses of AZD1222 against 
Wuhan-Hu-1 28 days post-dose 1
Previously vaccinated
Pre-study primary vaccination: 
  P1222 (2 doses of AZD1222) or
    PmRNA (2 doses of an mRNA vaccine)
Treatment received: 
    B1222 (1 booster dose of AZD1222) or 
B2816 (1 booster dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
[P1222:B1222:V] = 
Immunogenicity in participants 
who were previously vaccinated 
with 2 doses of AZD1222 as 
primary vaccination series and 
received a single boost dose of 
AZD1222 against the B.1.351 
variant 

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Table 19
Immunogenicity Descriptive Analysis for Previously Unvaccinated Treatment Groups (with Separate Seronegative 
and Seropositive Analyses)
Objective
Treatment
Dosing 
interval
Strain
Timepoint
Endpoint
Index
Analysis Key
To describe the humoral immune responses induced 
by a 2-dose primary vaccination with AZD1222 with 
a 4-week interval in unvaccinated participants
AZD1222
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
1
[P4:1222:W:1]†
Seroresponse
2
28 days after 2nd dose
GMT
3
[P4:1222:W:2]
Seroresponse
4
B.1.351
28 days after 1st dose
GMT
5
[P4:1222:V:1] †
Seroresponse
6
28 days after 2nd dose
GMT
7
[P4:1222:V:2]
Seroresponse
8
To describe the humoral immune responses induced 
by a 2-dose primary vaccination with AZD2816 with 
a 4-week dosing interval in unvaccinated participants
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
9
[P4:2816:W:1] ‡
Seroresponse
10
28 days after 2nd dose
GMT
11
[P4:2816:W:2]
Seroresponse
12
B.1.351
28 days after 1st dose
GMT
13
[P4:2816:V:1] ‡
Seroresponse
14
28 days after 2nd dose
GMT
15
[P4:2816:V:2]
Seroresponse
16
To describe the humoral immune responses against 
induced by a 2-dose primary heterologous 
vaccination with AZD1222/AZD2816 with a 4-week 
dosing interval in unvaccinated participants
AZD1222/2816
4 weeks
Wuhan-Hu-1
28 days after 2nd dose
GMT
17
[P4:1222/2816:W:2]
Seroresponse
18
B.1.351
28 days after 2nd dose
GMT
19
[P4:1222/2816:V:2]
Seroresponse
20
To describe the humoral immune responses induced 
by a 2-dose primary vaccination with AZD2816 with 
a 12-week interval in unvaccinated participants
AZD2816
12 weeks
Wuhan-Hu-1
28 days after 1st dose
GMT
21
[P12:2816:W:2]
Seroresponse
22
B.1.351
28 days after 2nd dose
GMT
23
[P12:2816:V:2]
Seroresponse
24
† descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD1222 as their first dose (ie, homologous and heterologous series).
‡ descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD2816 as their first dose (4-week interval and 12-week interval treatment arms).
GMT: Geometric mean titre

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Table 20
Immunogenicity Descriptive Analysis for Previously Vaccinated Treatment Groups (with Separate 
Seronegative and Seropositive Analyses)
Objective
Primary 
vaccination
Booster 
Treatment
Strain
Timepoint
Endpoint
Index
Analysis Key
To assess the humoral immune response 
induced by 1 dose of AZD1222 in 
participants previously vaccinated with 
AZD1222
AZD1222
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
1
[P1222:B1222:W]
Seroresponse
2
B.1.351
28 days after 
booster dose
GMT
3
[P1222:B1222:V]
Seroresponse
4
To assess the humoral immune response 
induced by 1 dose of AZD2816 in 
participants previously vaccinated with 
AZD1222
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
5
[P1222:B2816:W]
Seroresponse
6
B.1.351
28 days after 
booster dose
GMT
7
[P1222:B2816:V]
Seroresponse
8
To assess the humoral immune response 
induced by 1 dose of AZD2816 in 
participants previously vaccinated with a 
SARS-CoV-2 mRNA vaccine
mRNA
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
9
[PmRNA:B2816:W]
Seroresponse
10
B.1.351
28 days after 
booster dose
GMT
11
[PmRNA:B2816:V]
Seroresponse
12
To assess the humoral immune response 
induced by 1 dose of AZD1222 in 
participants previously vaccinated with a 
SARS-CoV-2 mRNA vaccine
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
13
[PmRNA:B1222:W]
Seroresponse
14
B.1.351
28 days after 
booster dose
GMT
15
[PmRNA:B1222:V]
Seroresponse
16
GMT: Geometric mean titre

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In addition to descriptive immunogenicity assessments for all treatment arms, geometric mean 
titre ratios and differences in seroresponse will be evaluated for the pairs of groups as detailed 
in Table 21 and Table 22.  For each pair, the two-sided 95% confidence intervals for the ratio 
of the geometric mean titre and difference in seroresponse will be calculated.  The geometric 
mean titre ratio assume a normal distribution for the natural log of the concentration.  All 
confidence intervals will be unadjusted for multiple analyses and are provided solely as a 
guide to clinical and scientific judgment.  It is acknowledged that the chance of falsely 
concluding that one or more differences in immunogenicity outcomes exist will be greater 
than the nominal two-sided 0.05 level used for each individual comparison.
Table 21
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
To evaluate the immune responses 
elicited by a 2-dose primary 
vaccination with AZD2816 with a 
4-week dosing interval relative to the 
response elicited by a 2-dose primary
vaccination with AZD1222 with a 
4-week interval in previously 
unvaccinated participants
[P4:2816: V:2]
[P4: 1222: W:2]
[P4:2816: V: 2] −[P4: 1222: W:2]
[P4:2816: V:1]
[P4: 1222: W:1]
[P4:2816: V: 1] −[P4: 1222: W:1]
[P4: 2816: W:2]
[P4: 1222: W:2]
[P4:2816:W: 2] −[P4:1222: W:2]
[P4: 2816: W:1]
[!4: 1222: W:1]
[P4:2816:W: 1] −[P4:1222: W:1]
[P4:2816: V:2]
[P4:1222: V:2]
[P4:2816: V: 2] −[P4:1222: V: 2]
[!4:2816:V: 1]
[!4:1222:V: 1]
[P4:2816: V: 1] −[P4:1222: V: 1]
To evaluate the immune responses 
elicited by a 2-dose primary 
heterologous vaccination with 
AZD1222/AZD2816 with a 4-week 
dosing interval relative to the 
response elicited by a 2-dose primary 
homologous vaccination with 
AZD1222 with a 4-week interval in 
previously unvaccinated participants
[P4:1222/2816: V: 2]
[P4:1222: W:2]
[P4:1222/2816:V: 2] −[P4:1222: W: 2]
[P4:1222/2816: W:2]
[P4: 1222: W:2]
[P4:1222/2816: W:2] −[P4: 1222: W:2]
[P4:1222/2816: V: 2]
[P4:1222: V:2]
[P4:1222/2816: V: 2] −[P4: 1222: V: 2]
To evaluate the immune responses 
elicited by a 2-dose primary 
vaccination with AZD2816 with a 
12-week dosing interval relative to 
the response elicited by a 2-dose 
primary vaccination with AZD2816 
with a 4-week interval in previously 
unvaccinated participants
[P12:2816: W: 2]
[P4:2816: W:2]
[P12: 2816: W:2] −[P4:2816: W:2]
[P12: 2816: V: 2]
[P4:2816: V:2]
[P12:2816: V: 2] −[P4:2816: V: 2]

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Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 in 
participants previously vaccinated with 
AZD1222 relative to the response 
elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing 
interval in unvaccinated participants
[P1222:B2816: V]
[P4:1222: W: 2]
[P1222:B2816: V] −[P4:1222: W:2]
[P1222:B2816: W]
[P4:1222: W: 2]
[P1222:B2816: W] −[P4:1222: W: 2]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 in 
participants previously vaccinated with a
mRNA vaccine relative to the response 
elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing 
interval in unvaccinated participants
[PmRNA:B2816: V]
[P4:1222: W:2]
[PmRNA:B2816: V] −[P4: 1222: W:2]
[PmRNA:B2816: W]
[P4:1222: W:2]
[PmRNA:B2816:W] −[P4:1222: W:2]
To evaluate the immune responses
elicited by 1 dose of AZD2816 in 
participants previously vaccinated with
an mRNA vaccine relative to the 
response with 1 dose of AZD1222 in 
participants previously vaccinated with 
AZD1222
[PmRNA:B2816: V]
[P1222:B1222: W]
[PmRNA:B2816:V] −[P1222:B1222: W]
[PmRNA:B2816: W]
[P1222: B1222:W]
[PmRNA:B2816: W] −[P1222: B1222:W]
[PmRNA:B2816: V]
[P1222: B1222:V]
[PmRNA:B2816: V] −[P1222: B1222:V]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 relative 
to the response with 1 dose of AZD1222 
in participants previously vaccinated 
with AZD1222
[P1222:B2816: V]
[P1222:B1222: W]
[P1222:B2816: V] −[P1222: B1222:W]
[P1222:B2816: W]
[P1222:B1222: W]
[P1222: B2816:W] −[P1222:B1222: W]
[P1222:B2816: V]
[P1222:B1222: V]
[P1222: B2816: V] −[P1222:B1222: V]
To evaluate the immune responses 
elicited by 1 dose of AZD1222 in 
participants previously vaccinated with 
AZD1222 relative to the response 
elicited by a 2-dose primary vaccination 
with AZD1222 with a 4-week dosing 
interval in unvaccinated participants
[P1222:B1222: V]
[P4:1222: W: 2]
[P1222:B1222: V] −[P4:1222: W:2]
[P1222:B1222: W]
[P4:1222: W: 2]
[P1222:B1222: W] −[P4:1222: W: 2]
To evaluate the immune responses 
elicited by 1 dose of AZD1222 in 
[PmRNA:B1222: V]
[P4:1222: W:2]
[PmRNA:B1222: V] −[P4: 1222: W:2]

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Table 22
Immunogenicity Comparisons for Previously Vaccinated Groups
Objective
[	
	]
[]
∆= [			
	] −
[		]
participants previously vaccinated with 
an mRNA vaccine relative to the 
response elicited by a 2-dose primary 
vaccination with AZD1222 with a 4-
week dosing interval in unvaccinated 
participants
[PmRNA:B1222: W]
[P4:1222: W:2]
[PmRNA:B1222:W] −[P4:1222: W:2]
To evaluate the immune responses 
elicited by 1 dose of AZD2816 versus 
1 dose of AZD1222 in participants 
previously vaccinated with a SARS-
CoV-2 mRNA vaccine 
[PmRNA:B2816:V]
[PmRNA:B1222: W]
[PmRNA:B2816: V]
−[PmRNA:B1222:W]
[PmRNA:B2816: W]
[PmRNA:B1222: W]
[PmRNA:B2816: W]
−[PmRNA:B1222:W]
[PmRNA:B2816: V]
[PmRNA:B1222: V]
[PmRNA:B2816: V] −[PmRNA:B1222: V]
9.4.4
Data Safety Monitoring Board
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, to 
ensure safe and ethical conduct of the study.  During the study, the benefit/risk assessment 
will be continuously monitored by the Board to ensure that the balance remains favourable.  
Further details, composition, and operation of the COVID-19 Vaccine Data Safety Monitoring 
Board will be described in a separate charter. For further details, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Not applicable.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
∀
Applicable ICH/GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigators Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority.  This responsibility may be delegated to 
a contract research organization but the accountability remains with the Sponsor.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH/GCP guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all Food and 
Drug Administration (FDA) Regulations, as applicable and all other applicable local 
regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study.  Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH/GCP guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
!
The study medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples.  The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use.  Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

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!
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law.  The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committee Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A COVID-19 Vaccine Data Safety Monitoring Board comprised of independent experts will 
be convened to provide oversight and to ensure safe and ethical conduct of the study.  The 
COVID 19 Vaccine Data Safety Monitoring Board will have the responsibility of evaluating 
cumulative safety and other clinical study data at regular intervals and making appropriate 
recommendations based on the available data.  During the study, the benefit/risk assessment 
will be continuously monitored by the COVID-19 Vaccine Data Safety Monitoring Board to 
ensure that the balance remains favourable.  Full details of the COVID-19 Vaccine Data 
Safety Monitoring Board composition and operations can be found in the COVID-19 Vaccine 
Data Safety Monitoring Board Charter.
An independent Neurological AESI Expert Committee will be available to review and provide 
on request about the diagnosis and causality assessment of selected neurological AEs of 
special interest occurring in the study.  Details on the composition and operation of this 
committee are described in the Neurological AESI Expert Committee Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available.  The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

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!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
!
Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected, and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH/GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or ICH/GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both SAEs and non-SAEs and can include a deterioration of a 
pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout,
follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs.  
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used.  
In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a non-
SAE.  For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur.  Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as non-serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  Examples of important medical events include such events as listed 
below:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Intensity Rating Scale
A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events with 
an assigned severity grading including Grade 5.  
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 

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intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the investigational product.
!
Time Course.  Exposure to suspect drug.  Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect investigational product?
!
Consistency with known investigational product profile.  Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or drugs of the same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational medicinal product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the investigational product, but rather a human or 
process related failure while the investigational product is in control of the study site staff or 
participant.
Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the investigational product
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Investigational product name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration
!
Investigational product not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Investigational product not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong participant received the medication (excluding IRT errors)
!
Wrong investigational product administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from 
the participants while in storage at the study site until shipment or disposal (where 
appropriate) and records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
The Sponsor or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
The Sponsor ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented.  If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and the Sponsor are informed about the sample disposal.

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The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus.  Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814.  Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
!
Table 23: Clinical Abnormalities, Local Reactions to Injectable Product
!
Table 24: Clinical Abnormalities, Vital Signs
!
Table 25: Clinical Abnormalities, Systemic (General or Illness)
Table 23
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily
activity
ER visit or 
hospitalization
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalization
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded.
b
Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE e-Diary.
ER: emergency room.

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Table 24
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)a
Fever (°C/°F)
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
Emergency room visit 
or hospitalization for 
arrhythmia
Bradycardia 
(beats/minute)
50-54
45-49
< 45
Emergency room visit 
or hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
Emergency room visit 
or hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes.

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Table 25
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic 
(General)
Systemic Gradea
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/
vomiting
No interference with 
activity or 
1-2 episodes/24 hours
Some interference 
with activity or 
> 2 episodes/24 hours
Prevents daily activity, 
required outpatient 
intravenous hydration
Emergency room 
visit or 
hospitalization for 
hypotensive shock
Chills
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
Emergency room 
visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Systemic Illness
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations)
No interference with 
activity
Some interference 
with activity not 
requiring intervention
Prevents daily activity 
and required medical 
intervention
Emergency room 
visit or 
hospitalization

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Appendix E
Adverse Events of Special Interest
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 26
Adverse Events of Special Interest
Category
Medical Concept
Neurologic
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment or 
loss of consciousness.  
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis.
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population.
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (eg, weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, or other 
sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate.
Hematologic
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL.
Immunologic
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention.
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non-neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: a group of autoimmune inflammatory disorders 
characterized by an alteration in cellular homeostasis, which may or may not have an 
autoimmune aetiology.  A list of events is provided in Table 27. 

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis

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Table 27
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune haemolytic anaemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anaemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombotic events with thrombocytopenia and/or bleeding.  It is not intended to 
be a comprehensive guide to the management of all venous thromboembolic events.  
During the course of the study, the investigator will remain vigilant for occurrence of 
thrombotic events with thrombocytopenia and/or bleeding.  Appropriate investigations (eg, 
imaging) to diagnose these events should be made on a case-by-case basis.  The investigator is 
responsible for determining whether a participant meets criteria for thrombotic events with 
thrombocytopenia and/or bleeding at any point during the study.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombotic events with thrombocytopenia 
and/or bleeding.  The Study Physician contacts the investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data.  
Guidance from the International Society of Thrombosis and Haemostasis for management of 
thrombocytopenic thromboembolism occurring after vaccination can be found at 
www.isth.org.  Notably, participants should only be treated with heparin if a test for heparin-
induced thrombocytopenia antibodies is negative.  An alternative explanation for 
thrombocytopenia should be considered (eg, alcohol use, liver cirrhosis, concomitant 
medications, exposure to toxic chemicals, viral infections).
The investigator is responsible for recording data pertaining to thrombotic events with 
thrombocytopenia and/or bleeding and for reporting AEs and SAEs according to the outcome 
of the review and assessment in line with standard safety reporting processes.
F 2
Tests that Should Be Considered if Thrombotic Events With 
Thrombocytopenia and/or Bleeding Are Suspected
The following tests should be considered, but not limited to:
1. Measurement of platelet levels, prothrombin time, activated partial thromboplastin time, 
D-dimer levels, and fibrinogen levels
2. Complete blood count, reticulocyte count, blood film, haptoglobins
3. Anti-platelet factor 4 antibodies

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4. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, human 
leucocyte antigen B27, ADAMTS13 activity, anti-cardiolipin antibodies IgG + IgM, and 
anti-B2GPI antibodies IgG + IgM
5. Complement (eg, C3, C4, complement complex C5b-9, C5a), autoantibodies (eg, 
antinuclear IgG, anti-double stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG)
6. Factor V Leiden, Factor II (prothrombin) variant 
7. Platelet activation markers and functional assays (eg: sCD40L, soluble glycoproteins, 
degranulation markers [PF4, vWF, P-selectin, annexin V]), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 ELISA positive)
8. Inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13
9. Cell adhesion molecules: VCAM, ICAM, E-selectin
10. Adenovirus serology
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Ebstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19
12. COVID-19 testing, including PCR and serology
13. Calculation of an International Society of Thrombosis and Haemostatis score for 
Disseminated Intravascular Coagulation (derived from platelet levels, fibrinogen, and D-
Dimer)

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ChAdOx1 MERS
Chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
AZD1222 when initially developed by the University of Oxford
COVID-19
Coronavirus disease 2019
eCRF
Electronic case report form
e-Diary
Electronic diary
GMT
Geometric mean titre
ICF
Informed consent form
ICH/GCP
International Council for Harmonisation/Good Clinical Practice
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
MAAEs
Medically attended adverse events
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
S
Spike
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome-coronavirus-2

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Appendix H
Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment 1 (Protocol Version 2): 1 June 2021
Version 1 of the protocol was amended prior to the commencement of the study (ie, prior to 
approval of the protocol by an ethics committee) based on feedback from internal and 
regulatory authority reviews.  The most substantial changes were as follows:
!
addition of 2 treatment arms:  1) AZD1222 as a single booster vaccination in participants 
previously vaccinated with an mRNA COVID-19 vaccine and 2) heterologous 
vaccination with AZD1222 plus AZD2816 in previously unvaccinated participants
!
further definition of analysis sets
!
addition of thrombotic events with thrombocytopenia as a discontinuation criteria
In addition, corrections and revisions to text to improve readability were made.

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11
REFERENCES
Dejnirattisai et al 2021
Dejnirattisai W, Zhou D, Supasa P, Liu C, Mentzer AJ, et al. Antibody evasion by the 
Brazilian P.1 strain of SARS-CoV-2. Cell 2021;184:1-16.
EMA 2021
European Medicines Agency. Reflection paper on the regulatory requirements for vaccines 
intended to provide protection against variant strain(s) of SARS-CoV-2 (EMA/117973/2021), 
February 2021. Available at: https://www.ema.europa.eu/en/regulatory-requirements-
vaccines-intended-provide-protection-against-variant-strains-sars-cov-2.
FDA 2007
US Food and Drug Administration. Guidance for Industry. Toxicity grading scale for healthy 
adult and adolescent volunteers enrolled in preventive vaccine clinical trials, Sept 2007.
Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-
preventive-vaccine-clinical.
FDA 2021
US Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent 
COVID-19: Guidance for Industry, February 2021. Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-
authorization-vaccines-prevent-covid-19.
Folegatti et al 2020
Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A et al. Safety and 
immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored 
vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, Phase 1 trial. Lancet 
Infect Dis 2020;20:816-26.
JCVI 2021
Joint Committee on Vaccination and Immunisation. JCVI Statement on Use of the 
AstraZeneca COVID-19 Vaccine: 8 May 2021. Available at:
https://www.gov.uk/government/publications/use-of-the-astrazeneca-covid-19-vaccine-jcvi-
statement-7-may-2021/use-of-the-astrazeneca-covid-19-azd1222-vaccine-updated-jcvi-
statement-7-may-2021
Lu et al 2020
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology 
of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 
2020;395(10224):565-74. 

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Madhi et al 2021
Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AK, Fairlie L, et al. Efficacy of the 
ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Eng J Med 2021.
Ramasamy et al 2020
Ramasamy MN, Voysey M, Aley PK, Bibi S, Clutterbuck EA, et al. Safety and 
immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in 
young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. 
Lancet 2020; 396(10267):1979-93.
Rovira et al 2015
Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP et al. MAGNIMS 
consensus guidelines on the use of MRI multiple sclerosis—clinical implementation in the 
diagnostic process. Nature Rev Neurolog 2015;11(8):471-82.
SPEAC 2020
Safety Platform for Emergency Vaccines. D2.3 Priority list of adverse events of special 
interest: COVID-19. Work Package: WP2 Standards and Tools. v1.1. Available from: 
https://media.tghn.org/articles/COVID-19_AESIs_SPEAC_V1.1_5Mar2020.pdf.
Voysey et al 2021a
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al. Safety and efficacy of 
the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four 
randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397:99-111.
Voysey et al 2021b
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al.  Single-dose 
administration and the influence of the timing of the booster dose on immunogenicity and 
efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised 
trials. Lancet 2021;397:881-91.
Wang et al 2021
Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
B.1.1.7. Nature 2021;593:130-5.Zhou et al 2020
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus 
of probable bat origin. Nature 2020;579:270-3.
Zhou et al 2021
Zhou D, Dejnirattisai W, Supasa P, Liu C, Mentzer AJ, Ginn HM, et al. Evidence of escape of 
SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 2021;189:1-14.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7220c00001-csp-v1
Document Title:
D7220C00001 Clinical Study Protocol GBR1 Amendment
03Jun2021
Document ID:
Doc ID-004588859
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
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Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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Clinical Study Protocol
Study Intervention
AZD2816
Study Code
D7220C00001
Version
Amendment GBR-2
Date
30 July 2021
TITLE PAGE
A Phase II/III Partially Double-Blinded, Randomised, Multinational, 
Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults Ages 
30 and Above to Determine the Safety and Immunogenicity of AZD2816, a Vaccine for 
the Prevention of COVID-19 Caused by Variant Strains of SARS-CoV-2
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
EudraCT: 2021-002530-17
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Number: D7220C00001
Amendment Number: GBR-2
Study Intervention: AZD2816
Study Phase: II/III
Short Title: Phase II/III Study of AZD2816, a Vaccine for the Prevention of COVID-19 in 
Adults
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator:  Andrew J Pollard, FRCPCH PhD FMedSci
           University of Oxford
            Oxford, United Kingdom

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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Amendment GBR-2
30 July 2021
Amendment GBR-1
3 June 2021
Amendment 1
1 June 2021
Version 1
14 May 2021
Amendment GBR-2: 30 July 2021
The principal reason for this amendment was to
1) add an additional interim analysis to evaluate immunogenicity in a subset of 
AZD1222 previously vaccinated subjects boosted with AZD1222 or AZD2816
2) revise Objectives/Endpoints from descriptive to comparative, with ranking of primary, 
key secondary, other secondary, and exploratory objectives
3) add non-inferiority margins to primary analysis and add additional participants to 
maintain power.
This amendment has also been implemented in the global version of the study D7220C00001 
Clinical Study Protocol.

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis 
(Objectives and 
Endpoints)
Revised this section from 
primarily descriptive to 
primarily comparative.  
Comparative immunogenicity 
objectives created and ranked as 
primary, key secondary, other 
secondary.
Objectives of study 
changed from descriptive 
to comparative, testing for 
non-inferiority across 
treatment comparisons
Substantial
1.1 Synopsis 
(Number of 
Participants; Statistical 
Methods)
Overall size increased to 2590 
participants
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.1 Synopsis (Statistical 
Methods)
An additional interim analysis 
added. Second interim analysis 
changed to include only the 
previously vaccinated with 
AZD1222 cohort.
Interim analysis plan was 
reviewed and revised.
Substantial
1.2 Schema
Figures updated with increased 
participant numbers
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.3 Schedule of 
Activities
Table 2: footnote clarification 
added
Table 3: minor corrections
Clarification/Correction
Non-substantial
2.1 Study Rationale 
(and elsewhere in 
protocol)
Clarification on previous 
vaccination criteria
Clarification
Non-substantial
3 Objectives
Section completely rewritten.  
Divided into 2 sections: 
Previously unvaccinated and 
previously vaccinated.  
Immunogenicity objectives 
created for comparisons.  
Objectives ranked as primary, 
key secondary, other secondary, 
or exploratory.
Objectives of study 
changed to show non-
inferiority across 
treatments.  
Substantial
4.1 Overall design
Participant numbers increased
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
4.1 Overall design
Cap on age added
To ensure good 
representation across age 
groups
Substantial
8.3.2
Removal of severity grade 5
Correction
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
8.5.2.3
 
 
Addition of information on 
number of patients sampled for 
Clarification
Non-substantial
9.1 Statistical 
Hypotheses
Addition of statistical 
hypotheses
Include hypothesis being 
tested.
Substantial
9.2 Sample size 
determination
Confidence intervals for 
populations of 350 and 380 
added to Table 14 and Table 15
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
9.2 Sample size 
determination
Power estimates for populations 
of 350 and 380 added to Table 
17 and Table 18
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
9.4.1 General 
considerations
Details on the initial interim, 
second interim, and third interim 
analysis added
Include revised 
information on the 
analysis plan, including 
interim analyses
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Objectives removed from 
descriptive analysis Table 23 
and Table 24
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Section of  Immunogenicity 
Comparisons added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Table 25 and Table 26 on 
immunogenicity comparisons 
revised, aligned with the revised 
objectives/endpoints.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.4 Multiple 
Comparisons
Section added.
Objectives of study
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
In addition, the protocol has been revised with minor corrections and clarifications.
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................. 3
TABLE OF CONTENTS...................................................................................................... 6
1
PROTOCOL SUMMARY................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 22
1.3
Schedule of Activities....................................................................................... 23
2
INTRODUCTION............................................................................................ 29
2.1
Study Rationale ................................................................................................ 29
2.2
Background ...................................................................................................... 29
2.3
Benefit/Risk Assessment................................................................................... 32
2.3.1
Risk Assessment............................................................................................... 32
2.3.2
Benefit Assessment........................................................................................... 33
2.3.3
Benefit: Risk Assessment for Inclusion of Adults from 30 to 39 Years of Age .. 33
2.3.4
Overall Benefit: Risk Conclusion...................................................................... 34
3
OBJECTIVES AND ENDPOINTS................................................................... 35
3.1
Naïve unvaccinated cohort receiving a 2-dose primary vaccination................... 35
3.2
Previously vaccinated cohort receiving a 1-dose booster vaccination ................ 40
4
DESIGN........................................................................................................... 46
4.1
Overall Design.................................................................................................. 46
4.1.1
COVID-19 Assessments ................................................................................... 48
4.1.2
Screening.......................................................................................................... 48
4.1.3
Vaccination Visit .............................................................................................. 48
4.1.4
Follow-up visits................................................................................................ 49
4.2
Scientific Rationale for Study Design ............................................................... 49
4.2.1
Rationale for Study Design and Participant Population ..................................... 49
4.2.2
Rationale for Study Endpoints .......................................................................... 50
4.3
Justification for Dose........................................................................................ 51
4.4
End of Study Definition.................................................................................... 52
5
STUDY POPULATION ................................................................................... 52
5.1
Inclusion Criteria .............................................................................................. 52
5.1.1
All Participants:................................................................................................ 52
5.1.2
Previously COVID-19 Vaccinated Participants................................................. 54
5.2
Exclusion Criteria ............................................................................................. 54
5.3
Lifestyle Considerations ................................................................................... 56
5.4
Screen Failures ................................................................................................. 57
6
STUDY INTERVENTION............................................................................... 57

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6.1
Study Interventions Administered..................................................................... 57
6.1.1
Investigational Products.................................................................................... 57
6.1.2
Dosing Instructions........................................................................................... 58
6.2
Preparation/Handling/Storage/Accountability ................................................... 58
6.2.1
Dose Preparation and Administration................................................................ 59
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 59
6.3.1
Randomization.................................................................................................. 59
6.3.2
Blinding............................................................................................................ 60
6.3.3
Procedures for Unblinding ................................................................................ 61
6.4
Study Intervention Compliance......................................................................... 61
6.5
Concomitant Therapy........................................................................................ 62
6.5.1
Permitted Concomitant Medications ................................................................. 62
6.5.2
Prohibited Concomitant Medications ................................................................ 62
6.6
Dose Modification ............................................................................................ 63
6.7
Intervention After the End of the Study............................................................. 63
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 63
7.1
Discontinuation of Study Intervention............................................................... 63
7.2
Participant Withdrawal from the Study ............................................................. 64
7.3
Lost to Follow-up ............................................................................................. 64
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 65
8.1
Efficacy Assessments........................................................................................ 65
8.2
Safety Assessments........................................................................................... 65
8.2.1
Physical Examinations...................................................................................... 66
8.2.2
Vital Signs........................................................................................................ 66
8.2.3
Clinical Laboratory Assessments ...................................................................... 66
8.3
Adverse Events and Serious Adverse Events..................................................... 67
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 68
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 68
8.3.3
Causality Collection.......................................................................................... 69
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 69
8.3.5
Adverse Events Based on Examinations and Tests............................................ 69
8.3.6
Hy’s Law.......................................................................................................... 70
8.3.7
Solicited Adverse Events .................................................................................. 70
8.3.8
COVID-19 Assessment..................................................................................... 71
8.3.9
Medically-Attended Adverse Events................................................................. 72
8.3.10
Adverse Events of Special Interest.................................................................... 72
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest ................................ 72
8.3.10.2
Potential Neurological Adverse Events of Special Interest ................................ 73
8.3.11
Reporting of Serious Adverse Events................................................................ 75
8.3.12
Pregnancy......................................................................................................... 75
8.3.12.1
Maternal Exposure............................................................................................ 75

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8.3.13
Medication Error............................................................................................... 76
8.4
Overdose .......................................................................................................... 76
8.5
Human Biological Samples............................................................................... 77
8.5.1
Pharmacokinetics.............................................................................................. 77
8.5.2
Immunogenicity Assessments ........................................................................... 77
8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 78
8.5.2.2
8.5.2.3
8.5.2.4
8.5.3
Pharmacodynamics........................................................................................... 79
8.6
Human Biological Sample Biomarkers ............................................................. 79
8.7
Optional Genomics Initiative Sample................................................................ 79
8.8
Medical Resource Utilization and Health Economics ........................................ 79
9
STATISTICAL CONSIDERATIONS............................................................... 79
9.1
Statistical Hypotheses....................................................................................... 79
9.2
Sample Size Determination............................................................................... 80
9.3
Populations for Analyses .................................................................................. 86
9.4
Statistical Analyses........................................................................................... 86
9.4.1
General Considerations..................................................................................... 87
9.4.2
Safety ............................................................................................................... 88
9.4.2.1
Primary Endpoints ............................................................................................ 88
9.4.2.2
Other Safety Endpoints..................................................................................... 89
9.4.3
Immunogenicity................................................................................................ 89
9.4.3.1
Immunogenicity Endpoints ............................................................................... 89
9.4.4
Multiple Comparisons..................................................................................... 101
9.4.5
Data Safety Monitoring Board ........................................................................ 101
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 101
11
REFERENCES............................................................................................... 127
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LIST OF TABLES
Table 1
Schedule of Activities: Screening ............................................................ 23
Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine . 24
Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 4-Week Dosing 
Interval.................................................................................................... 25
Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 12-Week 
Dosing Interval........................................................................................ 27
Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination.............................. 36
Table 6
Study Objectives and Endpoints for Participants Receiving a 1-Dose 
Booster.................................................................................................... 41
Table 7
Highly Effective Methods of Contraception............................................. 54
Table 8
Investigational Products........................................................................... 57
Table 9
Laboratory Safety Variables..................................................................... 66
Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment....... 71
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)...... 80
Table 12
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set) .......................... 80
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes........... 81
Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Serorepsonse Rates and Proposed 
Sample Sizes ........................................................................................... 82
Table 15
Probability of detecting 1 or more safety events (N = 300)....................... 83
Table 16
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio .................................................................... 84
Table 17
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate .............................................................. 85
Table 18
Populations for Analysis .......................................................................... 86
Table 19 
Description of the Analysis Keys for Tables 19 and 20 ............................ 91

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 92
Table 21
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 93
Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups........ 97
Table 23
Immunogenicity Comparisons for Previously Vaccinated Group.............. 99
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable Product113
Table 25
Tables for Clinical Abnormalities: Vital Signs....................................... 114
Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness) ........... 115
Table 27
Adverse Events of Special Interest......................................................... 116
Table 28
List of Potential Immune-mediated Medical Conditions......................... 117
LIST OF FIGURES
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination................................................. 22
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster.................................................. 22
Figure 3
Neurology Testing Algorithm .................................................................. 74

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 102
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 107
Appendix C
Handling of Human Biological Samples ................................................ 111
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ........................... 113
Appendix E
Adverse Events of Special Interest......................................................... 116
Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding ....................................................... 120
Appendix G
Abbreviations ........................................................................................ 122
Appendix H
Protocol Amendment History................................................................. 123

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A phase II/III partially double-blinded, randomised, multinational, active-
controlled study in both previously vaccinated and unvaccinated adults to determine the safety 
and immunogenicity of AZD2816, a vaccine for the prevention of COVID-19 caused by 
variant strains of SARS-CoV-2.
Short Title: Phase II/III study of AZD2816, a vaccine for the prevention of COVID-19 in 
adults.
Rationale: Recently, several variants of the SARS-CoV-2 virus with increased
transmissibility have emerged, including B.1.1.7, first identified in the UK, P.1, first identified 
in Brazil, and B.1.351, first identified in South Africa.  In an ongoing clinical trial of 
AZD1222 in South Africa, interim results failed to show protection against mild to moderate 
disease caused by the B.1.351 variant; protection against severe disease could not be 
determined as no severe cases were identified (Madhi et al 2021). 
Based on available evidence about vaccine effectiveness and molecular epidemiology of 
emerging variants, B.1.351 is estimated to have a potential to escape vaccine-induced 
immunity. B.1.351 carries sequence mutations in common with other variants of concerns; 
immunity to B.1.351 therefore has the potential to provide some cross-immunity against other 
emerging strains. Development of candidate vaccines that include the B.1.351 S-protein 
variant is underway.  AstraZeneca is developing AZD2816, a vaccine against the B.1.351 
SARS-CoV-2 variant using the same ChAdOx1 platform and manufacturing processes used 
for AstraZeneca’s currently available COVD-19 vaccine, AZD1222.
Objectives and Endpoints:
The purpose of this study is to characterize the safety and immunogenicity of AZD2816, 
AstraZeneca’s candidate ChAdOx1 vector vaccine against SARS-CoV-2 variant strain 
B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative participants who previously 
received a 2-dose primary vaccination against SARS-CoV-2 with AZD1222 or an 
mRNA COVID-19 vaccine
!
As a 2-dose primary homologous vaccination to SARS-CoV-2 seronegative 
participants who are previously unvaccinated
!
As the second dose of 2-dose primary heterologous vaccination (with AZD1222 
as first dose) to SARS-CoV-2 seronegative participants who are unvaccinated.

