A Phase III Randomized, Double-blind, Placebo-controlled Multicenter Study in Adults, to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, for the Prevention of COVID-19
Phase: PHASE3
Conditions: COVID-19, SARS-CoV-2
Sponsor: AstraZeneca

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Clinical Study Protocol
Study Intervention
AZD1222
Study Code
D8110C00001
Version
Amendment 6
Date
19 February 2021
TITLE PAGE
A Phase III Randomized, Double-blind, Placebo-controlled 
Multicenter Study in Adults to Determine the Safety, Efficacy, and 
Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector 
Vaccine, for the Prevention of COVID-19
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): IND number 23522
NCT04516746
EudraCT number 2020-005226-28
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: D8110C00001
Amendment Number: 6
Study Intervention: AZD1222
Study Phase: III
Short Title: Phase III Double-blind, Placebo-controlled Study of AZD1222 for the Prevention 
of COVID-19 in Adults
Study Physician Name and Contact Information will be provided separately
USA Coordinating Investigators:
University of Rochester School of Medicine
Rochester, NY
Columbia University
New York, NY
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 6
19 February 2021
Amendment 5
18 January 2021
Amendment 4
14 December 2020
Amendment 3
26 October 2020
Amendment 2
17 September 2020
Amendment 1
10 August 2020
Original Protocol
15 July 2020

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Amendment 6 (19 February 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The principal reason for this amendment was to remove the extended dosing interval 
assessment and to remove adolescents from the study population that were added to 
Amendment 5. (Note: Amendment 5 was not implemented.)
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title Page,
1.1 Synopsis
Removed “and Adolescents” 
from the title
Given removal of 
adolescents from the 
study population
Substantial
1.1 Synopsis,
2.1 Study Rationale
Removed text from the study 
rationale regarding adolescents
1.1 Synopsis
Reduced the number of study 
sites from 300 to 150
To more realistically 
align with the actual 
number of sites
Non-substantial
1.1 Synopsis,
3 Objective and 
Endpoints,
Appendix F (Table 15)
Upgraded exploratory 
endpoint 5 to secondary 
endpoint 9
To gain information on 
efficacy following a 
single dose of AZD1222
Substantial
1.1 Synopsis,
1.2 Schema,
1.3 Schedule of 
Activities
3 Objectives and 
Endpoints,
4.1 Overall Design,
4.2 Scientific Rationale 
for Study Design,
4.3 Justification for 
Dose,
4.4 End of Study 
Definition,
5 Study Population,
6.1.2 Dosing 
Instructions,
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding,
7.1 Discontinuation of 
Study Intervention
8 Study Assessments 
Removed Appendix G Part 2
and any cross-references to 
Appendix G Part 2
Given removal of Part 2 
from the protocol
Substantial
Removed the “Part 1” label 
from the main study and 
corresponding substudy and 
immunogenicity cohort
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
and Procedures,
9 Statistical 
Considerations,
Appendix G Part 2 
1.1 Synopsis,
Appendix F 
(Table 15)
Removed specification that 
primary objective 3 and
secondary objectives 7-8 apply 
to both Part 1 and Part 2
Given removal of Part 2 
from the protocol
Substantial
3 Objectives and 
Endpoints
Removed specification that 
primary objective 3, secondary 
objectives 7-8, and exploratory 
objectives 5-13 apply to both 
Part 1 and Part 2
Given removal of Part 2 
from the protocol
Substantial
Removed footnote d from
Table 5 that indicated
exploratory endpoint 5 is an 
exploratory endpoint for Part 1, 
but a secondary endpoint for 
Part 2
4.2.2 Rationale for 
Study Endpoints,
8.3.9 Adverse Events of 
Special Interest,
11 References,
Appendix E
Removed the Serazin et al 2020 
and Vogel et al 2020 references
Given removal of the 
multisystem 
inflammatory syndrome 
in children and adults 
(MIS-C/A) and acute 
respiratory distress 
syndrome (ARDS) terms 
from Appendix E, 
Table 13
Non-substantial
8.1.2.1 SARS-CoV-2 
Testing and Other 
Virology Assessments
Added text to explain that 
genotypic evaluation of 
SARS-CoV-2 is planned at 
Days 1 and 14 illness visits but 
may be performed at Days 21 
and 28 illness visits based upon 
logistical constraints, safety 
signals, or emerging data on 
efficacy of AZD1222 against 
viral variants
Clarification
Non-substantial
9.4.2.2 Secondary 
Endpoints,
Appendix F (Table 15)
Revised the list of secondary 
endpoints to align with the 
Synopsis and Section 3 of the 
protocol
Consistency
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
A5 Committee 
Structure
Revised this section
To align with the current 
version of the statistical 
analysis plan
Non-substantial
Appendix E 
(Table 13)
Removed reference to MIS-C/A 
and ARDS
Given removal of the 
adolescent population
Non-substantial
Appendix G Part 2
Removed this appendix
Given removal of Part 2 
from the protocol
Substantial
Throughout
Minor editorial revisions
Minor, therefore, were 
not summarized
Non-substantial

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS...................................................................................................... 7
1
PROTOCOL SUMMARY................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 18
1.3
Schedule of Activities....................................................................................... 18
2
INTRODUCTION............................................................................................ 27
2.1
Study Rationale ................................................................................................ 27
2.2
Background ...................................................................................................... 27
2.3
Benefit/Risk Assessment................................................................................... 29
2.3.1
Risk Assessment............................................................................................... 30
2.3.2
Benefit Assessment........................................................................................... 30
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 30
3
OBJECTIVES AND ENDPOINTS................................................................... 30
4
STUDY DESIGN ............................................................................................. 34
4.1
Overall Design.................................................................................................. 34
4.2
Scientific Rationale for Study Design ............................................................... 36
4.2.1
Rationale for Study Design and Participant Population ..................................... 36
4.2.2
Rationale for Study Endpoints .......................................................................... 37
4.3
Justification for Dose........................................................................................ 37
4.4
End of Study Definition.................................................................................... 38
5
STUDY POPULATION ................................................................................... 39
5.1
Inclusion Criteria .............................................................................................. 39
5.2
Exclusion Criteria ............................................................................................. 41
5.3
Lifestyle Considerations ................................................................................... 42
5.4
Screen Failures ................................................................................................. 42
6
STUDY INTERVENTION............................................................................... 43
6.1
Study Interventions Administered..................................................................... 43
6.1.1
Investigational Products.................................................................................... 43
6.1.2
Dosing Instructions........................................................................................... 44
6.2
Preparation/Handling/Storage/Accountability ................................................... 44
6.2.1
Dose Preparation and Administration................................................................ 45
6.2.1.1
AZD1222.......................................................................................................... 45
6.2.1.2
Placebo............................................................................................................. 45
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 45
6.3.1
Randomization.................................................................................................. 45

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6.3.2
Blinding............................................................................................................ 46
6.3.3
Procedures for Unblinding ................................................................................ 46
6.4
Study Intervention Compliance......................................................................... 47
6.5
Concomitant Therapy........................................................................................ 47
6.5.1
Permitted Concomitant Medications ................................................................. 47
6.5.2
Prohibited Concomitant Medications ................................................................ 47
6.6
Dose Modification ............................................................................................ 48
6.7
Intervention After the End of the Study............................................................. 48
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 49
7.1
Discontinuation of Study Intervention............................................................... 49
7.1.1
Study Suspension or Termination...................................................................... 49
7.2
Participant Withdrawal from the Study ............................................................. 50
7.3
Lost to Follow-up ............................................................................................. 50
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 50
8.1
Efficacy Assessments........................................................................................ 51
8.1.1
Monitoring COVID-19 Symptoms.................................................................... 51
8.1.2
Illness Visits ..................................................................................................... 52
8.1.2.1
SARS-CoV-2 Testing and Other Virology Assessments.................................... 53
8.1.2.2
Digital Health Device ....................................................................................... 53
8.1.2.3
Illness e-Diary .................................................................................................. 54
8.1.3
Severe COVID-19 ............................................................................................ 55
8.1.4
Medical Notes Review...................................................................................... 55
8.1.5
Monitoring for Asymptomatic Infection............................................................ 55
8.2
Safety Assessments........................................................................................... 55
8.2.1
Physical Examinations...................................................................................... 56
8.2.2
Vital Signs........................................................................................................ 56
8.2.3
Clinical Laboratory Assessments ...................................................................... 56
8.3
Adverse Events and Serious Adverse Events..................................................... 57
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 57
8.3.2
Follow-up of AEs and SAEs ............................................................................. 57
8.3.3
Causality Collection.......................................................................................... 58
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 59
8.3.5
Adverse Events Based on Examinations and Tests............................................ 59
8.3.6
Hy’s Law.......................................................................................................... 59
8.3.7
Solicited Adverse Events (Only for Substudy) .................................................. 60
8.3.8
Medically Attended Adverse Events ................................................................. 61
8.3.9
Adverse Events of Special Interest.................................................................... 61
8.3.9.1
Potential Neurological AESIs ........................................................................... 61
8.3.10
Reporting of Serious Adverse Events................................................................ 63
8.3.11
Pregnancy......................................................................................................... 63
8.3.11.1
Maternal Exposure............................................................................................ 63
8.3.12
Medication Error............................................................................................... 64

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8.3.13
Medical Device Deficiencies............................................................................. 64
8.4
Overdose .......................................................................................................... 65
8.5
Human Biological Samples............................................................................... 65
8.5.1
Pharmacokinetics.............................................................................................. 65
8.5.2
Immunogenicity Assessments ........................................................................... 66
8.5.2.1
SARS-CoV-2 Serology Assessments ................................................................ 66
8.5.2.2
SARS-CoV-2 Neutralizing Antibody Assessments ........................................... 66
8.5.2.3
Assessment of Mucosal Responses ................................................................... 66
8.5.2.4
Assessment of Cell-mediated Immune Responses............................................. 66
8.5.2.5
Additional Serum Immunogenicity ................................................................... 67
8.5.3
Pharmacodynamics........................................................................................... 67
8.6
Human Biological Sample Biomarkers ............................................................. 67
8.6.1
Collection of Mandatory Samples for Biomarker Analysis................................ 67
8.6.1.1
Virologic Assessments...................................................................................... 67
8.6.1.2
Assessment of Viral Shedding .......................................................................... 68
8.6.2
Other Study-related Biomarker Research .......................................................... 68
8.7
Optional Genomics Initiative Sample................................................................ 68
8.8
Medical Resource Utilization and Health Economics........................................ 68
9
STATISTICAL CONSIDERATIONS............................................................... 68
9.1
Statistical Hypotheses....................................................................................... 68
9.2
Sample Size Determination............................................................................... 69
9.3
Populations for Analyses .................................................................................. 70
9.4
Statistical Analyses........................................................................................... 71
9.4.1
General Considerations..................................................................................... 72
9.4.2
Efficacy ............................................................................................................ 73
9.4.2.1
Primary Endpoint.............................................................................................. 73
9.4.2.2
Secondary Endpoints ........................................................................................ 75
9.4.2.3
Exploratory Endpoints ...................................................................................... 77
9.4.3
Safety ............................................................................................................... 77
9.4.3.1
Primary Endpoints ............................................................................................ 77
9.4.3.2
Other Safety Endpoints..................................................................................... 77
9.4.4
Methods for Multiplicity Control ...................................................................... 78
9.4.5
Sensitivity Analyses.......................................................................................... 79
9.4.6
Subgroup Analyses ........................................................................................... 79
9.5
Interim Analyses............................................................................................... 79
9.6
Data Safety Monitoring Committee................................................................... 80
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 80
11
REFERENCES............................................................................................... 129

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LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 18
Figure 2
Neurology Testing Algorithm .................................................................. 62
LIST OF TABLES
Table 1
Schedule of Activities: Screening Period ................................................. 19
Table 2
Schedule of Activities: Treatment and Follow-up Period – Main Study 
(Excluding Substudy and Immunogenicity Cohort Participants)............... 20
Table 3
Schedule of Activities: Treatment and Follow-up Period – Substudy and 
Immunogenicity Cohort (USA Participants Only).................................... 22
Table 4
Schedule of Activities: Illness Visits (Participants with Qualifying 
Clinical Symptoms) ................................................................................. 25
Table 5
Objectives and Endpoints......................................................................... 30
Table 6
Highly Effective Methods of Contraception............................................. 40
Table 7
Investigational Products........................................................................... 43
Table 8
List of Predefined Solicited Adverse Events for Reactogenicity 
Assessment.............................................................................................. 60
Table 9
Populations for Analysis .......................................................................... 70
Table 10
Tables for Clinical Abnormalities: Local Reactions to Injectable Product 94
Table 11
Tables for Clinical Abnormalities: Vital Signs......................................... 95
Table 12
Tables for Clinical Abnormalities: Systemic (General or Illness) ............. 96
Table 13
Adverse Events of Special Interest........................................................... 97
Table 14
List of Potential Immune-mediated Medical Conditions........................... 98
Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and 
Associated Case Definitions................................................................... 102
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 81
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........................................................... 97

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Appendix F
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and 
Associated Case Definitions................................................................... 101
Appendix G
Abbreviations ........................................................................................ 109
Appendix H
Protocol Amendment History................................................................. 111

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase III Randomized, Double-blind, Placebo-controlled Multicenter Study 
in Adults to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a 
Non-replicating ChAdOx1 Vector Vaccine, for the Prevention of COVID-19
Short Title: Phase III Double-blind, Placebo-controlled Study of AZD1222 for the Prevention 
of COVID-19 in Adults
Rationale: The aim of the study is to assess the safety, efficacy, and immunogenicity of 
AZD1222 for the prevention of COVID-19. The COVID-19 pandemic has caused major 
disruption to healthcare systems with significant socioeconomic impacts. Currently, there are 
no specific treatments available against COVID-19 and accelerated vaccine development is 
urgently needed. A safe and effective vaccine for COVID-19 prevention would have 
significant public health impact.
Objectives and Endpoints
Objective a
Estimand b Description/Endpoint
PRIMARY
1
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of COVID-19 
Population: Fully vaccinated analysis set
Endpoint: A binary response, whereby a participant with 
negative serostatus at baseline is defined as a COVID-19 
case if their first case of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurs ≥15 days post second dose of 
study intervention. Otherwise, a participant is not defined as 
a COVID-19 case.
Intercurrent events: For participants who withdraw from 
the study prior to having met the criteria for the primary 
efficacy endpoint, absence of data following these 
participants’ withdrawal will be treated as missing (ie,
counted as not having met the criteria); participants who 
withdraw before 15 days post second dose or who have a 
case prior to 15 days post second dose will be excluded from 
primary endpoint analysis. Participants unblinded to 
treatment assignment prior to having met the criteria for the 
primary efficacy endpoint will be censored at the date of 
unblinding.
Summary measure: VE, calculated as 1-relative risk.  
(Relative risk is the incidence in the vaccine group relative to 
the incidence in the control group.)