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It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to the previously-vaccinated cohort that will receive a single booster dose of AZD2816 or 
AZD1222.
The following table lists the primary and secondary endpoints:
Objectives
Endpoints
Safety Objectives: Previously unvaccinated participants
- Primary
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of 
a 2-dose primary heterologous vaccination with 1 
dose of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in previously unvaccinated 
seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary heterologous vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in previously unvaccinated 
seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives: Previously unvaccinated participants
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination

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Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 heterologous 
primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary vaccination 
is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination

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Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
Objectives
Endpoints
Safety Objectives: Previously vaccinated participants
- Primary

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To characterize the safety and tolerability of 
1 booster dose of AZD2816 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of 
1 booster dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 booster dose of AZD2816 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 booster dose of AZD1222 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 booster dose 
of AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster dose 
of AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster dose 
of AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster dose 
of AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives: previously vaccinated participants
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-hu-1
Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-hu-1
Wuhan-hu-1

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Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 
vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.4
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 
vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination

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Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants

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Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus  AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
SAEs: serious adverse events; MAAEs: medically attended adverse events; AESIs: adverse events of special 
interest.
a
At least a 4-fold increase in geometric mean titre from baseline

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Overall Design: This is a phase II/III, multinational, randomised, partially double-blind, 
controlled study in two distinct cohorts: previously vaccinated and previously unvaccinated 
participants. 
Disclosure Statement: This is a parallel-group preventive study with 8 treatment arms.
Number of Participants: Approximately 2590 SARS-CoV-2 nucleocapsid seronegative 
participants will be assigned to study intervention to support the primary and secondary 
objectives of this study. In addition, participants that are SARS-Cov-2 nucleocapsid 
seropositive at screening will be enrolled and assigned to study intervention for an exploratory 
analysis, with a cap of 10% of the seronegative population (ie, approximately 259 total 
participants).
Intervention Groups and Duration: Previously vaccinated participants will receive 1 dose 
of AZD1222 or AZD2816 on Day 1.  Previously unvaccinated participants will receive one of 
the following 2-dose vaccinations:
!
1 dose of AZD2816 on Day 1 and on Day 29
!
1 dose of AZD1222 on Day1 and on Day 29
!
1 dose of AZD1222 on Day 1 and 1 dose of AZD2816 on Day 29
!
1 dose of AZD2816 on Day 1 and on Day 85. 
Participants will be followed up for safety for 180 days after last study vaccine administration.
Data Monitoring Committee: A Data Safety Monitoring Board will provide oversight to 
ensure safe and ethical conduct of the study.
Statistical Methods:
Sample sizes of 300-380 seronegative participants per group are deemed appropriate based 
upon available immunogenicity data from previous clinical studies with AZD1222 for the 
primary and secondary objectives of this study.  
The safety analysis set for adverse events consists of all participants who have received at 
least one dose of study intervention.  The immunogenicity analysis set includes all participants 
in the safety analysis set who have no protocol deviations or intercurrent events judged to 
have the potential to interfere with the generation or interpretation of an immune response.
An initial interim analysis will be performed on a subset of previously AZD1222 vaccinated 
participants that have received a booster dose to consider unblinded sample size adjustment. A 
second interim analysis will be performed when all previously AZD1222 vaccinated 
participants have completed their Day 29 visit to support registration of a booster dose. A 
third interim analysis will be performed on a subset of naïve previously unvaccinated 

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participants that have received their second dose to consider blinded sample size adjustment in 
this population. The primary analysis will be performed when there are data from all naïve 
participatns28 days after the second dose of the 4-week dosing intervals to support assessment 
of these 2-dose primary vaccinations.  A secondary analysis will be performed on data from 
28 days after the second dose of the 12-week dosing interval to support assessment of this 2-
dose primary vaccination.  The final analysis will be performed on data from 6 months follow-
up after participant's vaccination.  

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1.2
Schema
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster 
Note:  In addition to the approximately 2590 seronegative participants enrolled to support the primary/secondary objectives, 
seropositive participants will also be enrolled in the study to support exploratory objectives in this population, with a cap of 
10% of the planned seronegative participants (ie, a maximum of 259 seropositive participants, bringing total enrollment to 
2849).

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1.3
Schedule of Activities
Table 1
Schedule of Activities: Screening 
Procedure
Day -14 to Day 1
See Section
Informed consent
X
5.1, Appendix A 3
Demography
X
-
Medical and surgical history
X
-
Prior and concomitant medications
X
6.5
Complete physical examination, including height and weight
X
8.2.1
Vital signs
X
8.2.2
Urine pregnancy test (for women of childbearing potential only) 
X
8.2.3
Clinical safety laboratory assessments
X
8.2.3
Assessment of serious adverse events
X
8.3, Appendix B
Blood sample for SARS-CoV-2 antibody testing (lateral flow test)
X
8.5.2
Verify eligibility criteria
X
5.1, 5.2
Note:  Screening activities can occur at same visit as initial vaccination with investigational product (ie, Visit 1 in 
Table 2, Table 3, and Table 4).

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Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine
Procedure
Treatment and Follow-up Period
Section
Day
1
8
15
29
180
Window (days)
-
±2
±2
±3
±14
Medical and surgical history
X
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
-
-
6.1.1
Immunological assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
-
8.3.7
e-Diary collected
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose) b
X
-
X
X
8.2.3
a
Only SAEs pre-dose
b
Not required to be repeated if performed on screening day prior to Day 1.
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: 
serious adverse event

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
Urine pregnancy test
(women of childbearing potential)
X 
-
-
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
X 
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample for SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample for additional immunogenicity
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
X
-
-
-
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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
X
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X
-
-
-
X
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X
-
-
-
X
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
X
-
-
-
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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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2
INTRODUCTION
AZD2816 is being developed for the prevention of COVID-19.  It is a modified version of the 
current AstraZeneca SARS-CoV-2 vaccine (referred to as AZD1222 in clinical 
documentation) that has been modified to also provide immunity against the newly emerging 
SARS-CoV-2 variant strain B.1.351.  Like AZD1222, AZD2816 is a recombinant replication-
defective chimpanzee adenovirus vector (ChAdOx1) expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tissue plasminogen activator leader sequence at the 
N terminus.  AZD2816 differs from AZD1222 in that the S glycoprotein gene sequence used 
is from the B.1.351 variant strain instead of the original Wuhan-Hu-1 variant.
2.1
Study Rationale
The aim of the study is to assess the safety and immunogenicity of AZD2816 for prevention 
of COVID-19 as both a 2-dose primary vaccination in previously unvaccinated participants 
and a 1-dose booster vaccination in participants previously vaccinated against the original 
Wuhan-Hu-1 strain of SARS-CoV-2 by either AZD1222 or an mRNA-based vaccine.  A safe 
and effective vaccine for COVID-19 prevention, including against the B.1.351 variant, would 
have significant global public health impact. 
The study will also investigate the safety and immunogenicity of 1) a heterologous 2-dose 
vaccination with AZD1222 as first dose and AZD2816 as the second dose and 2) a single dose 
of AZD1222 as a booster vaccination in participants that have been previously vaccinated 
with an mRNA COVID-19 vaccine targeting the original Wuhan-Hu-1 strain.  
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (
Zhou et al 2020).  The disease these patients contracted was subsequently named Coronavirus 
Disease 2019 (COVID-19).  The World Health Organization declared the novel coronavirus a 
pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the novel coronavirus 
SARS-CoV-2, has resulted in significant global morbidity and mortality as well as major 
disruption to healthcare systems.  Measures to change the course of the pandemic have 
included the accelerated development vaccines against the original Wuhan-Hu-1 strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes.  SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus,
and it is the seventh corona virus known to cause human infections and the third known to 

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cause severe disease after SARS-CoV and MERS-CoV. One fourth of the viral genome is 
responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 
and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 spike (S) glycoprotein is a type I trimeric, transmembrane protein that is 
located at the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s 
subunits are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the 
receptor binding domain and subsequent fusion of virus and cell membranes, thereby
mediating the entry of SARS-CoV-2 into the target cells.  The S protein has an essential role 
in virus entry and determines tissue and cell tropism, as well as host range.  The roles of the 
S-protein in receptor binding and membrane fusion have made it a desirable target for vaccine 
and antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947 
(ie, the Wuhan-Hu-1 isolate).
To date, 5 vaccines that rely upon the expression of the SARS CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 
NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b).  Immunogenicity data indicate that a 
single dose of AZD1222 elicits both humoral and cellular immunogenicity responses and that 
antibody responses are boosted after a second dose.  In a pooled analysis of the 4 studies 
conducted in the United Kingdom, Brazil, and South Africa (database lock 07 December 
2020), the vaccine was highly immunogenic; seroresponse of S binding antibody was > 98% 
after a single dose of AZD1222.  Seroresponse of live neutralising antibody was 82.4% after 1 
dose, which rose to 99.4% after a second dose.  Efficacy analyses of the pooled DCO2 data 
demonstrated effective protection of AZD1222 against COVID-19 with a vaccine efficacy of 
66.73% (95.84% CI: 57.41%, 74.01%) (p < 0.001) from 15 days after the second dose in 
seronegative participants receiving 2 doses.  The DCO2 data also demonstrated that the 
standard dose of AZD1222 (5 x 1010 viral particles) provides complete protection against 
COVID-19 hospital admission ≥ 22 days after the first dose in the seronegative analysis set 
(0 versus 14 cases in the control group, 2 of which were severe, including one with a fatal

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outcome).  Vaccine efficacy was similar in participants with pre-existing comorbidities, being 
those at greatest risk of severe outcomes of COVID-19, compared to that in the general 
population.  Recently available primary analysis data from a Phase III study performed in the 
United States and Latin America showed primary endpoint vaccine efficacy of 76% (95% CI: 
67.60%, 82.22%; p-value < 0.001). 
A sharp rise in COVID-19 cases was reported in late 2020, which was attributed to the 
emergence of new SARS-CoV-2 variant strains: B.1.1.7 in the United Kingdom, B.1.351 
in South Africa, and P.1 in Brazil.  These variant strains carry a number mutations in the 
S protein sequence: 9 amino acids in B.1.1.7, 10 amino acids in B.1.351, and 12 amino acids 
in P.1 compared with the Wuhan-Hu-1 sequence.  These mutations may result in an increase 
of transmissibility and/or reduced vaccine effectiveness.  Variant B.1.351 was first identified 
in South Africa in October 2020.  Its attributes include approximately 50% increased 
transmission and moderate impact of neutralization by monoclonal antibody therapeutics, 
convalescent plasma and vaccine sera.  In vitro neutralization assays suggest that the B.1.351 
lineage viruses may be the most antigenically distinct from the original Wuhan-like strains 
(Zhou et al 2021).  In addition, evidence suggests that AZD1222 may afford diminished 
protection against mild-moderate COVID-19 disease arising from the B.1.351 variant which 
is also antigenically the most different from the Wuhan-Hu-1 virus (Madhi et al 2021).  
The development of candidate vaccines that would be effective against the B.1.351 variant 
strain is underway.  AZD2816 is being developed as an updated ChADOx-nCOv19 vaccine 
designed to provide protective immunity against the newly arising B.1.351 variant strain, 
using the same ChAdOx1 platform and manufacturing processes used for AstraZeneca’s 
currently approved COVID-19 vaccine, AZD1222.  The purpose of this Phase II/III, 
multinational, randomised, partially double-blind, active-controlled study is to demonstrate 
the safety and characterize the immunogenicity of AZD2816, AstraZeneca’s candidate 
ChAdOx1 vector vaccine against B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative participants who have previously 
received a 2-dose primary vaccination series against the original SARS-CoV-2 Wuhan-
hu-1 strain (AZD1222 or an mRNA vaccine) 
!
As a 2-dose homologous primary vaccination to SARS-CoV-2 seronegative participants 
who have not been vaccinated previously. 
It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to the previously-vaccinated cohort that will receive a single booster dose.  
The immunogenicity of a 2-dose primary heterologous vaccination (with AZD1222 as first 
dose and AZD2816 as second dose) to SARS-CoV-2 seronegative participants who are 
unvaccinated and a single booster dose of AZD1222 to SARS-CoV-2 seronegative 

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participants who have previously received a 2-dose primary mRNA vaccination series against 
the original SARS-CoV-2 Wuhan-hu-1 strain will also be investigated.
SARS-CoV-2 seropositive participants will be enrolled in separate cohorts to support a 
parallel exploratory analysis in these participants.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD1222 and 
AZD2816 is provided in the respective Investigator’s Brochures.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD2816 and AZD1222 can be found in the respective Investigator’s Brochures.
2.3.1
Risk Assessment
AZD2816 has been developed using the same vaccine vector, ChAdOx1, as AZD1222 and 
only differs in the sequence for SARS-CoV-2 S glycoprotein that is inserted in the vector.  
The anticipated safety profile of AZD2816 is the same as the observed safety profile of 
AZD1222.  Risks associated with AZD2816 are thus the same as the risks associated with 
AZD1222, and no additional risks are anticipated due to the change in the targeted sequence.
A number of essentially mild and moderate adverse reactions to AZD1222 have been 
identified and resemble reactions frequently observed after many vaccines.  Based on pooled 
clinical data from studies with AZD1222, the most commonly expected local solicited AEs for 
participants in this study are vaccination site pain and tenderness.  The most commonly 
expected systemic solicited AEs are fatigue, headache, and malaise.  The majority of reported 
events have been mild or moderate in severity and resolved within 1 to 7 days.  Following the 
second dose, a general attenuation in the incidence and severity of local and systemic solicited 
AEs was observed. 
Post-authorisation hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk.
A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, 
has been observed very rarely following vaccination with COVID-19 Vaccine (ie, AZD1222) 
during post-authorisation use. No events have been observed in the AZD1222 clinical 
development programme.  Thrombosis in combination with thrombocytopenia is thus 
considered to be an important identified risk.  This includes cases presenting as venous 
thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein 
thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia.  Considering 
the frequency of this rare event and the size of this study, the risk for participants in this trial 
is considered to be low.  The protocol includes exclusion criteria and instructions for 

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heightened vigilance and thorough investigations for suspected cases to mitigate against 
further the risk for these rare event. 
Important potential risks are 1) neurologic events and potential immune-mediated neurologic 
conditions and 2) vaccine-associated enhanced disease, including vaccine-associated enhanced 
respiratory disease. 
2.3.2 Benefit Assessment
All participants will receive active treatment: either AZD1222, which has been shown to be 
effective in providing protection against SARS-CoV-2, or AZD2816, which as a modified 
form of AZD1222 designed to be effective against the emergent B.1.351 variant strain and 
may also provide participants with protection.  The information gained from this study will 
inform development decisions with regard to the efficacy of AZD2816 as both a primary 
2-dose vaccination in participants that have not been previously vaccinated and a 1-dose 
booster vaccination in participants previously vaccinated against SARS-CoV-2.
2.3.3 Benefit: Risk Assessment for Inclusion of Adults from 30 to 39 Years of 
Age
There have been reports of very rare adverse events of concurrent thrombosis and 
thrombocytopenia following vaccination with the first dose of AstraZeneca CoV-19 vaccine 
(AZD1222). There have been no safety concerns identified for thrombosis/thrombocytopenia 
associated with the second dose of the AstraZeneca (AZD1222) vaccine.  Up to 19 May 2021, 
the MHRA has received reports of 332 cases of major thromboembolic events with concurrent 
thrombocytopenia in the United Kingdom following vaccination with COVID-19 Vaccine 
AstraZeneca. The estimated number of first doses of COVID-19 Vaccine AstraZeneca 
administered was 24.2 million, and the estimated number of second doses was 10.7 million.
Any risk for serious thromboembolic events with thrombocytopenia is expected to be similar 
for AZD1222 and AZD2816 due to the similarity of the investigational products. 
In the context of this extremely rare adverse event, current advice from the United Kingdom’s 
Joint Committee on Vaccination and Immunization (JCVI) recommends that unvaccinated 
adults aged 30 to 39 years who are not in a clinical priority group at higher risk of severe 
COVID-19 disease should be preferentially offered an alternative to AZD1222 where possible 
and only where no substantial delay or barrier in access to vaccination would arise (JCVI 
2021).  The recommendations are not a contra-indication in this age group but a public 
vaccination policy recommendation in the context of a current low incidence of disease, the 
availability of alternative vaccines, and current speed and uptake of the vaccination 
programme overall in the UK.  The recommendations further advise that AZD1222 can be 

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used in the age group 30-39 if these factors deteriorate, stating that if other vaccines are not 
available “the benefits of receiving the AstraZeneca (AZD1222) vaccine outweigh the risks”.  
The participants of the proposed study differ from the general public in that they are carefully 
selected, with exclusion of individuals with a wide range of risk factors for 
thrombosis/thrombocytopenia, to minimize this risk.  The study also includes careful 
monitoring both pre-treatment and post-treatment to detect risk for thrombotic events with 
thrombocytopenia and promptly identify safety concerns at the individual participant level. 
The protocol and training for the investigators urges increased vigilance for these events of 
thrombosis with thrombocytopenia.  Furthermore, Appendix F provides guidance on 
identifying, treating, and assessing these very rare events.  The risk of these events occurring 
is disclosed in the Participant Information Sheet and Informed Consent Form.  Furthermore, 
participants are advised to be alert for the following side effects in the 28 days after 
vaccination: severe/unusual headache, new or unexplained bruising/bleeding, shortness of 
breath, chest pain, leg swelling, persistent abdominal pain.  The exclusion of individuals with 
a wide range of risk factors for thrombosis with thrombocytopenia and measures included in 
the study to ensure early detection of these events mitigates the risk for these rare events.
With regard to benefit, all patients enrolled in the study will receive active treatment, either 
with the approved AZD1222, which has a good safety profile and high efficacy in adults ages 
18 and over, including protection against severe disease, or the experimental but closely 
related AZD2816, which is expected to have a similar safety profile with the potential to have 
broader efficacy than AZD1222, including against the emergent B.1.351 variant.  
Furthermore, the inclusion of these patients in the trial is important to investigate safety and 
immunogenicity of AZD2816, as both a primary vaccination and a booster vaccination, across 
the age groups for which it may be administered in clinical practice.
To summarise, the risk of serious harm due to vaccine-induced thrombotic thrombocytopenia 
is known to be small.  As of 19 May 2021, the MHRA’s estimate of the overall incidence after 
first or unknown doses is 1.3 per 100,000 doses.  Thus, the risk of one of these events 
occurring in the sub-group of participants 30 to 39 year of age from a study population of 
around 2000 patients is extremely low. This risk is appropriately mitigated in the study 
protocol to the extent that the risk-benefit of patients 30 to 39 years of age participating in this 
study is considered to be small, acceptable, and justified by the potential public health benefits 
of the study.
2.3.4 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria and close monitoring of participants to 
minimize known and potential risks. 

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An independent Data Safety Monitoring Board will provide study oversight, evaluating 
cumulative safety and other clinical data at regular intervals. 
Taking these measures into account, the potential risks identified in association with the 
administration of AZD2816 and AZD1222 are justified by the anticipated benefit that may 
be afforded to participants for the prevention of COVID-19.
3
OBJECTIVES AND ENDPOINTS
3.1
Naïve unvaccinated cohort receiving a 2-dose primary vaccination
The primary safety objective for the cohort of previously unvaccinated participants receiving a 
2-dose dose primary vaccination is to characterize the safety and tolerability of a 2-dose 
primary vaccination with AZD2816 with a 4-week dosing interval in previously unvaccinated 
seronegative participants.
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary: 
1: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response against the original 
Wuhan-hu-1 strain elicited by a 2-dose AZD1222 vaccination.
Key secondary:
2.1: To determine if seroresponse against the B.1.351 variant elicited by a 2-dose AZD2816 
vaccination is non-inferior to seroresponse against the original Wuhan-hu-1 strain elicited by a 
2-dose AZD1222 vaccination.
2.2: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 2-dose 
AZD1222 vaccination.
2.3: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose heterologous AZD1222 + AZD2816 vaccination is non-inferior to the 
response against the original Wuhan-hu-1 strain elicited by a 2-dose AZD1222 vaccination
2.4: To determine if the neutralizing antibody GMT response against the original Wuhan-hu-1 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 2-dose 
AZD1222 vaccination

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The above primary and the key secondary immunogenicity objectives will be supported by 
other secondary immunogenicity objectives (see below) for which there will be no formal 
hypothesis testing.
Table 5 further describes the objectives and endpoints for this cohort of participants, including 
estimands for the immunogenicity objectives.
Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination
Safety Objectives
Objectives
Endpoints
- Primary
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 4-
week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of a 
heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 4-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety and tolerability of a 
heterologous primary vaccination with 1 dose
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 12-week dosing 
interval in unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
Immunogenicity Objectives
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:

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Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 
heterologous primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination

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To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a 2-dose homologous or 
! GMT of ChAdOx1 neutralizing antibody titres

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heterologous primary vaccination with AZD2816 
and/or AZD1222 in sub-groups of seronegative and 
seropositive participants
! Seroresponse rate of ChAdOx1 neutralizing 
antibody titres
Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody 
titres, 1 month after both Dose 1 and Dose 2
Exploratory Objectives
Objective
Endpoints
To explore the immune response elicited by a 2-dose 
AZD2816 primary vaccination with a 12-week dosing 
interval compared to the response elicited by a 2-dose 
AZD2814 primary vaccination with a 4-week dosing 
interval
! GMT ratio of pseudoneutralizing antibodies
! Seroresponse
To explore antibody response to selected SARS-CoV-2 
variants of interest/variants of concern following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! GMT of SARS-CoV-2 anti-S binding antibodies 
for selected variants of concern/variants of interest
! Seroresponse rate of SARS-CoV-2 specific   
binding antibody titres for selected variants of 
concern/variants of interest
! GMT of SARS-CoV-2 pseudoneutralizing 
antibody responses against the B.1.617.2 (delta) 
variant
! Seroresponse rate of SARS-CoV-2 
pseudoneutralizing antibody responses against the 
B.1.617.2 (delta) variant
To explore B-cell and T-cell responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! Intracellular cytokine staining and flow cytometry 
for T-cell responses over time
! Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 B.1.351 or Wuhan-Hu-1 S protein 
from day of dosing baseline over time
! Breadth and depth of peripheral blood B-cell and 
T-cell repertoire over time through 
immunosequencing
To monitor the incidence of SARS-CoV-2 infection 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or AZD1222 
in previously unvaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined 
by the seroresponse to nucleocapsid antibodies 
occurring post-second dose of study intervention 
To monitor the incidence of COVID-19 following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in previously 
unvaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses against the 
B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Magnitude of SARS-CoV-2 neutralization titres 
(geometric mean titre) as determined by a live 
virus neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific 
antibody binding and neutralization titres as 
determined by a live virus neutralization assay

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To explore additional immune responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in sub-groups of 
seronegative and seropositive participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity 
data
To explore the immunogenicity objectives in 
seropositive participants
! GMT of pseudoneutralizing antibodies
! Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.
3.2
Previously vaccinated cohort receiving a 1-dose booster 
vaccination
The primary safety objective for the cohort of seronegative previously vaccinated participants 
receiving a booster dose is to characterize the safety and tolerability of 1 booster dose of 
AZD2816 in participants previously vaccinated with AZD1222. 
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary:
1: To determine if the humoral immune response against the B.1.351 variant elicited by an 
AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior to 
the response against the original Wuhan-hu-1 strain elicited by 2-dose AZD1222 vaccination 
administered to vaccination naïve participants.
Key secondary:
2.1: To determine if the humoral immune response against the B.1.351 variant elicited by an 
AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior to 
the response elicited by 2-dose AZD1222 vaccination administered to vaccination naïve 
participants.
2.2:  To determine if the humoral immune response elicited against the B.1.351 variant by an 
AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 booster dose  
in participants previously vaccinated with AZD1222.
2.3: To determine if the humoral immune response against the original Wuhan-hu-1 strain 
elicited by an AZD2816 booster dose in participants previously vaccinated with AZD1222 is 
non-inferior to the response elicited by 2-dose AZD1222 vaccination administered to 
vaccination naïve participants.

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2.4: To determine if the humoral immune response against the original Wuhan-hu-1 strain 
elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222 is 
non-inferior to the response elicited by a 2-dose AZD1222 vaccination
2.5: To determine if the humoral immune response against the original Wuhan-hu-1 strain 
elicited by an AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 
booster dose in participants previously vaccinated with AZD1222.
The primary and key secondary immunogenicity objectives will be supported by other 
secondary objectives for which there will be no formal hypothesis testing.
Table 6 further describes the objectives and endpoints for this cohort of participants, including 
estimands for the primary and secondary immunogenicity objectives.
Table 6
Study Objectives and Endpoints for Previously Vaccinated Participants 
Receiving a 1-Dose Booster
Safety Objectives
Endpoints
- Primary
To characterize the safety and tolerability of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days 
post dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory measures 
for 28 days post-dose
- Secondary
To characterize the safety and tolerability of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the extended safety of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination

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To characterize the extended safety of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-hu-1
Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 
vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary (2.4)
Wuhan-hu-1
Wuhan-hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 
vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated with 
AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd  vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-hu-1
Wuhan-hu-1

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Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated with 
AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1

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Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated with 
an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-hu-1
Wuhan-hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus  AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-hu-1

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To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a booster dose of 
AZD2816 in sub-groups of seronegative and 
seropositive participants
! Magnitude of ChAdOx1 nAb titres (geometric mean 
titre)
! Seroresponse rate of ChAdOx1 neutralizing antibody 
titres
Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody titres, 1 
month after both Dose 1 and Dose 2
Exploratory Objectives
Endpoints
To explore antibody response to selected SARS-
CoV-2 variants of interest/variants of concern 
following a booster dose of AZD2816 and in a 
sub-group of seronegative participants
! Magnitude of SARS-CoV-2 specific antibody binding 
titres (geometric mean titre) for selected variants of 
concern/variants of interest
! Seroresponse rate of SARS-CoV-2 specific   antibody 
binding titres for selected variants of concern/variants of 
interest
! GMT of SARS-CoV-2 pseudoneutralizing antibody 
responses against the B.1.617.2 (delta) variant
! Seroresponse rate of SARS-CoV-2 pseudoneutralizing
antibody responses against the B.1.617.2 (delta) variant
To explore B-cell and T-cell responses following 
a booster dose of AZD2816 in a sub-group of 
seronegative participants
! Intracellular cytokine staining and flow cytometry for T-
cell responses over time

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! Quantification of (IFN-γ) ELISpot responses to SARS-
CoV-2 B.1.351 or Wuhan-Hu-1 S protein from day of 
dosing baseline over time
! Breadth and depth of peripheral blood B-cell and T-cell 
repertoire over time through immunosequencing
To monitor the incidence of SARS-CoV-2 
infection following a booster dose of AZD2816 in 
previously vaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by the 
presence of nucleocapsid antibodies occurring post-dose 
of study intervention 
To monitor the incidence of COVID-19 following 
a booster dose of AZD2816 in previously 
vaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the immunogenicity objectives in 
seropositive participants
! GMT of pseudoneutralizing antibodies
! Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest.
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.
4
DESIGN
4.1
Overall Design
This is a multi-country Phase II/III study to evaluate the safety and immunogenicity of 
AZD2816 as single-dose vaccination in previously vaccinated adult participants and as a 
2-dose primary vaccination in previously unvaccinated adult participants. 
A total of approximately 2590 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled across these 2 
populations with the goal of 1300 previously vaccinated participants receiving single-dose 
vaccination and 1050 unvaccinated participants receiving 2-dose primary vaccination. In 
addition, seropositive participants will be enrolled (with a cap of 10% of the seronegative 
population or 259 participants) to support exploratory analysis is these participants. 
The enrollment and randomization strategy is intended to minimize group differences in terms 
of age, gender and the presence of comorbidities; to support this strategy, the study 
randomisation will include caps to ensure that at least 25% of enrolled participants within 
each treatment arm will be ≥ 65 years of age.
In both the single-dose booster treatment regimen and the 2-dose primary vaccination 
treatment regimen, participants will receive study intervention consisting of intramuscular 
administration of either AZD1222 (5 ×1010 viral particles) or AZD2816 (5 ×1010 viral 
particles).

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Approximately 700 seronegative participants previously vaccinated with AZD1222 will be 
randomised 1:1 to receive a single intramuscular dose of either AZD1222 or AZD2816 in a 
double-blinded fashion.  
Approximately 600 seronegative participants previously vaccinated with an approved mRNA 
based vaccination against the original Wuhan-hu-1 strain will be randomised 1:1 to receive a 
single intramuscular dose of AZD2816 or AZD1222 in a double-blinded fashion.
It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to 1 of the 2 above previously-vaccinated groups.  
Approximately 1290 seronegative, previously unvaccinated participants will be randomised 
approximately 5:5:5:2 to receive a 2-dose primary vaccination of the following:
!
2 doses of AZD1222 with a 4-week dosing interval
!
2 doses of AZD2816 with a 4-week dosing interval
!
1 dose of AZD1222 followed by 1 dose of AZD2816 with a 4-week dosing interval
!
2 doses of AZD2816 with a 12-week dosing interval.
The 3 treatments with a 4-week dosing interval will be double-blinded while the treatment 
with the 12-week interval will be open-label due to the difference in dosing interval.  In 
addition, a smaller population seropositive participants (approximately 10% of the 
seronegative population), will be randomised to treatment in a similar manner as above.
Immunogenicity (ie, anti-Wuhan-Hu-1 and anti-B.1.351 immune responses including 
S-binding antibody titres and neutralizing antibody levels [pseudo-neutralization]) will be 
assessed in serum samples collected pre-dose on the day of each vaccination (baseline levels 
before vaccination), 14 and 28 days after each vaccination, and 180 days after the last 
vaccination.
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1-8 for all participants and Days 29-36 for the 4-week dosing interval and Days 85-92 
for the 12-week dosing interval).  An e-diary will be used to collect information on the timing 
and severity of the solicited signs and symptoms.
Follow-up visits will take place as per the schedule of assessment within respective windows.  
All participants will be assessed for local and systemic AE, physical examination, review of 
e-diaries at these time points as detailed in the schedule of assessment.  Blood will also be 
taken for safety assessments and immunology purposes.

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All study participants will be followed for safety for 180 days after administration of their last 
vaccination dose.  In every participant, solicited local and systemic events will be reported for 
up to 7 days after each dose, all unsolicited AEs will be reported for up to 28 days after each 
dose, and SAEs and AEs of special interest will be evaluated through study completion 
(up to 180 days after the last study vaccination).  
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, 
to ensure safe and ethical conduct of the study.
4.1.1
COVID-19 Assessments
Occurrence of COVID-19 in the trial will be reported as safety events, including monitoring 
of the potential risk of vaccine-induced enhanced disease as an AE of special interest (see 
Appendix E).  COVID-19 will be diagnosed and treated as per standard medical practice.  
In addition, experimental treatments are permitted.  Detailed information will be collected in 
a standard way and reported on a specific case report form. 
4.1.2
Screening 
All potential participants will be screened, which may take place at a visit up to 14 days prior 
to Day 1 or on Day 1 itself.  
Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the screening procedures specified in the Schedule of Activities (Section 1.3) will be 
undertaken including a medical history, physical examination, height and weight, a 
SARS-CoV-2 screening test and clinical safety laboratory assessments.  Baseline information 
collected in the previously vaccinated participants will include which vaccine was received, 
immunization dose interval, and time since last vaccination.
For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled.  (Note: Women with urine test results that are positive or undetermined will not be 
enrolled and should be advised to seek medical attendance outside the context of the trial if 
pregnancy is suspected.) 
The eligibility of the participants will be reviewed at the end of the screening visit and again 
when all results from the screening visit have been considered.  Decisions to exclude the 
participant from enrollment or to withdraw a participant from the study will be at the 
discretion of the Investigator.

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4.1.3
Vaccination Visit
Participants will be considered enrolled at the point of vaccination.  Before vaccination, the 
eligibility of the participant will be reviewed.  Body temperature will be observed and a 
medical history and physical examination will be undertaken before the first vaccination to 
determine need to postpone vaccination or screen fail the participant.  A negative pregnancy
test (urine test) will need to be obtained from women of childbearing potential before 
vaccination.  Baseline blood samples will be obtained before the first vaccination.
Participants will receive 1 dose of AZD2816 or AZD1222 at vaccination visits, administered 
by intramuscular injection.  Previously immunized participants will have a single vaccination 
visit, Day 1.  Participants that have not been previously vaccinated at baseline will have a 
second vaccination visit on Day 29 (4-week interval) or Day 85 (12-week interval).  
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1 to 8 and Days 29 to 36 or Days 85 to 92 when applicable).
4.1.4
Follow-up visits
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3).  All 
participants will be assessed for local and systemic AE, physical examination, review of the 
e-diary and blood tests at these time points as detailed in the Schedule of Activities.  Blood 
will also be taken for safety and immunogenicity assessments.
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate way until the last 
study visit in order to collect information on any SAEs/AE of special interest.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population includes adults ≥30 years of age.  Persons who are healthy or have 
medically stable underlying conditions will be eligible.  Adults with medically-stable chronic 
diseases may participate if, according to the judgement of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Some seropositive participants 
(capped at 10% of the seronegative participant population) will be enrolled to support an 
exploratory analysis.  

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Those enrolled in the single-dose vaccination part of the study must have received 2 doses of 
AZD1222 (with a dosing interval of 4-12 weeks) or 2 doses of an approved mRNA-based
COVID-19 vaccine (with a dosing interval of 3-12 weeks for the BNT162b2 mRNA vaccine 
[Pfizer-BioNTech] and 4-12 weeks for the mRNA-1273 vaccine [Moderna]) with the second 
doses administered at least 3 months prior to first study intervention administration. 
Pregnant/breastfeeding women, persons with severe immunodeficiency or severe underlying 
disease will be excluded from participation in the study.  Persons previously vaccinated with 
AZD1222 in the context of an AZD1222 vaccine trial are eligible for enrollment as previously 
vaccinated participants in the trial.  Persons who have previously received any other 
investigational product for the prevention of COVID-19 will be excluded from participation in 
this study.
Participants with known risk factors for thrombosis and thrombocytopenia (excluding 
contraceptive hormonal therapy or replacement hormonal therapy) are excluded.
4.2.2
Rationale for Study Endpoints
There is no statistical hypothesis testing planned for this study.  Descriptive statistics will 
support evaluation of safety, reactogenicity, and immunogenicity.
An interim analysis will occur when all previously vaccinated participants have completed 
their Day 29 visit. A second interim analysis may be conducted when previously unvaccinated 
participants have completed their Day 29 visit.
The primary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants randomised to a 4-week dosing interval have 
completed their Day 57 visit (ie, 28 days after their second dose).
A secondary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants (including those randomised to either a 4-week or a 
12-week dosing interval) have completed their Day 57/Day 113 visit (ie, 28 days after their
second dose). 
The final analysis will occur when data from all vaccinated participants are available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants/180 days after the second dose for unvaccinated participants).
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination 
will be summarized by day and overall.

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!
Incidence of unsolicited AEs for 28 days following each vaccination will be 
summarized by system organ class and preferred term, and by relationship to 
vaccination as assessed by the investigator.
!
SAEs and AEs of special interest following the first vaccination and throughout the 
study duration will be summarized by system organ class and preferred term and by 
relationship to vaccination as assessed by the investigator.
Solicited AEs will be collected for 7 days after each dose of study intervention, a period that 
has proven adequate to describe reactogenicity events in previous vaccine studies.  For all 
participants, AEs will be collected through 28 days after each dose of study intervention.  
SAEs, medically-attended AEs, and AEs of special interest and will be collected from Day 1 
through end of the study.  AEs of special interest include terms identified by the Brighton 
Collaboration involving events associated with vaccination in general .
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean titre
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean titre from baseline
Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of 
interest.
Immunogenicity against SARS-CoV-2 Wuhan-Hu-1 and B.1.351 strains will be characterized 
through the quantification of Spike-binding antibodies, pseudo-neutralization and, in a subset 
of participants, live neutralization.  Exploratory analysis of immunogenicity against other 
strains and induction of other immune effectors including cell-mediated immunity will be 
conducted. 
4.3
Justification for Dose
The AZD2816 nominal dose of 5 × 1010 viral particles is the same dose as the approved dose 
for AZD1222, which was based on the accumulated non-clinical data and clinical data from 
the AZD1222 clinical studies, as well as from other SARS-CoV-2 vaccines in development. 
Safety and immunogenicity data from an additional clinical study, MERS001(NCT03399578), 
using the same ChAdOx1 vector, also helped inform dose selection. MERS001 was the first 
clinical study of a ChAdOx1-vectored vaccine expressing the full-length S protein from a 
separate, but related, beta-coronavirus.  ChAdOx1 MERS has been given to 31 participants to 
date at doses ranging from 5 × 109 viral particles to 5 × 1010 viral particles.  Despite higher 
reactogenicity observed at the 5 × 1010 viral particles, this dose was safe, with self-limiting 
AEs and no serious adverse reactions recorded.  The 5 × 1010 viral particles was the most 
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virus assay (Folegatti et al 2020).  Given the immunogenicity findings and safety profile 
observed with the ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 viral particles 
dose was chosen for AZD1222.  
Based on accumulating nonclinical and clinical data gathered for AZD1222, a 2-dose regimen 
was selected for vaccination of unvaccinated participants with AZD2816 (AZD1222 
Investigators Brochure).  A single dose vaccination has been selected for participants 
previously vaccinated in line with both FDA and EMA guidance (FDA 2021, EMA 2021).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities (Section
1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as a protocol waiver or exemption, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1
All Participants: 
Age
1
Adult, ≥ 30 years of age at the time of consent
COVID-19
For inclusion in the SARS-CoV-2 seronegative population supporting the primary and 
secondary objectives: 
2
No history of laboratory-confirmed SARS-CoV-2 infection (ie, no positive nucleic acid 
amplification test and no positive antibody test).
3
Seronegative for SARS-CoV-2 at screening (lateral flow test to detect reactivity to the 
nucleoprotein).
Note, patients failing to meet criteria 2 and/or 3 may be included in the separate seropositive 
population supporting the seropositive exploratory objectives. 

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Type of Participant 
4
Medically stable such that, according to the judgment of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up
∀
- A stable medical condition is defined as disease not requiring significant change in 
therapy or hospitalization for worsening disease during the 3 months prior to enrollment
5
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator
6
Signed informed consent obtained before conducting any study-related procedures
Reproduction
7
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants:
(a) Women of childbearing potential must:
!
Have a negative pregnancy test on the day of screening and on days of 
vaccination
!
Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
30 days following administration of the last dose of study intervention.  A highly 
effective method of contraception is defined as one that can achieve a failure rate 
of less than 1% per year when used consistently and correctly (see Table 7).  
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy) or 
!
Post-menopausal:
!
For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥ 12 months amenorrhea prior to randomization, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and
o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal 
range, the participant is to be considered of childbearing potential
!
For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomization, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.

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Table 7
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing systema
Bilateral tubal occlusion
Vasectomized partner b
Sexual abstinence c
Combined (oestrogen- and progestogen-containing 
hormonal contraception
      Oral (combined pill)
      Intravaginal
     Transdermal (patch)
Progestogen-only hormonal contraception
#
     Oral 
#
     Injectable
#
     Implantable
a
This is also considered a hormonal method 
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse from 28 days prior to Day 1 through 30 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant
5.1.2
Previously COVID-19 Vaccinated Participants
8
Prior completion of a 2-dose primary homologous vaccination regimen against the 
original SARS-CoV-2 Wuhan-hu-1 strain with either AZD1222 (2 standard doses as 
authorized vaccine or as investigational product in a clinical trial with a 4- to 12-week 
dosing interval) or with an mRNA vaccine approved for emergency or conditional use 
(eg, BNT162b2 vaccine [Pfizer-BioNTech] with a 3- to 12-week dosing interval or 
mRNA-1273 vaccine [Moderna] with a 4- to 12-week dosing interval).  The second dose 
in all cases should have been administered at least 3 months prior to first administration 
of study intervention.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of allergy to any component of AZD1222/AZD2816.
2
History of Guillain-Barré syndrome, any demyelinating disease, or any other 
neuroimmunologic condition
3
Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) on the 
day prior to or day of randomization 
4
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia or HIV/AIDS.

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5
Recurrent severe infections and use of immunosuppressant medication within the past 
6 months (≥ 20 mg per day of prednisone or its equivalent, given daily or on alternate 
days for ≥ 15 days within 30 days prior to administration of study intervention)
The following exceptions are permitted:  
∀
Topical/inhaled steroids or short-term oral steroids (course lasting ≤14 days)
6
History of primary malignancy except for:
(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or for metastasis (for example, indolent 
prostate cancer) in the opinion of the site investigator.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
(c) Adequately treated uterine cervical carcinoma in situ without evidence of disease
(d) Localized prostate cancer
7
History of thrombocytopenia and/or thrombosis, including participants who have 
experienced major venous and/or arterial thrombosis in combination with 
thrombocytopenia following vaccination with any COVID-19 vaccine
8
History of heparin-induced thrombocytopenia, congenital thrombophilia (ie, factor V 
Leiden, prothrombin G20210A, antithrombin III deficiency, protein C deficiency and 
protein S deficiency, factor XIII mutation, familial dysfibrinogenemia), auto-immune 
thrombophilia (antiphospholipid syndrome, anti-cardiolipin antibodies, anti-β2-
glycoprotein 1 antibodies), or paroxysmal nocturnal haemoglobinuria.
9
Clinically significant bleeding (eg, factor deficiency, coagulopathy, or platelet disorder), 
or prior history of significant bleeding or bruising following intramuscular injections or 
venepuncture
10 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, or neurological illness, as judged 
by the Investigator (note, mild/moderate well-controlled comorbidities are allowed)
11 Any other significant disease, disorder, or finding that may significantly increase the risk 
to the participant because of participation in the study, affect the ability of the participant 
to participate in the study, or impair interpretation of the study data
12 Any autoimmune conditions, except mild psoriasis and vitiligo
Note: The AEs of special interest as outlined in Appendix E (including Table 28) should be 
considered when evaluating a participant for exclusion criteria as the presence of these AEs of 
special interest, especially if untreated or uncontrolled, may be a safety risk to the participant, 
affect the ability of the participant to participate in the study, and/or impair interpretation of 
the study data.  Investigators should review and consider the list of conditions in Appendix E.  
If any of these conditions are present in a participant, the Investigator is asked to utilize 
his/her clinical judgment in determining the participant’s eligibility for the study.  Should the 

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participant have conditions as outlined in Appendix E and the participant is enrolled, the 
Investigator is asked to document notes on site regarding the final rationale for enrollment.
Prior/Concomitant Therapy
13 Receipt of or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 with the exception of prior vaccination with 
AZD1222 or an mRNA COVID-10 vaccine (2 doses of the same vaccine within an 
approved dosing interval, see Section 5.1.2), which is allowed for participants in the 
previously vaccinated cohort 
Note: For participants who develop COVID-19, receipt of licensed treatment options 
and/or participation in investigational treatment studies is permitted
14 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to or after administration of study intervention
15 Receipt of any influenza vaccine (licensed or investigational) within 7 days prior to and 
after administration of AZD1222/AZD2816.
16 Receipt of immunoglobulins and/or any blood products within 3 months prior to 
administration of study intervention or expected receipt during the period of study 
follow-up
Other Exclusions
17 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)
18 Women who are currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, having given birth less than 3 months before or planning pregnancy during 
the study. 
19 Has donated ≥ 450 mL of blood products within 30 days prior to randomization or 
expects to donate blood within 90 days of administration of second dose of study 
intervention
20 Participants with a history of chronic alcohol or drug abuse or any condition associated 
with poor compliance.
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements or 
if vaccination would interfere with the participant’s ongoing treatment.
22 Previous enrollment in the present study.
5.3
Lifestyle Considerations
1
Participants must follow the contraception requirements outlined in Section 5.1
2
Restrictions relating to concomitant medications are described in Section 6.5

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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Only a single rescreening is allowed in the study.  Rescreened participants are 
required to sign a new ICF (Appendix A 3), and will be assigned a new participant number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical device utilized by a study participant according to 
the study protocol.  Study intervention is defined as AZD2816 or AZD1222 (Table 8).
6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 8
Investigational Products
Intervention 
Name
AZD2816
AZD1222
Type 
Vaccine
Vaccine
Dose Formulation
Unit Dose Strength
1 × 1011 viral particles/mL
1 × 1011 viral particles/mL
≥5 × 108 infectious units/mL
≥5 × 108 infectious units/mL
Dosage Level
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
≥ 2.5 × 108 infectious units
≥ 2.5 × 108 infectious units
Route
Intramuscular
Intramuscular
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
CCI
CCI

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Packaging and 
Labelling
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Current/Former 
Name
-
Previous clinical documentation:
ChAdOx1 nCoV-19
Current tradename: Vaxzevria
IMP: investigational medicinal product; NIMP: non-investigational medical product; w/v: weight/volume.
AZD2816
AZD2816 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD2816 has 
a label-claim volume of 5 mL and can provide up to ten 0.5 mL doses.
AZD1222
AZD1222 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD1222 has 
a label-claim volume of 4 mL and can provide up to eight 0.5 mL doses.
Unopened vials of AZD2816 and AZD1222 must be stored at 2-8 oC (36-46 oF) for the 
duration of the assigned shelf-life and must not be frozen.  Both investigational products must 
be kept in original packaging until use to prevent prolonged light exposure. 
6.1.2
Dosing Instructions
Previously unvaccinated participants will receive 2 doses of either AZD1222, AZD2816, or 
AZD1222 plus AZD2816, with the first dose administered on Day 1 and the second dose on 
Day 29 (for a 4-week dosing interval) (Table 3) or Day 85 (for a 12-week dosing interval) 
(Table 4). 
Previously vaccinated participants will receive 1 dose of either AZD1222 or AZD2816
(Table 2).  
It is recommended that the study interventions be administered as an intramuscular injection 
into the deltoid of the non-dominant arm. Other injection sites may be used if necessary.
All study participants will be observed in the clinic for at least 15 minutes after vaccination. 
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.
6.2
Preparation/Handling/Storage/Accountability
The procedures for preparation, handling, storage, and accountability are identical for 
AZD2816 and AZD1222.

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1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual or specified handling instructions.
6.2.1
Dose Preparation and Administration
Doses of AZD2816 and AZD1222 must be prepared by the unblinded pharmacist (or designee 
in accordance with local and institutional regulations) using aseptic technique. Each dose is 
prepared by withdrawing 0.5 mL from a vial of AZD2816 or AZD1222 in a sterile syringe.
AZD2816 and AZD1222 do not contain preservatives. Each vial must be assigned a beyond-
use-date of 6 hours at 2-30 °C (36-86 °F) from first needle puncture of the vial, after which 
any unused portion must be discarded.
Once an AZD2816 or AZD1222 dose is drawn into a syringe for administration, the dose must 
be administered within the beyond-use-date of the vial. If dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
The study contains 3 cohorts that are randomised to a total of 8 treatments: 
!
Participants that have previously been vaccinated with 2 doses of AZD1222 will be 
randomised 1:1 to 1 dose of AZD2816 or 1 dose of AZD1222.
!
Participants that have been previously vaccinated with an mRNA COVID-19 vaccine will 
be randomised 1:1 to 1 dose of AZD2816 or AZD1222.  
!
Vaccination naïve participants that will be randomised 2:2:2:1 to 2 doses of AZD2816 
with a 4-week dosing interval, 2 doses of AZD1222 with a 4-week dosing interval, 1 dose 
of AZD1222 followed by 1 dose of AZD216 with a 4-week dosing interval, or 2 doses of 
AZD2816 with a 12-week dosing interval.

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Separate populations of SARS-CoV-2 seronegative participants (supporting the primary and 
secondary objectives) and SARS-CoV-2 seropositive participants (supporting exploratory 
objectives) will be randomised/included in the above cohorts.
Randomization will be stratified based on age (less than 65, 65 and above), gender, and 
presence of at least one of the following comorbidities that are known risk factors for severe 
illness from COVID-19 (based on the participant’s past and current medical history):
!
Obesity (BMI ≥ 30 kg/m2 at baseline)
!
Significant cardiovascular disease (eg, heart failure, coronary artery disease, congenital 
heart disease, cardiomyopathies, or pulmonary hypertension)
!
Chronic lung disease (eg, chronic obstructive pulmonary disease, idiopathic pulmonary 
disease, cystic fibrosis, or moderate to severe asthma)
!
Diabetes .  
The randomised participants will be centrally assigned to randomised study intervention using 
an Interactive Response Technology (IRT)/Randomisation and Trial Supply Management.  
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 
the log in information & directions for the Randomisation and Trial Supply Management will 
be provided to each site.
Where a participant does not meet all the eligibility criteria but incorrectly received study 
intervention, the investigator should inform the Study Physician immediately, and a discussion 
should occur between the Study Physician and the investigator regarding whether to continue 
or discontinue the participant.
6.3.2
Blinding
Treatment will be double-blinded for previously vaccinated participants randomised to a 
single dose of either AZD2816 or AZD1222. Treatment will also be double-blind for 
previously unvaccinated participants randomised to 2 dose vaccinations with a 4-week dosing 
interval (ie, homologous AZD2816 or AZD1222 vaccination or heterologous 
AZD1222/AZD2816 vaccination).  Previously unvaccinated participants randomised to a  
homologous AZD2816 vaccination with a 12-week dosing interval will receive treatment in 
an open-label fashion due to the different dosing interval.
For the double-blinded treatments, neither the participant nor any of the investigators or 
Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
participants will be aware of the study intervention received.  Since AZD2816 and AZD1222 
are visually distinct prior to dose preparation (due to differences in container closure), all 
investigational product will be handled by an unblinded pharmacist (or designee in accordance 

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with local and institutional regulations) at the study site. Once drawn into syringes for 
administration, AZD2816 and AZD1222 are not visually distinct from each other.
The IRT will provide the investigators with a dose tracking number to be allocated to the 
participant at the dispensing visit.  Routines for this will be described in the IRT user manual 
that will be provided to each study site.
For participants receiving double-blinded treatments, the randomization code should not be 
broken except in medical emergencies when the appropriate management of the participant 
requires knowledge of the treatment randomization.  The investigator documents and reports 
the action to the Sponsor, without revealing the treatment given to participant to the Sponsor 
staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities.  Randomization codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.
6.3.3
Procedures for Unblinding
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
in which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment 
is warranted.  Participant safety must always be the first consideration in making such a 
determination.  If a participant’s intervention assignment is unblinded for safety, the Sponsor 
must be notified within 24 hours after breaking the blind. 
In the event that a study participant is contacted about receiving a licensed and/or authorized 
COVID-19 vaccine outside of this clinical study, unblinding instructions are being provided to 
the sites.  If the participant is unblinded, the Sponsor needs to be notified within 24 hours, and 
this should be documented in the site source documents.
6.4
Study Intervention Compliance
Participants are dosed at the study site, receiving study intervention directly from the 
investigator or designee, under medical supervision.  The date, and time if applicable, of dose 
administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.

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6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the period specified in the 
Schedule of Activities (Section 1.3), must be recorded in the eCRF along with the information 
listed below.  Vitamins and/or herbal supplements are not to be recorded.
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
!
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance.
!
Primary care providers, or where appropriate investigators, should prescribe appropriate 
concomitant medications or treatments deemed necessary to provide full supportive care 
and comfort during the study.
!
Participants who develop COVID-19 after receiving study intervention should be treated 
with licensed medications and interventions according to standard of care.  All routine 
vaccinations other than influenza are permitted beginning > 30 days after last dose of 
study intervention.  Licensed influenza vaccines are permitted 7 days before and 7 days 
after administration of study intervention.
!
Topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 days) are 
permitted
6.5.2
Prohibited Concomitant Medications
The following medications are prohibited and the Sponsor must be notified if a participant
receives any of these prohibited medications.  The use of the following concomitant 
medications and/or vaccines, however, will not definitively require withdrawal of the 
participant from the study, but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis set.
!
Primary or booster vaccinations, other than AZD2816 or AZD1222, for prevention of 
SARS-CoV-2 or COVID-19.
Note: Participants choosing to receive a licenced and/or authorized COVID-19 vaccine 
should inform the Investigator so it can be properly documented.  Participants, who 
receive a licenced and/or authorized COVID-19 vaccine outside the study, should be 
encouraged to continue study conduct to be followed for safety reporting and all 
assessments.

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!
Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention.  Thirty days after 
the second vaccination, other routine vaccinations are permitted as clinically indicated.
!
Glucocorticoids at a dose ≥ 20 mg/day of prednisone or equivalent given daily or on
alternate days for ≥ 14 consecutive days between randomization and the participant’s
scheduled final visit
!
Other systemically administered drugs with significant immunosuppressive activity,
such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy
between randomization and the participant’s scheduled final visit
!
Immunoglobulins and/or any blood product.
If a participant receives a prohibited concomitant medication, the investigator in consultation 
with the Sponsor will evaluate any potential impact on receipt of study intervention based on 
time the medication was administered, the medication’s pharmacology and pharmacokinetics, 
and whether the medication will compromise the participant’s safety or interpretation of the 
data (see Section 7.1). 
6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.  Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive the first or second dose (if applicable) of study 
intervention if any of the following occur in the participant in question:
1
Withdrawal of consent after signing informed consent
2
Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 
3
Participant is pregnant or nursing
4
Any grade 3 or greater allergic reaction including anaphylaxis that is assessed as related 
to study intervention 
5
Occurrence of any thrombosis with concurrent thrombocytopenia 
6
Any SAE assessed as related to study intervention

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7
Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardize the safety of the study participant 
8
Receipt of a prohibited concomitant medication that may jeopardize the safety of the 
study participant or interpretation of the data
Each participant who has received at least 1 dose of study intervention will be followed for the 
full study period unless consent is withdrawn specifically from further study participation, or 
the participant is lost to follow-up.  Participants who have not received study intervention, 
regardless of reason, will not be followed.
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine 
during the study, AstraZeneca needs to be notified within 24 hours and this should be 
documented in the site source documents. Participants who have received study intervention, 
regardless of reason, will be followed for the full study period.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent.  If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken should be 
carried out in line with what was stated in the informed consent and local regulation.  
The investigator must document the decision on use of existing samples in the site study 
records and inform the Sponsor Study Team.  If the participant does not specifically 
request withdrawal of consent for use of samples, then the samples collected prior to the 
consent withdrawal will be destroyed once per protocol analysis is complete.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

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!
The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the Schedule of Activities (Section
1.3).  Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities.
8.1
Efficacy Assessments
Not applicable.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).

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8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.  Each clinically significant 
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history, 
clinical signs, and symptoms and will include signs of thrombosis and/or 
thrombocytopenia.  Each clinically significant abnormal finding following vaccination 
will be recorded as an AE.
!
All physical examinations will be performed by a licensed healthcare provider 
(eg, physician, physician assistant, or licensed nurse practitioner). 
8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3).  The participant should be 
resting prior to the collection of vital signs.  On vaccination days, vital signs should be 
assessed prior to vaccine administration.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3).  Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the investigator, with the 
date and time of collection recorded in the appropriate eCRF.
The standard clinical chemistry and haematology analysis will be performed at a local 
laboratory at or near to the investigator site.  Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.  
The following laboratory variables will be measured:
Table 9
Laboratory Safety Variables
Blood
Serum/Plasma
Haemoglobin
Activated partial thromboplastin time
Leukocyte count
Prothrombin time
Leukocyte differential count (absolute count)
Fibrinogen

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Platelet count
D-dimer
-
Creatinine
-
Bilirubin, total
-
Alkaline phosphatase
-
Aspartate aminotransferase 
-
Alanine aminotransferase
In case a participant shows an aspartate aminotransferase or alanine aminotransferase 
≥3 × upper limit of normal together with total bilirubin ≥2 × the upper limit of normal, please 
refer to Section 8.3.6
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the Schedule of Activities (Section 1.3).  Urine pregnancy tests for 
∃-human chorionic gonadotropin may be performed at the site using a licensed dipstick test.  
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a e-diary (Section 8.3.7), and will be assessed separately 
from the (unsolicited) AEs collected during the study.  General information for AEs in this 
protocol excludes the reporting of solicited AEs via e-diary unless otherwise noted.. 
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.

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8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
AEs will be recorded for 28 days after each dose of study intervention. 
Solicited AEs will be recorded for 7 days after each dose of study intervention (ie, Day 1 
through Day 8). If a solicited AE is not resolved within the e-diary reporting period, the event 
will be reported as a non-solicited adverse event in the eCRF, with a start date of when started 
and the actual stop date. 
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact. 
See the Schedule of Activities for the scheduled timepoints (Section 1.3). 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Severity grade/maximum severity grade/changes in severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome

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In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA 2007) will be utilized for all unsolicited events. 
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol-mandated vital signs and laboratory safety 
assessments will be summarized in the Clinical Study Report. 

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Deterioration as compared to baseline in protocol-mandated vital signs and laboratory safety 
assessment should therefore only be reported as AEs if they fulfil any of the SAE or 
medically-attended AE criteria or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or 
non-planned visits were required).
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an SAE or medically-attended AE, and the associated vital sign 
will be considered as additional information. 
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation.  Any occurrences of aspartate aminotransferase or alanine aminotransferase 
≥3 × the upper limit of normal together with total bilirubin ≥2 × upper limit of normal at any 
point during the study following the administration of study medication should be reported to 
the Sponsor as a potential Hy's Law SAE within 1 day with a serious criteria of ‘Important 
medical event’ and causality assessment ‘yes/related’.
The study physician will contact the investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 10) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention via e-diary collection. If a solicited AE is not resolved within the e-diary 
reporting period, the event will be also reported as a non-solicited adverse event in the eCRF,
with a start date of when started and the actual stop date.
Solicited AEs should not be reported as unsolicited AEs unless they fulfil the criteria for SAEs 
or medically-attended AEs(see Sections 8.3 and 8.3.8, respectively).

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Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic 
Pain at the site of the injection 
Fever (> 100 °F/37.8 °C)
Redness/erythema at the site of the injection
Chills
Tenderness at the site of the injection
Muscle pains
Induration/swelling at the site of the injection 
Fatigue (physical or mental tiredness/exhaustion)
-
Headache
-
Malaise (general feeling of discomfort or uneasiness)
-
Nausea
-
Vomiting
Solicited AE e-Diary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given a thermometer, tape measure or ruler, and access to the Solicited 
AE e-Diary, with instructions on use, along with the emergency 24-hour telephone number to 
contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms. 
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorized representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix D.  Because 
solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention. 
8.3.8 COVID-19 Assessment
This study will describe the incidence of COVID-19 adverse events reported from Day 1 to 
180 days after the participant’s last/only dose of vaccine.
COVID-19 is defined as SARS-CoV 2-RT-PCR positive symptomatic illness.  At all clinic 
visits following the initial vaccination, participants will be asked if they have had a diagnosis 
of COVID-19 since their last clinic visit (see Schedule of Activities in Section 1.3). Medical 
records will be obtained for confirmation of a participant-reported diagnoses of COVID-19.  
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea.  Events will be reported as AEs/SAEs.

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If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed 
using RT-PCR.
8.3.9 Medically-Attended Adverse Events
Medically-attended AEs will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3).
Medically-attended AEs are defined as AEs leading to medically-attended visits that were not 
routine visits for physical examination or vaccination, such as an emergency room visit, or an 
otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. 
AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
illness visits will not be considered medically-attended AEs.
8.3.10
Adverse Events of Special Interest
AEs of special interest will be collected according to the timepoints specified in the Schedule 
of Activities (Section 1.3). 
AEs of special interest are events of scientific and medical interest specific to the further 
understanding of study intervention safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor.  AEs of special interest are based on 
Brighton Collaboration case definitions (SPEAC 2020), clinical experience, and scientific 
interest.  A list of events is provided in Appendix E.
An AE of special interest can be serious or non-serious.  All AEs of special interest will be 
recorded in the eCRF.  If any AE of special interest occurs in the course of the study, 
investigators or other site personnel will inform the appropriate Sponsor representatives within 
1 day ie, immediately but no later than 24 hours of when he or she becomes aware of it.  
Serious AEs of special interest will be recorded and reported as per Section 8.3.11.
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest
Both thrombotic, thromboembolic, and neurovascular events and thrombocytopenia events are 
considered to be adverse events of special interest.  The investigator should remain vigilant for 
the occurrence of thrombotic events with thrombocytopenia and/or bleeding.  If a participant 
experiences new onset thromboembolic events with thrombocytopenia, there should be 
prompt evaluation with a thorough haematological investigation.  COVID-19 testing, 
including PCR and serology (nucleoprotein antibodies), should also be performed.  See 
Appendix F for further guidance on investigation and management of suspected events.
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and whole genome 

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sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events.
8.3.10.2
Potential Neurological Adverse Events of Special Interest
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation, including referral to a neurology specialist for further 
evaluation and testing, as clinically indicated.  Testing can include evaluation for peripheral 
demyelinating conditions (eg, electromyography).  In cases of concern for spinal cord disease, 
see Figure 3 for a recommended testing algorithm. 
An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AEs of special interest occurring 
in the AZD1222 clinical development program (see Appendix A 5).  

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Figure 3
Neurology Testing Algorithm
a
Adapted from Rovira et al 2015
Ab: antibody; ACE: angiotensin converting enzyme; ADC: apparent diffusion coefficient; ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibodies; AQP4: 
aquaporin 4; CMV: cytomegalovirus; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebral spinal fluid; CT: computed tomography; DWI: diffusion-weighted 
image; EBV: Epstein-Barr virus; ED: emergency department; ENA: extractable nuclear antigen antibodies; ESR: erythrocyte sedimentation rate; FLAIR: fluid-attenuated inversion 
recovery; GRE: gradient echo; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IgG: immunoglobulin G; MOG: myelin oligodendrocyte glycoprotein; MRI: 
magnetic resonance image; PCR: polymerase chain reaction; RF: rheumatoid factor; RPR: rapid plasma reagin; STIR: short T1 inversion recovery; SWI: susceptibility-weighted 
imaging; TSH: thyroid stimulating hormone; TM: transverse myelitis; VDRL: Venereal Disease Research Laboratories; VZV: varicella-zoster virus. 

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8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedures.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Sponsor representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available.
The Sponsor representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness is the AZD1222 Investigators 
Brochure, Section 5.6. 
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor, except if the pregnancy is discovered 
before the participant has received any study intervention.
8.3.12.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2).  Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the study intervention may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 

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spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the participant was discontinued 
from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.11) and within 30 days for all other pregnancies 
that are not associated with an SAEs.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module may be used to report the outcome of the pregnancy.
8.3.13
Medication Error
If a medication error occurs, then the investigator or other site personnel informs the 
appropriate Sponsor representatives within 1 day, ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 3. 
8.4
Overdose
For this study, any dose of study intervention exceeding that specified in the protocol will be
considered an overdose.
There is no specific treatment for an overdose with AZD2816 or AZD1222.  If overdose 
occurs, the participant should be treated supportively with appropriate monitoring as 
necessary.

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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose occurs in the course of the study, the investigator or other site personnel inform 
appropriate Sponsor representatives immediately, but no later than 24 hours after when he or 
she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual.  Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality.  Further details on Handling of Human 
Biological Samples are provided in Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a
maximum of 15 years following issue of the Clinical Study Report.  Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses, eg, exploratory immunology, such 
as systems serology and profiling of B- and T-cell repertoire.  The results from further 
analysis will not be reported in the Clinical Study Report.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).  Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual.  Results for exploratory immunogenicity analyses may 
be reported separately from the CSR.

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8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the Schedule of Activities (Section 1.3).  Authorized laboratories 
will assess serologic responses to AZD1222 and AZD2816 using validated (or qualified, 
where appropriate) assays.  Serologic assessment to the S protein from different SARS-CoV-2 
variants (which include Wuhan-Hu-1, B.1.351, B.1.1.7, and P.1) will be assessed 
quantitatively using a validated multiplexed ECL based immunoassay.  Additionally, 
seroresponse will be assessed for each antigen over time.  The rate of SARS-CoV-2 infection 
in participants receiving AZD2816 versus AZD1222 will be determined by seroresponse in a 
SARS-CoV-2 nucleocapsid antigen in a multiplexed electrochemiluminescence-based assay 
performed at an authorized laboratory. Additional exploratory assessments may be performed 
to measure binding antibodies to SARS-CoV-2 variants of interest (which may include 
B.1.429, B.1.525, B.1.526, P.2, P.3, B.1.617, and the Q677H mutation observed in multiple 
variants).
8.5.2.2
 
 
 
 
 
 
 
 
 
8.5.2.3
 
 
 
 
 
 
 
 
 
CCI
CCI
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8.5.2.4
 
 
 
 
 
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Already collected samples may be analysed for biomarkers thought to play a role in 
COVID-19 severity or outcomes based upon emerging immunogenicity and 
pharmacodynamic analysis from this or other studies involving the study interventions. These 
analyses include but are not limited to serum or plasma cytokines, quantification of RNA, 
micro-RNA, and/or non-coding RNA using quantitative reverse transcriptase polymerase 
chain reaction (RT-PCR), microarray, sequencing, or other technologies in blood, or 
peripheral blood mononuclear cells to evaluate their association with AZD1222/2816 and 
observed clinical responses to these study interventions.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The overall hypothesis for this 8-armed study is that 28 days after vaccination (ie, following a 
single booster dose for the previously vaccinated participants or a second vaccination dose for 
previously unvaccinated participants), AZD2816 will be non-inferior to AZD1222 in terms of 
immunogenicity (ie, neutralising antibodies GMT ratio and difference in seroresponse).  The 
specific null and alternative hypotheses for each objective are presented in Section 9.4.3
CCI
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9.2
Sample Size Determination
Primary Objective: Characterise Immunogenicity (Precision)
Historical data were available for the immunogenicity responses (ie, pseudovirus neutralising 
antibodies, live virus neutralising antibodies, and spike protein binding antibodies) to 
AZD1222 from the pooled COV001/002/003/005 studies.  Table 11 presents the log 
transformed immunogenicity responses (ie, geometric mean titres) by assay for participants 
that received 2 standard doses of AZD1222.  These results indicate that the pseudo-
neutralising antibodies exhibited the largest variation (standard deviation of 1.20 and 1.10 for 
the 4-week and 12-week dosing intervals respectively), while live-neutralising antibodies had 
the lowest (standard deviation of 0.72 for the 4-week dosing interval).
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-week dosing intervalb
Assay
N
Mean
Std Dev
N
Mean
Std Dev
N
Mean
Std Dev
Pseudo
476
4.3
1.34
166
5.3
1.20
113
5.4
1.10
Live
51
4.9
1.15
42
6.2
0.72
0
-
-
Spike protein
1139
9.1
1.14
293
10.1
0.96
302
10.7
0.83
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval
Table 12 presents the seroresponse (ie, > 4 fold increase from baseline) by assay.  These 
results indicate that the pseudo-neutralising antibodies exhibited the lowest proportion of 
seroresponse (59.7% and 85.5% for the 4-week and 12-week dosing intervals respectively), 
while both live-neutralising and spike-binding seroresponse rates exceeded 95%.
Table 12
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-dose week intervalb
Assay
N
Proportion
N
Proportion
N
Proportion
Pseudo
499
32%
382
59.7%
117
85.5%
Live
96
75%
95
96.8%
-
-
Spike protein
940
96.6%
636
95.9%
304
99.3%
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval 

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Under the assumption that the immunogenicity responses (ie, geometric mean antibody titres) 
associated with AZD2816 will be similar to the responses associated with AZD1222 in 
participants that received 2 standard doses in the pooled COV001/002/003/005 studies, in 
which standard deviations ranged from 0.72 to 1.2 (Table 11), 150 participants will provide a 
95% confidence interval half-width between 0.115 and 0.192 (see Table 13).  Similarly, 380 
participants will provide a 95% confidence interval half-width between 0.072 and 0.120.
Under the assumption that the seroresponse rates associated with AZD2816 will be similar to 
the response rates in adults that received 2 standard doses of AZD1222 in the pooled 
COV001/002/003/005 studies (Table 12), 150 participants will provide a 95% confidence 
interval half-width between 1.33% and 7.85%, and 380 participants will provide a 95% 
confidence interval half-width between 0.84 % and 4.93 % (Table 14).
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes
Standard Deviation
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
0.72
150
0.115
300
0.081
350
0.075
380
0.072
0.83
150
0.133
300
0.094
350
0.087
380
0.084
0.96
150
0.154
300
0.109
350
0.101
380
0.097
1.1
150
0.176
300
0.124
350
0.115
380
0.111
1.2
150
0.192
300
0.136
350
0.126
380
0.120

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Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Serorepsonse Rates and Proposed 
Sample Sizes
Observed 
seroresponse rate
Number of participants
Estimated half-width of the 95% confidence interval 
59.7%
150
7.85%
300
5.55%
350
5.14%
380
4.93%
85.5%
150
5.63%
300
3.98%
350
3.69%
380
3.54%
95.9%
150
3.17%
300
2.24%
350
2.08%
380
1.99%
96.8%
150
2.82%
300
1.99%
350
1.84%
380
1.77%
99.3%
150
1.33%
300
0.94%
350
0.87%
380
0.84%
For a fixed sample size, the precision with which the 95% confidence interval of the binary 
seroresponse rate can be estimated is a function of the response rate.  Table 14 provides the 
lower bounds of the 95% confidence interval for selected response proportions for alternate 
sample sizes.  For a given response rate, we can be 95% confident that the true seroresponse 
rate is at least as large as the lower bound of the confidence interval.

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Primary Objective: Safety
Table 15 indicates the probability of observing 1 or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 
particular type for participants in each treatment arm.  With the sample size of 300 
participants, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 95%.
Table 15
Probability of detecting 1 or more safety events (N = 300)
Event Frequency
Probability (> 1 event)
≥ 10% (Very Common)
> 99%
≥ 1% (Common)
95%
≥ 0.1% (Uncommon)
26%
≥ 0.01% (Rare)
3%
Secondary Objective: Compare Immunogenicity
Under the assumption that there is no difference between treatment arms of interest (ie, a ratio 
of 1, difference on the log scale of 0), the power conferred by 150 and 380 participants 
respectively for the comparison of geometric mean titre ratio using a noninferiority margin of 
1.5 (equivalent to a difference on the log scale of 0.405) is presented in Table 16 and for the 
comparison of seroresponse rate using the non-inferiority margin of -15% as the upper bound 
of the difference is presented in Table 17.
If there is no difference between treatment arms of interest (ie, a ratio of 1) in the proportion 
of seroresponders, 300 participants provides 98% power for to establish non-inferiority to 
within margin of -15% if the seroresponse rate is >50%.  The observed pseudo-neutralising 
response rates (> 4 fold increase from baseline) from the COV001/002/003/005 studies for 
AZD1222 were 59.7% and 85.5% for the 4-week and 12-week dosing interval respectively 
(Table 12).  A population of 300 participants provides >90% power to detect non-inferiority 
(using a non-inferiority margin of -15%) if the observed response rate is 59.7% (Table 17).