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Objective a
Estimand b Description/Endpoint
2
To assess the safety and tolerability of 
2 IM doses of AZD1222 compared to 
saline placebo 
a) Incidence of AEs for 28 days post each dose of study 
intervention
b) Incidence of SAEs, MAAEs, and AESIs from Day 1 post 
treatment through Day 730
3
To assess the reactogenicity of 2 IM 
doses of AZD1222 compared to saline 
placebo 
(Substudy only)
Incidence of local and systemic solicited AEs for 7 days post 
each dose of study intervention 
SECONDARY
1
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of SARS-CoV-2 
infection
The incidence of the first post-treatment response (negative 
at baseline to positive post treatment with study intervention) 
for SARS-CoV-2 Nucleocapsid antibodies occurring 
≥15 days post second dose of study intervention c
2
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of symptomatic
COVID-19 using CDC criteria
The incidence of the first case of SARS-CoV-2 RT-PCR-
positive symptomatic illness occurring ≥15 days post second 
dose of study intervention using CDC criteria
3
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of University of 
Oxford-defined symptomatic COVID-19
The incidence of the first case of SARS-CoV-2 RT-PCR-
positive symptomatic illness occurring ≥15 days post second 
dose of study intervention using University of Oxford-
defined symptom criteria
4
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo in 
the prevention of COVID-19 in all study 
participants, regardless of evidence of 
prior SARS-CoV-2 infection
The incidence of the first case of SARS-CoV-2 RT-PCR-
positive symptomatic illness occurring ≥15 days post second 
dose of study intervention regardless of evidence of prior 
SARS-CoV-2 infection c
5
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of severe or critical 
symptomatic COVID-19 
a) The incidence of SARS-CoV-2 RT-PCR-positive severe 
or critical symptomatic illness occurring ≥15 days post 
second dose of study intervention c
b) The incidence of SARS-CoV-2 RT-PCR-positive severe 
or critical symptomatic illness occurring post first dose of 
study intervention
6
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of COVID-19-related 
Emergency Department visits
The incidence of COVID-19-related Emergency Department 
visits occurring ≥15 days post second dose of study 
intervention c
7
To assess antibody responses to 
AZD1222 S antigen following 2 IM 
doses of AZD1222 or saline placebo
(Substudy and Illness Visits only)
a) Post-treatment GMTs and GMFRs from day of dosing 
baseline value to 28 days post each dose in SARS-CoV-2 
S, RBD antibodies (MSD serology assay)
b) The proportion of participants who have a post-treatment 
seroresponse (≥4-fold rise in titers from day of dosing 
baseline value to 28 days post each dose) to the S, RBD 
antigens of AZD1222 (MSD serology assay)

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Objective a
Estimand b Description/Endpoint
8
To determine anti-SARS-CoV-2 
neutralizing antibody levels in serum 
following 2 IM doses of AZD1222 or 
saline placebo
(Substudy and Illness Visits only)
a) Post-treatment GMTs and GMFRs from day of dosing 
baseline value to 28 days post each dose in SARS-CoV-2 
neutralizing antibodies (wild-type assay or 
pseudo-neutralization assay)
b) Proportion of participants who have a post-treatment 
seroresponse (≥4-fold rise in titers from day of dosing 
baseline value to 28 days post each dose) to AZD1222 as 
measured by SARS-CoV-2 neutralizing antibodies 
(wild-type assay or pseudo-neutralization assay)
9
To estimate the efficacy of AZD1222 
compared to saline placebo for the 
prevention of COVID-19 following the 
first dose
The incidence of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring post first dose of study 
intervention
a
Substudy: The substudy will be conducted only in the USA. The first participants randomized in each 
age group in the USA, including 1 500 participants 18 to 55 years of age, 750 participants 56 to 69 years 
of age, and 750 participants ≥ 70 years of age, will also participate in a substudy assessing the 
reactogenicity and immunogenicity of AZD1222.
Illness Visits: Participants who present with qualifying symptoms will be tested for SARS-CoV-2 and if 
positive, will complete illness visits.
b
Estimand is the target of estimation to address the scientific question of interest posed by the primary 
objective. Attributes of an estimand include the population of interest, the variable (or endpoint) of 
interest, the specification of how intercurrent events are reflected in the scientific question of interest, 
and the population-level summary for the variable.
c
Key secondary endpoint.
AE = adverse event; AESI = adverse event of special interest; CDC = Centers for Disease Control and 
Prevention; COVID-19 = coronavirus disease 2019; GMFR = geometric mean fold rise; GMT = geometric 
mean titer; IFN-γ = interferon-gamma; IM = intramuscular; MAAE = medically attended adverse event; 
MSD = Meso Scale Discovery; RT-PCR = reverse transcriptase polymerase chain reaction; RBD = receptor
binding domain; S = Spike; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome-
coronavirus-2; USA = United States of America; VE = vaccine efficacy.
For exploratory objectives, see Section 3. 
Overall Design: D8110C00001 is a Phase III randomized, double-blind, placebo-controlled,
multicenter study assessing the safety, efficacy, and immunogenicity of AZD1222 compared 
to saline placebo for the prevention of COVID-19. Approximately 150 sites globally will
participate in this study.
Participants will be adults ≥18 years of age who are healthy or have medically-stable chronic 
diseases, and are at increased risk for SARS-CoV-2 acquisition and COVID-19. 
Approximately 30 000 participants will be randomized in a 2:1 ratio to receive 2 IM doses of 
either 5 × 1010 vp (nominal, ± 1.5 × 1010 vp) AZD1222 (n = approximately 20 000) or saline 
placebo (n = approximately 10 000) 4 weeks apart, on Days 1 and 29. Randomization will be 
stratified by age (≥18 to < 65 years, and ≥65 years), with at least 25% of participants to be 
enrolled in the older age stratum. Participants who received their first dose of study 
intervention between 28 August 2020 and 06 September 2020 will receive their second dose 
of study intervention outside of the study window.

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All participants will be assessed for efficacy and safety. The first participants randomized in 
each age group in the USA, including 1 500 participants 18 to 55 years of age, 
750 participants 56 to 69 years of age, and 750 participants ≥ 70 years of age, will also 
participate in a substudy assessing the reactogenicity and immunogenicity of AZD1222. 
To further investigate cell-mediated immunogenicity, in particular Th1/Th2 responses, after 
AZD1222 or saline placebo administration, an immunogenicity cohort of approximately 
300 participants was added.
A PSRT will provide support for blinded safety surveillance during the study. Additionally, an 
independent COVID-19 Vaccine DSMB organized by the National Institutes of Health, 
National Institute for Allergy and Infectious Diseases, will provide oversight, to ensure safe 
and ethical conduct of the study. An independent Neurological AESI Expert Committee will 
be available to review and provide advice to the PSRT and the COVID-19 Vaccine DSMB on 
request about the diagnosis and causality assessment of selected neurological AESIs.
Participants will remain on study for 2 years following administration of the first dose of study 
intervention (Day 730). If AZD1222 is proven to be safe and efficacious based on the primary 
endpoint analysis, following discussion at that time with the US FDA, other Regulators if 
appropriate, and the COVID-19 Vaccine DSMB, participants allocated to the saline placebo 
group will be offered AZD1222 when doses are available. Saline placebo participants treated 
with AZD1222 will continue to be followed in the study. 
Disclosure Statement: This is a parallel-group preventive study with 2 arms that is 
participant-, investigator-, and Sponsor-blinded.
Number of Participants: Approximately 33 000 participants will be screened to achieve up 
to approximately 30 000 participants randomly assigned to study intervention, including 
approximately 20 000 participants randomized to the AZD1222 arm and approximately 
10 000 participants randomized to the saline placebo arm. 
Note: ‘Enrolled’ means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomly assigned in the study, are considered ‘screen failures’. 
Intervention Groups and Duration: Participants will be randomized in a 2:1 ratio to receive 
2 IM doses of 5 × 1010 vp (nominal, ± 1.5 × 1010 vp) AZD1222 or saline placebo. Study 
intervention will be administered on Days 1 and 29. 
Data Monitoring Committee: Yes 

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Statistical Methods
Primary efficacy endpoint
The primary efficacy endpoint is a binary response, whereby a participant with negative 
serostatus at baseline is defined as a COVID-19 case if their first case of SARS-CoV-2 
RT-PCR-positive symptomatic illness occurs ≥15 days post second dose of study 
intervention. Otherwise, a participant is not defined as a COVID-19 case.
Sample size
Approximately 33 000 participants will be screened such that approximately 
30 000 participants will be randomized in a 2:1 ratio to receive 2 IM doses of either 
5 × 1010 vp (nominal, ± 1.5 × 1010 vp) AZD1222 (the active group, n = approximately 20 000) 
or saline placebo (the control group, n = approximately 10 000) 4 weeks apart, on Days 1 and 
29.
The sample size calculations are based on the primary efficacy endpoint and were derived 
following a modified Poisson regression approach (Zou 2004). The calculations account for an 
interim and primary analysis, and the timing of these analyses will be driven by the number of 
events observed in the study. The interim analysis will be carried out when approximately 
50% of the total amount of statistical information is available. A Lan-DeMets alpha-spending 
function has been used to control the overall type I error at 5% with 0.31% alpha at the interim 
analysis and 4.9% at the primary analysis. The calculations assume minimal loss to follow-up 
as it is anticipated that participants will remain engaged in the study. All participants will be 
followed for the entire duration of the study.
For the primary efficacy analysis, approximately 150 events meeting the primary efficacy 
endpoint definition within the population of participants who are seronegative at baseline are 
required across the active and control groups to detect a VE of 60% with > 90% power. These 
calculations assume an observed attack rate of approximately 0.8% and are based on a 2-sided 
test, where the lower bound of the 2-sided 95.10% CI for VE is required to be greater than
30% with an observed point estimate of at least 50%. 
An interim efficacy analysis will be conducted when approximately 75 events meeting the 
primary endpoint definition have been reported across the active and control groups within the 
population of participants who are seronegative at baseline, which will give > 70% power to 
detect a VE of 70% and > 90% power to detect a VE of 75%. These calculations assume an 
observed attack rate of approximately 0.4% and are based on a 2-sided test, where the lower 
bound of the 2-sided 99.69% CI for VE is required to be greater than 30% with an observed 
point estimate of at least 50%. A statistically significant finding at the interim analysis will not 
be considered a reason to stop the study, but instead will be interpreted as early assessment of 
efficacy. 

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Primary estimand
The primary estimand will be used for the analysis of the primary efficacy endpoint. It will be 
based on participants in the fully vaccinated analysis set, defined as all randomized 
participants who are seronegative at baseline, receive 2 doses of study intervention, and who 
remain on-study 15 days after their second dose without having had a prior SARS-CoV-2 
RT-PCR-positive confirmed COVID-19 infection, analyzed according to their randomized 
treatment. For participants with multiple events, only the first occurrence will be used for the 
primary efficacy endpoint analysis. The set of intercurrent events for this estimand consists of 
participants who withdraw from the study or are unblinded to treatment assignment prior to 
having met the primary efficacy endpoint. The intercurrent event of early study withdrawal 
will be handled using the treatment policy strategy and the absence of data following these 
participants’ withdrawal will be treated as missing (ie, counted as not having met the criteria).
Participants unblinded to treatment assignment prior to having met the criteria for the primary 
efficacy endpoint will be censored at the date of unblinding. Participants who withdraw before 
15 days post second dose or who have a case prior to 15 days post second dose will be 
excluded from primary endpoint analysis.
Primary efficacy analysis
As the primary efficacy analysis, the plan is to use the primary estimand and a Poisson 
regression model with robust variance (Zou 2004) to analyze the primary efficacy endpoint, 
including study arm and age as covariates as well as the log of the follow-up time as an offset. 
The VE will be estimated from the model, which will give the RRR in the incidence of 
SARS-CoV-2 RT-PCR-positive symptomatic illness. VE is calculated as 
RRR = 100*(1-relative risk), which is the incidence in the vaccine group relative to the 
incidence in the control group expressed as a percentage. At the interim analysis, the VE will 
be presented with a 2-sided 99.69% CI, and statistical significance will be achieved if the 2-
sided 99.69% CI is > 30%. The success criterion for the interim analysis will be statistical 
significance with an observed VE point estimate of at least 50%. At the primary analysis, VE 
will be presented with a 2-sided 95.10% CI, and statistical significance will be achieved if the 
2-sided 95.10% CI is > 30%. The success criterion for the primary analysis of the study will 
be statistical significance with an observed VE point estimate of at least 50%.  
Model assumptions will be checked and the robustness of the primary analysis will be 
assessed. The Poisson regression model with robust variance has the flexibility for exploring 
multiple imputation approaches using, eg, the observed placebo attack rate to impute missing 
data. If the Poisson regression model with robust variance fails to converge, an alternative 
approach will be implemented. Full details will be documented in the SAP.

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1.2
Schema
Figure 1
Study Design
a
Participants who present with qualifying symptoms will be tested for SARS-CoV-2 and if positive, will 
complete illness visits.
Red bars (Day 1 and Day 29): Administration of study intervention. 
Gray bars (Day 8 and Day 36): Visits will be telephone contacts, not study site visits.
Blue bars (Day 15 and Day 43): Visits will only be for participants in the substudy. The first participants 
randomized in each age group in the USA, including 1 500 participants 18 to 55 years of age, 750 participants 
56 to 69 years of age, and 750 participants ≥ 70 years of age, will also participate in the substudy assessing the
reactogenicity and immunogenicity of AZD1222. 
COVID-19 = coronavirus disease 2019; IM = intramuscular; SARS-CoV-2 = severe acute respiratory 
syndrome-coronavirus-2; USA = United States of America; vp = viral particles.
1.3
Schedule of Activities
The SoA tables include:

Table 1, Screening Period

Table 2, Treatment and Follow-up Period – Main Study (Excluding Substudy and 
Immunogenicity Cohort Participants)

Table 3, Treatment and Follow-up Period – Substudy and Immunogenicity Cohort
(USA Participants Only)

Table 4, Illness Visits (Participants with Qualifying Clinical Symptoms)

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Table 1
Schedule of Activities: Screening Period
Procedure / Study Day
Day -14 to Day 1 a
For details see Section
Informed consent: main study
X
5.1
Assignment SID number
X
6.3
Medical history
X
5.1, 5.2
Complete physical examination, including height and weight
X
8.2.1
Vital signs (including pulse oximetry)
X
8.2.2
Pregnancy test – urine or serum (WOCBP only) b
X
8.2.3
Assessment of SAEs
X
8.3
Concomitant medications
X
6.5
Verify eligibility criteria
X
5.1, 5.2
a
If screening and dosing occur at the same visit, only one evaluation is required. 
b
If urine tests positive or indeterminate, a quantitative serum β-hCG will be performed for confirmation.
β-hCG = beta-human chorionic gonadotropin; SAE = serious adverse event; SID = subject identification; 
WOCBP = women of childbearing potential.

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Table 2
Schedule of Activities: Treatment and Follow-up Period – Main Study (Excluding Substudy and 
Immunogenicity Cohort Participants)
Procedure
Treatment and Follow-up Period
For details 
see Section
Day
1
8 a
29
36 a
57
90
180
360
730
Window (days)
NA
± 3
-3 to +7
± 3
± 3
± 5
± 10
± 15
± 30
Medical history
X
5.1, 5.2
Targeted physical examination
X
8.2.1
Vital signs (including pulse oximetry)
X
8.2.2
Pregnancy test – urine or serum (WOCBP only) b
X
(predose)
X
(predose)
8.2.3
Concomitant medications
X
X
X
X
X
As applicable, for treatment of 
SAE, MAAE, or AESI c
6.5
Verify eligibility criteria
X
5.1, 5.2
Study intervention administration
X
X
6.1, 6.2
Efficacy assessments
Weekly telephone/email/text contacts -
monitoring for COVID-19 qualifying symptoms d
8.1.1
Nasal swab for SARS-CoV-2 RT-PCR 
(local laboratory)
X
(predose)
Serum sample for SARS-CoV-2 serology testing 
X
(predose)
X
(predose)
X
X
X
X
X
8.5.2
Immunogenicity assessments
Serum sample for exploratory assessment 
X
(predose)
X
(predose)
X
8.5.2.5
Safety assessments
AEs
X
X
X
X
X
8.3
SAEs, MAAEs, and AESIs
X
X
X
X
X
X
X
X
X
Telephone contact for safety monitoring
X
X

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Table 2
Schedule of Activities: Treatment and Follow-up Period – Main Study (Excluding Substudy and 
Immunogenicity Cohort Participants)
Procedure
Treatment and Follow-up Period
For details 
see Section
Day
1
8 a
29
36 a
57
90
180
360
730
Window (days)
NA
± 3
-3 to +7
± 3
± 3
± 5
± 10
± 15
± 30
a
Not a study site visit; participants will be contacted by telephone for safety monitoring.
b
If urine tests positive or indeterminate, a quantitative serum β-HCG will be performed for confirmation.
c
Vaccinations, other than AZD1222, for prevention of SARS-CoV-2 or COVID-19 should be recorded if administered at any time during the study.
d
Weekly contact with participants to remind them to present to the study site for SARS-CoV-2 testing if they have qualifying symptoms.
AE = adverse event; AESI = adverse event of special interest; β-hCG = beta-human chorionic gonadotropin; MAAE = medically attended adverse event;
NA = not applicable; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2; WOCBP = women of childbearing 
potential.