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Table 16
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
Sides
Null 
difference
Assumed mean 
treatment 
difference
Assumed 
standard 
deviation
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Upper
ln1.5 = 
0.405
0
0.72
150
300
0.025
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.83
150
300
0.998
150
350
0.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.96
150
300
0.988
150
350
0.991
150
380
0.992
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
1.10
150
300
0.957
150
350
0.965
150
380
0.968
300
300
0.994
300
350
0.997
300
380
0.997
350
380
0.999
350
350
0.998
380
380
>.999
1.20
150
300
0.920
150
350
0.932
150
380
0.937
300
300
0.985
300
350
0.990
300
380
0.992
350
380
0.995
350
350
0.994
380
380
0.996

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Table 17
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate
Sides
Null 
proportion 
difference
Assumed 
difference in 
proportion of 
seroresponders
Assumed 
proportion of 
seroresponders 
in both groups
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Lower
-0.15
0
0.597
150
300
0.025
0.878
150
350
0.894
150
380
0.902
300
300
0.964
300
350
0.975
300
380
0.979
350
380
0.986
350
350
0.982
380
380
0.989
0.855
150
300
0.993
150
350
0.995
150
380
0.996
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.959
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.968
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.993
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999

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9.3
Populations for Analyses
The following populations are defined:
Table 18
Populations for Analysis
Population
Description
All participants analysis set 
All participants screened for the study, to be used for reporting disposition and 
screening failures.
Full analysis set
All randomised participants who received study treatment, irrespective of their 
protocol adherence and continued participation in the study. Participants will be
analysed according to their randomised treatment, irrespective of whether or not 
they have prematurely discontinued, according to the intent-
to-treat principle. Participants who withdraw consent or assent to participate in the
study will be included up to the date of their study termination.
Safety analysis set
The safety analysis set consists of all participants who have received study 
treatment. Erroneously-treated participants (eg, those randomised to AZD2816, but 
were actually given treatment AZD12222) are accounted for in this analysis set by 
assigning them to the treatment they actually received.
Immunogenicity analysis set
The vaccine immunogenicity analysis set will include all randomised participants, 
received at least 1 dose of planned study treatment (ie, 1 dose of either AZD2816 or 
1 dose of AZD1222), had baseline and post-dose antibody measurements, have at 
least 1 post-dose quantifiable serum titre, and had no protocol deviations judged to 
have the potential to interfere with the generation or interpretation of an antibody 
response. The analyses conducted using this analysis set will be based on the actual
treatment received.
Seronegative 
immunogenicity analysis set 
The subset of the immunogenicity analysis set who were seronegative at baseline.
Seropositive 
immunogenicity analysis set
The subset of the immunogenicity analysis set who were seropositive at baseline.
Participants that are SARS-CoV-2 seropositive at screening will be included in seropositive 
analysis sets analogous to the above seronegative analysis sets. Further definition is provided 
in the Statistical Analysis Plan.
9.4
Statistical Analyses
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints.  A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to the interim analyses.

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9.4.1 General Considerations
An initial interim analysis will occur when a  subset of participants previously vaccinated with 
AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  This sample will 
include both participants randomised to receive both a booster dose of AZD2816 as well as 
those randomised to receive a booster dose of AZD1222.  Analyses presenting treatment arm 
summaries of both the raw and model adjusted immunogenicity will be reviewed by an 
unblinded team within AstraZeneca to make a decision regarding the potential need for 
sample size re-estimation.  Full details of this analyses are provided in the Interim Analysis 
Charter to be finalized prior to any interim analysis.
An second interim analysis will occur when all participants previously vaccinated with 
AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  It is estimated 
that this early analysis has the potential to provide clear signals about whether AZD2816 
provides a strong neutralizing response against the B.1.351 strain while retaining 
immunogenicity against the Wuhan strain, and thereby influence programmatic decisions 
early.  Analyses results will present treatment arm specific summaries of both the raw and 
model adjusted (baseline age and co-morbidities).  The raw data outputs will be stratified by 
age group (<65, ≥ 65) while the model adjusted summaries will pool data across age groups.  
Full details of this analyses are provided in the Interim Analysis Statistical analysis Plan to be 
finalized prior to any interim analysis.
A third interim analysis may be performed when a subset of previously unvaccinated 
participants have completed their Day 57 visit (ie, 56 days after fist dose).  The participant 
sample will include both participants randomised to AZD2816 as well as those randomised to 
AZD1222.  This analysis is intended to assess immunogenicity variability. The number of 
previously unvaccinated participants per treatment arm may be increased based upon the 
results of this analysis.  The details of this interim analysis, including the trigger and methods, 
will be specified in the Interim Analysis Charter Plan The primary analysis will occur when 
all participants have completed their Day 29 visit and safety and immunogenicity data from all 
unvaccinated participants randomised to a 4-week dosing interval are available through 
completion of their visit 28 days after the second priming dose.
A secondary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants (including those 
randomised to a 12-week dosing interval) are available through completion of the visit 28 
days after the second dose. 
The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).

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Further details of the primary analysis, secondary analysis and final analysis are contained 
within the Statistical Analysis Plan.
To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.
9.4.2 Safety
9.4.2.1
Primary Endpoints
Overview
Descriptive analyses will support evaluation of safety, reactogenicity and immunogenicity. 
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination will 
be summarised by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be summarised 
by system organ class and preferred term, and by relationship to vaccination as assessed 
by the investigator.
!
MAAEs, SAEs, and AESIs following the first vaccination and throughout the study 
duration will be summarised by system organ class and preferred term and by relationship 
to vaccination as assessed by the investigator. 
!
The change from baseline for safety laboratory measures at 7 and 28 days after 
vaccination.
AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities.  AEs will be presented for each treatment group by system organ class 
and preferred term.  Summaries will include the number and percentage of participants 
reporting at least one event, number of events and exposure adjusted rates, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs.  Summaries will present the relationship to 
study intervention as assessed by the investigator, maximum intensity, seriousness, and death.
A listing will cover details for each individual AE.  Full details of all AE analyses will be 
provided in the Statistical Analysis Plan, including intercurrent events for safety due to 
potential unblinding of participants for administration of licensed and/or approved SARS-
CoV-2 or COVID-19 vaccine.

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At the time of the interim analyses, group assignment will not be presented when safety event 
data has the potential to unblind participant’s study group attribution.
9.4.2.2
Other Safety Endpoints
Vital Signs
Vital sign measurements will be performed as specified in the Schedule of Activities (Section 
1.3).  The set of assessments will include pulse oximetry, blood pressure, and body
temperature.  
Details of all vital sign analyses will be provided in the Statistical Analysis Plan, which will 
include descriptive statistics presented for observed values for all vital sign parameters. 
COVID-19
This study will describe the incidence of COVID-19 adverse events from the first dose of the 
vaccine to study end (180 days post-vaccination). Descriptive statistics will be produced 
based on the safety analysis set. Full details will be documented in the statistical analysis plan.
9.4.3
Immunogenicity
9.4.3.1
Immunogenicity Endpoints
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean antibody titre.
!
Seroresponse, defined as ≥4-fold increase in the geometric mean antibody titre from 
baseline
Both the geometric mean antibody titre and seroresponse of participants will be summarized 
descriptively by strain, treatment arm, and timepoint for the immunogenicity population.
9.4.3.1.1
Estimand framework for immunogenicity descriptions and comparisons
Target populations: 
1) Previously unvaccinated participants 
a.
Seronegative Analysis Set: and with no evidence of prior or current infection  
2) Participants who previously received SARS-CoV-2 vaccination with either AZD1222 
or a licensed mRNA vaccine according to the authorized dose and dosing regimen at 
least 3 months prior to first study intervention (see Section 5.1.2).
Outcome variable: neutralizing antibody and binding titres to SARS-CoV-2 at 28 days after 
each treatment administration (1 treatment administration for the previously vaccinated 
population and 2 planned treatment administrations for the unvaccinated population). 

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Treatment conditions:
Previously unvaccinated population
!
2 doses of AZD1222 given on Day 1 and on Day 29 (4-week dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 29 (4-week dosing interval)
!
1 dose of AZD1222 given on Day 1 and 1 dose of AZD2816 on Day 29 (4-week 
dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 85 (12-week dosing interval)
Previously vaccinated population
!
1 dose of AZD1222 given on Day 1. 
!
1 dose of AZD2816 given on Day 1. 
Intercurrent events: the following intercurrent events could impact the antibody levels 
achieved:  
!
missing the second vaccination (for the unvaccinated population)  
!
receiving of immune-modifying drugs or vaccines 
!
subsequent infection with SARS-CoV-2. 
All immunogenicity descriptions and comparisons will use the principal stratum strategy, 
ie, all analyses will exclude participants who experience any of the above intercurrent events 
Population-level summary: 
Descriptive Analyses (see Table 20 and Table 21)
!
geometric means of the antibody titres 
!
seroresponse proportions
Comparative Analyses (see Table 22 and Table 23)
!
ratio of geometric means of the antibody titres.
!
difference in seroresponse proportion 

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Planned Descriptive Analyses: 
Table 20 and Table 21 present planned descriptive immunogenicity analyses for the 
unvaccinated and previously vaccinated populations respectively (each one exploring an 
individual treatment arm at a specific timepoint against a particular strain). 
The tables show that without introduction of further variants, there are 24 planned descriptive 
analyses for the unvaccinated population and 16 planned descriptive analyses for the 
previously immunised population (index).  Within each table there is an analysis key which 
describes the population (see Table 19). The descriptive analyses presented in Tables 19 and 
20 will be repeated for the subset of participants who are seropositive at screening.
Table 19
Description of the Analysis Keys for Tables 19 and 20
Population
Analysis Key
Example
Previously 
unvaccinated
Primary series dosing interval: 
    P4 (4-week dosing interval) or
    P12 (12-week dosing interval)
Treatment received: 
    1222 (2 doses of AZD1222) or 
    2816 (2 doses of AZD2816) or
1222/2816 (1 dose of AZD1222  
followed by 1 dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
Analysis Timepoint:
   1 (28 days post-dose 1)
   2 (28 days post-dose 2)
[P4:1222:W:1] = Immunogenicity 
following primary vaccination 
with a 4-week dosing interval of 
2 doses of AZD1222 against 
Wuhan-Hu-1 28 days post-dose 1
Previously vaccinated
Pre-study primary vaccination: 
  P1222 (2 doses of AZD1222) or
    PmRNA (2 doses of an mRNA vaccine)
Treatment received: 
    B1222 (1 booster dose of AZD1222) or 
B2816 (1 booster dose of AZD2816)
Strain: 
    W (Wuhan-Hu-1) or 
    V (Variant B.1.351)
[P1222:B1222:V] = 
Immunogenicity in participants 
who were previously vaccinated 
with 2 doses of AZD1222 as 
primary vaccination series and 
received a single boost dose of 
AZD1222 against the B.1.351 
variant 

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)
Treatment
Dosing 
interval
Strain
Timepoint
Endpoint
Index
Analysis Key
AZD1222
4 weeks
Wuhan-Hu-1
28 days after 
1st dose
GMT
1
[P4:1222:W:1]†
Seroresponse
2
28 days after 
2nd dose
GMT
3
[P4:1222:W:2]
Seroresponse
4
B.1.351
28 days after 
1st dose
GMT
5
[P4:1222:V:1] †
Seroresponse
6
28 days after 
2nd dose
GMT
7
[P4:1222:V:2]
Seroresponse
8
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 
1st dose
GMT
9
[P4:2816:W:1] ‡
Seroresponse
10
28 days after 
2nd dose
GMT
11
[P4:2816:W:2]
Seroresponse
12
B.1.351
28 days after 
1st dose
GMT
13
[P4:2816:V:1] ‡
Seroresponse
14
28 days after 
2nd dose
GMT
15
[P4:2816:V:2]
Seroresponse
16
AZD1222/
AZD2816
4 weeks
Wuhan-Hu-1
28 days after 
2nd dose
GMT
17
[P4:1222/2816:W:2]
Seroresponse
18
B.1.351
28 days after 
2nd dose
GMT
19
[P4:1222/2816:V:2]
Seroresponse
20
AZD2816
12 weeks
Wuhan-Hu-1
28 days after 
1st dose
GMT
21
[P12:2816:W:2]
Seroresponse
22
B.1.351
28 days after 
2nd dose
GMT
23
[P12:2816:V:2]
Seroresponse
24
† descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD1222 as their first dose 
(ie, homologous and heterologous series).
‡ descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD2816 as their first dose 
(4-week interval and 12-week interval treatment arms).
GMT: Geometric mean titre

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Table 21
Immunogenicity Descriptive Analysis for Previously 
Vaccinated Treatment Groups (with Separate Seronegative 
and Seropositive Analyses)
Primary 
vaccination
Booster 
Treatment
Strain
Timepoint
Endpoint
Index
Analysis Key
AZD1222
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
1
[P1222:B1222:W]
Seroresponse
2
B.1.351
28 days after 
booster dose
GMT
3
[P1222:B1222:V]
Seroresponse
4
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
5
[P1222:B2816:W]
Seroresponse
6
B.1.351
28 days after 
booster dose
GMT
7
[P1222:B2816:V]
Seroresponse
8
mRNA
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
9
[PmRNA:B2816:W]
Seroresponse
10
B.1.351
28 days after 
booster dose
GMT
11
[PmRNA:B2816:V]
Seroresponse
12
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
13
[PmRNA:B1222:W]
Seroresponse
14
B.1.351
28 days after 
booster dose
GMT
15
[PmRNA:B1222:V]
Seroresponse
16
GMT: Geometric mean titre
Immunogenicity comparisons:
Immunogenicity analysis
A number of comparisons of geometric mean titres and seroresponse rates between vaccine 
regimens and vaccine types are intended to be made. 
All non-inferiority comparisons of geometric mean titre ratios will be made utilizing the lower 
bound of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 
0.67
All non-inferiority comparisons of seroresponse rates will be made utilizing the lower bound 
of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 15%, and 
superiority comparisons of seroresponse rates will be made using one-sided Fisher’s exact test 
(α = 0.025). Comparisons of Ab titres between treatment groups will be conducted using 
geometric mean titre (GMT) ratios and seroresponse rates, facilitated by an analysis of 
covariance (ANCOVA) model of the log2 titre, which adjusts for the baseline level, time since 
previous vaccination (for previously vaccinated individuals), baseline co-morbidities and 

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gender as fixed effects. All analyses of antibody titres (GMT ratios and differences in 
seroresponse) will be repeated using the unadjusted (raw observed) concentration values.
Geometric Mean Titres 
The statistical methodology will be based on a 2-sided 95% CI of the ratio of the GMTs. Non-
inferiority will be demonstrated if the lower limit of the 2-sided 95% CI of the GMT ratio of 
the reference group and comparator group is >0.67 (see table xx). The 2-sided 95% CI for the 
ratio of GMTs will be calculated using normal approximation of log-transformed 
concentrations.
The 95% CI for the GMT ratio between 2 groups will be constructed as follows:
Logarithm transformation of the individual concentrations will be calculated.
The 95% CI for the difference in log(GMT) between 2 groups: GroupC and GroupR will 
be in the form:
 − ± 
1 − 2
 ,  +  −2 × 1 

+ 1 

Where  and  = log() are the means of the log-transformed concentration for 
 !"# and  !"#, respectively,
$ = [( −1)
$ + ( −1)
$]
( +  −2)
'
is the pooled sample variance,
 and  are the sample sizes for  !"# and  !"# , respectively,
 and  are the sample variances for  !"# and  !"# , respectively,

1 − 2
 ,  +  −2 is the 100 ,1 −
-
$. percentile of the t-distribution with degrees of 
freedom /0 =  +  −2
To test this hypothesis, a 2- sided 95% CI will be constructed around the ratio 
1234
1235, where 
 and  are the geometric mean of the antibody titres in the comparator and 
reference groups respectively, at the timepoints post vaccination for which the groups are 
being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 0.67. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.

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:;:  

≤0.67
:>:  

> 0.67
Or equivalently
:;: log() −log() ≤log(0.67)
:>: log() −log() > log(0.67)
For the separately considered GMT hypotheses, if the null hypothesis is rejected, then the 
alternative hypothesis of non-inferiority will be supported.
Seroresponse
The statistical methodology will be based on a 2-sided 95% CI of the difference in 
seroresponse. Non-inferiority will be demonstrated if the upper bound of the 2-sided 95% CI 
rate difference in seroresponse between the reference group and comparator group is <15%.  
The 95% CI of the difference in proportions ? −? will be computed using the Wilson score 
without continuity correction.
To test this hypothesis, a 2- sided 95% CI will be constructed around the difference ? −?, 
where? and ? are the proportions of participants in the comparator and reference groups 
respectively who are classified as seroresponders (> 4 fold increase from baseline) at the 
timepoints post vaccination for which the groups are being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 15%. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.
:;: ? −? < −15%
:>: ? −? ≥15%
If the null hypothesis is rejected, then the alternative hypothesis of non-inferiority will be 
supported.
Comparisons
The primary and secondary immunogenicity objectives and the GMT and seroresponse 
comparisons for the previously unvaccinated participants receiving a 2-dose primary 
vaccination are presented in Table 22.

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The immunogenicity objectives and the GMT and seroresponse comparisons for the 
previously vaccinated participants receiving a 1-dose booster vaccination are presented in
Table 23.  

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
[DEFGHIJKLKMHL]
[DEFLNONLNPGN]
∆= [RNLHLNSJHPSNGHIJKLKMHL] −
[RNLHLNSJHPSNLNONLNPGN]
To determine if the neutralizing antibody GMT 
response/seroresponse elicited by a 2-dose AZD2816 
primary vaccination is non-inferior to the response 
elicited by a 2-dose AZD1222 primary vaccination
[P4:2816: V: 2]
[P4: 1222: W:2]
(Primary)
[P4:2816: V: 2] −[P4: 1222: W:2]
(Key Secondary 2.1)
[P4:2816: V: 1]
[P4: 1222: W:1]
[P4:2816: V: 1] −[P4: 1222: W:1]
[P4: 2816: W:2]
[P4: 1222: W:2]
(Key Secondary 2.4)
[P4:2816:W: 2] −[P4:1222: W:2]
(Other Secondary)
[P4: 2816: W:1]
[?4: 1222: W:1]
[P4:2816:W: 1] −[P4:1222: W:1]
[P4:2816: V: 2]
[P4:1222: V: 2]
(Key Secondary 2.2)
[P4:2816: V: 2] −[P4:1222: V: 2]
(Other Secondary)
[?4:2816: V: 1]
[?4:1222: V: 1]
[P4:2816: V: 1] −[P4:1222: V: 1]
To determine if the neutralizing antibody GMT 
response/seroresponse elicited by a 2-dose AZD1222 
+ AZD2816 heterologous primary vaccination is non-
inferior to the response elicited by a 2-dose AZD1222 
primary vaccination
YP4: 1222
2816 : V: 2Z
[P4: 1222: W:2]
(Key Secondary 2.3)
[P4:1222
2816 : V: 2\ −[P4:1222: W:2]
(Other Secondary)
YP4: 1222
2816 : W: 2Z
[P4: 1222: W:2]
(Other Secondary)
[P4:1222/2816: W:2] −[P4: 1222: W:2]
(Other Secondary)

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
[DEFGHIJKLKMHL]
[DEFLNONLNPGN]
∆= [RNLHLNSJHPSNGHIJKLKMHL] −
[RNLHLNSJHPSNLNONLNPGN]
[P4:1222/2816: V: 2]
[P4:1222: V: 2]
(Other Secondary)
[P4:1222/2816: V: 2] −[P4: 1222: V: 2]
(Other Secondary)
To determine if the neutralizing antibody GMT 
response/seroresponse rate against the B.1.351 
variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose AZD2816 
primary vaccination
[P4: 2816: V: 2]/[P4:2816: W: 2]
(Other Secondary)
[P4:2816: V: 2] −[P4: 2816: W:2]
(Other Secondary)
To determine if the neutralizing antibody GMT 
response/seroresponse rate against the B.1.351 
variant is non-inferior to the rate against the original 
Wuhan-hu-1 strain following a 2-dose 
AZD1222/AZD2816 primary heterologous 
vaccination
[P4:1222/2816: V: 2]/[P4:1222/2816: W:2]
(Other Secondary)
[P4:1222/2816:V: 2]
−[P4: 1222/2816: W:2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[DEF〗GHIJKLKMHLh
〖[DEF〗LNONLNPGN]
〖[RNLHLNSJHPSN〗GHIJKLKMHLh −〖[RNLHLNSJHPSN〗LNONLNPGN]
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-
inferior to response elicited by a 2-dose 
AZD1222 vaccination
[P1222: B2816:V]/[P4:1222: W:2]
(Primary)
[P1222: B2816:V] −[P4:1222: W:2]
(Other Secondary)
[P1222:B2816: V]/[P4:1222:V: 2]
(Key Secondary 2.1)
[P1222:B2816: V] −[P4: 1222: V: 2]
(Other Secondary)
[P1222: B2816: W]/[P4:1222:W: 2]
(Key Secondary 2.3)
[P1222:B2816: W] −[P4: 1222: W:2]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster 
dose in participants previously vaccinated 
with AZD1222
[P1222:B2816: V]/[P1222: B1222:V]
(Key Secondary 2.2)
[P1222:B2816: V] −[P1222: B1222: V]
(Other Secondary)
[P1222:B2816: W]/[P1222: B1222:W]
(Key Secondary 2.5)
[P1222:B2816: W] −[P1222: B1222: W]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-
inferior to the response elicited by a 2-dose 
AZD1222 vaccination
[P1222: B1222: W]/[P4:1222:W: 2]
(Key Secondary 2.4)
[P1222:B1222: W] −[P4: 1222: W:2]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based 
vaccine is non-inferior to response elicited 
by a 2-dose AZD1222 vaccination
[PmRNA:B2816: V]/[P4:1222: W:2]
(Other Secondary)
[PmRNA:B2816: V] −[P4:1222:W: 2]
(Other Secondary)
[PmRNA:B2816: V]/[P4:1222: V: 2]
(Other Secondary)
[PmRNA:B2816:V] −[P4:1222: V: 2]
(Other Secondary)
[PmRNA:B2816: W]/[P4:1222: W:2]
(Other Secondary)
[PmRNA:B2816: W] −[P4:1222: W:2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[DEF〗GHIJKLKMHLh
〖[DEF〗LNONLNPGN]
〖[RNLHLNSJHPSN〗GHIJKLKMHLh −〖[RNLHLNSJHPSN〗LNONLNPGN]
To determine if the neutralizing antibody 
GMT response/seroresponse elicited by an 
AZD2816 booster dose is non-inferior to the 
response elicited by an AZD1222 booster 
dose in participants previously vaccinated 
with an mRNA-based vaccine
[PmRNA:B2816: W])/[PmRNA:B1222: W]
(Other Secondary)
[PmRNA:B2816: W] −[PmRNA:B1222:W]
(Other Secondary)
[PmRNA:B2816:V])/[PmRNA:B1222: V]
(Other Secondary)
[PmRNA:B2816: V] −[PmRNA:B1222:V]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse rate against the 
B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain 
following a 2816 booster dose
[P1222: B2816:V]/[P1222:B2816: W]
(Other Secondary)
[P1222:B2816: V] −[P1222: B2816: W]
(Other Secondary)
To determine if the neutralizing antibody 
GMT response/seroresponse rate against the 
B.1.351 variant is non-inferior to the rate 
against the original Wuhan-hu-1 strain 
following a 1222 booster dose
[P1222: B1222:V]/[P1222:B1222: W]
(Other Secondary)
[P1222: B1222:V] −[P1222:B1222: W]
(Other Secondary)

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9.4.4
Multiple Comparisons
A hierarchical approach will be used to control for multiplicity of the primary and key 
secondary efficacy endpoints. That is, the null hypotheses for the efficacy endpoints will be 
tested in a hierarchical order, and the subsequent null hypothesis will be tested only if the 
prior null hypothesis is rejected. Consequently, no adjustment to alpha for multiplicity will be 
made in the analysis of immune response. The primary Statistical comparisons of safety data 
will not be adjusted for multiple comparisons.  Further details are provided in the statistical 
analysis plan.
9.4.5
Data Safety Monitoring Board
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, to 
ensure safe and ethical conduct of the study.  During the study, the benefit/risk assessment 
will be continuously monitored by the Board to ensure that the balance remains favourable.  
Further details, composition, and operation of the COVID-19 Vaccine Data Safety Monitoring 
Board will be described in a separate charter. For further details, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Not applicable.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
∀
Applicable ICH/GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigators Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority.  This responsibility may be delegated to 
a contract research organization but the accountability remains with the Sponsor.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH/GCP guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all Food and 
Drug Administration (FDA) Regulations, as applicable and all other applicable local 
regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study.  Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH/GCP guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
!
The study medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples.  The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use.  Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

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!
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law.  The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committee Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A COVID-19 Vaccine Data Safety Monitoring Board comprised of independent experts will 
be convened to provide oversight and to ensure safe and ethical conduct of the study.  The 
COVID 19 Vaccine Data Safety Monitoring Board will have the responsibility of evaluating 
cumulative safety and other clinical study data at regular intervals and making appropriate 
recommendations based on the available data.  During the study, the benefit/risk assessment 
will be continuously monitored by the COVID-19 Vaccine Data Safety Monitoring Board to 
ensure that the balance remains favourable.  Full details of the COVID-19 Vaccine Data 
Safety Monitoring Board composition and operations can be found in the COVID-19 Vaccine 
Data Safety Monitoring Board Charter.
An independent Neurological AESI Expert Committee will be available to review and provide 
on request about the diagnosis and causality assessment of selected neurological AEs of 
special interest occurring in the study.  Details on the composition and operation of this 
committee are described in the Neurological AESI Expert Committee Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available.  The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

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!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
!
Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected, and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH/GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or ICH/GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both SAEs and non-SAEs and can include a deterioration of a 
pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs.  
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used.  
In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a non-
SAE.  For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur.  Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as non-serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  Examples of important medical events include such events as listed 
below:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Intensity Rating Scale
A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events.  
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 

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several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the investigational product.
!
Time Course.  Exposure to suspect drug.  Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect investigational product?
!
Consistency with known investigational product profile.  Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or drugs of the same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational medicinal product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the investigational product, but rather a human or 
process related failure while the investigational product is in control of the study site staff or 
participant.
Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the investigational product
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Investigational product name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration
!
Investigational product not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Investigational product not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong participant received the medication (excluding IRT errors)
!
Wrong investigational product administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from 
the participants while in storage at the study site until shipment or disposal (where 
appropriate) and records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
The Sponsor or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
The Sponsor ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented.  If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and the Sponsor are informed about the sample disposal.

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The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus.  Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814.  Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
!
Table 24: Clinical Abnormalities, Local Reactions to Injectable Product
!
Table 25: Clinical Abnormalities, Vital Signs
!
Table 26: Clinical Abnormalities, Systemic (General or Illness)
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalization
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded.
b
Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE e-Diary.
ER: emergency room.

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Table 25
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)a
Fever (°C/°F)
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
Emergency room visit 
or hospitalization for 
arrhythmia
Bradycardia 
(beats/minute)
50-54
45-49
< 45
Emergency room visit 
or hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
Emergency room visit 
or hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes.

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Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic 
(General)
Systemic Gradea
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/
vomiting
No interference with 
activity or 
1-2 episodes/24 hours
Some interference 
with activity or 
> 2 episodes/24 hours
Prevents daily activity, 
required outpatient 
intravenous hydration
Emergency room 
visit or 
hospitalization for 
hypotensive shock
Chills
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
Emergency room 
visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Systemic Illness
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations)
No interference with 
activity
Some interference 
with activity not 
requiring intervention
Prevents daily activity 
and required medical 
intervention
Emergency room 
visit or 
hospitalization

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Appendix E
Adverse Events of Special Interest
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 27
Adverse Events of Special Interest
Category
Medical Concept
Neurologic
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment or 
loss of consciousness.  
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis.
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population.
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (eg, weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, or other 
sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate.
Hematologic
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL.
Immunologic
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention.
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non-neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: a group of autoimmune inflammatory disorders 
characterized by an alteration in cellular homeostasis, which may or may not have an 
autoimmune aetiology.  A list of events is provided in Table 28. 

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune haemolytic anaemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anaemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombotic events with thrombocytopenia and/or bleeding.  It is not intended to 
be a comprehensive guide to the management of all venous thromboembolic events.  
During the course of the study, the investigator will remain vigilant for occurrence of 
thrombotic events with thrombocytopenia and/or bleeding.  Appropriate investigations (eg, 
imaging) to diagnose these events should be made on a case-by-case basis.  The investigator is 
responsible for determining whether a participant meets criteria for thrombotic events with 
thrombocytopenia and/or bleeding at any point during the study.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombotic events with thrombocytopenia 
and/or bleeding.  The Study Physician contacts the investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data.  
Guidance from the International Society of Thrombosis and Haemostasis for management of 
thrombocytopenic thromboembolism occurring after vaccination can be found at 
www.isth.org.  Notably, participants should only be treated with heparin if a test for heparin-
induced thrombocytopenia antibodies is negative.  An alternative explanation for 
thrombocytopenia should be considered (eg, alcohol use, liver cirrhosis, concomitant 
medications, exposure to toxic chemicals, viral infections).
The investigator is responsible for recording data pertaining to thrombotic events with 
thrombocytopenia and/or bleeding and for reporting AEs and SAEs according to the outcome 
of the review and assessment in line with standard safety reporting processes.
F 2
Tests that Should Be Considered if Thrombotic Events With 
Thrombocytopenia and/or Bleeding Are Suspected
The following tests should be considered, but not limited to:
1. Measurement of platelet levels, prothrombin time, activated partial thromboplastin time, 
D-dimer levels, and fibrinogen levels
2. Complete blood count, reticulocyte count, blood film, haptoglobins
3. Anti-platelet factor 4 antibodies

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4. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, human 
leucocyte antigen B27, ADAMTS13 activity, anti-cardiolipin antibodies IgG + IgM, and 
anti-B2GPI antibodies IgG + IgM
5. Complement (eg, C3, C4, complement complex C5b-9, C5a), autoantibodies (eg, 
antinuclear IgG, anti-double stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG)
6. Factor V Leiden, Factor II (prothrombin) variant 
7. Platelet activation markers and functional assays (eg: sCD40L, soluble glycoproteins, 
degranulation markers [PF4, vWF, P-selectin, annexin V]), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 ELISA positive)
8. Inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13
9. Cell adhesion molecules: VCAM, ICAM, E-selectin
10. Adenovirus serology
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Ebstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19
12. COVID-19 testing, including PCR and serology
13. Calculation of an International Society of Thrombosis and Haemostatis score for 
Disseminated Intravascular Coagulation (derived from platelet levels, fibrinogen, and D-
Dimer)

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ChAdOx1 MERS
Chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
AZD1222 when initially developed by the University of Oxford
COVID-19
Coronavirus disease 2019
eCRF
Electronic case report form
e-Diary
Electronic diary
GMT
Geometric mean titre
ICF
Informed consent form
ICH/GCP
International Council for Harmonisation/Good Clinical Practice
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
MAAEs
Medically attended adverse events
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
S
Spike
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome-coronavirus-2

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Appendix H
Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment  GBR-2
30 July 2021
Amendment GBR-1
3 June 2021
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment GBR-2: 30 July 2021
The principal reason for this amendment was to
1) add an additional interim analysis to evaluate immunogenicity in a subset of 
AZD1222 previously vaccinated subjects boosted with AZD1222 or AZD2816
2) revise Objectives/Endpoints from descriptive to comparative, with ranking of primary, 
key secondary, other secondary, and exploratory objectives
3) add non-inferiority margins to primary analysis and add additional participants to 
maintain power 
This amendment has also been implemented in the global version of the study D7220C00001 
Clinical Study Protocol.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis 
(Objectives and 
Endpoints)
Revised this section from 
primarily descriptive to 
primarily comparative.  
Comparative immunogenicity 
objectives created and ranked as 
primary, key secondary, other 
secondary.
Objectives of study 
changed from descriptive 
to comparative, testing for 
non-inferiority across 
treatment comparisons
Substantial
1.1 Synopsis 
(Number of 
Participants; Statistical 
Methods)
Overall size increased to 2590 
participants
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.1 Synopsis (Statistical 
Methods)
An additional interim analysis 
added. Second interim analysis 
changed to include only the 
Interim analysis plan was 
reviewed and revised.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
previously vaccinated with 
AZD1222 cohort.

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.2 Schema
Figures updated with increased 
participant numbers
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.3 Schedule of 
Activities
Table 2: footnote clarification 
added
Table 3: minor corrections
Clarification/Correction
Non-substantial
2.1 Study Rationale 
(and elsewhere in 
protocol)
Clarification on previous 
vaccination criteria
Clarification
Non-substantial
3 Objectives
Section completely rewritten.  
Divided into 2 sections: 
Previously unvaccinated and 
previously vaccinated.  
Immunogenicity objectives 
created for comparisons.  
Objectives ranked as primary, 
key secondary, other secondary, 
or exploratory.
Objectives of study 
changed to show non-
inferiority across 
treatments.  
Substantial
4.1 Overall design
Participant numbers increased
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
4.1 Overall design
Cap on age added
To ensure good 
representation across age 
groups
Substantial
8.3.2
Removal of severity grade 5
Correction
Non-substantial
8.5.2.3
 
 
Addition of information on 
number of patients sampled for 
Clarification
Non-substantial
9.1 Statistical 
Hypotheses
Addition of statistical 
hypotheses
Include hypothesis being 
tested.
Substantial
9.2 Sample size 
determination
Confidence intervals for 
populations of 350 and 380 
added to Table 14 and Table 15
Updated to include
current populations of 
350 and 380 participants
Non-substantial
9.2 Sample size 
determination
Power estimates for populations 
of 350 and 380 added to Table 
17 and Table 18
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
CCI
CCI

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
9.4.1 General 
considerations
Details on the initial interim, 
second interim, and third interim 
analysis added
Include revised 
information on the 
analysis plan, including 
interim analyses
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Objectives removed from 
descriptive analysis Table 23 
and Table 24
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Section of  Immunogenicity 
Comparisons added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Table 25 and Table 26 on 
immunogenicity comparisons 
revised, aligned with the revised 
objectives/endpoints.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.4 Multiple 
Comparisons
Section added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
In addition, the protocol has been revised with minor corrections and clarifications.
Amendment GBR-1 (Protocol Version 2): 1 June 2021
Version 1 of the protocol was amended prior to the commencement of the study (ie, prior to 
approval of the protocol by an ethics committee) based on feedback from internal and 
regulatory authority reviews.  The most substantial changes were as follows:
!
addition of 2 treatment arms:  1) AZD1222 as a single booster vaccination in participants 
previously vaccinated with an mRNA COVID-19 vaccine and 2) heterologous 
vaccination with AZD1222 plus AZD2816 in previously unvaccinated participants
!
further definition of analysis sets
!
addition of thrombotic events with thrombocytopenia as a discontinuation criteria
In addition, corrections and revisions to text to improve readability were made.

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11
REFERENCES
Dejnirattisai et al 2021
Dejnirattisai W, Zhou D, Supasa P, Liu C, Mentzer AJ, et al. Antibody evasion by the 
Brazilian P.1 strain of SARS-CoV-2. Cell 2021;184:1-16.
EMA 2021
European Medicines Agency. Reflection paper on the regulatory requirements for vaccines 
intended to provide protection against variant strain(s) of SARS-CoV-2 (EMA/117973/2021), 
February 2021. Available at: https://www.ema.europa.eu/en/regulatory-requirements-
vaccines-intended-provide-protection-against-variant-strains-sars-cov-2.
FDA 2007
US Food and Drug Administration. Guidance for Industry. Toxicity grading scale for healthy 
adult and adolescent volunteers enrolled in preventive vaccine clinical trials, Sept 2007.
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documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-
preventive-vaccine-clinical.
FDA 2021
US Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent 
COVID-19: Guidance for Industry, February 2021. Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-
authorization-vaccines-prevent-covid-19.
Folegatti et al 2020
Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A et al. Safety and 
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vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, Phase 1 trial. Lancet 
Infect Dis 2020;20:816-26.
JCVI 2021
Joint Committee on Vaccination and Immunisation. JCVI Statement on Use of the 
AstraZeneca COVID-19 Vaccine: 8 May 2021. Available at:
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statement-7-may-2021/use-of-the-astrazeneca-covid-19-azd1222-vaccine-updated-jcvi-
statement-7-may-2021
Lu et al 2020
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology 
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Madhi et al 2021
Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AK, Fairlie L, et al. Efficacy of the 
ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Eng J Med 2021.
Ramasamy et al 2020
Ramasamy MN, Voysey M, Aley PK, Bibi S, Clutterbuck EA, et al. Safety and 
immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in 
young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. 
Lancet 2020; 396(10267):1979-93.
Rovira et al 2015
Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP et al. MAGNIMS 
consensus guidelines on the use of MRI multiple sclerosis—clinical implementation in the 
diagnostic process. Nature Rev Neurolog 2015;11(8):471-82.
SPEAC 2020
Safety Platform for Emergency Vaccines. D2.3 Priority list of adverse events of special 
interest: COVID-19. Work Package: WP2 Standards and Tools. v1.1. Available from: 
https://media.tghn.org/articles/COVID-19_AESIs_SPEAC_V1.1_5Mar2020.pdf.
Voysey et al 2021a
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al. Safety and efficacy of 
the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four 
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Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, et al.  Single-dose 
administration and the influence of the timing of the booster dose on immunogenicity and 
efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised 
trials. Lancet 2021;397:881-91.
Wang et al 2021
Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
B.1.1.7. Nature 2021;593:130-5.
Zhou et al 2020
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus 
of probable bat origin. Nature 2020;579:270-3.
Zhou et al 2021
Zhou D, Dejnirattisai W, Supasa P, Liu C, Mentzer AJ, Ginn HM, et al. Evidence of escape of 
SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 2021;189:1-14.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7220C00001-csp-gbr2
Document Title:
D7220C00001 Clinical Study Protocol GBR2 Amendment
30Jul2021
Document ID:
Doc ID-004588859
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
02-Aug-2021 14:15 UTC
Content Approval
03-Aug-2021 08:02 UTC
Content Approval
03-Aug-2021 11:39 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
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Clinical Study Protocol
Study Intervention
AZD2816
Study Code
D7220C00001
Version
Amendment GBR-3
Date
13 October 2021
TITLE PAGE
A Phase II/III Partially Double-Blinded, Randomised, Multinational, 
Active-Controlled Study in Both Previously Vaccinated and Unvaccinated Adults Ages 
30 and Above to Determine the Safety and Immunogenicity of AZD2816, a Vaccine for 
the Prevention of COVID-19 Caused by Variant Strains of SARS-CoV-2
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
EudraCT: 2021-002530-17
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Number: D7220C00001
Amendment Number: GBR-3
Study Intervention: AZD2816
Study Phase: II/III
Short Title: Phase II/III Study of AZD2816, a Vaccine for the Prevention of COVID-19 in 
Adults
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator:  Andrew J Pollard, FRCPCH PhD FMedSci
           University of Oxford
            Oxford, United Kingdom

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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Amendment 3
13 October 2021
Amendment GBR-2
30 July 2021
Amendment GBR-1
3 June 2021
Amendment 1
1 June 2021
Version 1
14 May 2021
Amendment GBR-3: 13 October 2021
The principal reason for this amendment was to remove the age cap and revise the primary 
and key secondary non-inferiority analyses to included historical controls due to difficulties in 
recruiting the previously unvaccinated cohort.
This amendment has also been implemented in the global version of the study D7220C00001 
Clinical Study Protocol.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Synopsis
Section 4.1
Section 9.4..3.1.1
Inserted information on use of 
historical controls
Required based on anticipated 
confounding between 
previously vaccinated and 
previously unvaccinated 
cohorts.
Substantial
Section 3.2, Table 6
Inserted exploratory objectives on 
exploration of humoral immune 
response with live virus 
neutralization assay and 
exploration of additional immune 
response based on emerging data
Omitted in error
Non-substantial
Section 4.1
Deleted age cap ensuring at least 
25% enrolled participants were 
>65 years of age.
Due to enrollment difficulties 
in finding previously 
unvaccinated elderly
Substantial
Section 7.1
Inserted laboratory-confirmed 
SARS-CoV-2 infection as 
discontinuation of study 
intervention
To explicitly state this 
criterion (which is implicitly 
included in criteria 2) as a 
discontinuation of treatment 
criterion.
Non-substantial
Section 9.2
Section on immunogenicity 
comparisons and previous Table 
Had been placed under 
Secondary Objective in error
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
16 and Table 17 were moved up 
under the Primary Objective sub-
heading
Section 9.4.3.1.1
Table 19
Table 20
Table 21
Table 22
Table 23
Analysis key (abbreviations) 
revised
Improvements in 
abbreviations for clarity
Non-substantial
Section 9.4..3.1.1
Description of statistical approach 
to be used with historical control 
comparisons added. 
Inclusion of historical 
controls requires description 
of statistical methodology to 
be used.
Substantial
In addition, the protocol has been revised with minor rewordings, corrections, and 
clarifications which are all considered to be non-substantial.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................. 3
TABLE OF CONTENTS...................................................................................................... 5
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schema............................................................................................................. 21
1.3
Schedule of Activities....................................................................................... 22
2
INTRODUCTION............................................................................................ 28
2.1
Study Rationale ................................................................................................ 28
2.2
Background ...................................................................................................... 28
2.3
Benefit/Risk Assessment................................................................................... 31
2.3.1
Risk Assessment............................................................................................... 31
2.3.2
Benefit Assessment........................................................................................... 32
2.3.3
Benefit: Risk Assessment for Inclusion of Adults from 30 to 39 Years of Age .. 32
2.3.4
Overall Benefit: Risk Conclusion...................................................................... 33
3
OBJECTIVES AND ENDPOINTS................................................................... 34
3.1
Previously unvaccinated cohort receiving a 2-dose primary vaccination............ 34
3.2
Previously vaccinated cohort receiving a 1-dose booster vaccination ................ 39
4
DESIGN........................................................................................................... 45
4.1
Overall Design.................................................................................................. 45
4.1.1
COVID-19 Assessments ................................................................................... 47
4.1.2
Screening.......................................................................................................... 47
4.1.3
Vaccination Visit .............................................................................................. 48
4.1.4
Follow-up visits................................................................................................ 48
4.2
Scientific Rationale for Study Design ............................................................... 48
4.2.1
Rationale for Study Design and Participant Population ..................................... 48
4.2.2
Rationale for Study Endpoints .......................................................................... 49
4.3
Justification for Dose........................................................................................ 50
4.4
End of Study Definition.................................................................................... 51
5
STUDY POPULATION ................................................................................... 51
5.1
Inclusion Criteria .............................................................................................. 51
5.1.1
All Participants:................................................................................................ 51
5.1.2
Previously COVID-19 Vaccinated Participants................................................. 53
5.2
Exclusion Criteria ............................................................................................. 54
5.3
Lifestyle Considerations ................................................................................... 56
5.4
Screen Failures ................................................................................................. 56
6
STUDY INTERVENTION............................................................................... 56

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6.1
Study Interventions Administered..................................................................... 57
6.1.1
Investigational Products.................................................................................... 57
6.1.2
Dosing Instructions........................................................................................... 58
6.2
Preparation/Handling/Storage/Accountability ................................................... 58
6.2.1
Dose Preparation and Administration................................................................ 59
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 59
6.3.1
Randomization.................................................................................................. 59
6.3.2
Blinding............................................................................................................ 60
6.3.3
Procedures for Unblinding ................................................................................ 61
6.4
Study Intervention Compliance......................................................................... 61
6.5
Concomitant Therapy........................................................................................ 61
6.5.1
Permitted Concomitant Medications ................................................................. 61
6.5.2
Prohibited Concomitant Medications ................................................................ 62
6.6
Dose Modification ............................................................................................ 63
6.7
Intervention After the End of the Study............................................................. 63
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 63
7.1
Discontinuation of Study Intervention............................................................... 63
7.2
Participant Withdrawal from the Study ............................................................. 64
7.3
Lost to Follow-up ............................................................................................. 64
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 65
8.1
Efficacy Assessments........................................................................................ 65
8.2
Safety Assessments........................................................................................... 65
8.2.1
Physical Examinations...................................................................................... 65
8.2.2
Vital Signs........................................................................................................ 66
8.2.3
Clinical Laboratory Assessments ...................................................................... 66
8.3
Adverse Events and Serious Adverse Events..................................................... 67
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 67
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 68
8.3.3
Causality Collection.......................................................................................... 69
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 69
8.3.5
Adverse Events Based on Examinations and Tests............................................ 69
8.3.6
Hy’s Law.......................................................................................................... 69
8.3.7
Solicited Adverse Events .................................................................................. 70
8.3.8
COVID-19 Assessment..................................................................................... 71
8.3.9
Medically-Attended Adverse Events................................................................. 71
8.3.10
Adverse Events of Special Interest.................................................................... 71
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest ................................ 72
8.3.10.2
Potential Neurological Adverse Events of Special Interest ................................ 72
8.3.11
Reporting of Serious Adverse Events................................................................ 74
8.3.12
Pregnancy......................................................................................................... 74
8.3.12.1
Maternal Exposure............................................................................................ 74

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8.3.13
Medication Error............................................................................................... 75
8.4
Overdose .......................................................................................................... 75
8.5
Human Biological Samples............................................................................... 76
8.5.1
Pharmacokinetics.............................................................................................. 76
8.5.2
Immunogenicity Assessments ........................................................................... 76
8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 77
8.5.2.2
8.5.2.3
8.5.2.4
8.5.3
Pharmacodynamics........................................................................................... 78
8.6
Human Biological Sample Biomarkers ............................................................. 78
8.7
Optional Genomics Initiative Sample................................................................ 78
8.8
Medical Resource Utilization and Health Economics ........................................ 78
9
STATISTICAL CONSIDERATIONS............................................................... 78
9.1
Statistical Hypotheses....................................................................................... 78
9.2
Sample Size Determination............................................................................... 79
9.3
Populations for Analyses .................................................................................. 85
9.4
Statistical Analyses........................................................................................... 85
9.4.1
General Considerations..................................................................................... 86
9.4.2
Safety ............................................................................................................... 87
9.4.2.1
Primary Endpoints ............................................................................................ 87
9.4.2.2
Other Safety Endpoints..................................................................................... 88
9.4.3
Immunogenicity................................................................................................ 88
9.4.3.1
Immunogenicity Endpoints ............................................................................... 88
9.4.4
Multiple Comparisons..................................................................................... 100
9.4.5
Data Safety Monitoring Board ........................................................................ 100
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 100
11
REFERENCES............................................................................................... 127
CCI
CCI
CCI

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LIST OF TABLES
Table 1
Schedule of Activities: Screening ............................................................ 22
Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine . 23
Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 4-Week Dosing 
Interval.................................................................................................... 24
Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously 
Unvaccinated Participants Receiving Vaccination with a 12-Week 
Dosing Interval........................................................................................ 26
Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination.............................. 35
Table 6
Study Objectives and Endpoints for Previously Vaccinated Participants 
Receiving a 1-Dose Booster..................................................................... 40
Table 7
Highly Effective Methods of Contraception............................................. 53
Table 8
Investigational Products........................................................................... 57
Table 9
Laboratory Safety Variables..................................................................... 66
Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment....... 70
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)...... 79
Table 12
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set) .......................... 79
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes........... 80
Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroresponse Rates and Proposed 
Sample Sizes ........................................................................................... 81
Table 16
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio .................................................................... 82
Table 17
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate .............................................................. 83
Table 15
Probability of detecting 1 or more safety events (N = 300)....................... 84
Table 18
Populations for Analysis .......................................................................... 85
Table 19 
Description of the Analysis Keys for Tables 19 and 20 ............................ 90

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 91
Table 21
Immunogenicity Descriptive Analysis for Previously Vaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)................................................................................................. 92
Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups........ 96
Table 23
Immunogenicity Comparisons for Previously Vaccinated Group.............. 98
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable Product112
Table 25
Tables for Clinical Abnormalities: Vital Signs....................................... 113
Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness) ........... 114
Table 27
Adverse Events of Special Interest......................................................... 115
Table 28
List of Potential Immune-mediated Medical Conditions......................... 116
LIST OF FIGURES
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination................................................. 21
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster.................................................. 21
Figure 3
Neurology Testing Algorithm .................................................................. 73

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 101
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 106
Appendix C
Handling of Human Biological Samples ................................................ 110
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ........................... 112
Appendix E
Adverse Events of Special Interest......................................................... 115
Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding ....................................................... 119
Appendix G
Abbreviations ........................................................................................ 121
Appendix H
Protocol Amendment History................................................................. 122

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A phase II/III partially double-blinded, randomised, multinational, active-
controlled study in both previously vaccinated and unvaccinated adults to determine the safety 
and immunogenicity of AZD2816, a vaccine for the prevention of COVID-19 caused by 
variant strains of SARS-CoV-2.
Short Title: Phase II/III study of AZD2816, a vaccine for the prevention of COVID-19 in 
adults.
Rationale: Recently, several variants of the SARS-CoV-2 virus with increased
transmissibility have emerged, including B.1.1.7, first identified in the UK, P.1, first identified 
in Brazil, and B.1.351, first identified in South Africa.  In an ongoing clinical trial of 
AZD1222 in South Africa, interim results failed to show protection against mild to moderate 
disease caused by the B.1.351 variant; protection against severe disease could not be 
determined as no severe cases were identified (Madhi et al 2021). 
Based on available evidence about vaccine effectiveness and molecular epidemiology of 
emerging variants, B.1.351 is estimated to have a potential to escape vaccine-induced 
immunity. B.1.351 carries sequence mutations in common with other variants of concerns; 
immunity to B.1.351 therefore has the potential to provide some cross-immunity against other 
emerging strains. Development of candidate vaccines that include the B.1.351 S-protein 
variant is underway.  AstraZeneca is developing AZD2816, a vaccine against the B.1.351 
SARS-CoV-2 variant using the same ChAdOx1 platform and manufacturing processes used 
for AstraZeneca’s currently available COVD-19 vaccine, AZD1222.
Objectives and Endpoints:
The purpose of this study is to characterize the safety and immunogenicity of AZD2816, 
AstraZeneca’s candidate ChAdOx1 vector vaccine against SARS-CoV-2 variant strain 
B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative participants who previously 
received a 2-dose primary vaccination against SARS-CoV-2 with AZD1222 or an 
mRNA COVID-19 vaccine
!
As a 2-dose primary homologous vaccination to SARS-CoV-2 seronegative 
participants who are previously unvaccinated
!
As the second dose of 2-dose primary heterologous vaccination (with AZD1222 
as first dose) to SARS-CoV-2 seronegative participants who are unvaccinated.

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It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to the previously-vaccinated cohort that will receive a single booster dose of AZD2816 or 
AZD1222.
The following table lists the primary and secondary endpoints:
Objectives
Endpoints
Safety Objectives: Previously unvaccinated participants
- Primary
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
4-week dosing interval in unvaccinated seronegative 
participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of 
a 2-dose primary heterologous vaccination with 1 
dose of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
a 2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 4-week 
dosing interval in previously unvaccinated 
seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary heterologous vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of a 2-dose 
primary vaccination with AZD2816 with a 12-week 
dosing interval in previously unvaccinated 
seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives: Previously unvaccinated participants
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination

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Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-Hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 heterologous 
primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary vaccination 
is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination

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Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
Objectives
Endpoints
Safety Objectives: Previously vaccinated participants
- Primary

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To characterize the safety and tolerability of 
1 booster dose of AZD2816 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of 
1 booster dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 booster dose of AZD2816 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of 
1 booster dose of AZD1222 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of 1 booster dose 
of AZD2816 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster dose 
of AZD1222 in seronegative participants previously 
vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster dose 
of AZD2816 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster dose 
of AZD1222 in seronegative participants previously 
vaccinated with a SARS-CoV-2 mRNA vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives: previously vaccinated participants
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-Hu-1
Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-Hu-1
Wuhan-Hu-1

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Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 
vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.4
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 
vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-Hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated 
with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination

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Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated 
with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants

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Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus  AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-Hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-Hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
SAEs: serious adverse events; MAAEs: medically attended adverse events; AESIs: adverse events of special 
interest.
a
At least a 4-fold increase in geometric mean titre from baseline

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Overall Design: This is a phase II/III, multinational, randomised, partially double-blind, 
controlled study in two distinct cohorts: previously vaccinated and previously unvaccinated 
participants. 
Disclosure Statement: This is a parallel-group preventive study with 8 treatment arms.
Number of Participants: Approximately 2590 SARS-CoV-2 nucleocapsid seronegative 
participants will be assigned to study intervention to support the primary and secondary 
objectives of this study. In addition, participants that are SARS-Cov-2 nucleocapsid 
seropositive at screening will be enrolled and assigned to study intervention for an exploratory 
analysis, with a cap of 10% of the seronegative population (ie, approximately 259 total 
participants).
Intervention Groups and Duration: Previously vaccinated participants will receive 1 dose 
of AZD1222 or AZD2816 on Day 1.  Previously unvaccinated participants will receive one of 
the following 2-dose vaccinations:
!
1 dose of AZD2816 on Day 1 and on Day 29
!
1 dose of AZD1222 on Day1 and on Day 29
!
1 dose of AZD1222 on Day 1 and 1 dose of AZD2816 on Day 29
!
1 dose of AZD2816 on Day 1 and on Day 85. 
Participants will be followed up for safety for 180 days after last study vaccine administration.
Data Monitoring Committee: A Data Safety Monitoring Board will provide oversight to 
ensure safe and ethical conduct of the study.
Statistical Methods:
Sample sizes of 300-380 seronegative participants per group are deemed appropriate based 
upon available immunogenicity data from previous clinical studies with AZD1222 for the 
primary and secondary objectives of this study.  
Owing to national vaccine rollout in the recruitment countries, including the prioritization of 
elderly populations, it is anticipated that there will be critical differences between the 
previously vaccinated and previously unvaccinated cohorts that may confound the 
interpretation of the results.  Consequently, the primary and key secondary non-inferiority 
analyses across these two cohorts will compare the previously vaccinated participants that 
received a booster dose in this study with a subset of matched participants from the previously 
unvaccinated participants that received the 2-dose AZD1222 primary vaccine series in the 
AZD1222 Phase 3 trial, Study D8110C00001.

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The safety analysis set for adverse events consists of all participants who have received at 
least one dose of study intervention.  The immunogenicity analysis set includes all participants 
in the safety analysis set who have no protocol deviations or intercurrent events judged to 
have the potential to interfere with the generation or interpretation of an immune response.
An initial interim analysis will be performed on a subset of previously AZD1222 vaccinated 
participants that have received a booster dose to consider unblinded sample size adjustment. A 
second interim analysis will be performed when all previously AZD1222 vaccinated 
participants have completed their Day 29 visit to support registration of a booster dose. A 
third interim analysis will be performed on a subset of previously unvaccinated participants 
that have received their second dose to consider blinded sample size adjustment in this 
population. The primary analysis will be performed when there are data from all previously 
unvaccinated participants 28 days after the second dose of the 4-week dosing intervals to 
support assessment of these 2-dose primary vaccinations.  A secondary analysis will be 
performed on data from 28 days after the second dose of the 12-week dosing interval to 
support assessment of this 2-dose primary vaccination.  The final analysis will be performed 
on data from 6 months follow-up after participant's vaccination.  

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1.2
Schema
Figure 1
Study Design for Unvaccinated Seronegative/Seropositive Participants 
Receiving a 2-Dose Primary Vaccination
Figure 2
Study Design for Previously Vaccinated Seronegative/Seropositive 
Participants Receiving a 1-Dose Booster 
Note:  In addition to the approximately 2590 seronegative participants enrolled to support the primary/secondary objectives, 
seropositive participants will also be enrolled in the study to support exploratory objectives in this population, with a cap of 
10% of the planned seronegative participants (ie, a maximum of 259 seropositive participants, bringing total enrollment to 
2849).

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1.3
Schedule of Activities
Table 1
Schedule of Activities: Screening 
Procedure
Day -14 to Day 1
See Section
Informed consent
X
5.1, Appendix A 3
Demography
X
-
Medical and surgical history
X
-
Prior and concomitant medications
X
6.5
Complete physical examination, including height and weight
X
8.2.1
Vital signs
X
8.2.2
Urine pregnancy test (for women of childbearing potential only) 
X
8.2.3
Clinical safety laboratory assessments
X
8.2.3
Assessment of serious adverse events
X
8.3, Appendix B
Blood sample for SARS-CoV-2 antibody testing (lateral flow test)
X
8.5.2
Verify eligibility criteria
X
5.1, 5.2
Note:  Screening activities can occur at same visit as initial vaccination with investigational product (ie, Visit 1 in 
Table 2, Table 3, and Table 4).

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Table 2
Schedule of Activities: Treatment/Follow-up Period for Participants 
Previously Vaccinated with 2 Doses of AZD1222 or an mRNA Vaccine
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
Day
1
8
15
29
180
Window (days)
-
±2
±2
±3
±14
Medical and surgical history
X
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
-
-
6.1.1
Immunological assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
-
8.3.7
e-Diary collected
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose) b
X
-
X
X
8.2.3
a
Only SAEs pre-dose
b
Not required to be repeated if performed on screening day prior to Day 1.
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: 
serious adverse event

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
Urine pregnancy test
(women of childbearing potential)
X 
-
-
X 
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X 
-
-
X 
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample for SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample for additional immunogenicity
X (pre-dose)
-
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
X
-
-
-
8.3.7

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Table 3
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 4-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
Day
1
8
15
29
V4+7
V4+14
V4+28
V4+180
Window (days)
-
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
X
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
Medical and surgical history
X
-
-
-
-
-
-
-
-
-
Urine pregnancy test 
(women of childbearing potential)
X
-
-
-
X
-
-
-
-
8.2.3
Concomitant medications/vaccinations
X
X
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
-
-
-
-
-
-
-
-
5.1, 5.2
Monitoring of COVID-19
X
X
X
X
X
X
X
X
X
8.3.8
Vaccine administration (after screening 
activities, the activities listed above, and the 
pre-dose sampling activities listed below)
X
-
-
-
X
-
-
-
-
6.1.1
Immunogenicity assessments
Serum sample to assess SARS-CoV-2 
serology/neutralising antibodies 
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Serum sample to assess additional 
immunogenicity
X (pre-dose)
-
X
X
X (pre-dose)
-
X
X
X
8.5.2
Blood sample to assess B-cell and T-cell 
responses in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Blood sample for B-cell and T-cell response 
sequencing in a sub-group of participants
X (pre-dose)
-
X
X
X (pre-dose)
-
-
X
X
8.5.2.3
Safety assessments
Targeted physical examination
X
-
-
-
X
-
-
-
-
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
e-Diary provided with training
X
-
-
-
X
-
-
-
8.3.7

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Table 4
Schedule of Activities: Treatment/Follow-up Period for Previously Unvaccinated Participants Receiving 
Vaccination with a 12-Week Dosing Interval
Procedure
Treatment and Follow-up Period
Section
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
Day
1
8
15
29
85
V5+7
V5+14
V5+28
V5+180
Window (days)
-
±2
±2
±2
±3
±2
±2
±3
+14
e-Diary collected
-
X
-
-
-
X
-
-
-
8.3.7
Unsolicited AEs
X (post-dose)
X
X
X
X
X
X
X
-
8.3
MAAEs, SAEs, and AESIs
Xa
X
X
X
X
X
X
X
X
8.3.8, 
8.3.8
Clinical safety laboratory assessments
X (pre-dose)
X
-
X
X (pre-dose)
X
-
X
X
8.2.3
a
Only SAEs pre-dose
AE: adverse event; AESI: adverse event of special interest; MAAE: medically-attended adverse event; SAE: serious adverse event

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2
INTRODUCTION
AZD2816 is being developed for the prevention of COVID-19.  It is a modified version of the 
current AstraZeneca SARS-CoV-2 vaccine (referred to as AZD1222 in clinical 
documentation) that has been modified to also provide immunity against the newly emerging 
SARS-CoV-2 variant strain B.1.351.  Like AZD1222, AZD2816 is a recombinant replication-
defective chimpanzee adenovirus vector (ChAdOx1) expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tissue plasminogen activator leader sequence at the 
N terminus.  AZD2816 differs from AZD1222 in that the S glycoprotein gene sequence used 
is from the B.1.351 variant strain instead of the original Wuhan-Hu-1 variant.
2.1
Study Rationale
The aim of the study is to assess the safety and immunogenicity of AZD2816 for prevention 
of COVID-19 as both a 2-dose primary vaccination in previously unvaccinated participants 
and a 1-dose booster vaccination in participants previously vaccinated against the original 
Wuhan-Hu-1 strain of SARS-CoV-2 by either AZD1222 or an mRNA-based vaccine.  A safe 
and effective vaccine for COVID-19 prevention, including against the B.1.351 variant, would 
have significant global public health impact. 
The study will also investigate the safety and immunogenicity of 1) a heterologous 2-dose 
vaccination with AZD1222 as first dose and AZD2816 as the second dose and 2) a single dose 
of AZD1222 as a booster vaccination in participants that have been previously vaccinated 
with an mRNA COVID-19 vaccine targeting the original Wuhan-Hu-1 strain.  
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (
Zhou et al 2020).  The disease these patients contracted was subsequently named Coronavirus 
Disease 2019 (COVID-19).  The World Health Organization declared the novel coronavirus a 
pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the novel coronavirus 
SARS-CoV-2, has resulted in significant global morbidity and mortality as well as major 
disruption to healthcare systems.  Measures to change the course of the pandemic have 
included the accelerated development vaccines against the original Wuhan-Hu-1 strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes.  SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus,
and it is the seventh corona virus known to cause human infections and the third known to 

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cause severe disease after SARS-CoV and MERS-CoV. One fourth of the viral genome is 
responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 
and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 spike (S) glycoprotein is a type I trimeric, transmembrane protein that is 
located at the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s 
subunits are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the 
receptor binding domain and subsequent fusion of virus and cell membranes, thereby
mediating the entry of SARS-CoV-2 into the target cells.  The S protein has an essential role 
in virus entry and determines tissue and cell tropism, as well as host range.  The roles of the 
S-protein in receptor binding and membrane fusion have made it a desirable target for vaccine 
and antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947
(ie, the Wuhan-Hu-1 isolate).
To date, 5 vaccines that rely upon the expression of the SARS CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 
NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b).  Immunogenicity data indicate that a 
single dose of AZD1222 elicits both humoral and cellular immunogenicity responses and that 
antibody responses are boosted after a second dose.  In a pooled analysis of the 4 studies 
conducted in the United Kingdom, Brazil, and South Africa (database lock 07 December 
2020), the vaccine was highly immunogenic; seroresponse of S binding antibody was > 98% 
after a single dose of AZD1222.  Seroresponse of live neutralising antibody was 82.4% after 1 
dose, which rose to 99.4% after a second dose.  Efficacy analyses of the pooled DCO2 data 
demonstrated effective protection of AZD1222 against COVID-19 with a vaccine efficacy of 
66.73% (95.84% CI: 57.41%, 74.01%) (p < 0.001) from 15 days after the second dose in 
seronegative participants receiving 2 doses.  The DCO2 data also demonstrated that the 
standard dose of AZD1222 (5 x 1010 viral particles) provides complete protection against 
COVID-19 hospital admission ≥ 22 days after the first dose in the seronegative analysis set 
(0 versus 14 cases in the control group, 2 of which were severe, including one with a fatal

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outcome).  Vaccine efficacy was similar in participants with pre-existing comorbidities, being 
those at greatest risk of severe outcomes of COVID-19, compared to that in the general 
population.  Recently available primary analysis data from a Phase III study performed in the 
United States and Latin America showed primary endpoint vaccine efficacy of 76% (95% CI: 
67.60%, 82.22%; p-value < 0.001). 
A sharp rise in COVID-19 cases was reported in late 2020, which was attributed to the 
emergence of new SARS-CoV-2 variant strains: B.1.1.7 in the United Kingdom, B.1.351 
in South Africa, and P.1 in Brazil.  These variant strains carry a number mutations in the 
S protein sequence: 9 amino acids in B.1.1.7, 10 amino acids in B.1.351, and 12 amino acids 
in P.1 compared with the Wuhan-Hu-1 sequence.  These mutations may result in an increase 
of transmissibility and/or reduced vaccine effectiveness.  Variant B.1.351 was first identified 
in South Africa in October 2020.  Its attributes include approximately 50% increased 
transmission and moderate impact of neutralization by monoclonal antibody therapeutics, 
convalescent plasma and vaccine sera.  In vitro neutralization assays suggest that the B.1.351 
lineage viruses may be the most antigenically distinct from the original Wuhan-like strains 
(Zhou et al 2021).  In addition, evidence suggests that AZD1222 may afford diminished 
protection against mild-moderate COVID-19 disease arising from the B.1.351 variant which 
is also antigenically the most different from the Wuhan-Hu-1 virus (Madhi et al 2021).  
The development of candidate vaccines that would be effective against the B.1.351 variant 
strain is underway.  AZD2816 is being developed as an updated ChADOx-nCOv19 vaccine 
designed to provide protective immunity against the newly arising B.1.351 variant strain, 
using the same ChAdOx1 platform and manufacturing processes used for AstraZeneca’s 
currently approved COVID-19 vaccine, AZD1222.  The purpose of this Phase II/III, 
multinational, randomised, partially double-blind, active-controlled study is to demonstrate 
the safety and characterize the immunogenicity of AZD2816, AstraZeneca’s candidate 
ChAdOx1 vector vaccine against B.1.351, when administered:
!
As a single booster dose to SARS-CoV-2 seronegative participants who have previously 
received a 2-dose primary vaccination series against the original SARS-CoV-2 Wuhan-
Hu-1 strain (AZD1222 or an mRNA vaccine) 
!
As a 2-dose homologous primary vaccination to SARS-CoV-2 seronegative participants 
who have not been vaccinated previously. 
It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to the previously-vaccinated cohort that will receive a single booster dose.  
The immunogenicity of a 2-dose primary heterologous vaccination (with AZD1222 as first 
dose and AZD2816 as second dose) to SARS-CoV-2 seronegative participants who are 
unvaccinated and a single booster dose of AZD1222 to SARS-CoV-2 seronegative 

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participants who have previously received a 2-dose primary vaccination series against the 
original SARS-CoV-2 Wuhan-Hu-1 strain will also be investigated.
SARS-CoV-2 seropositive participants will be enrolled in separate cohorts to support a 
parallel exploratory analysis in these participants.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD1222 and 
AZD2816 is provided in the respective Investigator’s Brochures.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD2816 and AZD1222 can be found in the respective Investigator’s Brochures.
2.3.1
Risk Assessment
AZD2816 has been developed using the same vaccine vector, ChAdOx1, as AZD1222 and 
only differs in the sequence for SARS-CoV-2 S glycoprotein that is inserted in the vector.  
The anticipated safety profile of AZD2816 is the same as the observed safety profile of 
AZD1222.  Risks associated with AZD2816 are thus the same as the risks associated with 
AZD1222, and no additional risks are anticipated due to the change in the targeted sequence.
A number of essentially mild and moderate adverse reactions to AZD1222 have been 
identified and resemble reactions frequently observed after many vaccines.  Based on pooled 
clinical data from studies with AZD1222, the most commonly expected local solicited AEs for 
participants in this study are vaccination site pain and tenderness.  The most commonly 
expected systemic solicited AEs are fatigue, headache, and malaise.  The majority of reported 
events have been mild or moderate in severity and resolved within 1 to 7 days.  Following the 
second dose, a general attenuation in the incidence and severity of local and systemic solicited 
AEs was observed. 
Post-authorisation hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk.
A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, 
has been observed very rarely following vaccination with COVID-19 Vaccine (ie, AZD1222) 
during post-authorisation use. No events have been observed in the AZD1222 clinical 
development programme.  Thrombosis in combination with thrombocytopenia is thus 
considered to be an important identified risk.  This includes cases presenting as venous 
thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein 
thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia.  Considering 
the frequency of this rare event and the size of this study, the risk for participants in this trial 
is considered to be low.  The protocol includes exclusion criteria and instructions for 

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heightened vigilance and thorough investigations for suspected cases to mitigate against 
further the risk for these rare event. 
Important potential risks are 1) neurologic events and potential immune-mediated neurologic 
conditions and 2) vaccine-associated enhanced disease, including vaccine-associated enhanced 
respiratory disease. 
2.3.2 Benefit Assessment
All participants will receive active treatment: either AZD1222, which has been shown to be 
effective in providing protection against SARS-CoV-2, or AZD2816, which as a modified 
form of AZD1222 designed to be effective against the emergent B.1.351 variant strain and 
may also provide participants with protection.  The information gained from this study will 
inform development decisions with regard to the efficacy of AZD2816 as both a primary 
2-dose vaccination in participants that have not been previously vaccinated and a 1-dose 
booster vaccination in participants previously vaccinated against SARS-CoV-2.
2.3.3 Benefit: Risk Assessment for Inclusion of Adults from 30 to 39 Years of 
Age
There have been reports of very rare adverse events of concurrent thrombosis and 
thrombocytopenia following vaccination with the first dose of AstraZeneca CoV-19 vaccine 
(AZD1222). There have been no safety concerns identified for thrombosis/thrombocytopenia 
associated with the second dose of the AstraZeneca (AZD1222) vaccine.  Up to 19 May 2021, 
the MHRA has received reports of 332 cases of major thromboembolic events with concurrent 
thrombocytopenia in the United Kingdom following vaccination with COVID-19 Vaccine 
AstraZeneca. The estimated number of first doses of COVID-19 Vaccine AstraZeneca 
administered was 24.2 million, and the estimated number of second doses was 10.7 million.
Any risk for serious thromboembolic events with thrombocytopenia is expected to be similar 
for AZD1222 and AZD2816 due to the similarity of the investigational products. 
In the context of this extremely rare adverse event, current advice from the United Kingdom’s 
Joint Committee on Vaccination and Immunization (JCVI) recommends that unvaccinated 
adults aged 30 to 39 years who are not in a clinical priority group at higher risk of severe 
COVID-19 disease should be preferentially offered an alternative to AZD1222 where possible 
and only where no substantial delay or barrier in access to vaccination would arise (JCVI 
2021).  The recommendations are not a contra-indication in this age group but a public 
vaccination policy recommendation in the context of a current low incidence of disease, the 
availability of alternative vaccines, and current speed and uptake of the vaccination 
programme overall in the UK.  The recommendations further advise that AZD1222 can be 

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used in the age group 30-39 if these factors deteriorate, stating that if other vaccines are not 
available “the benefits of receiving the AstraZeneca (AZD1222) vaccine outweigh the risks”.  
The participants of the proposed study differ from the general public in that they are carefully 
selected, with exclusion of individuals with a wide range of risk factors for 
thrombosis/thrombocytopenia, to minimize this risk.  The study also includes careful 
monitoring both pre-treatment and post-treatment to detect risk for thrombotic events with 
thrombocytopenia and promptly identify safety concerns at the individual participant level. 
The protocol and training for the investigators urges increased vigilance for these events of 
thrombosis with thrombocytopenia.  Furthermore, Appendix F provides guidance on 
identifying, treating, and assessing these very rare events.  The risk of these events occurring 
is disclosed in the Participant Information Sheet and Informed Consent Form.  Furthermore, 
participants are advised to be alert for the following side effects in the 28 days after 
vaccination: severe/unusual headache, new or unexplained bruising/bleeding, shortness of 
breath, chest pain, leg swelling, persistent abdominal pain.  The exclusion of individuals with 
a wide range of risk factors for thrombosis with thrombocytopenia and measures included in 
the study to ensure early detection of these events mitigates the risk for these rare events.
With regard to benefit, all patients enrolled in the study will receive active treatment, either 
with the approved AZD1222, which has a good safety profile and high efficacy in adults ages 
18 and over, including protection against severe disease, or the experimental but closely 
related AZD2816, which is expected to have a similar safety profile with the potential to have 
broader efficacy than AZD1222, including against the emergent B.1.351 variant.  
Furthermore, the inclusion of these patients in the trial is important to investigate safety and 
immunogenicity of AZD2816, as both a primary vaccination and a booster vaccination, across 
the age groups for which it may be administered in clinical practice.
To summarise, the risk of serious harm due to vaccine-induced thrombotic thrombocytopenia 
is known to be small.  As of 19 May 2021, the MHRA’s estimate of the overall incidence after 
first or unknown doses is 1.3 per 100,000 doses.  Thus, the risk of one of these events 
occurring in the sub-group of participants 30 to 39 year of age from a study population of 
around 2000 patients is extremely low. This risk is appropriately mitigated in the study 
protocol to the extent that the risk-benefit of patients 30 to 39 years of age participating in this 
study is considered to be small, acceptable, and justified by the potential public health benefits 
of the study.
2.3.4 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria and close monitoring of participants to 
minimize known and potential risks. 