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Table 3
Schedule of Activities: Treatment and Follow-up Period – Substudy and Immunogenicity Cohort (USA
Participants Only)
Procedure
Treatment and Follow-up Period
For details 
see Section
Day
1
8 a
15
29
36 a
43
57
90
180
360
730
Window (days)
NA
± 3
± 1
-3 to +7
± 3
± 3
± 3
± 5
± 10
± 15
± 30
Medical history
X
5.1, 5.2
Targeted physical examination
X
8.2.1
Vital signs (including pulse oximetry)
X
8.2.2
Pregnancy test – urine or serum
(WOCBP only) b
X
(predose)
X
(predose)
8.2.3
Concomitant medications
X
X
X
X
X
X
X
As applicable, for treatment of 
SAE, MAAE, or AESI c
6.5
Verify eligibility criteria
X
5.1, 5.2
Study intervention administration
X
X d
6.1.1
Efficacy assessments
Weekly telephone/email/text contacts -
monitoring for COVID-19 qualifying 
symptoms e
8.1.1
Nasal swab for SARS-CoV-2 RT-PCR 
(local laboratory)
X
(predose)
Serum sample for SARS-CoV-2 
serology testing 
X
(predose)
X
X
(predose)
X
X
X
X
X
X
8.5.2
Immunogenicity assessments
Serum sample for ChAdOx1 nAbs 
assessment
X
(predose)
X
(predose)
X
X
X
X
8.5.2
Serum sample for seasonal CoV 
serology testing
X
(predose)
X
(predose)
X
X
X

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Table 3
Schedule of Activities: Treatment and Follow-up Period – Substudy and Immunogenicity Cohort (USA
Participants Only)
Procedure
Treatment and Follow-up Period
For details 
see Section
Day
1
8 a
15
29
36 a
43
57
90
180
360
730
Window (days)
NA
± 3
± 1
-3 to +7
± 3
± 3
± 3
± 5
± 10
± 15
± 30
PBMCs for assessment of B-cell and 
T-cell responses f
X
(predose)
X
X
X
8.5.2
Serum sample for SARS-CoV-2 nAbs 
assessment
X
(predose)
X
X
(predose)
X
X
X
X
Nasal adsorption for SARS-CoV-2 
mucosal responses (optional)
X
(predose)
X
X
(predose)
X
X
X
X
Serum sample for ACE2 competition 
serology
X
(predose)
X
(predose)
X
X
Safety assessments
Local and systemic predefined 
solicited AEs (recorded daily by 
participant in Solicited AE e-Diary) –
Substudy only
X
(through 
Day 8)
X
(through 
Day 36)
8.3.7
AEs
X
X
X
X
X
X
X
8.3
SAEs, MAAEs, and AESIs
X
X
X
X
X
X
X
X
X
X
X
Telephone contact for safety 
monitoring
X
X
a
Not a study site visit; participants will be contacted by telephone for safety monitoring.
b
If urine tests positive or indeterminate, a quantitative serum β-hCG will be performed for confirmation. 
c
Vaccinations, other than AZD1222, for prevention of SARS-CoV-2 or COVID-19 should be recorded if administered at any time during the study.
d
Participants who received their first dose of study intervention between 28 August 2020 and 06 September 2020, will receive their second dose of study 
intervention outside of the study window.
e
Weekly contact with participants to remind them to present to the study site for SARS-CoV-2 testing if they have qualifying symptom.
f
PBMCs will be isolated from up to 300 participants in the substudy and approximately 300 participants in the immunogenicity cohort at select study sites, 
as outlined in the laboratory manual.

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Table 3
Schedule of Activities: Treatment and Follow-up Period – Substudy and Immunogenicity Cohort (USA
Participants Only)
Procedure
Treatment and Follow-up Period
For details 
see Section
Day
1
8 a
15
29
36 a
43
57
90
180
360
730
Window (days)
NA
± 3
± 1
-3 to +7
± 3
± 3
± 3
± 5
± 10
± 15
± 30
ACE2 = angiotensin-converting enzyme 2; AE = adverse event (treatment-emergent); AESI = adverse event of special interest; β-hCG = beta-human chorionic 
gonadotropin; CoV = coronavirus; COVID-19 = coronavirus disease 2019; MAAE = medically attended adverse event; NA = not applicable; 
nAb = neutralizing antibody; PBMC = peripheral blood mononuclear cell; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome-
coronavirus-2; USA = United States of America; WOCBP = women of childbearing potential.

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Table 4
Schedule of Activities: Illness Visits (Participants with Qualifying Clinical Symptoms)
Procedure a
Site Visit
Home Collection by Participant
Site Visit for SARS-CoV-2 
Positive Participants Only
For details 
see Section
Day
1
3
5
8
11
14
21
28
Window (days)
NA
± 1
± 1
± 2
± 2
± 2
± 2
± 2
Medical history 
X
X
X
X
8.1
Brief physical examination
X
X
X
X
8.2.1
Vital signs (including pulse oximetry)
X
X
X
X
8.2.2
Concomitant medication
6.5
Efficacy assessments
Digital health device
8.1.2.2
Symptoms associated with COVID-19
(recorded daily by participant in Illness e-Diary)
8.1.2.3
Virology assessments
Nasal swab for SARS-CoV-2 RT-PCR 
(local laboratory)
X
8.1.2.1
Nasopharyngeal swab 
SARS-CoV-2 RT-PCR (central laboratory)
X
X
X
X
8.1.2.1
SARS-CoV-2 sequencing (central laboratory)
X
X
Respiratory panel
X
8.6.1.1
Saliva sample for viral shedding b
X
X 
X
X
X
X
X
X
8.6.1.2
Immunogenicity assessments
PBMCs for B-cell and T-cell responses 
X c
X
8.5.2
Serum sample for SARS-CoV-2 nAbs assessment
X
X
X
Nasal adsorption for SARS-CoV-2 mucosal 
responses (optional)
X
X
X

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Table 4
Schedule of Activities: Illness Visits (Participants with Qualifying Clinical Symptoms)
Procedure a
Site Visit
Home Collection by Participant
Site Visit for SARS-CoV-2 
Positive Participants Only
For details 
see Section
Day
1
3
5
8
11
14
21
28
Window (days)
NA
± 1
± 1
± 2
± 2
± 2
± 2
± 2
Serum sample for ACE2 competition serology
X
X
X
8.5.2
Serum sample for exploratory assessments
X
X
X
Safety assessments
SAEs, MAAEs, and AESIs
8.3
Telephone contact for safety monitoring
X
X
a
Following availability of the SARS-CoV-2 RT-PCR results, only participants who test positive will continue with the illness visits, including any home 
collection requirements. Participants who test negative for SARS-CoV-2 will be instructed to stop all illness visit assessments and return the digital health 
device (see Section 8.1.2.2). 
b
Collection of saliva sample for viral shedding is optional in non-USA sites and may occur after a feasibility assessment has been completed.
c
PBMCs will be collected from up to approximately the first 3 000 participants, where operationally feasible, on Day 1 illness visit and any participants with 
a Day 1 SARS-CoV-2 positive test result by local RT-PCR test (see Section 8.5.2.4).
ACE2 = angiotensin-converting enzyme 2; AESI = adverse events of special interest; CoV = coronavirus; COVID-19 = coronavirus disease 2019; 
MAAE = medically attended adverse event; NA = not applicable; nAb = neutralizing antibody; PBMC = peripheral blood mononuclear cell; RT-PCR = reverse 
transcriptase polymerase chain reaction; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2. 

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2
INTRODUCTION
AZD1222 is being developed for the prevention of COVID-19. AZD1222 is a recombinant 
replication-defective chimpanzee adenovirus expressing the SARS-CoV-2 S surface 
glycoprotein driven by the human cytomegalovirus major immediate early promoter that 
includes intron A with a human tPA leader sequence at the N terminus. 
2.1
Study Rationale
The aim of the study is to assess the safety, efficacy, and immunogenicity of AZD1222 for 
prevention of COVID-19. The COVID-19 pandemic has caused major disruption to healthcare 
systems with significant socioeconomic impacts. Currently, there are no licensed preventions 
available against COVID-19 and accelerated vaccine development is urgently needed. A safe 
and effective vaccine for COVID-19 prevention 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, known as 2019-nCoV (Zhu et al 2020). The virus was subsequently 
renamed to SARS-CoV-2 because it is similar to the coronavirus responsible for SARS-CoV, 
a lineage B Betacoronavirus. SARS-CoV-2 shares more than 79% of its sequence with 
SARS-CoV, and 50% with the coronavirus responsible for MERS-CoV, a member of the 
lineage C Betacoronavirus (Lu et al 2020). COVID-19 is the infectious disease caused by 
SARS-CoV-2. By January 2020 there was increasing evidence of human-to-human 
transmission as the number of cases rapidly began to increase in China. Spread of the virus 
has been rapid and now encompasses the globe. The WHO declared the novel coronavirus a 
pandemic on 11 March 2020. As of 18 October 2020, there have been more than 40 million 
confirmed cases and > 1.1 million deaths globally (WHO 2020). It is believed that evolution 
of the pandemic will vary across countries, affected in part by different containment strategies 
ranging from extreme lockdown to relative inaction. As a result, there may be regional waves 
of the disease and pockets of vulnerable populations. Globally, governments have 
acknowledged that an effective vaccine against COVID-19 is the only way to guarantee a safe 
and sustained exit strategy from repeated lockdowns.
CoVs are spherical, enveloped viruses with positive-sense single-stranded RNA genomes. 
One fourth of their 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 whilst the S protein is 
involved in receptor binding, mediating virus entry into host cells during CoVs infection via 
different receptors (Li 2016). SARS-CoV-2 belongs to the phylogenetic lineage B of the 
genus Betacoronavirus and it recognizes the ACE2 as the entry receptor (Zhou et al 2020). It 

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is the seventh CoV known to cause human infections and the third known to cause severe 
disease after SARS-CoV and MERS-CoV. 
AZD1222 is a recombinant replication-defective chimpanzee adenovirus expressing the 
SARS-CoV-2 S surface glycoprotein. Development of AZD1222, previously referred to as 
ChAdOx1 nCoV-19, was initiated by the University of Oxford with subsequent transfer of 
development activities to the Sponsor. Nonclinical studies found AZD1222 to be 
immunogenic in BALB/c and CD-1 mice, ferret, porcine, and NHP models. Whilst a single 
dose of AZD1222 induced antigen-specific antibody and T-cell responses, a booster 
immunization enhanced antibody responses, particularly in pigs, with significant increases in 
SARS-CoV-2 neutralising antibody titres (Graham et al 2020). Further, in a SARS-CoV-2 
challenge NHP model, a single administration of AZD1222 significantly reduced viral load in 
bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated rhesus macaques as 
compared to vector controls. Importantly, no evidence of VAERD following SARS-CoV-2 
challenge in vaccinated rhesus macaques was observed (van Doremalen et al 2020).
The clinical development program for AZD1222 was initiated by the University of Oxford, 
and currently has 4 ongoing studies being conducted in the UK (FIH COV001 
[NCT04324606], COV002 [NCT04400838]), Brazil (COV003 [ISRCTN89951424], and 
South Africa (COV005 [NCT04444674]). The Sponsor, in addition to this study, has 
2 ongoing studies in Russia (D8111C00001 [NCT04540393]) and Japan (D8111C00002).
Preliminary unblinded data are available for the FIH Study COV001 and Study COV002.
Study COV001 enrolled the first participant on 23 April 2020 and completed enrollment on 
21 May 2020 with 1 077 participants. Preliminary data as of 24 July 2020 from 
544 participants who received at least one dose of 5 × 1010 vp AZD1222 and 10 participants 
who received a second dose of 5 × 1010 vp AZD1222 4 weeks later found the vaccine was 
generally tolerated, with no treatment-related SAEs reported through 28 days post dose. The 
most common local solicited AEs were vaccination site pain and tenderness. The most 
common systemic solicited AEs were chills, feverishness, fever, headache, malaise, and 
myalgia. The majority of events were 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. 
Preliminary immunogenicity data from Study COV001 suggest that a single dose can elicit 
both humoral and cellular immunogenicity responses and that antibody responses are boosted 
after a second dose. S-specific T-cell responses peaked on Day 14. Anti-S IgG responses rose 
by Day 28, and were boosted 3-fold following a second dose. 
Neutralizing antibody responses against SARS-CoV-2 were detected in 32 (91%) of 
35 participants after a single dose when measured in microneutralization assay (MNA80) and 
in 35 (100%) participants when measured in plaque reduction neutralization test (PRNT50). 

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After the second dose, all participants had neutralizing activity (9 of 9 in MNA80 at Day 42 
and 10 of 10 in Marburg virus neutralization assay on Day 56). Neutralizing antibody 
responses correlated strongly with antibody levels measured by ELISA (Folegatti et al 2020b).
As of 01 October 2020, Study COV002 enrolled 10 013 participants, including 
5 152 participants who received at least one dose of AZD1222 ranging from 2.2 × 1010 vp to 
5 × 1010 vp. Based on preliminary data as of 24 July 2020, the local and systemic solicited-AE
profile following a single dose of 5 × 1010 vp in participants 18 to 55 years of age was 
generally comparable to results in Study COV001. In general, a decline in the incidence and 
severity of solicited AEs was observed across the age groups (18-55, 56-69, and ≥70 years).
Another ChAdOx1-vectored vaccine expressing the full-length S protein from a related 
betacoronavirus, MERS-CoV, has been given to 53 participants as part of 2 ongoing 
dose-escalation Phase I studies (MERS001 [NCT03399578] and MERS002 [NCT04170829], 
sponsored by the University of Oxford) at doses ranging from 5 × 109 vp to 5 × 1010 vp. 
Preliminary immunogenicity data from MERS001 suggested that a single dose of ChAdOx1 
MERS can elicit both humoral and cellular responses. Overall, the vaccine was safe and 
generally well tolerated, with no serious adverse reactions reported in either study. 
The ChAdOx1 platform has been used in 14 clinical studies sponsored by the University of 
Oxford with immunogens from multiple pathogens such as influenza, tuberculosis, malaria, 
chikungunya, Zika, MERS-CoV, and Meningitis B. Over 360 healthy adult participants have 
received ChAdOx1-vectored vaccines in these studies. These vaccines demonstrated robust
immunogenicity after a single dose and favorable safety profiles, with no vaccine-related 
SAEs.
See the AZD1222 IB, Sections 4 and 5 for additional information on nonclinical and clinical 
studies, respectively, of AZD1222 and related ChAdOx1-vectored vaccines. Detail on the 
development and chemistry of AZD1222 is provided in the IB, Section 3.
Overall, the preliminary data from the AZD1222 clinical and nonclinical studies, and the 
acceptable safety and efficacy data for the MERS-CoV vaccine and other ChAdOx1-vectored 
vaccines, support further development of AZD1222 for the prevention of COVID-19.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD1222 can be found in the AZD1222 IB.

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2.3.1
Risk Assessment
AZD1222
Based on preliminary clinical data from Study COV001 and Study COV002, the most 
common local solicited AEs were vaccination site pain and tenderness. Common systemic 
solicited AEs across the 2 studies included chills, feverishness, fever, fatigue, headache, joint 
pain, malaise, and myalgia. The majority of events were mild or moderate in severity and 
resolved within 1 to 7 days (Section 2.2 and AZD1222 IB).
There are no identified risks for AZD1222. Important potential risks are immunologic 
reactions: serious hypersensitivity (anaphylactic reactions) and vasculitides; neurologic 
reactions: demyelinating diseases; and vaccine-associated enhanced respiratory disease. A 
summary of risks associated with AZD1222 and safety information reported across the 
AZD1222 clinical studies are provided in the current version of the AZD1222 IB.
2.3.2 Benefit Assessment
Recipients of AZD1222 do not have any guaranteed benefit, however, AZD1222 may be 
efficacious and offer participants protection from COVID-19. The information gained from 
this study will inform development decisions. 
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, close monitoring of participants, and 
stopping criteria. An independent DSMB 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 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
Objectives and Endpoints
Objective a
Estimand b Description/Endpoint
PRIMARY
1
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of COVID-19 
Population: Fully vaccinated analysis set
Endpoint: A binary response, whereby a participant with 
negative serostatus at baseline is defined as a COVID-19 
case if their first case of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurs ≥15 days post second dose of 
study intervention. Otherwise, a participant is not defined as 
a COVID-19 case.