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An independent Data Safety Monitoring Board will provide study oversight, evaluating 
cumulative safety and other clinical data at regular intervals. 
Taking these measures into account, the potential risks identified in association with the 
administration of AZD2816 and AZD1222 are justified by the anticipated benefit that may 
be afforded to participants for the prevention of COVID-19.
3
OBJECTIVES AND ENDPOINTS
3.1
Previously unvaccinated cohort receiving a 2-dose primary 
vaccination
The primary safety objective for the cohort of previously unvaccinated participants receiving a 
2-dose dose primary vaccination is to characterize the safety and tolerability of a 2-dose 
primary vaccination with AZD2816 with a 4-week dosing interval in previously unvaccinated 
seronegative participants.
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary: 
1: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response against the original 
Wuhan-Hu-1 strain elicited by a 2-dose AZD1222 vaccination.
Key secondary:
2.1: To determine if seroresponse against the B.1.351 variant elicited by a 2-dose AZD2816 
vaccination is non-inferior to seroresponse against the original Wuhan-Hu-1 strain elicited by 
a 2-dose AZD1222 vaccination.
2.2: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 2-dose 
AZD1222 vaccination.
2.3: To determine if the neutralizing antibody GMT response against the B.1.351 variant 
elicited by a 2-dose heterologous AZD1222 + AZD2816 vaccination is non-inferior to the 
response against the original Wuhan-Hu-1 strain elicited by a 2-dose AZD1222 vaccination
2.4: To determine if the neutralizing antibody GMT response against the original Wuhan-Hu-
1 elicited by a 2-dose AZD2816 vaccination is non-inferior to the response elicited by a 2-
dose AZD1222 vaccination

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The above primary and the key secondary immunogenicity objectives will be supported by 
other secondary immunogenicity objectives (see below) for which there will be no formal 
hypothesis testing.
Table 5 further describes the objectives and endpoints for this cohort of participants, including 
estimands for the immunogenicity objectives.
Table 5
Study Objectives and Endpoints for Previously Unvaccinated 
Participants Receiving a 2-Dose Primary Vaccination
Safety Objectives
Objectives
Endpoints
- Primary
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 4-
week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory 
measures for 28 days post-dose
- Secondary
To characterize the safety and tolerability of a 
heterologous primary vaccination with 1 dose of 
AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the safety and tolerability of a 
2-dose primary vaccination with AZD2816 with a 
12-week dosing interval in previously unvaccinated 
seronegative participants
! Incidence of local and systemic solicited AEs for 
7 days post-dose
! Incidence of unsolicited AEs, including MAAEs, 
SAEs, and AESIs for 28 days post-dose
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 4-week dosing 
interval in previously unvaccinated seronegative 
participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety and tolerability of a 
heterologous primary vaccination with 1 dose
of AZD1222 followed by 1 dose of AZD2816 
administered with a 4-week dosing interval in 
previously unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
To characterize the extended safety of a 2-dose primary 
vaccination with AZD2816 with a 12-week dosing 
interval in unvaccinated seronegative participants
! Incidence of MAAEs, SAEs, and AESIs from Day 
1 through 6 months post-vaccination
Immunogenicity Objectives
To determine if the pseudoneutralizing antibody GMT response elicited by a 2-dose AZD2816 primary 
vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary vaccination 
Estimand:

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Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Primary
B.1.351
Wuhan-Hu-1
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.4
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 vaccination/AZD1222 
vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD2816 primary vaccination is non-inferior to the 
seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.1
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 vaccination - AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by a 2-dose AZD1222+AZD2816 
heterologous primary vaccination is non-inferior to the response elicited by a 2-dose AZD1222 primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Key Secondary 2.3
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222+AZD2816 
vaccination/AZD1222 vaccination
To determine if the seroresponse rate elicited by a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination is non-inferior to the seroresponse rate elicited by a 2-dose AZD1222 primary vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective Level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD1222+AZD2816 vaccination - AZD1222 vaccination

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To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD2816 primary vaccination
Estimand:
Treatment
AZD2816 vaccination
AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the 
response against the original Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary 
vaccination 
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following a 2-dose AZD1222+AZD2816 heterologous primary vaccination
Estimand:
Treatment
AZD1222+AZD2816 vaccination
AZD1222+AZD2816 vaccination
Population
Seronegative participants with no prior 
COVID-19 vaccination
Seronegative participants with no prior 
COVID-19 vaccination
Dosing interval
4 weeks
4 weeks
Timepoint
28 days after second vaccination dose
28 days after second vaccination dose
Objective level:
Serotype comparison: 
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) against B.1.351 versusWuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives
To also determine the neutralizing antibody GMT responses 28 days after first vaccination dose in the above 
primary and key secondary objectives
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a 2-dose homologous or 
! GMT of ChAdOx1 neutralizing antibody titres

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heterologous primary vaccination with AZD2816 
and/or AZD1222 in sub-groups of seronegative and 
seropositive participants
! Seroresponse rate of ChAdOx1 neutralizing 
antibody titres
Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody 
titres, 28 days after both Dose 1 and Dose 2
Exploratory Objectives
Objective
Endpoints
To explore the immune response elicited by a 2-dose 
AZD2816 primary vaccination with a 12-week dosing 
interval compared to the response elicited by a 2-dose 
AZD2814 primary vaccination with a 4-week dosing 
interval
! GMT ratio of pseudoneutralizing antibodies
! Seroresponse
To explore antibody response to selected SARS-CoV-2 
variants of interest/variants of concern following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! GMT of SARS-CoV-2 anti-S binding antibodies 
for selected variants of concern/variants of interest
! Seroresponse rate of SARS-CoV-2 specific   
binding antibody titres for selected variants of 
concern/variants of interest
! GMT of SARS-CoV-2 pseudoneutralizing 
antibody responses against the B.1.617.2 (delta) 
variant
! Seroresponse rate of SARS-CoV-2 
pseudoneutralizing antibody responses against the 
B.1.617.2 (delta) variant
To explore B-cell and T-cell responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in a sub-group of 
seronegative participants
! Intracellular cytokine staining and flow cytometry 
for T-cell responses over time
! Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 B.1.351 or Wuhan-Hu-1 S protein 
from day of dosing baseline over time
! Breadth and depth of peripheral blood B-cell and 
T-cell repertoire over time through 
immunosequencing
To monitor the incidence of SARS-CoV-2 infection 
following a 2-dose homologous or heterologous 
primary vaccination with AZD2816 and/or AZD1222 
in previously unvaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined 
by the seroresponse to nucleocapsid antibodies 
occurring post-second dose of study intervention 
To monitor the incidence of COVID-19 following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in previously 
unvaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses against the 
B.1.351 and Wuhan-Hu-1 strains induced by a 
2-dose homologous or heterologous primary 
vaccination with AZD2816 and/or AZD1222 in sub-
groups of seronegative and seropositive participants
! Geometric mean titre of SARS-CoV-2 
neutralization as determined by a live virus 
neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific 
antibody binding and neutralization titres as 
determined by a live virus neutralization assay

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To explore additional immune responses following a 2-
dose homologous or heterologous primary vaccination 
with AZD2816 and/or AZD1222 in sub-groups of 
seronegative and seropositive participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity 
data
To explore the immunogenicity objectives in 
seropositive participants
! GMT of pseudoneutralizing antibodies
! Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.
3.2
Previously vaccinated cohort receiving a 1-dose booster 
vaccination
The primary safety objective for the cohort of seronegative previously vaccinated participants 
receiving a booster dose is to characterize the safety and tolerability of 1 booster dose of 
AZD2816 in participants previously vaccinated with AZD1222. 
The primary and key secondary immunogenicity objectives for this cohort are as follows:
Primary:
1: To determine if the humoral immune response against the B.1.351 variant elicited by an 
AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior to 
the response against the original Wuhan-Hu-1 strain elicited by 2-dose AZD1222 vaccination 
administered to previously unvaccinated participants.
Key secondary:
2.1: To determine if the humoral immune response against the B.1.351 variant elicited by an 
AZD2816 booster dose in participants previously vaccinated with AZD1222 is non-inferior to 
the response elicited by 2-dose AZD1222 vaccination administered to previously 
unvaccinated participants.
2.2:  To determine if the humoral immune response elicited against the B.1.351 variant by an 
AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 booster dose  
in participants previously vaccinated with AZD1222.
2.3: To determine if the humoral immune response against the original Wuhan-Hu-1 strain 
elicited by an AZD2816 booster dose in participants previously vaccinated with AZD1222 is 
non-inferior to the response elicited by 2-dose AZD1222 vaccination administered to 
previously unvaccinated participants.

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2.4: To determine if the humoral immune response against the original Wuhan-Hu-1 strain 
elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222 is 
non-inferior to the response elicited by a 2-dose AZD1222 vaccination
2.5: To determine if the humoral immune response against the original Wuhan-Hu-1 strain 
elicited by an AZD2816 booster dose is non-inferior to the response elicited by an AZD1222 
booster dose in participants previously vaccinated with AZD1222.
The primary and key secondary immunogenicity objectives will be supported by other 
secondary objectives for which there will be no formal hypothesis testing.
Table 6 further describes the objectives and endpoints for this cohort of participants, including 
estimands for the primary and secondary immunogenicity objectives.
Table 6
Study Objectives and Endpoints for Previously Vaccinated Participants 
Receiving a 1-Dose Booster
Safety Objectives
Endpoints
- Primary
To characterize the safety and tolerability of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days 
post dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs, for 28 days post-dose
! The change from baseline for safety laboratory measures 
for 28 days post-dose
- Secondary
To characterize the safety and tolerability of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with AZD1222
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 
booster dose of AZD2816 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the safety and tolerability of 1 
booster dose of AZD1222 in seronegative 
participants previously vaccinated with a SARS-
CoV-2 mRNA vaccine
! Incidence of local and systemic solicited AEs for 7 days 
post-dose
! Incidence of unsolicited AEs, including MAAEs, SAEs, 
and AESIs for 28 days post-dose
To characterize the extended safety of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with AZD1222
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
To characterize the extended safety of 1 booster 
dose of AZD2816 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination

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To characterize the extended safety of 1 booster 
dose of AZD1222 in seronegative participants 
previously vaccinated with a SARS-CoV-2 mRNA 
vaccine
! Incidence of MAAEs, SAEs, and AESIs from Day 1 
through 6 months post-vaccination
Immunogenicity objectives
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Primary 
B.1.351
Wuhan-Hu-1
Key Secondary 2.1
B.1.351
B.1.351
Key Secondary 2.3
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 
vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
response elicited by an AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Key Secondary 2.2
B.1.351
B.1.351
Key Secondary 2.5
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD2816 booster/AZD1222 booster
To determine if the neutralizing antibody GMT response elicited by an AZD1222 booster dose in patients 
previously vaccinated with AZD1222 is non-inferior to the response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective Level:
Serotype comparison:
Key Secondary (2.4)
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
GMT ratio of pseudoneutralizing antibodies for AZD1222 booster/AZD1222 
vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated with 
AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd  vaccination dose
Objective level:
Serotype comparison:
Other secondary
B.1.351
Wuhan-Hu-1
Other secondary
B.1.351
B.1.351
Other secondary
Wuhan-Hu-1
Wuhan-Hu-1

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Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to response elicited by an 
AZD1222 booster dose in participants previously vaccinated with AZD1222
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint 
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 booster
To determine if the seroresponse elicited by an AZD1222 booster dose in participants previously vaccinated with 
AZD1222 is non-inferior to response elicited by a 2-dose AZD1222 vaccination 
Estimand:
Treatment
AZD1222 booster
AZD1222 primary vaccination
Population
AZD1222 vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose in participants 
previously vaccinated with an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 
vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 vaccination
To determine if the neutralizing antibody GMT response elicited by an AZD2816 booster dose is non-inferior to 
the response elicited by an AZD1222 booster dose in participants previously vaccinated with an mRNA-based 
vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1

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Other Secondary
B.1.351
B.1.351
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for AZD2816 
booster/AZD1222 booster
To determine if the seroresponse elicited by an AZD2816 booster dose in participants previously vaccinated with 
an mRNA-based vaccine is non-inferior to response elicited by a 2-dose AZD1222 vaccination
Estimand:
Treatment
AZD2816 booster
AZD1222 primary vaccination
Population
mRNA vaccine vaccinated 
seronegative participants
Seronegative participants with no prior 
COVID-19 vaccination
Timepoint
28 days after booster administration
28 days after 2nd vaccination dose
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus AZD1222 primary vaccination
To determine if the seroresponse elicited by an AZD2816 booster dose is non-inferior to the response elicited by 
an AZD1222 booster dose in participants previously vaccinated with an mRNA-based vaccine
Estimand:
Treatment
AZD2816 booster
AZD1222 booster
Population
mRNA vaccine vaccinated 
seronegative participants
mRNA vaccine vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
Wuhan-Hu-1
Wuhan-Hu-1
Other Secondary
B.1.351
B.1.351
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for AZD2816 booster versus  AZD1222 booster
To determine if the neutralizing antibody GMT response rate against the B.1.351 variant is non-inferior to the 
rate against the original Wuhan-Hu-1 strain following an AZD2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1
To determine if the neutralizing antibody GMT response against the B.1.351 variant is non-inferior to the rate 
against the original Wuhan-Hu-1 strain following An AZD1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Geometric mean titre ratio of pseudoneutralizing antibodies for B.1.351/Wuhan-Hu-1

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To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following an AZD2816 booster dose. 
Estimand:
Treatment
AZD2816 booster
AZD2816 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To determine if the seroresponse rate against the B.1.351 variant is non-inferior to the rate against the original 
Wuhan-Hu-1 strain following an AZD1222 booster dose. 
Estimand:
Treatment
AZD1222 booster
AZD1222 booster
Population
AZD1222 vaccinated 
seronegative participants
AZD1222 vaccinated 
seronegative participants
Timepoint
28 days after booster administration
28 days after booster administration
Objective level:
Serotype comparison:
Other Secondary
B.1.351
Wuhan-Hu-1
Endpoint
Difference in seroresponse (>4-fold increase from baseline in pseudoneutralizing 
antibodies) for B.1.351/Wuhan-Hu-1
To also determine non-inferiority of the s-protein binding antibody response for the above comparisons as other 
secondary objectives.
To explore anti-vector responses to the ChAdOx-1 
adenovirus vector following a booster dose of 
AZD2816 in sub-groups of seronegative and 
seropositive participants
! Magnitude of ChAdOx1 nAb titres (geometric mean 
titre)
! Seroresponse rate of ChAdOx1 neutralizing antibody 
titres
Pairwise correlations between anti-S, pseudo-
neutralization, and ChAdOx1 neutralizing antibody titres, 1 
month after both Dose 1 and Dose 2
Exploratory Objectives
Endpoints
To explore antibody response to selected SARS-
CoV-2 variants of interest/variants of concern 
following a booster dose of AZD2816 and in a 
sub-group of seronegative participants
! Magnitude of SARS-CoV-2 specific antibody binding 
titres (geometric mean titre) for selected variants of 
concern/variants of interest
! Seroresponse rate of SARS-CoV-2 specific   antibody 
binding titres for selected variants of concern/variants of 
interest
! GMT of SARS-CoV-2 pseudoneutralizing antibody 
responses against the B.1.617.2 (delta) variant
! Seroresponse rate of SARS-CoV-2 pseudoneutralizing 
antibody responses against the B.1.617.2 (delta) variant
To explore B-cell and T-cell responses following 
a booster dose of AZD2816 in a sub-group of 
seronegative participants
! Intracellular cytokine staining and flow cytometry for T-
cell responses over time

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! Quantification of (IFN-γ) ELISpot responses to SARS-
CoV-2 B.1.351 or Wuhan-Hu-1 S protein from day of 
dosing baseline over time
! Breadth and depth of peripheral blood B-cell and T-cell 
repertoire over time through immunosequencing
To monitor the incidence of SARS-CoV-2 
infection following a booster dose of AZD2816 in 
previously vaccinated seronegative participants
! The incidence of SARS-CoV-2 infection defined by the 
presence of nucleocapsid antibodies occurring post-dose 
of study intervention 
To monitor the incidence of COVID-19 following 
a booster dose of AZD2816 in previously 
vaccinated seronegative participants
! Incidence of COVID-19, defined as SARS-CoV-2 
RT-PCR-positive symptomatic illness.
To explore the humoral immune responses against 
the B.1.351 and Wuhan-Hu-1 strains induced by a 
booster dose of  AZD2816 or AZD1222 in sub-
groups of seronegative and seropositive 
participants
! Geometric mean titre of SARS-CoV-2 neutralization as 
determined by a live virus neutralization assay
! Seroresponsea rate of SARS-CoV-2 specific antibody 
binding and neutralization titres as determined by a live 
virus neutralization assay
To explore additional immune responses 
following a booster dose of  AZD2816 or 
AZD1222 participants
! Other exploratory assays for humoral and cellular 
immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity data
To explore the immunogenicity objectives in 
seropositive participants
! GMT of pseudoneutralizing antibodies
! Seroresponse rates
MAAEs: medically attended adverse events; SAEs: serious adverse events; AESIs: adverse events of special 
interest.
a
Seroresponse:  An at least 4-fold increase in geometric mean titre from baseline.
4
DESIGN
4.1
Overall Design
This is a multi-country Phase II/III study to evaluate the safety and immunogenicity of 
AZD2816 as single-dose vaccination in previously vaccinated adult participants and as a 
2-dose primary vaccination in previously unvaccinated adult participants. 
A total of approximately 2590 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled across these 2 
populations with the goal of 1300 previously vaccinated participants receiving single-dose 
vaccination and 1050 unvaccinated participants receiving 2-dose primary vaccination. In 
addition, seropositive participants will be enrolled (with a cap of 10% of the seronegative 
population or 259 participants) to support exploratory analysis is these participants. 
The enrollment and randomization strategy is intended to minimize group differences in terms 
of age, gender and the presence of comorbidities.

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In both the single-dose booster treatment regimen and the 2-dose primary vaccination 
treatment regimen, participants will receive study intervention consisting of intramuscular 
administration of either AZD1222 (5 ×1010 viral particles) or AZD2816 (5 ×1010 viral 
particles).
Approximately 700 seronegative participants previously vaccinated with AZD1222 will be 
randomised 1:1 to receive a single intramuscular dose of either AZD1222 or AZD2816 in a 
double-blinded fashion.  
Approximately 600 seronegative participants previously vaccinated with an approved mRNA 
based vaccination against the original Wuhan-Hu-1 strain will be randomised 1:1 to receive a 
single intramuscular dose of AZD2816 or AZD1222 in a double-blinded fashion.
It is anticipated that the majority of the patients recruited in the United Kingdom will belong 
to 1 of the 2 above previously-vaccinated groups.  
Approximately 1290 seronegative, previously unvaccinated participants will be randomised 
approximately 5:5:5:2 to receive a 2-dose primary vaccination of the following:
!
2 doses of AZD1222 with a 4-week dosing interval
!
2 doses of AZD2816 with a 4-week dosing interval
!
1 dose of AZD1222 followed by 1 dose of AZD2816 with a 4-week dosing interval
!
2 doses of AZD2816 with a 12-week dosing interval.
The 3 treatments with a 4-week dosing interval will be double-blinded while the treatment 
with the 12-week interval will be open-label due to the difference in dosing interval.  
In addition, a smaller population seropositive participants (approximately 10% of the 
seronegative population), will be randomised to treatment in a similar manner as above.
Owing to national vaccine rollout in the recruitment countries, including the prioritization of 
elderly populations, it is anticipated that there will be critical differences between the 
previously vaccinated and previously unvaccinated cohorts that may confound the 
interpretation of the results.  Consequently, the primary and key secondary non-inferiority 
analyses across these two cohorts will compare the previously vaccinated participants that 
received a booster dose in this study with a subset of matched participants from the previously 
unvaccinated participants that received the 2-dose AZD1222 primary vaccine series in the 
AZD1222 Phase 3 trial, Study D8110C00001. 
Immunogenicity (ie, anti-Wuhan-Hu-1 and anti-B.1.351 immune responses including 
S-binding antibody titres and neutralizing antibody levels [pseudo-neutralization]) will be 
assessed in serum samples collected pre-dose on the day of each vaccination (baseline levels 

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before vaccination), 14 and 28 days after each vaccination, and 180 days after the last 
vaccination.
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1-8 for all participants and Days 29-36 for the 4-week dosing interval and Days 85-92 
for the 12-week dosing interval).  An e-diary will be used to collect information on the timing 
and severity of the solicited signs and symptoms.
Follow-up visits will take place as per the schedule of assessment within respective windows.  
All participants will be assessed for local and systemic AE, physical examination, review of 
e-diaries at these time points as detailed in the schedule of assessment.  Blood will also be 
taken for safety assessments and immunology purposes.
All study participants will be followed for safety for 180 days after administration of their last 
vaccination dose.  In every participant, solicited local and systemic events will be reported for 
up to 7 days after each dose, all unsolicited AEs will be reported for up to 28 days after each 
dose, and SAEs and AEs of special interest will be evaluated through study completion 
(up to 180 days after the last study vaccination).  
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, 
to ensure safe and ethical conduct of the study.
4.1.1
COVID-19 Assessments
Occurrence of COVID-19 in the trial will be reported as safety events, including monitoring 
of the potential risk of vaccine-induced enhanced disease as an AE of special interest (see 
Appendix E).  COVID-19 will be diagnosed and treated as per standard medical practice.  
In addition, experimental treatments are permitted.  Detailed information will be collected in 
a standard way and reported on a specific case report form. 
4.1.2
Screening 
All potential participants will be screened, which may take place at a visit up to 14 days prior 
to Day 1 or on Day 1 itself.  
Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the screening procedures specified in the Schedule of Activities (Section 1.3) will be 
undertaken including a medical history, physical examination, height and weight, a 
SARS-CoV-2 screening test and clinical safety laboratory assessments.  Baseline information 
collected in the previously vaccinated participants will include which vaccine was received, 
immunization dose interval, and time since last vaccination.

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For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled.  (Note: Women with urine test results that are positive or undetermined will not be 
enrolled and should be advised to seek medical attendance outside the context of the trial if 
pregnancy is suspected.) 
The eligibility of the participants will be reviewed at the end of the screening visit and again 
when all results from the screening visit have been considered.  Decisions to exclude the 
participant from enrollment or to withdraw a participant from the study will be at the 
discretion of the Investigator.
4.1.3
Vaccination Visit
Participants will be considered enrolled at the point of vaccination.  Before vaccination, the 
eligibility of the participant will be reviewed.  Body temperature will be observed and a 
medical history and physical examination will be undertaken before the first vaccination to 
determine need to postpone vaccination or screen fail the participant.  A negative pregnancy 
test (urine test) will need to be obtained from women of childbearing potential before 
vaccination.  Baseline blood samples will be obtained before the first vaccination.
Participants will receive 1 dose of AZD2816 or AZD1222 at vaccination visits, administered 
by intramuscular injection.  Previously immunized participants will have a single vaccination 
visit, Day 1.  Participants that have not been previously vaccinated at baseline will have a 
second vaccination visit on Day 29 (4-week interval) or Day 85 (12-week interval).  
All participants will be given a thermometer, tape measure or ruler, and a proprietary e-diary 
application designed for use with a smart device with instructions for use.  All participants 
will be asked to report on solicited signs and symptoms for 7 days following vaccination 
(Days 1 to 8 and Days 29 to 36 or Days 85 to 92 when applicable).
4.1.4
Follow-up visits
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3).  All 
participants will be assessed for local and systemic AE, physical examination, review of the 
e-diary and blood tests at these time points as detailed in the Schedule of Activities.  Blood 
will also be taken for safety and immunogenicity assessments.
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate way until the last 
study visit in order to collect information on any SAEs/AE of special interest.

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4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population includes adults ≥30 years of age.  Persons who are healthy or have 
medically stable underlying conditions will be eligible.  Adults with medically-stable chronic 
diseases may participate if, according to the judgement of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Some seropositive participants 
(capped at 10% of the seronegative participant population) will be enrolled to support an 
exploratory analysis.  
Those enrolled in the single-dose vaccination part of the study must have received 2 doses of 
AZD1222 (with a dosing interval of 4-12 weeks) or 2 doses of an approved mRNA-based
COVID-19 vaccine (with a dosing interval of 3-12 weeks for the BNT162b2 mRNA vaccine 
[Pfizer-BioNTech] and 4-12 weeks for the mRNA-1273 vaccine [Moderna]) with the second 
doses administered at least 90 days prior to first study intervention administration. 
Pregnant/breastfeeding women, persons with severe immunodeficiency or severe underlying 
disease will be excluded from participation in the study.  Persons previously vaccinated with 
AZD1222 in the context of an AZD1222 vaccine trial are eligible for enrollment as previously 
vaccinated participants in the trial.  Persons who have previously received any other 
investigational product for the prevention of COVID-19 will be excluded from participation in 
this study.
Participants with known risk factors for thrombosis and thrombocytopenia (excluding 
contraceptive hormonal therapy or replacement hormonal therapy) are excluded.
4.2.2
Rationale for Study Endpoints
There is no statistical hypothesis testing planned for this study.  Descriptive statistics will 
support evaluation of safety, reactogenicity, and immunogenicity.
An interim analysis will occur when all previously vaccinated participants have completed 
their Day 29 visit. A second interim analysis may be conducted when previously unvaccinated 
participants have completed their Day 29 visit.
The primary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants randomised to a 4-week dosing interval have 
completed their Day 57 visit (ie, 28 days after their second dose).

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A secondary analysis will occur when all participants have completed their Day 29 visit AND 
all previously unvaccinated participants (including those randomised to either a 4-week or a 
12-week dosing interval) have completed their Day 57/Day 113 visit (ie, 28 days after their
second dose). 
The final analysis will occur when data from all vaccinated participants are available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants/180 days after the second dose for unvaccinated participants).
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination 
will be summarized by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be 
summarized by system organ class and preferred term, and by relationship to 
vaccination as assessed by the investigator.
!
SAEs and AEs of special interest following the first vaccination and throughout the 
study duration will be summarized by system organ class and preferred term and by 
relationship to vaccination as assessed by the investigator.
Solicited AEs will be collected for 7 days after each dose of study intervention, a period that 
has proven adequate to describe reactogenicity events in previous vaccine studies.  For all 
participants, AEs will be collected through 28 days after each dose of study intervention.  
SAEs, medically-attended AEs, and AEs of special interest and will be collected from Day 1 
through end of the study.  AEs of special interest include terms identified by the Brighton 
Collaboration involving events associated with vaccination in general .
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean titre
!
Seroresponse, defined as ≥ 4-fold increase in the geometric mean titre from baseline
Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of 
interest.
Immunogenicity against SARS-CoV-2 Wuhan-Hu-1 and B.1.351 strains will be characterized 
through the quantification of Spike-binding antibodies, pseudo-neutralization and, in a subset 
of participants, live neutralization.  Exploratory analysis of immunogenicity against other 
strains and induction of other immune effectors including cell-mediated immunity will be 
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4.3
Justification for Dose
The AZD2816 nominal dose of 5 × 1010 viral particles is the same dose as the approved dose 
for AZD1222, which was based on the accumulated non-clinical data and clinical data from 
the AZD1222 clinical studies, as well as from other SARS-CoV-2 vaccines in development. 
Safety and immunogenicity data from an additional clinical study, MERS001(NCT03399578), 
using the same ChAdOx1 vector, also helped inform dose selection. MERS001 was the first 
clinical study of a ChAdOx1-vectored vaccine expressing the full-length S protein from a 
separate, but related, beta-coronavirus.  ChAdOx1 MERS has been given to 31 participants to 
date at doses ranging from 5 × 109 viral particles to 5 × 1010 viral particles.  Despite higher 
reactogenicity observed at the 5 × 1010 viral particles, this dose was safe, with self-limiting 
AEs and no serious adverse reactions recorded.  The 5 × 1010 viral particles was the most 
immunogenic, in terms of inducing neutralizing antibodies against MERS-CoV using a live 
virus assay (Folegatti et al 2020).  Given the immunogenicity findings and safety profile 
observed with the ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 viral particles 
dose was chosen for AZD1222.  
Based on accumulating nonclinical and clinical data gathered for AZD1222, a 2-dose regimen 
was selected for vaccination of unvaccinated participants with AZD2816 (AZD1222 
Investigators Brochure).  A single dose vaccination has been selected for participants 
previously vaccinated in line with both FDA and EMA guidance (FDA 2021, EMA 2021).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities (Section
1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as a protocol waiver or exemption, is not permitted.

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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1
All Participants: 
Age
1
Adult, ≥ 30 years of age at the time of consent
COVID-19
For inclusion in the SARS-CoV-2 seronegative population supporting the primary and 
secondary objectives: 
2
No history of laboratory-confirmed SARS-CoV-2 infection (ie, no positive nucleic acid 
amplification test and no positive antibody test).
3
Seronegative for SARS-CoV-2 at screening (lateral flow test to detect reactivity to the 
nucleoprotein).
Note, patients failing to meet criteria 2 and/or 3 may be included in the separate seropositive 
population supporting the seropositive exploratory objectives. 
Type of Participant 
4
Medically stable such that, according to the judgment of the investigator, hospitalization 
within the study period is not anticipated and the participant appears likely to be able to 
remain on study through the end of protocol-specified follow-up
- A stable medical condition is defined as disease not requiring significant change in 
therapy or hospitalization for worsening disease during the 90 days prior to enrollment
5
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator
6
Signed informed consent obtained before conducting any study-related procedures
Reproduction
7
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants:
(a) Women of childbearing potential must:
!
Have a negative pregnancy test on the day of screening and on days of 
vaccination
!
Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
30 days following administration of the last dose of study intervention.  A highly 

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effective method of contraception is defined as one that can achieve a failure rate 
of less than 1% per year when used consistently and correctly (see Table 7).  
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy) or 
!
Post-menopausal:
!
For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥ 12 months amenorrhea prior to randomization, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and
o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal 
range, the participant is to be considered of childbearing potential
!
For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomization, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.
Table 7
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing systema
Bilateral tubal occlusion
Vasectomized partner b
Sexual abstinence c
Combined (oestrogen- and progestogen-containing 
hormonal contraception
      Oral (combined pill)
      Intravaginal
     Transdermal (patch)
Progestogen-only hormonal contraception
∀
     Oral 
∀
     Injectable
∀
     Implantable
a
This is also considered a hormonal method 
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse from 28 days prior to Day 1 through 30 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant

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5.1.2
Previously COVID-19 Vaccinated Participants
8
Prior completion of a 2-dose primary homologous vaccination regimen against the 
original SARS-CoV-2 Wuhan-Hu-1 strain with either AZD1222 (2 standard doses as 
authorized vaccine or as investigational product in a clinical trial with a 4- to 12-week 
dosing interval) or with an mRNA vaccine approved for emergency or conditional use 
(eg, BNT162b2 vaccine [Pfizer-BioNTech] with a 3- to 12-week dosing interval or 
mRNA-1273 vaccine [Moderna] with a 4- to 12-week dosing interval).  The second dose 
in all cases should have been administered at least 90 days prior to first administration of 
study intervention.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of allergy to any component of AZD1222/AZD2816.
2
History of Guillain-Barré syndrome, any demyelinating disease, or any other 
neuroimmunologic condition
3
Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) on the 
day prior to or day of randomization 
4
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia or HIV/AIDS.
5
Recurrent severe infections and use of immunosuppressant medication within the past 
6 months (≥ 20 mg per day of prednisone or its equivalent, given daily or on alternate 
days for ≥ 15 days within 30 days prior to administration of study intervention)
The following exceptions are permitted:  
#
Topical/inhaled steroids or short-term oral steroids (course lasting ≤14 days)
6
History of primary malignancy except for:
(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or for metastasis (for example, indolent 
prostate cancer) in the opinion of the site investigator.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
(c) Adequately treated uterine cervical carcinoma in situ without evidence of disease
(d) Localized prostate cancer
7
History of thrombocytopenia and/or thrombosis, including participants who have 
experienced major venous and/or arterial thrombosis in combination with 
thrombocytopenia following vaccination with any COVID-19 vaccine

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8
History of heparin-induced thrombocytopenia, congenital thrombophilia (ie, factor V 
Leiden, prothrombin G20210A, antithrombin III deficiency, protein C deficiency and 
protein S deficiency, factor XIII mutation, familial dysfibrinogenemia), auto-immune 
thrombophilia (antiphospholipid syndrome, anti-cardiolipin antibodies, anti-β2-
glycoprotein 1 antibodies), or paroxysmal nocturnal haemoglobinuria.
9
Clinically significant bleeding (eg, factor deficiency, coagulopathy, or platelet disorder), 
or prior history of significant bleeding or bruising following intramuscular injections or 
venepuncture
10 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, or neurological illness, as judged 
by the Investigator (note, mild/moderate well-controlled comorbidities are allowed)
11 Any other significant disease, disorder, or finding that may significantly increase the risk 
to the participant because of participation in the study, affect the ability of the participant 
to participate in the study, or impair interpretation of the study data
12 Any autoimmune conditions, except mild psoriasis and vitiligo
Note: The AEs of special interest as outlined in Appendix E (including Table 28) should be 
considered when evaluating a participant for exclusion criteria as the presence of these AEs of 
special interest, especially if untreated or uncontrolled, may be a safety risk to the participant, 
affect the ability of the participant to participate in the study, and/or impair interpretation of 
the study data.  Investigators should review and consider the list of conditions in Appendix E.  
If any of these conditions are present in a participant, the Investigator is asked to utilize 
his/her clinical judgment in determining the participant’s eligibility for the study.  Should the 
participant have conditions as outlined in Appendix E and the participant is enrolled, the 
Investigator is asked to document notes on site regarding the final rationale for enrollment.
Prior/Concomitant Therapy
13 Receipt of or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 with the exception of prior vaccination with 
AZD1222 or an mRNA COVID-10 vaccine (2 doses of the same vaccine within an 
approved dosing interval, see Section 5.1.2), which is allowed for participants in the 
previously vaccinated cohort 
Note: For participants who develop COVID-19, receipt of licensed treatment options 
and/or participation in investigational treatment studies is permitted
14 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to or after administration of study intervention
15 Receipt of any influenza vaccine (licensed or investigational) within 7 days prior to and 
after administration of AZD1222/AZD2816.

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16 Receipt of immunoglobulins and/or any blood products within 90 days prior to 
administration of study intervention or expected receipt during the period of study 
follow-up
Other Exclusions
17 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)
18 Women who are currently pregnant (confirmed with positive pregnancy test), 
breastfeeding, having given birth less than 90 days before or planning pregnancy during 
the study. 
19 Has donated ≥ 450 mL of blood products within 30 days prior to randomization or 
expects to donate blood within 90 days of administration of second dose of study 
intervention
20 Participants with a history of chronic alcohol or drug abuse or any condition associated 
with poor compliance.
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements or 
if vaccination would interfere with the participant’s ongoing treatment.
22 Previous enrollment in the present study.
5.3
Lifestyle Considerations
1
Participants must follow the contraception requirements outlined in Section 5.1
2
Restrictions relating to concomitant medications are described in Section 6.5
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Only a single rescreening is allowed in the study.  Rescreened participants are 
required to sign a new ICF (Appendix A 3), and will be assigned a new participant number.

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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical device utilized by a study participant according to 
the study protocol.  Study intervention is defined as AZD2816 or AZD1222 (Table 8).
6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 8
Investigational Products
Intervention 
Name
AZD2816
AZD1222
Type 
Vaccine
Vaccine
Dose Formulation
Unit Dose Strength
1 × 1011 viral particles/mL
1 × 1011 viral particles/mL
≥5 × 108 infectious units/mL
≥5 × 108 infectious units/mL
Dosage Level
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
5 × 1010 viral particles 
(nominal, ± 1.5 × 1010 viral particles)
≥ 2.5 × 108 infectious units
≥ 2.5 × 108 infectious units
Route
Intramuscular
Intramuscular
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labelling
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Will be provided in vials within a carton.  
Each carton and vial will be labelled as 
required per country requirement
Current/Former 
Name
-
Previous clinical documentation:
ChAdOx1 nCoV-19
Current tradename: Vaxzevria
IMP: investigational medicinal product; NIMP: non-investigational medical product; w/v: weight/volume.
AZD2816
AZD2816 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD2816 has 
a label-claim volume of 5 mL and can provide up to ten 0.5 mL doses.
AZD1222
CCI
CCI

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AZD1222 will be supplied by the Sponsor as a vial solution for injection. It is a sterile, clear 
to slightly opaque solution, practically free from visible particles.  Each vial of AZD1222 has 
a label-claim volume of 4 mL and can provide up to eight 0.5 mL doses.
Unopened vials of AZD2816 and AZD1222 must be stored at 2-8 oC (36-46 oF) for the 
duration of the assigned shelf-life and must not be frozen.  Both investigational products must 
be kept in original packaging until use to prevent prolonged light exposure. 
6.1.2
Dosing Instructions
Previously unvaccinated participants will receive 2 doses of either AZD1222, AZD2816, or 
AZD1222 plus AZD2816, with the first dose administered on Day 1 and the second dose on 
Day 29 (for a 4-week dosing interval) (Table 3) or Day 85 (for a 12-week dosing interval) 
(Table 4). 
Previously vaccinated participants will receive 1 dose of either AZD1222 or AZD2816
(Table 2).  
It is recommended that the study interventions be administered as an intramuscular injection 
into the deltoid of the non-dominant arm. Other injection sites may be used if necessary.
All study participants will be observed in the clinic for at least 15 minutes after vaccination. 
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.
6.2
Preparation/Handling/Storage/Accountability
The procedures for preparation, handling, storage, and accountability are identical for 
AZD2816 and AZD1222.
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).

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4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual or specified handling instructions.
6.2.1
Dose Preparation and Administration
Doses of AZD2816 and AZD1222 must be prepared by the unblinded pharmacist (or designee 
in accordance with local and institutional regulations) using aseptic technique. Each dose is 
prepared by withdrawing 0.5 mL from a vial of AZD2816 or AZD1222 in a sterile syringe.
AZD2816 and AZD1222 do not contain preservatives. Each vial must be assigned a beyond-
use-date of 6 hours at 2-30 °C (36-86 °F) from first needle puncture of the vial, after which 
any unused portion must be discarded.
Once an AZD2816 or AZD1222 dose is drawn into a syringe for administration, the dose must 
be administered within the beyond-use-date of the vial. If dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
The study contains 3 cohorts that are randomised to a total of 8 treatments: 
!
Participants that have previously been vaccinated with 2 doses of AZD1222 will be 
randomised 1:1 to 1 dose of AZD2816 or 1 dose of AZD1222.
!
Participants that have been previously vaccinated with an mRNA COVID-19 vaccine will 
be randomised 1:1 to 1 dose of AZD2816 or AZD1222.  
!
Previously unvaccinated participants that will be randomised 2:2:2:1 to 2 doses of 
AZD2816 with a 4-week dosing interval, 2 doses of AZD1222 with a 4-week dosing 
interval, 1 dose of AZD1222 followed by 1 dose of AZD216 with a 4-week dosing 
interval, or 2 doses of AZD2816 with a 12-week dosing interval.
Separate populations of SARS-CoV-2 seronegative participants (supporting the primary and 
secondary objectives) and SARS-CoV-2 seropositive participants (supporting exploratory 
objectives) will be randomised/included in the above cohorts.
Randomization will be stratified based on age (less than 65, 65 and above), gender, and 
presence of at least one of the following comorbidities that are known risk factors for severe 
illness from COVID-19 (based on the participant’s past and current medical history):
!
Obesity (BMI ≥ 30 kg/m2 at baseline)
!
Significant cardiovascular disease (eg, heart failure, coronary artery disease, congenital 
heart disease, cardiomyopathies, or pulmonary hypertension)

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!
Chronic lung disease (eg, chronic obstructive pulmonary disease, idiopathic pulmonary 
disease, cystic fibrosis, or moderate to severe asthma)
!
Diabetes .  
The randomised participants will be centrally assigned to randomised study intervention using 
an Interactive Response Technology (IRT)/Randomisation and Trial Supply Management.  
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 
the log in information & directions for the Randomisation and Trial Supply Management will 
be provided to each site.
Where a participant does not meet all the eligibility criteria but incorrectly received study 
intervention, the investigator should inform the Study Physician immediately, and a discussion 
should occur between the Study Physician and the investigator regarding whether to continue 
or discontinue the participant.
6.3.2
Blinding
Treatment will be double-blinded for previously vaccinated participants randomised to a 
single dose of either AZD2816 or AZD1222. Treatment will also be double-blind for 
previously unvaccinated participants randomised to 2 dose vaccinations with a 4-week dosing 
interval (ie, homologous AZD2816 or AZD1222 vaccination or heterologous 
AZD1222/AZD2816 vaccination).  Previously unvaccinated participants randomised to a  
homologous AZD2816 vaccination with a 12-week dosing interval will receive treatment in 
an open-label fashion due to the different dosing interval.
For the double-blinded treatments, neither the participant nor any of the investigators or 
Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
participants will be aware of the study intervention received.  Since AZD2816 and AZD1222 
are visually distinct prior to dose preparation (due to differences in container closure), all 
investigational product will be handled by an unblinded pharmacist (or designee in accordance 
with local and institutional regulations) at the study site. Once drawn into syringes for 
administration, AZD2816 and AZD1222 are not visually distinct from each other.
The IRT will provide the investigators with a dose tracking number to be allocated to the 
participant at the dispensing visit.  Routines for this will be described in the IRT user manual 
that will be provided to each study site.
For participants receiving double-blinded treatments, the randomization code should not be 
broken except in medical emergencies when the appropriate management of the participant 
requires knowledge of the treatment randomization.  The investigator documents and reports 
the action to the Sponsor, without revealing the treatment given to participant to the Sponsor 
staff.

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The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities.  Randomization codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.
6.3.3
Procedures for Unblinding
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
in which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment 
is warranted.  Participant safety must always be the first consideration in making such a 
determination.  If a participant’s intervention assignment is unblinded for safety, the Sponsor 
must be notified within 24 hours after breaking the blind. 
In the event that a study participant is contacted about receiving a licensed and/or authorized 
COVID-19 vaccine outside of this clinical study, unblinding instructions are being provided to 
the sites.  If the participant is unblinded, the Sponsor needs to be notified within 24 hours, and 
this should be documented in the site source documents.
6.4
Study Intervention Compliance
Participants are dosed at the study site, receiving study intervention directly from the 
investigator or designee, under medical supervision.  The date, and time if applicable, of dose 
administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the period specified in the 
Schedule of Activities (Section 1.3), must be recorded in the eCRF along with the information 
listed below.  Vitamins and/or herbal supplements are not to be recorded.
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.

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6.5.1
Permitted Concomitant Medications
!
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance.
!
Primary care providers, or where appropriate investigators, should prescribe appropriate 
concomitant medications or treatments deemed necessary to provide full supportive care 
and comfort during the study.
!
Participants who develop COVID-19 after receiving study intervention should be treated 
with licensed medications and interventions according to standard of care.  All routine 
vaccinations other than influenza are permitted beginning > 30 days after last dose of 
study intervention.  Licensed influenza vaccines are permitted 7 days before and 7 days 
after administration of study intervention.
!
Topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 days) are 
permitted
6.5.2
Prohibited Concomitant Medications
The following medications are prohibited and the Sponsor must be notified if a participant 
receives any of these prohibited medications.  The use of the following concomitant 
medications and/or vaccines, however, will not definitively require withdrawal of the 
participant from the study, but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis set.
!
Primary or booster vaccinations, other than AZD2816 or AZD1222, for prevention of 
SARS-CoV-2 or COVID-19.
Note: Participants choosing to receive a licenced and/or authorized COVID-19 vaccine 
should inform the Investigator so it can be properly documented.  Participants, who 
receive a licenced and/or authorized COVID-19 vaccine outside the study, should be 
encouraged to continue study conduct to be followed for safety reporting and all 
assessments.
!
Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention.  Thirty days after 
the second vaccination, other routine vaccinations are permitted as clinically indicated.
!
Glucocorticoids at a dose ≥ 20 mg/day of prednisone or equivalent given daily or on
alternate days for ≥ 14 consecutive days between randomization and the participant’s
scheduled final visit
!
Other systemically administered drugs with significant immunosuppressive activity,
such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy
between randomization and the participant’s scheduled final visit
!
Immunoglobulins and/or any blood product.
If a participant receives a prohibited concomitant medication, the investigator in consultation 
with the Sponsor will evaluate any potential impact on receipt of study intervention based on 

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time the medication was administered, the medication’s pharmacology and pharmacokinetics, 
and whether the medication will compromise the participant’s safety or interpretation of the 
data (see Section 7.1). 
6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.  Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive the first or second dose (if applicable) of study 
intervention if any of the following occur in the participant in question:
1
Withdrawal of consent after signing informed consent
2
Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 
3
Laboratory-confirmed SARS-CoV-2 infection
4
Participant is pregnant or nursing
5
Any grade 3 or greater allergic reaction including anaphylaxis that is assessed as related 
to study intervention 
6
Occurrence of any thrombosis with concurrent thrombocytopenia 
7
Any SAE assessed as related to study intervention
8
Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardize the safety of the study participant 
9
Receipt of a prohibited concomitant medication that may jeopardize the safety of the 
study participant or interpretation of the data
Each participant who has received at least 1 dose of study intervention will be followed for the 
full study period unless consent is withdrawn specifically from further study participation, or 
the participant is lost to follow-up.  Participants who have not received study intervention, 
regardless of reason, will not be followed.
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine 
during the study, AstraZeneca needs to be notified within 24 hours and this should be 

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documented in the site source documents. Participants who have received study intervention, 
regardless of reason, will be followed for the full study period.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent.  If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken should be 
carried out in line with what was stated in the informed consent and local regulation.  
The investigator must document the decision on use of existing samples in the site study 
records and inform the Sponsor Study Team.  If the participant does not specifically 
request withdrawal of consent for use of samples, then the samples collected prior to the 
consent withdrawal will be destroyed once per protocol analysis is complete.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the Schedule of Activities (Section
1.3).  Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities.
8.1
Efficacy Assessments
Not applicable.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.  Each clinically significant 
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history, 
clinical signs, and symptoms and will include signs of thrombosis and/or 
thrombocytopenia.  Each clinically significant abnormal finding following vaccination 
will be recorded as an AE.
!
All physical examinations will be performed by a licensed healthcare provider 
(eg, physician, physician assistant, or licensed nurse practitioner). 

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8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3).  The participant should be 
resting prior to the collection of vital signs.  On vaccination days, vital signs should be 
assessed prior to vaccine administration.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3).  Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the investigator, with the 
date and time of collection recorded in the appropriate eCRF.
The standard clinical chemistry and haematology analysis will be performed at a local 
laboratory at or near to the investigator site.  Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.  
The following laboratory variables will be measured:
Table 9
Laboratory Safety Variables
Blood
Serum/Plasma
Haemoglobin
Activated partial thromboplastin time
Leukocyte count
Prothrombin time
Leukocyte differential count (absolute count)
Fibrinogen
Platelet count
D-dimer
-
Creatinine
-
Bilirubin, total
-
Alkaline phosphatase
-
Aspartate aminotransferase 
-
Alanine aminotransferase
In case a participant shows an aspartate aminotransferase or alanine aminotransferase 
≥3 × upper limit of normal together with total bilirubin ≥2 × the upper limit of normal, please 
refer to Section 8.3.6
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the Schedule of Activities (Section 1.3).  Urine pregnancy tests for 
∃-human chorionic gonadotropin may be performed at the site using a licensed dipstick test.  

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8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a e-diary (Section 8.3.7), and will be assessed separately 
from the (unsolicited) AEs collected during the study.  General information for AEs in this 
protocol excludes the reporting of solicited AEs via e-diary unless otherwise noted.. 
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
AEs will be recorded for 28 days after each dose of study intervention. 
Solicited AEs will be recorded for 7 days after each dose of study intervention (ie, Day 1 
through Day 8). If a solicited AE is not resolved within the e-diary reporting period, the event 
will be reported as a non-solicited adverse event in the eCRF, with a start date of when started 
and the actual stop date. 
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact. 
See the Schedule of Activities for the scheduled timepoints (Section 1.3). 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the Sponsor.

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8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
Date when the AE started and stopped
!
Severity grade/maximum severity grade/changes in severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA 2007) will be utilized for all unsolicited events. 

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8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol-mandated vital signs and laboratory safety 
assessments will be summarized in the Clinical Study Report. 
Deterioration as compared to baseline in protocol-mandated vital signs and laboratory safety 
assessment should therefore only be reported as AEs if they fulfil any of the SAE or 
medically-attended AE criteria or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or 
non-planned visits were required).
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an SAE or medically-attended AE, and the associated vital sign 
will be considered as additional information. 
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation.  Any occurrences of aspartate aminotransferase or alanine aminotransferase 
≥3 × the upper limit of normal together with total bilirubin ≥2 × upper limit of normal at any 
point during the study following the administration of study medication should be reported to 
the Sponsor as a potential Hy's Law SAE within 1 day with a serious criteria of ‘Important 
medical event’ and causality assessment ‘yes/related’.

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The study physician will contact the investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 10) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention via e-diary collection. If a solicited AE is not resolved within the e-diary 
reporting period, the event will be also reported as a non-solicited adverse event in the eCRF,
with a start date of when started and the actual stop date.
Solicited AEs should not be reported as unsolicited AEs unless they fulfil the criteria for SAEs 
or medically-attended AEs(see Sections 8.3 and 8.3.8, respectively).
Table 10
Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic 
Pain at the site of the injection 
Fever (> 100 °F/37.8 °C)
Redness/erythema at the site of the injection
Chills
Tenderness at the site of the injection
Muscle pains
Induration/swelling at the site of the injection 
Fatigue (physical or mental tiredness/exhaustion)
-
Headache
-
Malaise (general feeling of discomfort or uneasiness)
-
Nausea
-
Vomiting
Solicited AE e-Diary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given a thermometer, tape measure or ruler, and access to the Solicited 
AE e-Diary, with instructions on use, along with the emergency 24-hour telephone number to 
contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms. 
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorized representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix D.  Because 

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solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention. 
8.3.8 COVID-19 Assessment
This study will describe the incidence of COVID-19 adverse events reported from Day 1 to 
180 days after the participant’s last/only dose of vaccine.
COVID-19 is defined as SARS-CoV 2-RT-PCR positive symptomatic illness.  At all clinic 
visits following the initial vaccination, participants will be asked if they have had a diagnosis 
of COVID-19 since their last clinic visit (see Schedule of Activities in Section 1.3). Medical 
records will be obtained for confirmation of a participant-reported diagnoses of COVID-19.  
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea.  Events will be reported as AEs/SAEs.
If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed 
using RT-PCR.
8.3.9 Medically-Attended Adverse Events
Medically-attended AEs will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3).
Medically-attended AEs are defined as AEs leading to medically-attended visits that were not 
routine visits for physical examination or vaccination, such as an emergency room visit, or an 
otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. 
AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
illness visits will not be considered medically-attended AEs.
8.3.10
Adverse Events of Special Interest
AEs of special interest will be collected according to the timepoints specified in the Schedule 
of Activities (Section 1.3). 
AEs of special interest are events of scientific and medical interest specific to the further 
understanding of study intervention safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor.  AEs of special interest are based on 
Brighton Collaboration case definitions (SPEAC 2020), clinical experience, and scientific 
interest.  A list of events is provided in Appendix E.
An AE of special interest can be serious or non-serious.  All AEs of special interest will be 
recorded in the eCRF.  If any AE of special interest occurs in the course of the study, 
investigators or other site personnel will inform the appropriate Sponsor representatives within 

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1 day ie, immediately but no later than 24 hours of when he or she becomes aware of it.  
Serious AEs of special interest will be recorded and reported as per Section 8.3.11.
8.3.10.1
Vascular/Hematologic Adverse Events of Special Interest
Both thrombotic, thromboembolic, and neurovascular events and thrombocytopenia events are 
considered to be adverse events of special interest.  The investigator should remain vigilant for 
the occurrence of thrombotic events with thrombocytopenia and/or bleeding.  If a participant 
experiences new onset thromboembolic events with thrombocytopenia, there should be 
prompt evaluation with a thorough haematological investigation.  COVID-19 testing, 
including PCR and serology (nucleoprotein antibodies), should also be performed.  See 
Appendix F for further guidance on investigation and management of suspected events.
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and whole genome 
sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events.
8.3.10.2
Potential Neurological Adverse Events of Special Interest
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation, including referral to a neurology specialist for further 
evaluation and testing, as clinically indicated.  Testing can include evaluation for peripheral 
demyelinating conditions (eg, electromyography).  In cases of concern for spinal cord disease, 
see Figure 3 for a recommended testing algorithm. 
An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AEs of special interest occurring 
in the AZD1222 clinical development program (see Appendix A 5).  

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Figure 3
Neurology Testing Algorithm
a
Adapted from Rovira et al 2015
Ab: antibody; ACE: angiotensin converting enzyme; ADC: apparent diffusion coefficient; ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibodies; AQP4: 
aquaporin 4; CMV: cytomegalovirus; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebral spinal fluid; CT: computed tomography; DWI: diffusion-weighted 
image; EBV: Epstein-Barr virus; ED: emergency department; ENA: extractable nuclear antigen antibodies; ESR: erythrocyte sedimentation rate; FLAIR: fluid-attenuated inversion 
recovery; GRE: gradient echo; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IgG: immunoglobulin G; MOG: myelin oligodendrocyte glycoprotein; MRI: 
magnetic resonance image; PCR: polymerase chain reaction; RF: rheumatoid factor; RPR: rapid plasma reagin; STIR: short T1 inversion recovery; SWI: susceptibility-weighted 
imaging; TSH: thyroid stimulating hormone; TM: transverse myelitis; VDRL: Venereal Disease Research Laboratories; VZV: varicella-zoster virus. 

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8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedures.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Sponsor representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available.
The Sponsor representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness is the AZD1222 Investigators 
Brochure, Section 5.6. 
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor, except if the pregnancy is discovered 
before the participant has received any study intervention.
8.3.12.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2).  Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the study intervention may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 

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spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the participant was discontinued 
from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.11) and within 30 days for all other pregnancies 
that are not associated with an SAEs.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module may be used to report the outcome of the pregnancy.
8.3.13
Medication Error
If a medication error occurs, then the investigator or other site personnel informs the 
appropriate Sponsor representatives within 1 day, ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 3. 
8.4
Overdose
For this study, any dose of study intervention exceeding that specified in the protocol will be 
considered an overdose.
There is no specific treatment for an overdose with AZD2816 or AZD1222.  If overdose 
occurs, the participant should be treated supportively with appropriate monitoring as 
necessary.

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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose occurs in the course of the study, the investigator or other site personnel inform 
appropriate Sponsor representatives immediately, but no later than 24 hours after when he or 
she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual.  Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality.  Further details on Handling of Human 
Biological Samples are provided in Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a 
maximum of 15 years following issue of the Clinical Study Report.  Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses, eg, exploratory immunology, such 
as systems serology and profiling of B- and T-cell repertoire.  The results from further 
analysis will not be reported in the Clinical Study Report.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).  Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual.  Results for exploratory immunogenicity analyses may 
be reported separately from the CSR.

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8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the Schedule of Activities (Section 1.3).  Authorized laboratories 
will assess serologic responses to AZD1222 and AZD2816 using validated (or qualified, 
where appropriate) assays.  Serologic assessment to the S protein from different SARS-CoV-2 
variants (which include Wuhan-Hu-1, B.1.351, B.1.1.7, and P.1) will be assessed 
quantitatively using a validated multiplexed ECL based immunoassay.  Additionally, 
seroresponse will be assessed for each antigen over time.  The rate of SARS-CoV-2 infection 
in participants receiving AZD2816 versus AZD1222 will be determined by seroresponse in a 
SARS-CoV-2 nucleocapsid antigen in a multiplexed electrochemiluminescence-based assay 
performed at an authorized laboratory. Additional exploratory assessments may be performed 
to measure binding antibodies to SARS-CoV-2 variants of interest (which may include 
B.1.429, B.1.525, B.1.526, P.2, P.3, B.1.617, and the Q677H mutation observed in multiple 
variants).
8.5.2.2
 
 
 
 
 
 
 
 
 
8.5.2.3
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

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8.5.2.4
 
 
 
 
 
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Already collected samples may be analysed for biomarkers thought to play a role in 
COVID-19 severity or outcomes based upon emerging immunogenicity and 
pharmacodynamic analysis from this or other studies involving the study interventions. These 
analyses include but are not limited to serum or plasma cytokines, quantification of RNA, 
micro-RNA, and/or non-coding RNA using quantitative reverse transcriptase polymerase 
chain reaction (RT-PCR), microarray, sequencing, or other technologies in blood, or 
peripheral blood mononuclear cells to evaluate their association with AZD1222/2816 and 
observed clinical responses to these study interventions.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The overall hypothesis for this 8-armed study is that 28 days after vaccination (ie, following a 
single booster dose for the previously vaccinated participants or a second vaccination dose for 
previously unvaccinated participants), AZD2816 will be non-inferior to AZD1222 in terms of 
immunogenicity (ie, neutralising antibodies GMT ratio and difference in seroresponse).  The 
specific null and alternative hypotheses for each objective are presented in Section 9.4.3
CCI
CCI
CCI

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9.2
Sample Size Determination
Immunogenicity response
Historical data were available for the immunogenicity responses (ie, pseudovirus neutralising 
antibodies, live virus neutralising antibodies, and spike protein binding antibodies) to 
AZD1222 from the pooled COV001/002/003/005 studies.  Table 11 presents the log 
transformed immunogenicity responses (ie, geometric mean titres) by assay for participants 
that received 2 standard doses of AZD1222.  These results indicate that the pseudo-
neutralising antibodies exhibited the largest variation (standard deviation of 1.20 and 1.10 for 
the 4-week and 12-week dosing intervals respectively), while live-neutralising antibodies had 
the lowest (standard deviation of 0.72 for the 4-week dosing interval).
Table 11
Historic Immunogenicity Responses by Dosing Interval (Geometric 
Mean Antibody Titres, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-week dosing intervalb
Assay
N
Mean
Std Dev
N
Mean
Std Dev
N
Mean
Std Dev
Pseudo
476
4.3
1.34
166
5.3
1.20
113
5.4
1.10
Live
51
4.9
1.15
42
6.2
0.72
0
-
-
Spike protein
1139
9.1
1.14
293
10.1
0.96
302
10.7
0.83
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
interval
Table 12 presents the seroresponse (ie, > 4 fold increase from baseline) by assay.  These 
results indicate that the pseudo-neutralising antibodies exhibited the lowest proportion of 
seroresponse (59.7% and 85.5% for the 4-week and 12-week dosing intervals respectively), 
while both live-neutralising and spike-binding seroresponse rates exceeded 95%.
Table 12
Historic Seroresponse Rates by Dosing Interval (>4-fold Increase from 
Baseline, Standard Dose Immunogenicity Analysis Set)
Post-1st Dose
Post-2nd dose with a 
4-week dosing intervala
Post-2nd dose with a 
12-dose week intervalb
Assay
N
Proportion
N
Proportion
N
Proportion
Pseudo
499
32%
382
59.7%
117
85.5%
Live
96
75%
95
96.8%
-
-
Spike protein
940
96.6%
636
95.9%
304
99.3%
a
Estimates from pooled COV001/002/003/005 study data from participants with 2- to 6-week dosing interval
b
Estimates from pooled COV001/002/003/005 study data from participants with 10- to 14-week dosing 
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Under the assumption that the immunogenicity responses (ie, geometric mean antibody titres) 
associated with AZD2816 will be similar to the responses associated with AZD1222 in 
participants that received 2 standard doses in the pooled COV001/002/003/005 studies, in 
which standard deviations ranged from 0.72 to 1.2 (Table 11), 150 participants will provide a 
95% confidence interval half-width between 0.115 and 0.192 (see Table 13).  Similarly, 380 
participants will provide a 95% confidence interval half-width between 0.072 and 0.120.
Under the assumption that the seroresponse rates associated with AZD2816 will be similar to 
the response rates in adults that received 2 standard doses of AZD1222 in the pooled 
COV001/002/003/005 studies (Table 12), 150 participants will provide a 95% confidence 
interval half-width between 1.33% and 7.85%, and 380 participants will provide a 95% 
confidence interval half-width between 0.84 % and 4.93 % (Table 14).
Table 13
Estimated Half-width of the 95% Confidence Intervals for 
Immunogenicity Responses (Geometric Mean Titres) Based on Historic 
Immunogenicity Assay Variances and the Proposed Sample Sizes
Standard Deviation
Number of participants
Estimated half-width of the 95% confidence interval 
(natural log scale)
0.72
150
0.115
300
0.081
350
0.075
380
0.072
0.83
150
0.133
300
0.094
350
0.087
380
0.084
0.96
150
0.154
300
0.109
350
0.101
380
0.097
1.1
150
0.176
300
0.124
350
0.115
380
0.111
1.2
150
0.192
300
0.136
350
0.126
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Table 14
Estimated Half-Width of the 95% Confidence Interval for the 
Seroresponse Rates based on Historic Seroresponse Rates and Proposed 
Sample Sizes
Observed 
seroresponse rate
Number of participants
Estimated half-width of the 95% confidence interval 
59.7%
150
7.85%
300
5.55%
350
5.14%
380
4.93%
85.5%
150
5.63%
300
3.98%
350
3.69%
380
3.54%
95.9%
150
3.17%
300
2.24%
350
2.08%
380
1.99%
96.8%
150
2.82%
300
1.99%
350
1.84%
380
1.77%
99.3%
150
1.33%
300
0.94%
350
0.87%
380
0.84%
For a fixed sample size, the precision with which the 95% confidence interval of the binary 
seroresponse rate can be estimated is a function of the response rate.  Table 14 provides the 
lower bounds of the 95% confidence interval for selected response proportions for alternate 
sample sizes.  For a given response rate, we can be 95% confident that the true seroresponse 
rate is at least as large as the lower bound of the confidence interval.

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Immunogenicity Comparisons: Non-inferiority
Under the assumption that there is no difference between treatment arms of interest (ie, a ratio 
of 1, difference on the log scale of 0), the power conferred by 150 and 380 participants 
respectively for the comparison of geometric mean titre ratio using a noninferiority margin of 
1.5 (equivalent to a difference on the log scale of 0.405) is presented in Table 15 and for the 
comparison of seroresponse rate using the non-inferiority margin of -15% as the upper bound 
of the difference is presented in Table 16.
If there is no difference between treatment arms of interest (ie, a ratio of 1) in the proportion 
of seroresponders, 300 participants provides 98% power for to establish non-inferiority to 
within margin of -15% if the seroresponse rate is >50%.  The observed pseudo-neutralising 
response rates (> 4 fold increase from baseline) from the COV001/002/003/005 studies for 
AZD1222 were 59.7% and 85.5% for the 4-week and 12-week dosing interval respectively 
(Table 12).  A population of 300 participants provides >90% power to detect non-inferiority 
(using a non-inferiority margin of -15%) if the observed response rate is 59.7% (Table 16).
Table 15
Power for Non-inferiority Using 1.5 as the Upper Bound of the 
Geometric Mean Titre Ratio
Sides
Null 
difference
Assumed mean 
treatment 
difference
Assumed 
standard 
deviation
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Upper
ln1.5 = 
0.405
0
0.72
150
300
0.025
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.83
150
300
0.998
150
350
0.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.96
150
300
0.988
150
350
0.991
150
380
0.992
300
300
>.999
300
350
>.999
300
380
>.999

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350
380
>.999
350
350
>.999
380
380
>.999
1.10
150
300
0.957
150
350
0.965
150
380
0.968
300
300
0.994
300
350
0.997
300
380
0.997
350
380
0.999
350
350
0.998
380
380
>.999
1.20
150
300
0.920
150
350
0.932
150
380
0.937
300
300
0.985
300
350
0.990
300
380
0.992
350
380
0.995
350
350
0.994
380
380
0.996
Table 16
Power for Non-inferiority Using -15% as the Upper Bound of the 
Difference in Seroresponse Rate
Sides
Null 
proportion 
difference
Assumed 
difference in 
proportion of 
seroresponders
Assumed 
proportion of 
seroresponders 
in both groups
Number in 
comparator 
group
Number in 
reference 
group
Alpha
Power
Lower
-0.15
0
0.597
150
300
0.025
0.878
150
350
0.894
150
380
0.902
300
300
0.964
300
350
0.975
300
380
0.979
350
380
0.986
350
350
0.982
380
380
0.989
0.855
150
300
0.993
150
350
0.995
150
380
0.996
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.959
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999

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350
380
>.999
350
350
>.999
380
380
>.999
0.968
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
0.993
150
300
>.999
150
350
>.999
150
380
>.999
300
300
>.999
300
350
>.999
300
380
>.999
350
380
>.999
350
350
>.999
380
380
>.999
Primary Objective: Safety
Table 17 indicates the probability of observing 1 or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 
particular type for participants in each treatment arm.  With the sample size of 300 
participants, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 95%.
Table 17
Probability of detecting 1 or more safety events (N = 300)
Event Frequency
Probability (> 1 event)
≥ 10% (Very Common)
> 99%
≥ 1% (Common)
95%
≥ 0.1% (Uncommon)
26%
≥ 0.01% (Rare)
3%

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9.3
Populations for Analyses
The following populations are defined:
Table 18
Populations for Analysis
Population
Description
All participants analysis set 
All participants screened for the study, to be used for reporting disposition and 
screening failures.
Full analysis set
All randomised participants who received study treatment, irrespective of their 
protocol adherence and continued participation in the study. Participants will be
analysed according to their randomised treatment, irrespective of whether or not 
they have prematurely discontinued, according to the intent-
to-treat principle. Participants who withdraw consent or assent to participate in the
study will be included up to the date of their study termination.
Safety analysis set
The safety analysis set consists of all participants who have received study 
treatment. Erroneously-treated participants (eg, those randomised to AZD2816, but 
were actually given treatment AZD12222) are accounted for in this analysis set by 
assigning them to the treatment they actually received.
Immunogenicity analysis set
The vaccine immunogenicity analysis set will include all randomised participants, 
received at least 1 dose of planned study treatment (ie, 1 dose of either AZD2816 or 
1 dose of AZD1222), had baseline and post-dose antibody measurements, have at 
least 1 post-dose quantifiable serum titre, and had no protocol deviations judged to 
have the potential to interfere with the generation or interpretation of an antibody 
response. The analyses conducted using this analysis set will be based on the actual 
treatment received.
Seronegative 
immunogenicity analysis set 
The subset of the immunogenicity analysis set who were seronegative at baseline.
Seropositive 
immunogenicity analysis set
The subset of the immunogenicity analysis set who were seropositive at baseline.
Participants that are SARS-CoV-2 seropositive at screening will be included in seropositive 
analysis sets analogous to the above seronegative analysis sets. Further definition is provided 
in the Statistical Analysis Plan.
9.4
Statistical Analyses
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints.  A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to the interim analyses.

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9.4.1 General Considerations
An initial interim analysis will occur when a  subset of participants previously vaccinated with 
AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  This sample will 
include both participants randomised to receive both a booster dose of AZD2816 as well as 
those randomised to receive a booster dose of AZD1222.  Analyses presenting treatment arm 
summaries of both the raw and model adjusted immunogenicity will be reviewed by an 
unblinded team within AstraZeneca to make a decision regarding the potential need for 
sample size re-estimation.  Full details of this analyses are provided in the Interim Analysis 
Charter to be finalized prior to any interim analysis.
An second interim analysis will occur when all participants previously vaccinated with 
AZD1222 have completed their Day 29 visit (ie, 28 days after booster dose).  It is estimated 
that this early analysis has the potential to provide clear signals about whether AZD2816 
provides a strong neutralizing response against the B.1.351 strain while retaining 
immunogenicity against the Wuhan strain, and thereby influence programmatic decisions 
early.  Analyses results will present treatment arm specific summaries of both the raw and 
model adjusted (baseline age and co-morbidities).  The raw data outputs will be stratified by 
age group (<65, ≥ 65) while the model adjusted summaries will pool data across age groups.  
Full details of this analyses are provided in the Interim Analysis Statistical analysis Plan to be 
finalized prior to any interim analysis.
A third interim analysis may be performed when a subset of previously unvaccinated 
participants have completed their Day 57 visit (ie, 56 days after fist dose).  The participant 
sample will include both participants randomised to AZD2816 as well as those randomised to 
AZD1222.  This analysis is intended to assess immunogenicity variability. The number of 
previously unvaccinated participants per treatment arm may be increased based upon the 
results of this analysis.  The details of this interim analysis, including the trigger and methods, 
will be specified in the Interim Analysis Charter Plan The primary analysis will occur when 
all participants have completed their Day 29 visit and safety and immunogenicity data from all 
unvaccinated participants randomised to a 4-week dosing interval are available through 
completion of their visit 28 days after the second priming dose.
A secondary analysis will occur when all participants have completed their Day 29 visit and 
safety and immunogenicity data from all unvaccinated participants (including those 
randomised to a 12-week dosing interval) are available through completion of the visit 28 
days after the second dose. 
The final analysis will occur when data from all vaccinated participants is available through 
completion of the last study visit (180 days after the single dose for previously vaccinated 
participants / 180 days after the second dose for unvaccinated participants).

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Further details of the primary analysis, secondary analysis and final analysis are contained 
within the Statistical Analysis Plan.
To maintain trial integrity sponsor roles with direct input into participant management and 
safety monitoring will not have access to unblinded participant level data or associated outputs 
from the interim analyses until end of study.
Further details on the tools and processes to maintain the blind will be presented in the Study 
Integrity Plan.
9.4.2 Safety
9.4.2.1
Primary Endpoints
Overview
Descriptive analyses will support evaluation of safety, reactogenicity and immunogenicity. 
The primary safety analysis includes: 
!
Incidence of local and systemic solicited AEs for 7 days following each vaccination will 
be summarised by day and overall.
!
Incidence of unsolicited AEs for 28 days following each vaccination will be summarised 
by system organ class and preferred term, and by relationship to vaccination as assessed 
by the investigator.
!
MAAEs, SAEs, and AESIs following the first vaccination and throughout the study 
duration will be summarised by system organ class and preferred term and by relationship 
to vaccination as assessed by the investigator. 
!
The change from baseline for safety laboratory measures at 7 and 28 days after 
vaccination.
AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities.  AEs will be presented for each treatment group by system organ class 
and preferred term.  Summaries will include the number and percentage of participants 
reporting at least one event, number of events and exposure adjusted rates, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs.  Summaries will present the relationship to 
study intervention as assessed by the investigator, maximum intensity, seriousness, and death.
A listing will cover details for each individual AE.  Full details of all AE analyses will be 
provided in the Statistical Analysis Plan, including intercurrent events for safety due to 
potential unblinding of participants for administration of licensed and/or approved SARS-
CoV-2 or COVID-19 vaccine.