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Table 5
Objectives and Endpoints
Objective a
Estimand b Description/Endpoint
Intercurrent events: For participants who withdraw from 
the study prior to having met the criteria for the primary 
efficacy endpoint, absence of data following these 
participants’ withdrawal will be treated as missing (ie, 
counted as not having met the criteria); participants who 
withdraw before 15 days post second dose or who have a 
case prior to 15 days post second dose will be excluded from 
primary endpoint analysis. Participants unblinded to 
treatment assignment prior to having met the criteria for the 
primary efficacy endpoint will be censored at the date of 
unblinding.
Summary measure: VE, calculated as 1-relative risk.  
(Relative risk is the incidence in the vaccine group relative to 
the incidence in the control group.)
2
To assess the safety and tolerability of 
2 IM doses of AZD1222 compared to 
saline placebo
a) Incidence of AEs for 28 days post each dose of study 
intervention
b) Incidence of SAEs, MAAEs, and AESIs from Day 1 post 
treatment through Day 730
3
To assess the reactogenicity of 2 IM 
doses of AZD1222 compared to saline 
placebo
(Substudy only)
Incidence of local and systemic solicited AEs for 7 days post 
each dose of study intervention 
SECONDARY
1
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of SARS-CoV-2 
infection
The incidence of the first post-treatment response (negative 
at baseline to positive post treatment with study intervention) 
for SARS-CoV-2 Nucleocapsid antibodies occurring 
≥15 days post second dose of study intervention c
2
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of symptomatic
COVID-19 using CDC criteria
The incidence of the first case of SARS-CoV-2 RT-PCR-
positive symptomatic illness occurring ≥15 days post second 
dose of study intervention using CDC criteria
3
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of University of 
Oxford-defined symptomatic COVID-19
The incidence of the first case of SARS-CoV-2 RT-PCR-
positive symptomatic illness occurring ≥15 days post second 
dose of study intervention using University of Oxford-
defined symptom criteria
4
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo in 
the prevention of COVID-19 in all study 
participants, regardless of evidence of 
prior SARS-CoV-2 infection
The incidence of the first case of SARS-CoV-2 RT-PCR-
positive symptomatic illness occurring ≥15 days post second 
dose of study intervention regardless of evidence of prior 
SARS-CoV-2 infection c
5
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of severe or critical 
symptomatic COVID-19 
a) The incidence of SARS-CoV-2 RT-PCR-positive severe 
or critical symptomatic illness occurring ≥15 days post 
second dose of study intervention c
b) The incidence of SARS-CoV-2 RT-PCR-positive severe 
or critical symptomatic illness occurring post first dose of 
study intervention

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Table 5
Objectives and Endpoints
Objective a
Estimand b Description/Endpoint
6
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for the prevention of COVID-19-related 
Emergency Department visits
The incidence of COVID-19-related Emergency Department 
visits occurring ≥15 days post second dose of study 
intervention c
7
To assess antibody responses to 
AZD1222 S antigen following 2 IM 
doses of AZD1222 or saline placebo
(Substudy and Illness Visits only)
a) Post-treatment GMTs and GMFRs from day of dosing 
baseline value to 28 days post each dose in SARS-CoV-2 
S, RBD antibodies (MSD serology assay)
b) The proportion of participants who have a post-treatment 
seroresponse (≥4-fold rise in titers from day of dosing 
baseline value to 28 days post each dose) to the S, RBD 
antigens of AZD1222 (MSD serology assay)
8
To determine anti-SARS-CoV-2 
neutralizing antibody levels in serum 
following 2 IM doses of AZD1222 or 
saline placebo
(Substudy and Illness Visits only)
a) Post-treatment GMTs and GMFRs from day of dosing 
baseline value to 28 days post each dose in SARS-CoV-2 
neutralizing antibodies (wild-type assay or 
pseudo-neutralization assay)
b) Proportion of participants who have a post-treatment 
seroresponse (≥4-fold rise in titers from day of dosing 
baseline value to 28 days post each dose) to AZD1222 as 
measured by SARS-CoV-2 neutralizing antibodies 
(wild-type assay or pseudo-neutralization assay)
9
To estimate the efficacy of AZD1222 
compared to saline placebo for the 
prevention of COVID-19 following the 
first dose
The incidence of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring post first dose of study 
intervention
EXPLORATORY
1
To estimate the efficacy of 2 IM doses of
AZD1222 compared to saline placebo 
for the all-cause mortality
The incidence of all-cause mortality from Day 1 through 
Day 730
2
To estimate the efficacy of 2 IM doses of 
AZD1222 compared to saline placebo 
for COVID-19-related deaths
The incidence of COVID-19-related deaths occurring from 
Day 1 through Day 730
3
To estimate the efficacy of 2 IM doses of
AZD1222 compared to saline placebo 
for the prevention of COVID-19-related 
hospitalizations
a) The incidence of COVID-19-related hospitalizations
occurring ≥15 days post second dose of study 
intervention
b) The incidence of COVID-19-related hospitalizations 
occurring post first dose of study intervention
4
To estimate the efficacy of 2 IM doses of
AZD1222 compared to saline placebo 
for the prevention of COVID-19-related 
ICU admissions
a) The incidence of COVID-19-related ICU admissions
occurring ≥15 days post second dose of study 
intervention
b) The incidence of COVID-19-related ICU admissions
occurring post first dose of study intervention
5
To quantify SARS-Cov-2 viral loads in 
infected participants treated with 2 IM 
doses of AZD1222 or saline placebo
(Illness Visits only)
Viral genome copies in NP swabs collected at Illness Visits 
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Table 5
Objectives and Endpoints
Objective a
Estimand b Description/Endpoint
6
To characterize sequence variations in 
SARS-CoV-2 through genotypic 
analyses in participants treated with 2 IM 
doses of AZD1222 or saline placebo
(Illness Visits only)
Genotypic analysis of SARS-CoV-2 from NP swabs 
collected on Day 1 illness visit  
7
To quantify duration of viral shedding in 
symptomatic SARS-CoV-2 infected 
participants treated with 2 IM doses of 
AZD1222 or saline placebo
(Illness Visits only)
Duration of SARS-CoV-2 shedding in saliva over time 
8
To assess the biometric profiles 
associated with COVID-19 using a 
biosensor in participants treated with 
2 IM doses of AZD1222 or saline 
placebo
(Illness Visits only)
Biophysical parameters, including but not limited to serial 
measurements of skin temperature, heart rate, respiratory 
rate, blood oxygen saturation, and physical activity, recorded 
using a biosensor from illness visits Day 1 through Day 28 
9
To assess symptoms associated with 
COVID-19 using an e-Diary in 
participants treated with 2 IM doses of 
AZD1222 or saline placebo
(Illness Visits only)
Symptoms recorded by participants in an Illness e-Diary 
from illness visits Day 2 through Day 28 
10
To assess SARS-CoV-2 specific 
antibodies in an ACE2 competition assay 
following 2 IM doses of AZD1222 or 
saline placebo
(Substudy only)
a) Post-treatment GMTs and GMFRs from Day 1 baseline 
value to 28 days post each dose in ACE2 competing 
antibodies from serum samples
b) Proportion of participants who have a post-treatment 
seroresponse (≥4-fold rise in titers from day of dosing 
baseline value to 28 days post each dose) in ACE2 
competing antibodies
11
To assess B- and T-cell responses 
following 2 IM doses of AZD1222 or 
saline placebo
(Substudy only)
a) Quantification of (IFN-γ) ELISpot responses to 
SARS-CoV-2 S protein from day of dosing baseline to 
14 days post each dose
b) Intracellular cytokine staining and flow cytometry for 
B- and T-cell responses from day of dosing baseline to 
14 days post each dose
12
To assess SARS-CoV-2 antibodies in 
nasal secretions following 2 IM doses of 
AZD1222 or saline placebo
(Substudy only)
a) Post-treatment GMTs and GMFRs from Day 1 baseline 
value to 28 days post each dose in SARS-CoV-2 S, RBD, 
and Nucleocapsid antibodies (MSD serology assay) 
b) Proportion of participants who have a post-treatment 
seroresponse (≥ 4-fold rise in titers from Day 1 baseline 
value to 28 days post each dose) to SARS-CoV-2 S, 
RBD, and Nucleocapsid antigens (MSD serology assay)
13
To assess anti-vector responses to the 
ChAdOx-1 adenovirus vector following 
2 IM doses of AZD1222 or saline 
placebo
(Substudy only)
Proportion of participants who have a post-treatment 
seroresponse (≥ 4-fold rise in titers from Day 1 baseline 
value to 28 days post each dose) to AZD1222 as measured 
by ChAdOx1 neutralizing antibodies

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Table 5
Objectives and Endpoints
Objective a
Estimand b Description/Endpoint
14
To assess additional immune responses 
following 2 IM doses of AZD1222 or 
saline placebo
Other exploratory assays for humoral and cellular immune 
responses may be performed based upon emerging safety, 
efficacy, and immunogenicity data
a
Substudy: The substudy will be conducted only in the USA. The first participants randomized in each 
age group in the USA, including 1 500 participants 18 to 55 years of age, 750 participants 56 to 69 years 
of age, and 750 participants ≥ 70 years of age, will also participate in a substudy assessing the 
reactogenicity and immunogenicity of AZD1222.
Illness Visits: Participants who present with qualifying symptoms will be tested for SARS-CoV-2 and if 
positive, will complete illness visits.
b
Estimand is the target of estimation to address the scientific question of interest posed by the primary 
objective. Attributes of an estimand include the population of interest, the variable (or endpoint) of 
interest, the specification of how intercurrent events are reflected in the scientific question of interest, and 
the population-level summary for the variable.
c
Key secondary endpoint.
ACE2 = angiotensin-converting enzyme 2; AE = adverse event; AESI = adverse event of special interest; 
CDC = Centers for Disease Control and Prevention; COVID-19 = coronavirus disease 2019; ELISpot = 
enzyme-linked immunospot; GMFR = geometric mean fold rise; GMT = geometric mean titer; ICU = 
intensive care unit; IFN-γ = interferon-gamma; IM = intramuscular; MAAE = medically attended adverse 
event; MSD = Meso Scale Discovery; NP = nasopharyngeal; RT-PCR = reverse transcriptase polymerase 
chain reaction; qRT-PCR = quantitative reverse transcriptase polymerase chain reaction, RBD = receptor
binding domain; S = Spike; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome-
coronavirus-2; USA = United States of America; VE = vaccine efficacy.
4
STUDY DESIGN
4.1
Overall Design
D8110C00001 is a Phase III randomized, double-blind, placebo-controlled, multicenter study 
assessing the safety, efficacy, and immunogenicity of AZD1222 compared to saline placebo 
for the prevention of COVID-19. Participants will be adults ≥18 years of age who are healthy 
or have medically-stable chronic diseases, and are at increased risk for SARS-CoV-2 
acquisition and COVID-19. Approximately 30 000 participants will be randomized in a 
2:1 ratio to receive 2 IM doses of either 5 × 1010 vp (nominal, ± 1.5 × 1010 vp) AZD1222 
(n = approximately 20 000) or saline placebo (n = approximately 10 000) 4 weeks apart, on 
Days 1 and 29. Randomization will be stratified by age (≥ 18 and < 65 years, and ≥65 years), 
with at least 25% of participants to be enrolled in the older age stratum. Participants who 
received their first dose of study intervention between 28 August 2020 and 
06 September 2020 will receive their second dose of study intervention outside of the study 
window. 
Participants who present with at least one of the qualifying symptoms listed below through 
Day 360 will be assessed for COVID-19. With the exception of fever, shortness of breath, or 
difficulty breathing, the symptom must be present for 2 or more days. Participants with a 
COVID-19 qualifying symptom(s) will be tested for SARS-CoV-2, and if positive will 

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complete illness visit assessments, as presented in Table 4. See Section 8.1 for details on 
COVID-19 assessments.
COVID-19 Qualifying Symptoms
Participant must present with at least one of the following symptoms 
Duration
Symptom
No minimum duration 
Fever
Shortness of breath
Difficulty breathing
Must be present for ≥ 2 
consecutive days
Chills
Cough
Fatigue
Muscle aches
Body aches
Headache
New loss of taste 
New loss of smell
Sore throat
Congestion
Runny nose
Nausea
Vomiting
Diarrhea
Adapted from (CDC 2020).
Safety will be assessed for the duration of the study. AEs will be recorded for 28 days post 
each dose of study intervention (ie, until Day 29 post first dose and Day 57 post second dose), 
and SAEs, MAAEs, and AESIs will be recorded through Day 730. See Sections 8.3, 8.3.8, and 
8.3.9 for definitions of these events. 
The first participants randomized in each age group in the USA, including 1 500 participants 
18 to 55 years of age, 750 participants 56 to 69 years of age, and 750 participants ≥ 70 years 
of age, will also participate in a substudy assessing the reactogenicity and immunogenicity of 
AZD1222. These 3 000 participants in the substudy will have additional assessments for 
predefined solicited AEs for 7 days post each dose of study intervention and for humoral and 
cellular immune responses. Solicited AEs are defined in Section 8.3.7. 
Table 2 and Table 3 provide the SoA for the main study and substudy, respectively. 

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To further investigate cell-mediated immunogenicity, in particular Th1/Th2 responses, after 
AZD1222 or saline placebo administration, an immunogenicity cohort of approximately 
300 participants will be added. Participants will follow the SoA in Table 3 except they will not 
record reactogenicity.
All participants will remain on study for 2 years following administration of first dose of study 
intervention (Day 730). If AZD1222 is proven to be safe and efficacious based on the primary 
endpoint analysis (see Section 9.4.2.1), following discussion at that time with the US FDA, 
other Regulators if appropriate, and the COVID-19 Vaccine DSMB, participants allocated to 
the saline placebo group will be offered AZD1222 when doses are available. Saline placebo 
participants treated with AZD1222 will continue to be followed in the study.
A PSRT will provide support for blinded safety surveillance during the study. Additionally, an 
independent COVID-19 Vaccine DSMB will provide oversight, to ensure safe and ethical 
conduct of the study. The COVID-19 Vaccine DSMB will facilitate the interim analysis for 
efficacy and have the responsibility of evaluating cumulative safety and other clinical study 
data at regular intervals and for making appropriate recommendations based on the available 
data. An independent Neurological AESI Expert Committee will be available to review and 
provide advice to the PSRT and the COVID-19 Vaccine DSMB on request about the 
diagnosis and causality assessment of selected neurological AESIs occurring in the AZD1222 
clinical development program. See Appendix A 5 for additional detail.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The participant population is male and female adults ≥ 18 years of age who are not 
immunosuppressed, but are at increased risk of SARS-Cov-2 infection due to their locations 
or circumstances. Inclusion of older adults is based on data that are being gathered from the 
ongoing University of Oxford-sponsored studies. Study COV001 (NCT04324606) enrolled 
adults 18 to 55 years of age. Study COV002 (NCT04400838) enrolled adults 18 years of age 
and older.
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. 
The study will exclude females who are pregnant or breast-feeding and individuals less than
18 years of age. Women who are pregnant or breast-feeding are excluded at this point as 
nonclinical developmental and reproductive toxicity studies to support vaccinating these 
individuals have yet to be performed. Additionally, it is planned that children and adolescents 

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will be evaluated for their response to the vaccine once safety and efficacy have been 
established in adults.  
Participants who have been previously diagnosed with laboratory-confirmed SARS-CoV-2 
infection are excluded from study participation. Participants with previous asymptomatic or 
undiagnosed infection are not excluded. Participant’s baseline serostatus will be determined 
but baseline serostatus will not be used as a basis for exclusion from the study. Participants 
who are seropositive at baseline are enrolled in order to gather safety data in this group as it is 
anticipated that, if proven to be efficacious, the vaccine will rapidly be distributed to millions 
of individuals and that these individuals will not be tested for serologic evidence of previous 
infection prior to vaccination. Participant’s baseline serostatus will be determined so that 
subgroup analyses for both safety and efficacy can be performed by baseline serostatus. 
The study population represents the initial target population for AZD1222. If AZD1222 
demonstrates efficacy for the prevention of COVID-19, the safety and immunogenicity of the 
vaccine in additional groups such as the immunosuppressed, pregnant women, and children 
and adolescents may be assessed in future studies. 
4.2.2
Rationale for Study Endpoints
The efficacy endpoints in this study are analogous to endpoints used for evaluating the 
efficacy of influenza vaccines. These definitions have 4 components: (1) a definition of 
clinical illness; (2) a method of respiratory specimen sampling for the detection of associated 
shedding of the relevant virus; (3) an assay method for laboratory confirmation; and (4) a 
defined surveillance period. Assessment of AZD1222 efficacy will begin ≥ 15 days after the 
second dose of study intervention as this time period is considered necessary for the vaccine to 
induce protective immune responses. 
In the substudy, solicited AEs will be collected for 7 days post 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 post each dose of 
study intervention. SAEs, MAAEs, and AESIs and will be collected from Day 1 through end 
of the study. AESIs include terms identified by the Brighton Collaboration involving events 
associated with vaccination in general (SPEAC 2020).
4.3
Justification for Dose
The AZD1222 dose of 5 × 1010 vp was selected based on accumulated clinical experience with 
this vaccine in ongoing clinical studies sponsored by the University of Oxford (see 
Section 2.2). Safety and immunogenicity data from an additional clinical study, MERS001
(NCT03399578), using the same ChAdOx1 vector, also helped inform dose selection. 

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MERS001 was the first clinical study of a ChAdOx1-vectored vaccine expressing the 
full-length S protein from a separate, but related, betacoronavirus. ChAdOx1 MERS has been 
given to 31 participants to date at doses ranging from 5 × 109 vp to 5 × 1010 vp. Despite higher 
reactogenicity observed at the 5 × 1010 vp, this dose was safe, with self-limiting AEs and no 
serious adverse reactions recorded. The 5 × 1010 vp was the most immunogenic, in terms of 
inducing neutralizing antibodies against MERS-CoV using a live virus assay (Folegatti et al 
2020a). Given the immunogenicity findings and safety profile observed with the 
ChAdOx1-vectored vaccine against MERS-CoV, the 5 × 1010 vp dose was chosen for 
AZD1222. See the AZD1222 IB.
Based on accumulating nonclinical and clinical data gathered for AZD1222 as well as for 
other SARS-CoV-2 vaccines in development, a 2-dose regimen was selected for the study in 
order to enhance the immune responses to the virus (AZD1222 IB).
In an NHP challenge study, 6 macaques received a second dose of AZD1222 4 weeks after the 
first dose. The second dose resulted in increases in both ELISA and neutralizing antibody 
titers, and fewer areas of the lung contained viral RNA in prime boost group compared to the 
prime group. In a porcine model, 3 pigs also received a second dose of AZD1222 4 weeks 
after the first dose. In the animals that received the booster dose, both antibodies to the 
SARS-CoV-2 RBD and neutralizing antibodies were boosted after the second dose.
In Study COV001, 10 participants received a second dose of AZD1222 4 weeks after the first 
dose. Antibody responses to both the first and second doses were evaluated using an ELISA 
assay, through the MSD platform and by both neutralization and pseudo-neutralization assays. 
Notable increases in antibody levels to the S protein were seen with the ELISA assay and 
increases to both the S protein and RBD were noted using the MSD platform. Similarly, 
increases in antibody levels following the second dose were also seen with neutralization and 
pseudo-neutralization assays. Though based on small numbers, the second dose of the vaccine 
appeared to result in a lower rate of systemic solicited AEs.
The 4-week interval was selected based on the interval used in the nonclinical studies and 
Study COV001. 
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 SoA (Section 1.3).
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
(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 protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Adult, ≥ 18 years of age at the time of consent
Type of Participant 
2
Increased risk of SARS-CoV-2 infection

Defined as adults whose locations or circumstances put them at appreciable risk of 
exposure to SARS-CoV-2 and COVID-19, based on available risk assessment 
contemporaneous to enrollment (believed to be at risk/exposure)
3
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
4
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
Reproduction
5
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies 
6
Female participants
(a) Women of childbearing potential must:

Have a negative pregnancy test on the day of screening and on Day 1

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 
60 days following administration of the second 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.

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(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 system 
(IUS) a
•
Bilateral tubal occlusion
•
Vasectomized partner b
•
Sexual abstinence c
•
Combined (estrogen- 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 60 days following administration of the second dose of 
study intervention, and if it is the preferred and usual lifestyle of the participant
Informed Consent
7
Capable of giving signed informed consent as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol

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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 the vaccine
2
History of Guillain-Barré syndrome or any other demyelinating 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
History of laboratory-confirmed SARS-CoV-2 infection
5
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
asplenia
6
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)

Human immunodeficiency virus-positive stable participants on stable antiretroviral 
therapy, eg, (NIH 2020, Waldrop et al 2016)
7
History of primary malignancy except for:
(a) Malignancy with low potential risk for recurrence after curative treatment (for 
example, history of childhood leukaemia) or 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
8
Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet 
disorder), or prior history of significant bleeding or bruising following IM injections or 
venepuncture
9
Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder, and neurological illness, as 
judged by the Investigator (mild/moderate well-controlled comorbidities are allowed)
10 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
Note: The AESIs as outlined in Appendix E (including Table 14) should be considered 
when evaluating a participant for Exclusion Criterion 10, as the presence of these AESIs, 

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especially if untreated or uncontrolled, may be a safety risk to the participant, affect the 
ability of the participant to participate in the study, or impair interpretation of the study 
data. Investigators should review and consider the list of conditions in Appendix F. 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
11 Receipt of, or planned receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-2 or COVID-19 
Note: For participants who become hospitalized with COVID-19, receipt of licensed 
treatment options and/or participation in investigational treatment studies is permitted
12 Receipt of any vaccine (licensed or investigational) other than licensed influenza vaccines 
within 30 days prior to and after administration of study intervention
13 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
14 Involvement in the planning and/or conduct of this study (applies to both Sponsor staff 
and/or staff at the study site)
15 For women only - currently pregnant (confirmed with positive pregnancy test) or 
breast-feeding 
16 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
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
3
Agree to wear digital health device if diagnosed with COVID-19 as described in 
Section 8.1.2.2
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
In general, study intervention is defined as any investigational intervention(s), marketed 
product(s), or placebo intended to be administered to or medical device(s) utilized by a study 
participant according to the study protocol. For this study, study intervention is defined as 
AZD1222 or saline placebo (Table 7). The third party medical device used for assessment of 
COVID-19 symptoms (ie, digital health device [Section 8.1.2.2]) is not considered a study 
intervention.
6.1
Study Interventions Administered
6.1.1
Investigational Products
Table 7
Investigational Products
Intervention Name
AZD1222
Placebo
Type 
Vaccine
Placebo
Dose Formulation
10 mM histidine, 7.5% (w/v) sucrose, 
35 mM sodium chloride, 1 mM magnesium 
chloride, 0.1%  (w/v) polysorbate 80, 
0.1 mM edetate disodium, 0.5% (w/v) 
ethanol, at pH 6.6.
0.9% (w/v) saline
Unit Dose Strength(s)
≥0.7 × 1011 vp/mL
Dosage Level(s)
5 × 1010 vp (nominal, ± 1.5 × 1010 vp)
Route of Administration
Intramuscular
Intramuscular
Use
Experimental
Placebo
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor 
Sourced locally
Packaging and Labeling
Will be provided in vials within a carton. 
Each carton and vial will be labelled as 
required per country requirement
Not applicable
Current/Former Name or Alias
ChAdOx1 nCoV-19
Not applicable
IMP = investigational medicinal product; NIMP = non-investigational medical product; vp = viral particles; 
w/v = weight/volume.

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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, with a label-claim volume 
of 5 mL.
Unopened vials of AZD1222 vials must be stored at 2-8 °C (36-46 °F) for the duration of 
assigned shelf-life and must not be frozen. AZD1222 must be kept in original packaging until 
use to prevent prolonged light exposure.
Placebo
Commercially available 0.9% (w/v) saline for injection will be sourced locally for placebo.
6.1.2 Dosing Instructions
Participants will receive 2 doses of either AZD1222 or saline placebo. The first dose will be 
administered on Day 1 and the second dose on Day 29 (see Table 2 and Table 3). 
It is recommended that the study interventions be administered as an IM 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
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
6.2.1.1
AZD1222
Doses of 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 AZD1222 in a sterile syringe.
AZD1222 does not contain preservatives. Each vial must be assigned a beyond-use-date of 
6 hours from first needle puncture of the AZD1222 vial, after which any unused portion must 
be discarded. 
Once an AZD1222 dose is drawn into a syringe for administration, the dose must be 
administered within the beyond-use-date of the vial. If AZD1222 dose administration is not 
completed within the 6-hour vial beyond-use-date, a new dose must be prepared from a new 
vial. 
Each vial of AZD1222 has a label-claim volume of 5 mL and can provide up to ten 
0.5 mL doses.
6.2.1.2
Placebo
Doses of saline placebo must be prepared by the unblinded pharmacist (or designee in 
accordance with local and institutional regulations) using aseptic technique. Each saline 
placebo dose is prepared by withdrawing 0.5 mL from a 0.9% (w/v) saline vial or IV bag in a 
sterile syringe. If 0.9% (w/v) saline is extracted from IV bags, the manufacturers’
recommendation for maximum number of needle punctures of the IV bag port must not be 
exceeded.
Saline (0.9% [w/v]) does not contain preservatives. Each vial or IV bag must be assigned a 
beyond-use-date of 6 hours from first needle puncture, after which any unused portion must be 
discarded. 
Once a saline placebo dose is drawn into a syringe for administration, the dose must be 
administered within the beyond-use-date of the vial/IV bag. If saline placebo dose 
administration is not completed within the 6-hour vial/IV bag beyond-use-date, a new dose 
must be prepared from a new vial or IV bag.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization
All participants will be centrally assigned to randomized study intervention using an IRT. 
Before the study is initiated, user guides, the log in information, and directions for the IRT 
will be provided to each study site. Randomization will be stratified by age (≥ 18 to 

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< 65 years, and ≥65 years), with at least 25% of participants to be enrolled in the older age 
stratum.
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
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 AZD1222 and saline placebo are visually distinct prior to dose 
preparation (due to differences in container closure), IMP 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, AZD1222 and saline placebo are not 
visually distinct from each other.
The IRT will provide the investigator(s) or pharmacists 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.
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. 

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In the event that a study participant is contacted about receiving a licensed and/or authorized
COVID-19 vaccine, 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. In addition, a participant information sheet has been developed for 
guidance on decision discussions between the participant and Investigator.
6.4
Study Intervention Compliance
When participants are dosed at the study site, they will receive 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 
SoA (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 at any time.
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 

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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.
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).

Investigational products indicated for the treatment of SARS-CoV-2 or COVID-19 
Note: For participants who become hospitalized with COVID-19, receipt of licensed 
treatment options and/or participation in investigational treatment studies is permitted. 

Experimental vaccinations, other than 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 (eg, Dose 1 and 
Dose 2). Thirty (30) 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
6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.2. 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).

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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Each participant will receive 2 doses of study intervention (see Section 6). An individual 
participant will not receive the first or second dose 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 allergic reaction including anaphylaxis that is assessed as related to study 
intervention
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 one 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. 
7.1.1
Study Suspension or Termination
The Sponsor reserves the right to temporarily suspend or permanently terminate this study or a 
component of the study at any time. The reasons for temporarily suspending the study may 
include, but are not limited, to the following:

Any death, SAE, or other safety finding assessed as related to study intervention that in 
the opinion of the Sponsor may preclude further administration of study intervention
No additional participants will be randomized or treated with study intervention until review 
by the COVID-19 Vaccine DSMB is complete (see Appendix A 5 for COVID-19 Vaccine 
DSMB information).

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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, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

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.
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 SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.

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
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 SoA
(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 SoA.
8.1
Efficacy Assessments
8.1.1
Monitoring COVID-19 Symptoms
Study sites will contact participants weekly (telephone/email/text) through Day 360 with 
reminders to monitor for COVID-19 symptoms. Participants who present with at least one of 
the COVID-19 qualifying symptoms listed below must contact the study team. With the 
exception of fever, shortness of breath, or difficulty breathing, the symptom must be present 
for 2 or more days. During the 7 days following administration of each dose of study 
intervention, investigator judgement should be used to determine which participants should 
initiate illness visits as symptoms may be due to the reactogenicity of the study intervention as 
opposed to potentially due to infection with SARS-CoV-2.
If a participant presents with a COVID-19 qualifying symptom(s) on Days 1-3, the nasal swab 
collected on Day 1 will be tested locally for SARS-CoV-2 (see Section 8.6.1.1). If positive, 
the participant will be instructed to initiate illness visits. If negative, the participant will 
continue with scheduled assessments per their assigned study (ie, main study [Table 2] or 
substudy [Table 3]).
Participants who present with a COVID-19 qualifying symptom(s) after Day 3 will be 
instructed to initiate illness visits and be tested for SARS-CoV-2. 

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COVID-19 Qualifying Symptoms
Participant must present with at least one of the following symptoms 
Duration
Symptom
No minimum duration 
Fever
Shortness of breath
Difficulty breathing
Must be present for ≥ 2 
consecutive days
Chills
Cough
Fatigue
Muscle aches
Body aches
Headache
New loss of taste 
New loss of smell
Sore throat
Congestion
Runny nose
Nausea
Vomiting
Diarrhea
Adapted from (CDC 2020).
8.1.2
Illness Visits
Symptomatic participants (as defined in Section 8.1.1) will be instructed to visit the study site 
for initiation of illness assessments (Table 4); where supported, home or mobile visits may be 
substituted for the site visits. Symptomatic participants will complete the Day 1 illness visit 
and will be instructed to continue with the home collection requirements (eg, digital health 
device and Illness e-Diary recordings, and saliva samples). SARS-CoV-2 RT-PCR results will 
be available during the home collection period and participants will be informed of their 
status. The results of the COVID-19 RT-PCR testing should also be reported to the 
participants’ primary care providers. Only participants who test positive will be instructed to 
continue with the illness visits, including home collection of saliva samples and digital health 
device and Illness e-Diary recordings. Participants who test negative for SARS-CoV-2 will be 
instructed to stop all illness visit assessments and return the digital health device. Should 
symptoms persist despite a negative test result, Investigators should provide appropriate 
clinical follow-up of participants, as clinically indicated. Once Illness visits are discontinued, 

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participants will continue with follow-up visits per their assigned study (ie, main study [Table 
2] or substudy [Table 3]). 
8.1.2.1
SARS-CoV-2 Testing and Other Virology Assessments
At the Day 1 illness visit, mid-turbinate nasal swabs and nasopharyngeal swabs will be 
collected and tested for SARS-COV-2 by authorized RT-PCR assays (see Section 8.6.1.1). 
Saliva will be collected during site illness visits and by self-collection at home throughout the 
illness visits to quantify duration of viral shedding (see Section 8.6.1.2). Other virology 
assessments are described in Section 8.6.
Genotypic evaluation of SARS-CoV-2 is planned at Day 1 and Day 14 illness visits but may 
be performed at Day 21 and Day 28 illness visits based upon logistical constraints, safety 
signals, or emerging data on efficacy of AZD1222 against viral variants.
8.1.2.2
Digital Health Device
At the Day 1 illness visit, participants will receive a wearable, digital health device 
(eg, Current Health Monitoring System) and be trained on use of the biosensor. The digital 
health device will continuously track biophysical parameters, including but not limited to, 
serial measurements of skin temperature, heart rate, respiratory rate, blood oxygen saturation, 
and physical activity. 
Data will be obtained from the biosensor and transmitted via a wireless hub from the 
participant to the vendor platform. The vendor platform will be monitored remotely 24 hours a 
day by a team which includes registered nurses. The monitoring team will receive technical
alerts if there are data or device issues, and physiologic alerts if participants’ vital signs meet 
prespecified criteria. The physiologic alerts are intended to provide an early indication of 
worsening health status that would allow the monitoring team and investigator to provide 
appropriate follow-up. All alerts will be triaged and followed up by the monitoring team
according to agreed-upon monitoring protocols. A registered nurse will review the alerts 
requiring clinical attention and will apply clinical judgement (based on the Schmitt-Thompson 
COVID-19 - Diagnosed or Suspected After Hours Telephone Triage Protocols) (Schmitt-
Thompson 2020) to determine which alerts can be addressed directly with the participant via 
telephone, and which alerts should be escalated to the on-call clinician at the site. If escalation 
is required, the nurse will contact the on-call clinician by telephone and the clinician will then 
be responsible for subsequent follow-up. For all technical and physiologic alerts, details
regarding the nature of the alert and action taken will be documented within the Current 
Health Monitoring System and an informational email will be sent to the investigator within 
2 hours for further follow-up if required. If local regulations prohibit the monitoring team 
from collecting identifying information about participants, or from contacting study 
participants directly, the Investigator and site staff will be responsible for monitoring the 
transmitted data and responding to both technical and physiologic alerts 24 hours a day.