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At the time of the interim analyses, group assignment will not be presented when safety event 
data has the potential to unblind participant’s study group attribution.
9.4.2.2
Other Safety Endpoints
Vital Signs
Vital sign measurements will be performed as specified in the Schedule of Activities (Section 
1.3).  The set of assessments will include pulse oximetry, blood pressure, and body
temperature.  
Details of all vital sign analyses will be provided in the Statistical Analysis Plan, which will 
include descriptive statistics presented for observed values for all vital sign parameters. 
COVID-19
This study will describe the incidence of COVID-19 adverse events from the first dose of the 
vaccine to study end (180 days post-vaccination). Descriptive statistics will be produced based 
on the safety analysis set. Full details will be documented in the statistical analysis plan.
9.4.3
Immunogenicity
9.4.3.1
Immunogenicity Endpoints
The immunogenicity endpoints of interest in this study are: 
!
Geometric mean antibody titre.
!
Seroresponse, defined as ≥4-fold increase in the geometric mean antibody titre from 
baseline
Both the geometric mean antibody titre and seroresponse of participants will be summarized 
descriptively by strain, treatment arm, and timepoint for the immunogenicity population.
9.4.3.1.1
Estimand framework for immunogenicity descriptions and comparisons
Target populations: 
1) Previously unvaccinated participants 
a.
Seronegative Analysis Set: and with no evidence of prior or current infection  
2) Participants who previously received SARS-CoV-2 vaccination with either AZD1222 
or a licensed mRNA vaccine according to the authorized dose and dosing regimen at 
least 90 days prior to first study intervention (see Section 5.1.2).
Outcome variable: neutralizing antibody and binding titres to SARS-CoV-2 at 28 days after 
each treatment administration (1 treatment administration for the previously vaccinated 
population and 2 planned treatment administrations for the unvaccinated population). 

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Treatment conditions:
Previously unvaccinated population
!
2 doses of AZD1222 given on Day 1 and on Day 29 (4-week dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 29 (4-week dosing interval)
!
1 dose of AZD1222 given on Day 1 and 1 dose of AZD2816 on Day 29 (4-week 
dosing interval)
!
2 doses of AZD2816 given on Day 1 and on Day 85 (12-week dosing interval)
Previously vaccinated population
!
1 dose of AZD1222 given on Day 1. 
!
1 dose of AZD2816 given on Day 1. 
Intercurrent events: the following intercurrent events could impact the antibody levels 
achieved:  
!
missing the second vaccination (for the unvaccinated population)  
!
receiving of immune-modifying drugs or vaccines 
!
subsequent infection with SARS-CoV-2. 
All immunogenicity descriptions and comparisons will use the principal stratum strategy, 
ie, all analyses will exclude participants who experience any of the above intercurrent events 
Population-level summary: 
Descriptive Analyses (see Table 20 and Table 21)
!
geometric means of the antibody titres 
!
seroresponse proportions
Comparative Analyses (see Table 22 and Table 23)
!
ratio of geometric means of the antibody titres.
!
difference in seroresponse proportion 

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Planned Descriptive Analyses: 
Table 20 and Table 21 present planned descriptive immunogenicity analyses for the 
unvaccinated and previously vaccinated populations respectively (each one exploring an 
individual treatment arm at a specific timepoint against a particular strain). 
The tables show that without introduction of further variants, there are 24 planned descriptive 
analyses for the unvaccinated population and 16 planned descriptive analyses for the 
previously immunised population (index).  Within each table there is an analysis key which 
describes the population (see Table 19). The descriptive analyses presented in Tables 19 and 
20 will be repeated for the subset of participants who are seropositive at screening.
Table 19
Description of the Analysis Keys for Tables 19 and 20
Population
Analysis Key
Example
Previously 
unvaccinated
Vaccination treatment received: 
    V1222 (2 doses of AZD1222) or 
    V2816 (2 doses of AZD2816) or
V1222/2816 (1 dose of AZD1222  
followed by 1 dose of AZD2816) or
HV1222: ([historical] 2 doses of AZD1222 
from study D8110C00001) 
Dosing interval: 
   (4): 4-week dosing interval or
   (12): 12-week dosing interval
Strain: 
    Wuhan: Wuhan-Hu-1 or 
    Beta: Variant B.1.351
Analysis Timepoint:
   D1: 28 days post-dose 1
   D2 (28 days post-dose 2
[V1222 (4):Wuhan:D2] = 
Immunogenicity following 
primary vaccination with 2 doses 
of AZD1222 using a 4-week 
dosing interval against Wuhan-
Hu-1 28 days post-dose 2
Previously vaccinated
Pre-study primary vaccination: 
  V1222: 2 doses of AZD1222 or
    VmRNA: 2 doses of an mRNA vaccine
Treatment received: 
    B1222: 1 booster dose of AZD122) or 
B2816: 1 booster dose of AZD2816
Strain: 
    Wuhan:Wuhan-Hu-1 or 
    Beta: Variant B.1.351
[V1222:B1222:Beta] = 
Immunogenicity in participants 
who were previously vaccinated 
with 2 doses of AZD1222 as 
primary vaccination series and 
received a single boost dose of 
AZD1222 against the B.1.351 
variant 

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Table 20
Immunogenicity Descriptive Analysis for Previously Unvaccinated 
Treatment Groups (with Separate Seronegative and Seropositive 
Analyses)
Treatment
Dosing 
interval
Strain
Timepoint
Endpoint
Index
Analysis Key
AZD1222
4 weeks
Wuhan-Hu-
1
28 days after 
1st dose
GMT
1
[V1222(4):Wuhan:D1]†
Seroresponse
2
28 days after 
2nd dose
GMT
3
[V1222(4):Wuhan:D2]
Seroresponse
4
B.1.351
28 days after 
1st dose
GMT
5
[V1222(4):Beta:D1] †
Seroresponse
6
28 days after 
2nd dose
GMT
7
[V1222(4):Beta:D2]
Seroresponse
8
AZD2816
4 weeks
Wuhan-Hu-
1
28 days after 
1st dose
GMT
9
[V2816(4):Wuhan:D1] ‡
Seroresponse
10
28 days after 
2nd dose
GMT
11
[V2816(4):Wuhan:D2]
Seroresponse
12
B.1.351
28 days after 
1st dose
GMT
13
[V2816(4):Beta:D1] ‡
Seroresponse
14
28 days after 
2nd dose
GMT
15
[V2816(4):Beta:D2]
Seroresponse
16
AZD1222/
AZD2816
4 weeks
Wuhan-Hu-
1
28 days after 
2nd dose
GMT
17
[V1222/2816(4):Wuhan:D2]
Seroresponse
18
B.1.351
28 days after 
2nd dose
GMT
19
[V1222/2816(4):Beta:D2]
Seroresponse
20
AZD2816
12 weeks
Wuhan-Hu-
1
28 days after 
2nd dose
GMT
21
[V2816(12):Wuhan:D2]
Seroresponse
22
B.1.351
28 days after 
2nd dose
GMT
23
[V2816(12):Beta:D2]
Seroresponse
24
† descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD1222 as their first dose 
(ie, homologous and heterologous series).
‡ descriptive summaries for 28 days after 1st dose will pool all treatment groups who received AZD2816 as their first dose 
(4-week interval and 12-week interval treatment arms).
GMT: Geometric mean titre

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Table 21
Immunogenicity Descriptive Analysis for Previously 
Vaccinated Treatment Groups (with Separate Seronegative 
and Seropositive Analyses)
Primary 
vaccination
Booster 
Treatment
Strain
Timepoint
Endpoint
Index
Analysis Key
AZD1222
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
1
[V1222:B1222:Wuhan]
Seroresponse
2
B.1.351
28 days after 
booster dose
GMT
3
[V1222:B1222:Beta]
Seroresponse
4
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
5
[V1222:B2816:Wuhan]
Seroresponse
6
B.1.351
28 days after 
booster dose
GMT
7
[V1222:B2816:Beta]
Seroresponse
8
mRNA
AZD2816
Wuhan-Hu-1
28 days after 
booster dose
GMT
9
[VmRNA:B2816:Wuhan]
Seroresponse
10
B.1.351
28 days after 
booster dose
GMT
11
[VmRNA:B2816:Beta]
Seroresponse
12
AZD1222
Wuhan-Hu-1
28 days after 
booster dose
GMT
13
[VmRNA:B1222:Wuhan]
Seroresponse
14
B.1.351
28 days after 
booster dose
GMT
15
[VmRNA:B1222:Beta]
Seroresponse
16
GMT: Geometric mean titre
Immunogenicity comparisons:
Immunogenicity analysis
A number of comparisons of geometric mean titres and seroresponse rates between vaccine 
regimens and vaccine types are intended to be made. 
All non-inferiority comparisons of geometric mean titre ratios will be made utilizing the lower 
bound of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 
0.67
All non-inferiority comparisons of seroresponse rates will be made utilizing the lower bound 
of two-sided score-based confidence intervals (α = 0.05) with non-inferiority margin 15%, and 
superiority comparisons of seroresponse rates will be made using one-sided Fisher’s exact test 
(α = 0.025). Comparisons of antibody titres between treatment groups will be conducted using 
geometric mean titre (GMT) ratios and seroresponse rates, facilitated by an analysis of 
covariance (ANCOVA) model of the log2 titre, which adjusts for the baseline level, time since 
previous vaccination (for previously vaccinated individuals), baseline co-morbidities and 

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gender as fixed effects. All analyses of antibody titres (GMT ratios and differences in 
seroresponse) will be repeated using the unadjusted (raw observed) concentration values.
Geometric Mean Titres 
The statistical methodology will be based on a 2-sided 95% CI of the ratio of the GMTs. Non-
inferiority will be demonstrated if the lower limit of the 2-sided 95% CI of the GMT ratio of 
the reference group and comparator group is >0.67 (see Table 22 and Table 23). The 2-sided 
95% CI for the ratio of GMTs will be calculated using normal approximation of log-
transformed concentrations.
The 95% CI for the GMT ratio between 2 groups will be constructed as follows:
Logarithm transformation of the individual concentrations will be calculated.
The 95% CI for the difference in log(GMT) between 2 groups: GroupC and GroupR will 
be in the form:
 − ± 
1 − 2
 ,  +  −2 × 1 

+ 1 

Where  and  = log() are the means of the log-transformed concentration for 
 !"# and  !"#, respectively,
$ = [( −1)
$ + ( −1)
$]
( +  −2)
'
is the pooled sample variance,
 and  are the sample sizes for  !"# and  !"# , respectively,
 and  are the sample variances for  !"# and  !"# , respectively,

1 − 2
 ,  +  −2 is the 100 ,1 −
-
$. percentile of the t-distribution with degrees of 
freedom /0 =  +  −2
To test this hypothesis, a 2- sided 95% CI will be constructed around the ratio 
1234
1235, where 
 and  are the geometric mean of the antibody titres in the comparator and 
reference groups respectively, at the timepoints post vaccination for which the groups are 
being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 0.67. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.

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:;:  

≤0.67
:>:  

> 0.67
Or equivalently
:;: log() −log() ≤log(0.67)
:>: log() −log() > log(0.67)
For the separately considered GMT hypotheses, if the null hypothesis is rejected, then the 
alternative hypothesis of non-inferiority will be supported.
Seroresponse
The statistical methodology will be based on a 2-sided 95% CI of the difference in 
seroresponse. Non-inferiority will be demonstrated if the upper bound of the 2-sided 95% CI 
rate difference in seroresponse between the reference group and comparator group is <15%.  
The 95% CI of the difference in proportions ? −? will be computed using the Wilson score 
without continuity correction.
To test this hypothesis, a 2- sided 95% CI will be constructed around the difference ? −?, 
where? and ? are the proportions of participants in the comparator and reference groups 
respectively who are classified as seroresponders (> 4 fold increase from baseline) at the 
timepoints post vaccination for which the groups are being compared.
The hypothesis will be supported by the data, if the lower bound of the calculated of the 
calculated 95% CI is > 15%. This is equivalent to testing the null hypothesis using a 1-sided 
type-I error rate of 0.025.
:;: ? −? < −15%
:>: ? −? ≥15%
If the null hypothesis is rejected, then the alternative hypothesis of non-inferiority will be 
supported.
Comparisons
The primary and secondary immunogenicity objectives and the GMT and seroresponse 
comparisons for the previously unvaccinated participants receiving a 2-dose primary 
vaccination are presented in Table 22.

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The immunogenicity objectives and the GMT and seroresponse comparisons for the 
previously vaccinated participants receiving a 1-dose booster vaccination are presented in
Table 23.  
Owing to national vaccine rollout in the recruitment countries, including the prioritization of 
elderly populations, it is anticipated that there will be critical differences between the 
previously vaccinated and previously unvaccinated cohorts with respect to age and presence 
of important underlying comorbidities that may confound the interpretation of the results.  
Consequently, the primary and key secondary non-inferiority analyses across these two 
cohorts will compare the previously vaccinated participants that received a booster dose in this 
study with a subset of matched participants from the previously unvaccinated participants that 
received the 2-dose AZD1222 primary vaccine series in the AZD1222 Phase 3 trial Study 
D8110C00001, which was performed in the US, Chile, and Peru. 
This historical control group will be matched, at a minimum, to the previously vaccinated 
AZD1222 booster cohort in the D7220C00001 study based on age, gender, and presence of 
baseline comorbidities. These matched samples will then serve as the control arm for all 
planned non-inferiority analyses (both geometric mean titre [GMT] ratio and difference in 
seroresponse) of the previously vaccinated cohort treatment arms to the primary series 
vaccination. Comparisons of antibody titres between the previously vaccinated cohort in this 
study and the historical controls from Study D8110C00001 will be conducted using the 
immunogenicity analysis described above (ie,  using an adjusted ANCOVA model to 
calculated adjusted means and standard errors for the historical comparators).
For immunogenicity data not already available, preserved sera samples from the matched 
controls will be used to generate immune response by the primary series parent vaccine 
against variant strains. AstraZeneca confirms that study D8110C00001 utilizes the same 
validated pseudovirus neutralising antibody assay for the Wuhan-Hu-1 strain and that residual 
sera are available from these study participants that will be tested in a pseudovirus neutralising 
antibody assay against the beta (B.1.351) variant (Monogram Biosciences, South San 
Francisco, USA).  
Further details on the matching procedures and reporting of historical samples are provided in 
the Statistical Analysis Plan.

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
[DEFGHIJKLKMHL]
[DEFLNONLNPGN]
∆= [RNLHLNSJHPSNGHIJKLKMHL] −[RNLHLNSJHPSNLNONLNPGN]
To determine if the 
neutralizing antibody GMT 
response/seroresponse elicited 
by a 2-dose AZD2816 primary 
vaccination is non-inferior to 
the response elicited by a 2-
dose AZD1222 primary 
vaccination
[V2816(4): Beta: D2]/[V1222(4): Wuhan:D2]
(Primary)
[V2816(4): Beta:D2] −[V1222(4): Wuhan:D2]
(Key Secondary 2.1)
[V2816(4): Beta:D1]/[V1222(4): Wuhan: D1]
[V2816(4): Beta:D1] −[V1222(4): Wuhan:D1]
[V2816(4): Wuhan:D2]/[V1222(4):Wuhan:D2]
(Key Secondary 2.4)
[V2816(4): Wuhan: D2] −[V1222(4): Wuhan:D2]
(Other Secondary)
[V2816(4): Wuhan:D1]/[V1222(4):Wuhan:D1]
[V2816(4): Wuhan:D1] −[V1222(4): Wuhan:D1]
[V2816(4): Beta:D2]/[V1222(4):Beta: D2]
(Key Secondary 2.2)
[V2816(4): Beta:D2] −[V1222(4): Beta:D2]
(Other Secondary)
[V2816(4): Beta:D1]/[V1222(4):Beta: D1]
[V2816(4): Beta:D1] −[V1222(4): Beta:D1]
To determine if the 
neutralizing antibody GMT 
response/seroresponse elicited 
by a 2-dose AZD1222 + 
AZD2816 heterologous 
primary vaccination is non-
inferior to the response 
elicited by a 2-dose AZD1222 
primary vaccination
[V1222/2816(4): Beta:D2]/[V1222(4): Wuhan:D2]
(Key Secondary 2.3)
[V1222/2816(4): Beta:D2] −[V1222(4): Wuhan: D2]
(Other Secondary)
[V1222/2816(4): Wuhan: D2]/[V1222(4): Wuhan:D2]
(Other Secondary)
V1222/2816(4): Wuhan: D2] −[V1222(4): Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Wuhan: D2]/[V1222(4): Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Wuhan:D2] −[V1222(4): Wuhan:D2]
(Other Secondary)

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Table 22
Immunogenicity Comparisons for Previously Unvaccinated Groups
Objective
[DEFGHIJKLKMHL]
[DEFLNONLNPGN]
∆= [RNLHLNSJHPSNGHIJKLKMHL] −[RNLHLNSJHPSNLNONLNPGN]
To determine if the 
neutralizing antibody GMT 
response/seroresponse rate 
against the B.1.351 variant is 
non-inferior to the rate against 
the original Wuhan-Hu-1
strain following a 2-dose 
AZD2816 primary vaccination
[V2816(4): Beta:D2]/[V2816(4): Wuhan:D2]
(Other Secondary)
[V2816(4): Beta:D2] −[V2816(4): Wuhan:D2]
(Other Secondary)
To determine if the 
neutralizing antibody GMT 
response/seroresponse rate 
against the B.1.351 variant is 
non-inferior to the rate against 
the original Wuhan-Hu-1
strain following a 2-dose 
AZD1222/AZD2816 primary 
heterologous vaccination
[V1222/2816(4): Beta: D2]/[V1222/2816(4): Wuhan:D2]
(Other Secondary)
[V1222/2816(4): Beta:D2]
−[V1222/2816(4): Wuhan:D2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[DEF〗GHIJKLKMHLf
〖[DEF〗LNONLNPGN]
〖[RNLHLNSJHPSN〗GHIJKLKMHLf −〖[RNLHLNSJHPSN〗LNONLNPGN]
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose 
in participants previously vaccinated 
with AZD1222 is non-inferior to 
response elicited by a 2-dose 
AZD1222 vaccination
V1222: B2816: Beta]/[HV1222(4): Wuhan:D2]
(Primary)
[V1222: B2816: Beta] −[HV1222(4): Wuhan:D2]
(Other Secondary)
[V1222: B2816:Beta]/[HV1222(4): Beta:D2]
(Key Secondary 2.1)
[V1222: B2816:Beta] −[HV1222(4): Beta:D2]
(Other Secondary)
[V1222: B2816: Wuhan]/[HV1222(4): Wuhan:D2]
(Key Secondary 2.3)
[V1222: B2816: Wuhan] −[HV1222(4): Wuhan:D2
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose 
is non-inferior to response elicited by 
an AZD1222 booster dose in 
participants previously vaccinated 
with AZD1222
[V1222: B2816: Beta]/[V1222:B1222: Beta]
(Key Secondary 2.2)
[V1222: B2816: Beta] −[V1222: B1222: Beta]
(Other Secondary)
[V1222: B2816:Wuhan]/[V1222:B1222: Wuhan]
(Key Secondary 2.5)
[V1222: B2816:Wuhan] −[V1222: B1222: Wuhan]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD1222 booster dose 
in patients previously vaccinated with 
AZD1222 is non-inferior to the 
response elicited by a 2-dose 
AZD1222 vaccination
[V1222: B1222: Wuhan]/[HV1222(4): Wuhan:D2]
(Key Secondary 2.4)
[V1222: B1222: Wuhan] −[HV1222(4): Wuhan:D2
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose 
in participants previously vaccinated 
with an mRNA-based vaccine is non-
[VmRNA:B2816: Beta]/[HV1222(4): Wuhan:D2]
(Other Secondary)
[VmRNA:B2816: Beta] −[HV1222(4): Wuhan:D2]
(Other Secondary)
[VmRNA:B2816: Beta]/[HV1222(4): Beta:D2]
(Other Secondary)
[VmRNA:B2816: Beta] −[HV1222(4): Beta: D2]
(Other Secondary)

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Table 23
Immunogenicity Comparisons for Previously Vaccinated Group
Objective
〖[DEF〗GHIJKLKMHLf
〖[DEF〗LNONLNPGN]
〖[RNLHLNSJHPSN〗GHIJKLKMHLf −〖[RNLHLNSJHPSN〗LNONLNPGN]
inferior to response elicited by a 2-
dose AZD1222 vaccination
[VmRNA:B2816:Wuhan]
/[HV1222(4): Wuhan: D2]
(Other Secondary)
[VmRNA:B2816: Wuhan] −[HV1222(4): Wuhan:D2]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
elicited by an AZD2816 booster dose 
is non-inferior to the response elicited 
by an AZD1222 booster dose in 
participants previously vaccinated 
with an mRNA-based vaccine
[VmRNA:B2816: Wuhan])
/[VmRNA:B1222: Wuhan]
(Other Secondary)
[VmRNA:B2816:Wuhan] −[VmRNA:B1222: Wuhan]
(Other Secondary)
[VmRNA:B2816:Beta])/[VmRNA:B1222: Beta]
(Other Secondary)
[V1222: B2816: Beta]/[V1222:B2816: Wuhan]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
rate against the B.1.351 variant is 
non-inferior to the rate against the 
original Wuhan-Hu-1 strain following 
an AZD2816 booster dose
[V1222: B2816: Beta]/[V1222:B2816: Wuhan]
(Other Secondary)
[V1222: B2816: Beta] −[V1222: B2816: Wuhan]
(Other Secondary)
To determine if the neutralizing 
antibody GMT response/seroresponse 
rate against the B.1.351 variant is 
non-inferior to the rate against the 
original Wuhan-Hu-1 strain following 
an AZD1222 booster dose
[V1222: B1222: Beta]/[V1222:B1222: Wuhan]
(Other Secondary)
[V1222: B1222: Beta] −[V1222: B1222:Wuhan]
(Other Secondary)

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9.4.4
Multiple Comparisons
A hierarchical approach will be used to control for multiplicity of the primary and key 
secondary immunogenicity endpoints. That is, the null hypotheses for the immunogenicity 
endpoints will be tested in a hierarchical order, and the subsequent null hypothesis will be 
tested only if the prior null hypothesis is rejected. Consequently, no adjustment to alpha for 
multiplicity will be made in the analysis of immune response. The primary Statistical 
comparisons of safety data will not be adjusted for multiple comparisons.  Further details are 
provided in the statistical analysis plan.
9.4.5
Data Safety Monitoring Board
An independent COVID-19 Vaccine Data Safety Monitoring Board will provide oversight, to 
ensure safe and ethical conduct of the study.  During the study, the benefit/risk assessment 
will be continuously monitored by the Board to ensure that the balance remains favourable.  
Further details, composition, and operation of the COVID-19 Vaccine Data Safety Monitoring 
Board will be described in a separate charter. For further details, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Not applicable.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
#
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
#
Applicable ICH/GCP Guidelines
#
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigators Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority.  This responsibility may be delegated to 
a contract research organization but the accountability remains with the Sponsor.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH/GCP guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all Food and 
Drug Administration (FDA) Regulations, as applicable and all other applicable local 
regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
#
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study.  Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH/GCP guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
!
The study medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples.  The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use.  Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

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!
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law.  The level of disclosure and use 
of their data must also be explained to the participant in the informed consent. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committee Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A COVID-19 Vaccine Data Safety Monitoring Board comprised of independent experts will 
be convened to provide oversight and to ensure safe and ethical conduct of the study.  The 
COVID 19 Vaccine Data Safety Monitoring Board will have the responsibility of evaluating 
cumulative safety and other clinical study data at regular intervals and making appropriate 
recommendations based on the available data.  During the study, the benefit/risk assessment 
will be continuously monitored by the COVID-19 Vaccine Data Safety Monitoring Board to 
ensure that the balance remains favourable.  Full details of the COVID-19 Vaccine Data 
Safety Monitoring Board composition and operations can be found in the COVID-19 Vaccine 
Data Safety Monitoring Board Charter.
An independent Neurological AESI Expert Committee will be available to review and provide 
on request about the diagnosis and causality assessment of selected neurological AEs of 
special interest occurring in the study.  Details on the composition and operation of this 
committee are described in the Neurological AESI Expert Committee Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available.  The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

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!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
!
Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected, and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH/GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study.  
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or ICH/GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both SAEs and non-SAEs and can include a deterioration of a 
pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs.  
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used.  
In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a non-
SAE.  For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur.  Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as non-serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  Examples of important medical events include such events as listed 
below:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Intensity Rating Scale
A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events.  
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 

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several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the investigational product.
!
Time Course.  Exposure to suspect drug.  Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect investigational product?
!
Consistency with known investigational product profile.  Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or drugs of the same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational medicinal product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the investigational product, but rather a human or 
process related failure while the investigational product is in control of the study site staff or 
participant.
Medication error includes situations where an error. 
!
Occurred
!
Was identified and intercepted before the participant received the investigational product
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Investigational product name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Investigational product not administered as indicated, for example, wrong route or wrong 
site of administration
!
Investigational product not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Investigational product not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong participant received the medication (excluding IRT errors)
!
Wrong investigational product administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from 
the participants while in storage at the study site until shipment or disposal (where
appropriate) and records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
The Sponsor or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
The Sponsor ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented.  If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and the Sponsor are informed about the sample disposal.

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The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus.  Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814.  Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. 
They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
!
Table 24: Clinical Abnormalities, Local Reactions to Injectable Product
!
Table 25: Clinical Abnormalities, Vital Signs
!
Table 26: Clinical Abnormalities, Systemic (General or Illness)
Table 24
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalization
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded.
b
Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE e-Diary.
ER: emergency room.

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Table 25
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)a
Fever (°C/°F)
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
Emergency room visit 
or hospitalization for 
arrhythmia
Bradycardia 
(beats/minute)
50-54
45-49
< 45
Emergency room visit 
or hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
Emergency room visit 
or hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
Emergency room visit 
or hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes.

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Table 26
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic 
(General)
Systemic Gradea
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/
vomiting
No interference with 
activity or 
1-2 episodes/24 hours
Some interference 
with activity or 
> 2 episodes/24 hours
Prevents daily activity, 
required outpatient 
intravenous hydration
Emergency room 
visit or 
hospitalization for 
hypotensive shock
Chills
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
Emergency room 
visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room 
visit or 
hospitalization
Systemic Illness
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations)
No interference with 
activity
Some interference 
with activity not 
requiring intervention
Prevents daily activity 
and required medical 
intervention
Emergency room 
visit or 
hospitalization

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Appendix E
Adverse Events of Special Interest
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 27
Adverse Events of Special Interest
Category
Medical Concept
Neurologic
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment or 
loss of consciousness.  
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis.
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population.
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (eg, weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, or other 
sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate.
Hematologic
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL.
Immunologic
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention.
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non-neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: a group of autoimmune inflammatory disorders 
characterized by an alteration in cellular homeostasis, which may or may not have an 
autoimmune aetiology.  A list of events is provided in Table 28. 

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis

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Table 28
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune haemolytic anaemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anaemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Actions Required in Cases of Thrombotic Events With 
Thrombocytopenia and/or Bleeding
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombotic events with thrombocytopenia and/or bleeding.  It is not intended to 
be a comprehensive guide to the management of all venous thromboembolic events.  
During the course of the study, the investigator will remain vigilant for occurrence of 
thrombotic events with thrombocytopenia and/or bleeding.  Appropriate investigations (eg, 
imaging) to diagnose these events should be made on a case-by-case basis.  The investigator is 
responsible for determining whether a participant meets criteria for thrombotic events with 
thrombocytopenia and/or bleeding at any point during the study.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombotic events with thrombocytopenia 
and/or bleeding.  The Study Physician contacts the investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data.  
Guidance from the International Society of Thrombosis and Haemostasis for management of 
thrombocytopenic thromboembolism occurring after vaccination can be found at 
www.isth.org.  Notably, participants should only be treated with heparin if a test for heparin-
induced thrombocytopenia antibodies is negative.  An alternative explanation for 
thrombocytopenia should be considered (eg, alcohol use, liver cirrhosis, concomitant 
medications, exposure to toxic chemicals, viral infections).
The investigator is responsible for recording data pertaining to thrombotic events with 
thrombocytopenia and/or bleeding and for reporting AEs and SAEs according to the outcome 
of the review and assessment in line with standard safety reporting processes.
F 2
Tests that Should Be Considered if Thrombotic Events With 
Thrombocytopenia and/or Bleeding Are Suspected
The following tests should be considered, but not limited to:
1. Measurement of platelet levels, prothrombin time, activated partial thromboplastin time, 
D-dimer levels, and fibrinogen levels
2. Complete blood count, reticulocyte count, blood film, haptoglobins
3. Anti-platelet factor 4 antibodies

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4. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, human 
leucocyte antigen B27, ADAMTS13 activity, anti-cardiolipin antibodies IgG + IgM, and 
anti-B2GPI antibodies IgG + IgM
5. Complement (eg, C3, C4, complement complex C5b-9, C5a), autoantibodies (eg, 
antinuclear IgG, anti-double stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG)
6. Factor V Leiden, Factor II (prothrombin) variant 
7. Platelet activation markers and functional assays (eg: sCD40L, soluble glycoproteins, 
degranulation markers [PF4, vWF, P-selectin, annexin V]), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 ELISA positive)
8. Inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13
9. Cell adhesion molecules: VCAM, ICAM, E-selectin
10. Adenovirus serology
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Ebstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19
12. COVID-19 testing, including PCR and serology
13. Calculation of an International Society of Thrombosis and Haemostatis score for 
Disseminated Intravascular Coagulation (derived from platelet levels, fibrinogen, and D-
Dimer)

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ChAdOx1 MERS
Chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
AZD1222 when initially developed by the University of Oxford
COVID-19
Coronavirus disease 2019
eCRF
Electronic case report form
e-Diary
Electronic diary
GMT
Geometric mean titre
ICF
Informed consent form
ICH/GCP
International Council for Harmonisation/Good Clinical Practice
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
MAAEs
Medically attended adverse events
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
S
Spike
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome-coronavirus-2

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Appendix H
Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment GBR-3
13 October 2021
Amendment  GBR-2
30 July 2021
Amendment GBR-1
3 June 2021
Amendment 1
2 June 2021
Version 1
14 May 2021
Amendment GBR-3: 13 October 2021
The principal reason for this amendment was to remove the age cap and revise the primary 
and key secondary non-inferiority analyses to included historical controls due to difficulties in 
recruiting the previously unvaccinated cohort.

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Synopsis
Section 4.1
Section 9.4..3.1.1
Inserted information on use of 
historical controls
Required based on 
anticipated confounding 
between previously 
vaccinated and previously 
unvaccinated cohorts.
Substantial
Section 3.2, Table 6
Inserted exploratory objectives 
on exploration of humoral 
immune response with live virus 
neutralization assay and 
exploration of additional 
immune response based on 
emerging data
Omitted in error
Non-substantial
Section 4.1
Deleted age cap ensuring at least 
25% enrolled participants were 
>65 years of age.
Due to enrollment 
difficulties in finding 
previously unvaccinated 
elderly
Substantial
Section 7.1
Inserted laboratory-confirmed 
SARS-CoV-2 infection as 
discontinuation of study 
intervention
To explicitly state this 
criterion (which is 
implicitly included in 
criteria 2) as a 
discontinuation of 
treatment criterion.
Non-substantial
Section 9.2
Section on immunogenicity 
comparisons and previous Table 
16 and Table 17 were moved up 
under the Primary Objective 
sub-heading
Had been placed under 
Secondary Objective in 
error
Non-substantial
Section 9.4.3.1.1
Table 19
Table 20
Table 21
Table 22
Table 23
Analysis key (abbreviations) 
revised
Improvements in 
abbreviations for clarity
Non-substantial
Section 9.4..3.1.1
Description of statistical 
approach to be used with 
historical control comparisons 
added. 
Inclusion of historical 
controls requires 
description of statistical 
methodology to be used.
Substantial
In addition, the protocol has been revised with minor rewordings, corrections, and 
clarifications which are all considered to be non-substantial.

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Amendment GBR-2: 30 July 2021
The principal reason for this amendment was to
1) add an additional interim analysis to evaluate immunogenicity in a subset of 
AZD1222 previously vaccinated subjects boosted with AZD1222 or AZD2816
2) revise Objectives/Endpoints from descriptive to comparative, with ranking of primary, 
key secondary, other secondary, and exploratory objectives
3) add non-inferiority margins to primary analysis and add additional participants to 
maintain power 
This amendment has also been implemented in the global version of the study D7220C00001 
Clinical Study Protocol.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis 
(Objectives and 
Endpoints)
Revised this section from 
primarily descriptive to 
primarily comparative.  
Comparative immunogenicity 
objectives created and ranked as 
primary, key secondary, other 
secondary.
Objectives of study 
changed from descriptive 
to comparative, testing for 
non-inferiority across 
treatment comparisons
Substantial
1.1 Synopsis 
(Number of 
Participants; Statistical 
Methods)
Overall size increased to 2590 
participants
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.1 Synopsis (Statistical 
Methods)
An additional interim analysis 
added. Second interim analysis 
changed to include only the 
previously vaccinated with 
AZD1222 cohort.
Interim analysis plan was 
reviewed and revised.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.2 Schema
Figures updated with increased 
participant numbers
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
1.3 Schedule of 
Activities
Table 2: footnote clarification 
added
Table 3: minor corrections
Clarification/Correction
Non-substantial
2.1 Study Rationale 
(and elsewhere in 
protocol)
Clarification on previous 
vaccination criteria
Clarification
Non-substantial
3 Objectives
Section completely rewritten.  
Divided into 2 sections: 
Previously unvaccinated and 
previously vaccinated.  
Immunogenicity objectives 
created for comparisons.  
Objectives ranked as primary, 
key secondary, other secondary, 
or exploratory.
Objectives of study 
changed to show non-
inferiority across 
treatments.  
Substantial
4.1 Overall design
Participant numbers increased
Adjustments made to 
maintain power with the 
added non-inferiority 
margins
Substantial
4.1 Overall design
Cap on age added
To ensure good 
representation across age 
groups
Substantial
8.3.2
Removal of severity grade 5
Correction
Non-substantial
8.5.2.3
 
 
Addition of information on 
number of patients sampled for 
Clarification
Non-substantial
9.1 Statistical 
Hypotheses
Addition of statistical 
hypotheses
Include hypothesis being 
tested.
Substantial
9.2 Sample size 
determination
Confidence intervals for 
populations of 350 and 380 
added to Table 14 and Table 15
Updated to include
current populations of 
350 and 380 participants
Non-substantial
9.2 Sample size 
determination
Power estimates for populations 
of 350 and 380 added to Table 
17 and Table 18
Updated to include 
current populations of 
350 and 380 participants
Non-substantial
CCI
CCI

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
9.4.1 General 
considerations
Details on the initial interim, 
second interim, and third interim 
analysis added
Include revised 
information on the 
analysis plan, including 
interim analyses
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Objectives removed from 
descriptive analysis Table 23 
and Table 24
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Section of  Immunogenicity 
Comparisons added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.3.1.1 Estimand 
framework for 
immunogenicity 
descriptions and 
comparisons
Table 25 and Table 26 on 
immunogenicity comparisons 
revised, aligned with the revised 
objectives/endpoints.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
9.4.4 Multiple 
Comparisons
Section added.
Objectives of study 
changed from descriptive 
to comparative, showing 
non-inferiority across 
treatments
Substantial
In addition, the protocol has been revised with minor corrections and clarifications.
Amendment GBR-1 (Protocol Version 2): 1 June 2021
Version 1 of the protocol was amended prior to the commencement of the study (ie, prior to 
approval of the protocol by an ethics committee) based on feedback from internal and 
regulatory authority reviews.  The most substantial changes were as follows:
!
addition of 2 treatment arms:  1) AZD1222 as a single booster vaccination in participants 
previously vaccinated with an mRNA COVID-19 vaccine and 2) heterologous 
vaccination with AZD1222 plus AZD2816 in previously unvaccinated participants
!
further definition of analysis sets
!
addition of thrombotic events with thrombocytopenia as a discontinuation criteria
In addition, corrections and revisions to text to improve readability were made.

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11
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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7220C00001-csp-gbr3
Document Title:
D7220C00001 Clinical Study Protocol GBR3 Amendment
13Oct2021
Document ID:
Doc ID-004588859
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
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Meaning of Signature
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Content Approval
13-Oct-2021 13:57 UTC
Justin Green
Management Approval
14-Oct-2021 10:09 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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