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The data from the biosensor and remote monitoring are not intended to substitute for 
protocol-mandated standard safety monitoring, participant self-reporting, or participant 
oversight, which remains the responsibility of the investigator.  
Along with the device, participants will be provided with a paper-based Quick Start Guide 
containing general instructions for the device as well as frequently asked questions. A 
reference copy of the document will be retained in the Site Master File. 
Participants who test positive for SARS-CoV-2 will be instructed to continue wearing the 
digital health device until the COVID-19-associated symptoms resolve or until the Day 28 
illness visit. Participants who test negative and stop the illness visits will be instructed to
return the digital health device.
8.1.2.3
Illness e-Diary
An Illness e-Diary will be used to collect self-reported information about COVID-19-
associated symptoms (listed below per CDC (CDC 2020). At the Day 1 illness visit, 
participants (or, if applicable, their caregiver, surrogate, or legally authorized representative)
will be given access to the Illness e-Diary and trained by study staff on how to record the 
information and assess the severity of the symptoms.
Participants who test positive for SARS-CoV-2 will be instructed to continue recording in the 
Illness e-Diary until symptoms resolve or until the Day 28 illness visit. Participants who test 
negative will be instructed to stop Illness e-Diary recording.
Study sites will monitor the health status of participants via Illness e-Diary responses after the 
Day 1 illness visit, and will call participants as needed based on these responses. 
COVID-19 Symptoms

Fever

New loss of taste 

Shortness of breath

New loss of smell

Difficulty breathing

Sore throat

Chills

Congestion

Cough

Runny nose

Fatigue

Nausea

Muscle aches

Vomiting

Body aches

Diarrhea

Headache

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8.1.3
Severe COVID-19
The severity of COVID-19 will be evaluated in participants with symptoms of COVID-19. A 
diagnosis of severe or critical COVID-19 will include laboratory-confirmed COVID-19 
(SARS-CoV-2 RT-PCR-positive symptomatic illness) plus any of the following:

Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 breaths per 
minute, heart rate ≥125 beats per minute,  oxygen saturation ≤ 93% on room air at sea 
level, or partial pressure of oxygento fraction of inspired oxygenratio < 300 mm Hg)

Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation or extracorporeal membrane oxygenation)

Evidence of shock (systolic blood pressure < 90 mm Hg, diastolic blood pressure 
< 60 mm Hg, or requiring vasopressors)

Significant acute renal, hepatic, or neurologic dysfunction

Admission to an intensive care unit

Death
8.1.4
Medical Notes Review
With the participant’s consent, the study team will request access to medical notes or submit a 
data collection form for completion by attending clinical staff on any medically-attended 
COVID-19 episodes. Any data relevant for assessment of the efficacy endpoints or 
vaccine-associated enhanced respiratory disease (see Section 8.3.9) will be collected. These 
are likely to include, but not limited to, information on intensive care unit admissions, clinical 
parameters such as oxygen saturation, respiratory rates and vital signs, need for oxygen 
therapy, need for ventilatory support, imaging, blood tests results, and overall outcome 
(survival or death).
8.1.5
Monitoring for Asymptomatic Infection
Blood samples will be collected according to the SoA (Section 1.3) for SARS-CoV-2 serology 
testing to monitor participants for asymptomatic infection. See description of assessment in 
Section 8.5.2.1. 
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (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 SoA (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. 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 SoA (Section 1.3). The participant should be resting prior to the 
collection of vital signs.
Data collected through the digital health device on heart rate, respiratory rate, temperature, 
and oxygen saturation level will be recorded as exploratory efficacy measurements and should 
not be reported as AEs unless resulting in an MAAE or SAE.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Laboratory Assessments
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical study.
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the SoA (Section 1.3). Urine pregnancy tests for -hCG may be 
performed at the site using a licensed test (dipstick). If urine tests positive or indeterminate, a 
quantitative serum β-hCG will be performed for confirmation.  
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator

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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. 
All AEs are considered to be unsolicited AEs (collected by ‘open question’ at study visits) 
unless categorized as solicited AEs recorded in the substudy only. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in a Solicited AE e-Diary only for participants in the substudy
(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 solicited AEs. 
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 AE and SAE Information
AEs will be recorded for 28 days post each dose of study intervention. 
Solicited AEs will be recorded only for participants in the substudy for 7 days post each dose 
of study intervention.
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact.
MAAEs and AESIs will be recorded from Day 1, post treatment, through the last participant 
contact. 
See the SoA (Section 1.3) for the scheduled timepoints. 
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 AEs and SAEs
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 

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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
The grading scales 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. 
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?’

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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 will be summarized in the 
CSR. 
Deterioration as compared to baseline in protocol-mandated vital signs should therefore only 
be reported as AEs if they fulfil any of the SAE or MAAE 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 MAAE, 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 AST or ALT ≥3 × ULN together with total bilirubin 
≥2 × ULN and confirmed as a Hy's Law case should be reported as an SAE.
Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug. The elevation in transaminases must 
precede or be coincident with (ie, on the same day) the elevation in TBL, but there is no 
specified timeframe within which the elevations in transaminases and TBL must occur.

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8.3.7 Solicited Adverse Events (Only for Substudy)
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 8) will be 
collected in a Solicited AE e-Diary for 7 days following administration of each dose of study 
intervention only from participants in the substudy. 
Solicited AEs should not be reported as unsolicited AEs (see Section 8.3). However, solicited 
AEs should be reported as SAEs or MAAEs if they fulfil the criteria (see Sections 8.3 and 
8.3.8, respectively).
Table 8
List of Predefined Solicited Adverse Events for Reactogenicity 
Assessment
Local 
Systemic 
Pain at the site of injection 
Fever (> 100 °F [> 37.8 °C]) a
Erythema/redness at the site of injection b
Chills
Tenderness
Muscle pains
Induration/swelling at the site of the injection b
Fatigue
Headache
Malaise
Nausea
Vomiting
a
Fever measured by any route. Investigators who consider a temperature lower than this cutoff as a fever 
or a ‘fever’ reported by participants without documentation by a thermometer should record the event as 
‘elevated body temperature.’
b
Swelling and redness must be ≥ 0.25 inches (≥0.6 centimeters) in diameter.
Solicited AE e-Diary
On Day 1, participants in the substudy (or, if applicable, their caregiver, surrogate, or legally 
authorized representative) will be given an oral thermometer, tape measure, 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 Medically Attended Adverse Events
MAAEs will be collected according to the timepoints specified in the SoA (Section 1.3).
MAAEs 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 MAAEs.
8.3.9
Adverse Events of Special Interest
AESIs will be collected according to the timepoints specified in the SoA (Section 1.3). 
AESIs 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. AESIs for AZD1222 are based on Brighton Collaboration case 
definitions (SPEAC 2020), clinical experience, and scientific interest. See Appendix E for a 
listing and description of AZD1222 AESIs. 
An AESI can be serious or non-serious. All AESIs will be recorded in the eCRF. If any AESI 
occurs in the course of the study, investigators or other site personnel will inform the 
appropriate Sponsor representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. Serious AESIs will be recorded and reported 
as per Section 8.3.10.
8.3.9.1
Potential Neurological AESIs
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paresthesias, 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, EMG). In cases of concern for spinal cord disease, see Figure 2
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 AESIs occurring in the AZD1222 
clinical development program (see Appendix A 5). 

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Figure 2
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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8.3.10
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 procedure(s). 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 one 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 
one 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 
one calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated Sponsor representative.
If the EDC 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.
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 IB, Section 5.6. 
8.3.11
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.
8.3.11.1
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 
spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without 

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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 8.3.10) 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.
8.3.12
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 8.3.10) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 4. 
8.3.13
Medical Device Deficiencies
Any deficiency observed with the digital health device (third-party medical device) will be 
collected and reported to the manufacturer by the investigators or other site personnel within 
one day ie, immediately but no later than 24 hours of when he or she becomes aware of it.
A medical device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Medical device deficiencies include 
malfunctions, use errors, and information supplied by the manufacturer.
The manufacturer’s medical device complaint report will be used to collect the deficiency. 

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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 AZD1222. If overdose occurs, the 
participant should be treated supportively with appropriate monitoring as necessary.

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 one or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.10) 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 CSR 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 CSR. 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 CSR.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.

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8.5.2
Immunogenicity Assessments
Serum samples for immunogenicity assessments will be collected according to the SoA 
(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.
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 SoA (Section 1.3). Authorized laboratories will assess 
serologic responses to AZD1222 by the rate of participants seroconverting from negative to 
positive as defined by a validated immunoassay directed at the SARS-CoV-2 S antigen. The 
rate of asymptomatic SARS-CoV-2 infection in participants receiving AZD1222 vs saline 
placebo will be determined by seroconversion in a SARS-CoV-2 Nucleocapsid assay operated 
by an authorized laboratory. Serologic assessment to S, RBD, and Nucleocapsid antigens will 
also be assessed quantitatively using a validated multiplexed MSD immunoassay.
8.5.2.2
SARS-CoV-2 Neutralizing Antibody Assessments
Serum samples to measure SARS-CoV-2 neutralizing antibody levels will be collected from 
participants in the substudy according to the timepoints specified in the SoA (Section 1.3). 
Authorized laboratories will measure neutralizing antibodies to SARS-CoV-2 using validated 
wild-type neutralization assay or pseudo-neutralization assays.
8.5.2.3
Assessment of Mucosal Responses 
Nasal samples to evaluate SARS-CoV-2 antigen-specific antibody responses in nasal 
secretions will be collected from participants in the substudy, from participants enrolled in the 
immunogenicity cohort, and during illness visits according to the SoA (Section 1.3). Nasal 
adsorption specimens will be collected by synthetic absorptive matrix sampling as outlined in 
the laboratory manual. Antibody responses to SARS-CoV-2 S, RBD, and Nucleocapsid
antigens may be assessed in a qualified multiplexed MSD immunoassay and stratified by 
antibody isotype (IgA, IgG, IgM).  
8.5.2.4
Assessment of Cell-mediated Immune Responses
Cell-mediated immune responses (ie, B-cell and T-cell responses) will be assessed by 
characterizing PBMCs using methods that may include T-cell ELISpot assays to 
SARS-CoV-2 antigens, flow cytometry after intracellular cytokine staining, single-cell RNA 
sequencing, B-cell and T-cell receptor sequencing, and other methodology as determined by 
the Sponsor and/or authorized laboratories. Data on Th1/Th2 polarization after AZD1222 
vaccination will be provided and may be reported separately from the CSR. Samples will be 
collected from up to 300 participants in the substudy, from approximately 300 participants in 
the immunogenicity cohort, and from up to approximately the first 3 000 participants, where 

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operationally feasible, during the Day 1 illness visit, as well as participants who have a 
positive SARS-CoV-2 RT-PCR result at timepoints specified in the SoA (Section 1.3).
Additionally, plasma will be isolated from the whole blood samples collected to isolate 
PBMCs, which may be utilized for exploratory immunogenicity and biomarker analyses as 
outlined in Section 8.6.2.
8.5.2.5
Additional Serum Immunogenicity
Additional serum samples for exploratory immunogenicity evaluation will be obtained 
according to the SoA (Section 1.3). Serologic assessment to seasonal coronavirus antigens 
will also be assessed quantitatively using a qualified multiplexed MSD immunoassay, while 
anti-vector immune responses (ie, ChAdOx1 neutralizing antibody responses) will 
characterize the induction of antibodies to the ChAdOx1vector and the persistence of these 
antibodies over time. Exploratory sera samples may be utilized to investigate additional 
humoral and cellular immune responses as well as potential correlates of protection as 
determined by the Sponsor and/or authorized laboratories based upon emerging safety, 
efficacy, and immunogenicity data.
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to participate in the study, the participant consents to participate in the 
mandatory research components of the study.
Samples for biomarker research are required and will be collected from participants during 
illness visits as specified in the SoA (Section 1.3). Mid-turbinate nasal and nasopharyngeal 
swabs will be collected at site illness visits for virologic assessments. Saliva samples will be 
collected at site illness visits and by the participants during the home-collection period. These 
biomarker measurements will support our understanding of potential correlates of protection, 
duration of immune responses, and correlations between immunogenicity and reactogenicity. 
Details for sample collection, processing, and testing will be provided in the Laboratory 
Manual.
Any results from such analyses may be reported separately from the CSR.
8.6.1.1
Virologic Assessments
Instructions for obtaining and processing mid-turbinate nasal swabs and nasopharyngeal swab 
samples are provided in the Laboratory Manual. Mid-turbinate nasal and nasopharyngeal 
swabs will be assessed by authorized RT-PCR assays for the detection of SARS-CoV-2 by 

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local and central laboratories, respectively. Genotypic analysis of the viral S protein will be 
performed by next generation sequencing modalities. Additionally, a validated multiplexed 
respiratory panel may be utilized to assess for the presence of other respiratory pathogens in 
nasopharyngeal swabs in a central laboratory operated on behalf of the Sponsor.
8.6.1.2
Assessment of Viral Shedding
Viral shedding will be assessed in saliva samples collected using a Spectrum DNA 
(SDNA-1000) collection kit or other saliva collection devices at site illness visits or 
self-collected at home, by an authorized RT-PCR assay for the measurement of SARS-CoV-2. 
Collection of saliva sample for viral shedding is optional in non-USA sites and may occur 
after a feasibility assessment has been completed.
8.6.2
Other Study-related Biomarker Research
Already collected samples may be analyzed for different biomarkers thought to play a role in 
COVID-19 severity or outcomes including, but not limited to serum, plasma or mucosal 
cytokines, quantification of RNA, micro-RNA, and/or non-coding RNA using quantitative 
RT-PCR, microarray, sequencing, or other technology in blood, PBMCs, or mucosal 
specimens to evaluate their association with observed clinical responses to AZD1222. Other 
study-related biomarker research excludes genetic analysis.
For storage, re-use, and destruction of biomarker samples see Section 8.5. 
8.7
Optional Genomics Initiative Sample
Optional Genomics Initiative research is not applicable anymore to this study.
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 primary efficacy endpoint is a binary response, whereby a participant is defined as a 
COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurs ≥15 days post second dose of study intervention. Otherwise, a participant is not 
defined as a COVID-19 case. VE will be calculated as 1-relative risk, which is the incidence 
in the vaccine group relative to the incidence in the control group. The null hypothesis is: VE 
is equal to 30%. Whereas, the alternative hypothesis is: VE is not equal to 30%. That is:

Null hypothesis: VE = 30%

Alternative hypothesis: VE ≠ 30%

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The primary efficacy endpoint will be formally assessed at 2 time points during the study, 
giving an interim analysis and a primary analysis. A Lan-DeMets alpha-spending function has 
been used to control the overall type I error at 5% with 0.31% alpha at the interim and 4.9% at 
the primary analysis. At the interim analysis, the VE will be presented with a 2-sided 99.69% 
CI, and statistical significance will be achieved if the 2-sided 99.69% CI is > 30%. The 
success criterion for the interim analysis will be statistical significance with an observed VE 
point estimate of at least 50%. At the primary analysis VE will be presented with a 2-sided 
95.10% CI, and statistical significance will be achieved if the 2-sided 95.10% CI is > 30%.
The success criterion for the primary analysis of the study will be statistical significance with 
an observed VE point estimate of at least 50%.  
In the event that the results of the interim or primary analysis are statistically significant for 
the primary efficacy endpoint, an additional analysis with 5% alpha will be performed once all 
participants have completed their first year of follow up. 
9.2
Sample Size Determination
Approximately 33 000 participants will be screened such that approximately 
30 000 participants will be randomized in a 2:1 ratio to receive 2 IM doses of either 
5 × 1010 vp (nominal, ± 1.5 × 1010 vp) AZD1222 (the active group, n = approximately 20 000) 
or saline placebo (the control group, n = approximately 10 000) 4 weeks apart.
Note: ‘Enrolled’ means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomly assigned/assigned in the study, are considered ‘screen failures’, unless 
otherwise specified by the protocol.
The sample size calculations are based on the primary efficacy endpoint and were derived 
following a modified Poisson regression approach (Zou 2004). The calculations account for an 
interim and primary analysis, and the timing of these analyses will be driven by the number of 
events observed in the study. The interim analysis will be carried out when approximately 
50% of the total amount of statistical information is available. A Lan-DeMets alpha-spending 
function has been used to account for multiplicity, where the Type I error at the interim and 
primary analyses is with 0.31% alpha at the interim analysis and 4.9% at the primary analysis 
such that the overall Type I error is controlled at 5%. The calculations assume minimal loss to 
follow-up as it is anticipated that participants will remain engaged in the study. All 
participants will be followed for the entire duration of the study.
For the primary efficacy analysis, approximately 150 events meeting the primary efficacy 
endpoint definition are required across the active and control groups within the population of 
participants who are seronegative at baseline to detect a VE of 60% with > 90% power. These 

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calculations assume an observed attack rate of approximately 0.8% and are based on a 2-sided 
test, where the lower bound of the 2-sided 95.10% CI for VE is required to be greater than 
30% with an observed point estimate of at least 50%.
An interim efficacy analysis will be conducted when approximately 75 events meeting the 
primary efficacy endpoint definition have been reported across the active and control groups 
within the population of participants who are seronegative at baseline, which will give > 70% 
power to detect a VE of 70% and > 90% power to detect a VE of 75%. These calculations 
assume an observed attack rate of approximately 0.4% and are based on a 2-sided test, where 
the lower bound of the 2-sided 99.69% CI for VE is required to be greater than 30% with an 
observed point estimate of at least 50%. A statistically significant finding at the interim 
analysis will not be considered a reason to stop the study, but instead will be interpreted as 
early assessment of efficacy.
9.3
Populations for Analyses
The following populations are defined:
Table 9
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 randomized participants who received at least one dose of study 
intervention, irrespective of their protocol adherence and continued 
participation in the study. Participants will be analyzed 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 or assent to participate in the study will be included up to the 
date of their study withdrawal.
Fully vaccinated analysis set
The fully vaccinated analysis set will include all participants in the full analysis 
set who are seronegative at baseline, receive 2 doses of study intervention, and 
who remain on-study 15 days after their second dose without having had a 
prior SARS-CoV-2 RT-PCR-positive confirmed COVID-19 infection.
Per-protocol analysis set
The per-protocol analysis set will include participants in the fully vaccinated
analysis set who receive the correct dose of randomized treatment and who do 
not have a serious protocol deviation. Detailed criteria defining this analysis set 
will be documented in the Statistical Analysis Plan.
Erroneously-treated participants who receive one dose of active study 
intervention and one dose of saline placebo, regardless of the sequence, will be 
excluded from this analysis set.

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Table 9
Populations for Analysis
Population
Description
Safety analysis set
The safety analysis set consists of all participants who have received at least 
one dose of study intervention.
Erroneously-treated participants (eg, those randomized to treatment A but were 
actually given treatment B) 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.
Immunogenicity analysis set
The immunogenicity analysis population will include all participants in the 
safety analysis set who have no protocol deviations judged to have the 
potential to interfere with the generation or interpretation of an immune 
response. Examples of protocol violations will be documented in the Statistical 
Analysis Plan.  
COVID-19 = coronavirus disease 2019; RT-PCR = reverse transcriptase polymerase chain reaction; SARS-
CoV-2 = severe acute respiratory syndrome-coronavirus 2.
9.4
Statistical Analyses
The primary DBL will occur after approximately 150 events have been observed for the 
primary endpoint (see Section 9.2) within the population of participants who are seronegative
at baseline. All participants in the study will be assessed for efficacy and safety for 2 years 
following the first dose of study intervention (Day 730). The final DBL will occur when all 
participants have completed the study.
This section is 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 SAP, and an approved version will be finalized
prior to the interim analyses (see Section 9.5).
All personnel involved in the analyses of the study will remain blinded until the primary DBL 
and protocol deviations are identified, unless the DSMB determines that the efficacy and 
safety have been definitively established during interim analysis. In this case, the DSMB will 
notify the Oversight Group who will then determine the course of action for the study, which 
may include unblinding personnel from the Sponsor or its representatives associated with the 
analyses and regulatory submission of interim results.
Analyses will be performed by the Sponsor or its representatives.
Categorical variables will be summarized using frequency and percentages, where the 
denominator for calculation is the underlying analysis set population unless otherwise stated.

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Continuous variables will be summarized with descriptive statistics of number of available 
observations, mean, standard deviation, median, minimum and maximum, and quartiles where 
more appropriate.
All point estimates will be presented together with a 95% CI, unless otherwise stated. 
P-values, corresponding to a 2-sided test, will be presented for comparisons between 
treatments. Methods for controlling multiplicity across endpoints are discussed in 
Section 9.4.4.
9.4.1 General Considerations
The primary efficacy analysis will be based on the double-blind, placebo-controlled phase of 
the study, and will compare participants randomized to receive 2 nominal doses of 5 × 1010 vp 
(± 1.5 × 1010 vp) AZD1222 against participants randomized to saline placebo.
The primary estimand will be used for the analysis of the primary efficacy endpoint. It will be 
based on participants in the fully vaccinated analysis set, defined as all randomized 
participants who are seronegative at baseline, receive 2 doses of study intervention, and who 
remain on-study 15 days after their second dose without having had a prior SARS-CoV-2 
RT-PCR-positive confirmed COVID-19 infection, analyzed according to their randomized 
treatment. For participants with multiple events, only the first occurrence will be used for the 
primary efficacy endpoint analysis. The set of intercurrent events for this estimand consists of 
participants who withdraw from the study or are unblinded to treatment assignment prior to 
having met the primary efficacy endpoint. The intercurrent event of early study withdrawal 
will be handled using the treatment policy strategy and the absence of data following these 
participants’ withdrawal will be treated as missing (ie, counted as not having met the criteria). 
Participants unblinded to treatment assignment prior to having met the criteria for the primary 
efficacy endpoint will be censored at the date of unblinding. Participants who withdraw before 
15 days post second dose or who have a case prior to 15 days post second dose will be 
excluded from primary endpoint analysis.
Additional estimands will be specified for the primary efficacy endpoint to carry out 
sensitivity analyses for assessing the robustness of results. These sensitivity analyses will 
explore different methods for handling intercurrent events and different assumptions for 
missing data. Estimands will also be specified for the analysis of secondary endpoints. Full 
details will be provided in the SAP.
Demography and baseline characteristics will be summarized by treatment for the fully 
vaccinated analysis set, safety analysis set, and immunogenicity analysis set. 

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9.4.2 Efficacy 
An overview of the primary and secondary efficacy objectives, endpoints, and the associated 
case definitions is presented in Appendix F.
A blinded independent efficacy adjudication committee will review relevant data of potential 
cases for the COVID-19-related efficacy endpoint evaluations. More detail on this process 
will be provided in the SAP and the Efficacy Adjudication Committee Charter (see also 
Appendix A 5).
9.4.2.1
Primary Endpoint
The primary endpoint is the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring ≥ 15 days post second dose of study intervention, in a participant with negative 
serostatus at baseline. Participants will be included in the primary endpoint if they have 
RT-PCR-confirmed SARS-CoV-2 and meet the following criteria at any point from their 
initial illness visit at the site (Day 1) through their second illness visit (Day 14):
1
One or more Category A findings
OR
2
Two or more Category B findings
Category A:

Pneumonia diagnosed by chest x-ray, or computed tomography scan

Oxygen saturation of ≤ 94% on room air or requiring either new initiation or escalation in 
supplemental O2

New or worsening dyspnea/shortness of breath
Category B:

Fever > 100 °F (> 37.8 °C) or feverishness

New or worsening cough

Myalgia/muscle pain

Fatigue that interferes with activities of daily living

Vomiting and/or diarrhea (only one finding to be counted toward endpoint definition)

Anosmia and/or ageusia (only one finding to be counted toward endpoint definition)
The primary efficacy endpoint will be assessed at 2 milestones during the study, giving an 
interim analysis (see Section 9.5) and a primary analysis. The timing of these analyses will be 
driven by the number of events observed in the study within the subset of participants who are 
seronegative at baseline. The interim analysis will be carried out when approximately 

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75 events meeting the primary efficacy endpoint definition have been observed, and the 
primary analysis will be carried out when approximately 150 events meeting the primary
efficacy endpoint definition have been observed (see Section 9.2). A final analysis will also be 
carried out when all participants have completed the 2-year study. However, the final analysis 
will not be controlled for multiplicity and statistical hypotheses will be tested at a nominal 
5% significance level (based on a 2-sided test).
As the primary efficacy analysis, the plan is to use the primary estimand and a Poisson 
regression model with robust variance (Zou 2004) to analyze the primary efficacy endpoint, 
including study arm and age as covariates as well as the log of the follow-up time as an offset. 
The VE will be estimated from the model, which will give the RRR in the incidence of 
SARS-CoV-2 RT-PCR-positive symptomatic illness. VE is calculated as 
RRR = 100*(1-relative risk), which is the incidence in the vaccine group relative to the 
incidence in the control group expressed as a percentage. For the interim analysis the VE will 
be presented with a 2-sided 99.69% CI, and statistical significance will be achieved if the 
2-sided 99.69% CI is > 30%. The success criterion for the interim analysis will be statistical 
significance with an observed VE point estimate of at least 50%. At the primary analysis VE 
will be presented with a 2-sided 95.10% CI, and statistical significance will be achieved if the 
2-sided 95.10% CI is > 30%. The success criterion for the primary analysis of the study will 
be statistical significance with an observed VE point estimate of at least 50%.  The CIs are
based on a Lan-DeMets alpha-spending function for 2-group sequential tests. 
In the event that the results of the interim or primary analysis are statistically significant for 
the primary efficacy endpoint, an additional analysis will be performed once all participants 
have completed their first year of follow up. For this analysis, VE will be presented with a 2-
sided 95% CI, and statistical significance will be achieved if the 2-sided 95% CI is > 0%. 
Model assumptions will be checked and the robustness of the primary analysis will be 
assessed. The Poisson regression model with robust variance has the flexibility for exploring 
multiple imputation approaches using, eg, the observed placebo attack rate to impute missing 
data. If the Poisson regression model with robust variance fails to converge, an alternative 
approach will be implemented. Full details will be documented in the SAP.
To support the primary analysis, a Cox proportional hazard model will be fitted to the data as 
well as Kaplan-Meier curves presented for the active and control groups, showing the 
cumulative incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring ≥ 15 days post second dose of study intervention. In addition, descriptive statistics 
for the vaccine and control groups will also be produced. Full details will be documented in 
the SAP.

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9.4.2.2
Secondary Endpoints
The set of secondary endpoints include the following summary measures, derived from binary 
outcomes:

Incidence of the first post-treatment response (negative at baseline to positive post 
treatment with study intervention) for SARS-CoV-2 Nucleocapsid antibodies occurring 
≥15 days post second dose of study intervention (key secondary endpoint)

Incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring ≥15 days post second dose of study intervention using CDC criteria (see 
Section 8.1.1 for definition)

Incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness
occurring ≥ 15 days post second dose of study intervention using University of Oxford-
defined symptom criteria. Cases are defined as RT-PCR-confirmed SARS-CoV-2 and 
having at least one of the following symptoms
1
New onset of fever (> 100 °F [> 37.8 °C]), OR 
2
Cough, OR 
3
Shortness of breath, OR 
4
Anosmia/ageusia

Incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring ≥15 days post second dose of study intervention regardless of evidence of prior 
SARS-CoV-2 infection (key secondary endpoint)

Incidence of SARS-CoV-2 RT-PCR-positive severe or critical symptomatic COVID-19 
occurring ≥15 days post second dose of study intervention (see Section 8.1.3 for 
definition) (key secondary endpoint)

Incidence of SARS-CoV-2 RT-PCR-positive severe or critical symptomatic COVID-19 
occurring post first dose of study intervention

Incidence of COVID-19-related Emergency Department visits occurring ≥ 15 days post 
second dose of study intervention (key secondary endpoint)

Post-treatment GMTs and GMFRs from day of dosing baseline value to 28 days post each 
dose in SARS-CoV-2 S, RBD antibodies (MSD serology assay)

The proportion of participants who have a post-treatment seroresponse (≥4-fold rise in 
titers from day of dosing baseline value to 28 days post each dose) to the S, RBD antigens 
of AZD1222 (MSD serology assay)

Post-treatment GMTs and GMFRs from day of dosing baseline value to 28 days post each 
dose in SARS-CoV-2 neutralizing antibodies (wild-type assay or pseudo-neutralization 
assay)

Proportion of participants who have a post-treatment seroresponse (≥4-fold rise in titers 
from day of dosing baseline value to 28 days post each dose) to AZD1222 as measured by 
SARS-CoV-2 neutralizing antibodies (wild-type assay or pseudo-neutralization assay)

The incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post first 
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Following the same methodology outlined for the primary endpoint, each of the key secondary 
endpoints will be analysed by a separate Poisson regression model with robust variance (Zou 
2004), including study arm and age as covariates according to the hierarchical approach for 
multiplicity protection (refer to Section 9.4.4). 
For non-key secondary endpoints, the same methodology outlined for the primary endpoint 
will be applied however the RRR will be estimated from each model, with a corresponding 
95% CI. A p-value, corresponding to a 2-sided test, will be presented to compare the vaccine 
against the control. The p-value will be nominal as non-key secondary endpoints are not 
controlled for multiplicity. To support these analyses, descriptive statistics will be produced 
for the vaccine and control groups. Full details will be documented in the SAP.
To assess immune response, the set of secondary endpoints also includes:

Post-treatment GMTs and GMFRs from day of dosing baseline values to 28 days post 
each dose in SARS-CoV-2 S, RBD antibodies (MSD serology assay)

Proportion of participants who have a post-treatment seroresponse (≥ 4-fold rise in titers 
from day of dosing baseline values to 28 days post each dose) to the S, RBD antigens of 
AZD1222 (MSD serology assay)

Post-treatment GMTs and GMFRs from day of dosing baseline values to 28 days post 
each dose in SARS-CoV-2 neutralizing antibodies (wild-type assay or 
pseudo-neutralization assay)

Proportion of participants who have a post-treatment seroresponse (≥ 4-fold rise in titers 
from day of dosing baseline value to 28 days post each dose) to AZD1222 as measured by 
SARS-CoV-2 neutralizing antibodies (wild-type assay or pseudo-neutralization assay)
The proportion of participants who have a post-treatment seroresponse to the S and RBD 
antigens of AZD1222 will be derived for the vaccine and control groups, with corresponding 
95% Clopper-Pearson exact CIs. Similarly, the proportion of participants who have a 
post-treatment seroresponse to AZD1222 as measured by SARS-CoV-2 neutralizing 
antibodies will be derived for the vaccine and control groups, with corresponding 
95% Clopper-Pearson exact CIs.  
The GMT and GMFR endpoints will be analysed on the log (base 2) scale by separate analysis 
of variance (ANOVA) models, and will include study arm and age as categorical covariates.  
On the log scale, the models will be used to estimate a mean response for the vaccine and 
control groups and the difference (vaccine - control), with corresponding 95% confidence 
limits. These values will then be back-transformed to give geometric means for the vaccine 
and control groups and a ratio of geometric means (vaccine/control), with corresponding 
95% confidence limits. A p-value, corresponding to a 2-sided test, will be presented to 

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compare the vaccine against the control. The p-value will be nominal as secondary endpoints 
are not controlled for multiplicity.
To support these analyses, descriptive statistics will be produced for the vaccine and control 
groups. Full details will be documented in the SAP.
9.4.2.3
Exploratory Endpoints
Full details of the analyses for the exploratory endpoints will be specified in the SAP. 
9.4.3 Safety
9.4.3.1
Primary Endpoints
Overview
The safety of AZD1222 will primarily be assessed by:

Incidence of AEs for 28 days post each dose of study intervention

Incidence of SAEs from Day 1 post treatment through Day 730

Incidence of MAAE (defined in Section 8.3.8) and AESIs (defined in Section 8.3.9) from 
Day 1 post treatment through Day 730

Incidence of local and systemic solicited AEs for 7 days post each dose of study 
intervention
AE severity will be graded according to 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 SAP, 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.
9.4.3.2
Other Safety Endpoints
Vital Signs
For SARS-CoV-2-positive participants, vital sign measurements will be performed as 
specified in the SoA (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 SAP, which will include descriptive 
statistics presented for observed and change from baseline values for all vital sign parameters. 
9.4.4
Methods for Multiplicity Control
The primary efficacy endpoint and 4 key secondary endpoints will be assessed at 2 time points 
during the study, given an interim analysis and a primary analysis. A Lan-DeMets alpha-
spending function has been used to account for multiplicity of the primary endpoint across the 
2 time points, with 0.31% alpha at the interim analysis and 4.9% at the primary analysis. Thus, 
the interim and primary analyses will present estimates with 2-sided 99.69% and 95.10% CIs, 
respectively, and statistical significance will be achieved if the 2-sided CIs are > 30%. At the 
interim or primary analysis, the success criterion for the study will be statistical significance 
with an observed VE point estimate of at least 50%. If the primary endpoint achieves 
statistical significance at the 0.31% level at the interim (or at the 4.9% level at the primary), a 
hierarchical approach will be used to control for multiplicity of the primary and key secondary 
efficacy endpoints. That is, the null hypotheses for these efficacy endpoints will be tested in a 
hierarchical order, and the subsequent null hypothesis will be tested at a significance level of 
0.31% or 4.9% (2-sided), at the interim and primary analysis, respectively, only if the prior 
null hypothesis is rejected.
A formal assessment of the key secondary efficacy endpoints at the interim or primary will 
only be conducted if the statistical significance of the primary efficacy endpoint is 
demonstrated at 2-sided alpha of 0.31% at the interim or 4.9% at the primary analysis. With 
that, the overall Type I error is controlled at 0.05. Therefore, no further multiplicity 
adjustment is necessary.
The testing strategy at the interim analysis or primary analysis will be as follows:
Step 1:
1
Interim analysis: Perform the test of primary endpoint with 0.31% alpha level. If the 
2-sided 99.69% CI is > 30% with VE point estimate ≥ 50%, then proceed to Step 2. 
Otherwise no null hypothesis is rejected for the interim analysis.
2
Primary analysis: Perform the test of primary endpoint with 4.9% alpha level. If the 
2-sided 95.10% CI is > 30% with VE point estimate ≥ 50%, then proceed to Step 2. 
Otherwise no null hypothesis is rejected for the primary analysis.
Step 2: 
1
Interim analysis: Test the 4 key secondary endpoints at the significance level of 0.31% 
using hierarchical fixed-sequence testing in the order below. If the 2-sided 99.69% CI is 
> 0%, then proceed to the next endpoint. 

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2
Primary analysis: Test the 4 key secondary endpoints at the significance level of 4.9% 
using hierarchical fixed-sequence testing in the order below. If the two-sided 95.10% CI 
is > 0%, then proceed to the next endpoint. 
(a) Key Secondary Endpoint 1: Incidence of the first case of SARS-CoV-2 RT-PCR-
positive symptomatic illness occurring ≥ 15 days post second dose of study 
intervention regardless of evidence of prior SARS-CoV-2 infection.
(b) Key Secondary Endpoint 2: Incidence of the first case of SARS-CoV-2 RT-PCR-
positive severe or critical symptomatic COVID-19 occurring ≥ 15 days post second 
dose of study intervention.
(c) Key Secondary Endpoint 3: Incidence of COVID-19-related Emergency Department 
visits occurring ≥ 15 days post second dose of study intervention.
(d) Key Secondary Endpoint 4: Incidence of the first post-treatment response (negative at 
baseline to positive post treatment with study intervention) for SARS-CoV-2 
Nucleocapsid antibodies occurring ≥ 15 days post second dose of study intervention.
In the event that the results of the interim or primary analysis are statistically significant for 
the primary efficacy endpoint based on the above testing strategy, an additional analysis will 
be performed once all participants have completed their first year of follow up. This analysis 
will use the same testing strategy described above for primary and key secondary endpoints, 
with a 5% alpha level.
9.4.5
Sensitivity Analyses
Sensitivity analyses will be explored to assess the robustness of treatment effects for the 
primary efficacy endpoint, where different missing data mechanisms will be explored using 
multiple imputation approaches. Full details of the sensitivity analyses will be specified in the 
SAP, and documented prior to the primary DBL.
9.4.6
Subgroup Analyses
Subgroup analyses will be carried out to assess the consistency of the treatment effect across 
key, pre-defined, subgroups. These analyses will focus on the primary efficacy endpoint, and 
they may be performed on secondary and exploratory endpoints if deemed appropriate. The 
list of subgroups includes, but may not be limited to: gender, age, and serostatus at baseline. 
Full details of all subgroup analyses will be described in the SAP, including hypotheses that 
will be tested and the covariates and interaction terms to be included in the statistical models.
9.5
Interim Analyses 
The study has been powered to include an interim efficacy analysis, based on the primary 
efficacy endpoint. The statistical analysis described in Section 9.4.2.1 will be carried out by 
the COVID-19 Vaccine DSMB when approximately 75 events have been reported across the 

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active and control groups (ie, when approximately 50% of the total amount of statistical 
information is available) within the population of participants who are seronegative at 
baseline. A statistically significant finding at the interim analysis (ie, 2-sided 99.69% CI is 
> 30%) will not be considered a reason to stop the study, but instead will be interpreted as 
early assessment of efficacy. The SAP will describe the planned interim analyses in greater 
detail.
9.6
Data Safety Monitoring Committee
An independent COVID-19 Vaccine DSMB 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 COVID-19 Vaccine DSMB to ensure that the balance remains favorable. 
Further details, composition, and operation of the COVID-19 Vaccine DSMB will be 
described in a separate COVID-19 Vaccine DSMB charter.
For details on the COVID-19 Vaccine DSMB, refer to Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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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, IB, 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 
CRO 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 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 

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review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.
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 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 

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names or any information which would make the participant identifiable will not be 
transferred.

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 Patient Safety. Issues identified will be addressed; for 
instance, this could involve amendments to the Clinical Study Protocol and letters to 
investigators. 
A PSRT comprised of Sponsor, COVID-19 Prevention Network, Biomedical Advanced 
Research and Development Authority, and NIAID medical officers will be convened to 
oversee blinded safety surveillance of participants during the study. Further details, 
composition, and operation of the PSRT will be described in a separate COVID-19 Prevention 
Network PSRT Charter.
A COVID-19 Vaccine DSMB organized by the National Institutes of Health, National 
Institute for Allergy and Infectious Diseases, comprised of independent experts will be 
convened to provide oversight, to ensure safe and ethical conduct of the study. The 
COVID-19 Vaccine DSMB will facilitate the interim analysis for safety and efficacy and 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 
DSMB to ensure that the balance remains favorable. For example, events of potential 
vaccine-associated enhanced respiratory disease will be evaluated by periodic reviews of 
COVID-19 cases by the DSMB. Harm for severe COVID-19 cases is any VE ≤0 for which 
Fisher’s exact test (1-sided) is statistically significant at the 5% level. This assessment will 
begin after 8 cases of severe COVID-19 have accrued in the study and will be performed in 
real time as events occur. Harm monitoring will include all COVID-19 cases and all severe 
COVID-19 cases from Day 1 for participants in the full analysis set. Harm monitoring for 
overall COVID-19 cases will use the same boundary as severe COVID-19 cases (ie, VE ≤0 
for which Fisher’s exact test [1-sided] is statistically significant at the 5% level) but will be 
performed on a weekly basis. Full details of the COVID-19 Vaccine DSMB composition and 
operations can be found in the COVID-19 Vaccine DSMB Charter.

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An independent Neurological AESI Expert Committee will be available to review and provide 
advice to the PSRT and the COVID-19 Vaccine DSMB on request about the diagnosis and 
causality assessment of selected neurological AESIs occurring in the AZD1222 clinical 
development program. Details on the composition and operation of this committee are 
described in the Neurological AESI Expert Committee Charter. 
A blinded independent efficacy adjudication committee will review relevant data of potential 
cases for the COVID-19-related efficacy endpoint evaluations. More detail on this process 
will be provided in the SAP and the Efficacy Adjudication 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.

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 verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; 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.

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
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.
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 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 IECs/IRBs, 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.

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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 multicenter 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 unfavorable 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 tumors 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 tumor event should be assessed and reported as a non-SAE. For 
example, if the tumor is included as medical history and progression occurs during the study, 
but the progression does not change treatment and/or prognosis of the malignant tumor, the 
AE may not fulfil the attributes for being assessed as serious, although reporting of the 
progression of the malignant tumor as an AE is valid and should occur. Also, some types of 
malignant tumors, 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
The grading scales 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. 
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.
B 3
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 IMP.

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 IMP?

Consistency with known IMP profile. Was the AE consistent with the previous 
knowledge of the suspect IMP (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 IMP?

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 IMP 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 IMP?

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 4
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 IMP, but rather a human or process related 
failure while the IMP 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 IMP

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:

IMP name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

IMP  not administered as indicated, for example, wrong route or wrong site of 
administration

IMP not taken as indicated eg, tablet dissolved in water when it should be taken as a solid 
tablet 

IMP 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 IMP 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 

Participant accidentally missed IMP dose(s) eg, forgot to take medication

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 
analyzed, 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 10: Clinical Abnormalities, Local Reactions to Injectable Product

Table 11: Clinical Abnormalities, Vital Signs

Table 12: Clinical Abnormalities, Systemic (General or Illness)

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Table 10
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 centimeters) 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 11
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign a
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening (Grade 4)
Fever (°C) b
(°F) b
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
ER visit or 
hospitalization for 
arrhythmia
Bradycardia 
(beats/minute) c
50-54
45-49
< 45
ER visit or 
hospitalization for 
arrhythmia
Hypertension;  systolic 
(mm Hg)
141-150
151-155
> 155
ER visit or 
hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
ER visit or 
hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
ER visit or 
hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Note: Record vital signs as adverse events only if clinically relevant and changed from baseline.
a
Participant should be at rest for vital signs measurements
b
No recent hot or cold beverages or smoking
c
Use clinical judgment when characterizing bradycardia among some healthy participant populations, for 
example, conditioned athletes
ER = emergency room; Hg = mercury.

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Table 12
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic (General)
Systemic Grade
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 hrs
Some interference 
with activity or 
> 2 episodes/24 hrs
Prevents daily 
activity, required 
outpatient IV 
hydration
ER visit or 
hospitalization 
for hypotensive 
shock
Chills
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Headache
No interference 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hrs or 
some interference 
with activity
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity
ER visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
ER 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
ER visit or 
hospitalization
ER = emergency room; hrs = hours; IV = intravenous.

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Appendix E
Adverse Events of Special Interest
AZD1222 AESIs 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 AESIs. 
Table 13
Adverse Events of Special Interest
AESI
Medical Concept
Neurologic
Generalized convulsion: Seizures are episodes of neuronal hyperactivity most 
commonly resulting in sudden, involuntary muscular contractions. They may also 
manifest as sensory disturbances, autonomic dysfunction and behavioral abnormalities, 
and impairment or loss of consciousness. 
Guillain-Barré syndrome: GBS is a peripheral nerve demyelinating disease, which can 
present as temporary ascending paralysis.
Acute disseminated encephalomyelitis: ADEM is 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 pediatric population.
Other neurologic events: These events would include new onset event (acute or 
subacute) motor and sensory disturbances (eg, weakness, numbness, paresthesias, 
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: These are 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: Thrombocytopenia is 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: Vasculitides are a group of related disorders characterized by 
inflammation of blood vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: 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: The pathogenicity of VAERD 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).

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Table 13
Adverse Events of Special Interest
AESI
Medical Concept
Potential immune-mediated conditions: These conditions are 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 14. 
ADEM = acute disseminated encephalomyelitis; AESI = adverse event of special interest; GBS = Guillain-
Barré syndrome; VAERD = vaccine-associated enhanced respiratory disease.
Table 14
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 14
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, Behcet's 
syndrome, leukocytoclastic vasculitis

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Table 14
List of Potential Immune-mediated Medical Conditions
Category
Condition
Other
Antiphospholipid syndrome
Autoimmune hemolytic anemia
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 anemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis

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Appendix F
Overview of Primary and Secondary Efficacy Objectives,
Endpoints, and Associated Case Definitions

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Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and Associated Case Definitions
Objective
Endpoint
Case Definition
Primary
To estimate the efficacy of 
2 IM doses of AZD1222 
compared to saline placebo for 
the prevention of COVID-19 
A binary response, whereby a 
participant with negative serostatus at 
baseline is defined as a COVID-19 
case if their first case of SARS-CoV-2 
RT-PCR-positive symptomatic illness 
occurs ≥15 days post second dose of 
study intervention. Otherwise, a 
participant is not defined as a 
COVID-19 case.
Participant must have RT-PCR-confirmed SARS-CoV-2 and meet 
the following criteria at any point from their initial illness visit at the 
site (Day 1) through their second illness visit (Day 14):
1
One or more Category A findings 
OR
2
Two or more Category B findings
Category A:
•
Pneumonia diagnosed by chest x-ray, or computed tomography
scan
•
Oxygen saturation of ≤ 94% on room air or requiring either 
new initiation or escalation in supplemental O2
•
New or worsening dyspnea/shortness of breath
Category B:
•
Fever > 100 °F (> 37.8 °C) or feverishness
•
New or worsening cough
•
Myalgia/muscle pain
•
Fatigue that interferes with activities of daily living
•
Vomiting and/or diarrhea (only one finding to be counted 
toward endpoint definition)
•
Anosmia and/or ageusia (only one finding to be counted toward 
endpoint definition)

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Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and Associated Case Definitions
Objective
Endpoint
Case Definition
Secondary
To estimate the efficacy of 
2 IM doses of AZD1222 
compared to saline placebo for 
the prevention of SARS-CoV-2 
infection
The incidence of the first post-
treatment response (negative at 
baseline to positive post treatment 
with study intervention) for SARS-
CoV-2 Nucleocapsid antibodies 
occurring ≥15 days post second dose 
of study intervention (key secondary 
endpoint)
The first post-treatment response (negative at baseline to positive 
post treatment with study intervention) for SARS-CoV-2 
Nucleocapsid antibodies occurring ≥15 days post second dose of 
study intervention
To estimate the efficacy of 
2 IM doses of AZD1222 
compared to saline placebo for 
the prevention of symptomatic
COVID-19 using CDC criteria
The incidence of the first case of 
SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring 
≥15 days post second dose of study 
intervention using CDC criteria
The first case of SARS-CoV-2 RT-PCR-positive symptomatic 
illness for a participant occurring ≥15 days post second dose of 
study intervention using criteria from the CDC (CDC 2020):
Fever
Shortness of breath
Difficulty breathing
Chills
Cough
Fatigue
Muscle aches
Body aches
Headache
New loss of taste 
New loss of smell
Sore throat
Congestion
Runny nose
Nausea
Vomiting
Diarrhea

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Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and Associated Case Definitions
Objective
Endpoint
Case Definition
Secondary
To estimate the efficacy of 
2 IM doses of AZD1222 
compared to saline placebo for 
the prevention of University of 
Oxford-defined symptomatic 
COVID-19
The incidence of the first case of 
SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring 
≥15 days post second dose of study 
intervention using University of 
Oxford-defined symptom criteria
First case of SARS-CoV-2 RT-PCR-positive symptomatic illness for 
a participant occurring ≥ 15 days post second dose of study 
intervention using University of Oxford-defined symptom criteria. 
Cases are defined as RT-PCR-confirmed SARS-CoV-2 and having 
at least one of the following symptoms:  
1
New onset of fever (> 100 °F [> 37.8 °C]), OR 
2
Cough, OR 
3
Shortness of breath, OR 
4
Anosmia/ageusia

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Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and Associated Case Definitions
Objective
Endpoint
Case Definition
Secondary
To estimate the efficacy of 
2 IM doses of AZD1222 
compared to saline placebo in 
the prevention of COVID-19 in
all study participants, 
regardless of evidence of prior 
SARS-CoV-2 infection
The incidence of the first case of 
SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring 
≥15 days post second dose of study 
intervention regardless of evidence of 
prior SARS-CoV-2 infection (key 
secondary endpoint
Participant must have RT-PCR-confirmed SARS-CoV-2 and meet 
the following criteria at any point from their initial illness visit at the 
site (Day 1) through their second illness visit (Day 14):
1
One or more Category A findings 
OR
2
Two or more Category B findings
Category A:
•
Pneumonia diagnosed by chest x-ray, or computed tomography
scan
•
Oxygen saturation of ≤ 94% on room air or requiring either 
new initiation or escalation in supplemental O2
•
New or worsening dyspnea/shortness of breath
Category B:
•
Fever > 100 °F (> 37.8 °C) or feverishness
•
New or worsening cough
•
Myalgia/muscle pain
•
Fatigue that interferes with activities of daily living
•
Vomiting and/or diarrhea (only one finding to be counted 
toward endpoint definition)
•
Anosmia and/or ageusia (only one finding to be counted toward 
endpoint definition)

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Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and Associated Case Definitions
Objective
Endpoint
Case Definition
Secondary
To estimate the efficacy of 
2 IM doses of AZD1222 
compared to saline placebo for 
the prevention of severe or 
critical symptomatic
COVID-19
a) The incidence of SARS-CoV-2 
RT-PCR-positive severe or critical 
symptomatic illness occurring 
≥15 days post second dose of 
study intervention (key secondary 
endpoint)
Participant must have laboratory-confirmed COVID-19 
(SARS-CoV-2 RT-PCR-positive symptomatic illness) plus any of 
the following:
•
Clinical signs at rest indicative of severe systemic illness 
(respiratory rate ≥ 30 breaths per minute, heart rate ≥125 beats 
per minute,  oxygen saturation ≤ 93% on room air at sea level, 
or partial pressure of oxygen to fraction of inspired oxygen ratio 
< 300 mm Hg)
•
Respiratory failure (defined as needing high-flow oxygen, 
noninvasive ventilation, mechanical ventilation or 
extracorporeal membrane oxygenation)
•
Evidence of shock (systolic blood pressure < 90 mm Hg, 
diastolic blood pressure < 60 mm Hg, or requiring 
vasopressors)
•
Significant acute renal, hepatic, or neurologic dysfunction
•
Admission to an intensive care unit
•
Death
b) The incidence of SARS-CoV-2 
RT-PCR positive severe or critical 
symptomatic illness occurring post 
first dose of study intervention
To estimate the efficacy of 
2 IM doses of AZD1222 
compared to saline placebo for 
the prevention of COVID-19-
related Emergency Department 
visits
The incidence of COVID-19-related 
Emergency Department visits
occurring ≥15 days post second dose 
of study intervention (key secondary 
endpoint)
COVID-19-related Emergency Department visits occurring 
≥15 days post second dose of study intervention

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Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and Associated Case Definitions
Objective
Endpoint
Case Definition
Secondary
To assess antibody responses to 
AZD1222 S antigen following 
2 IM doses of AZD1222 or 
saline placebo
(Substudy and Illness Visits 
only)
a) Post-treatment GMTs and GMFRs 
from day of dosing baseline value 
to 28 days post each dose in 
SARS-CoV-2 S, RBD antibodies 
(MSD serology assay)
a) Post-treatment GMTs and GMFRs from day of dosing baseline 
value to 28 days post each dose in SARS-CoV-2 S, RBD
antibodies (MSD serology assay)
b) The proportion of participants who 
have a post-treatment seroresponse 
(≥4-fold rise in titers from day of 
dosing baseline value to 28 days 
post each dose) to the S, RBD 
antigens of AZD1222 (MSD 
serology assay)
b) Post-treatment seroresponse (≥4-fold rise in titers from day of 
dosing baseline value to 28 days post each dose) to the S, RBD 
antigens of AZD1222 (MSD serology assay)
To determine anti-SARS-CoV-
2 neutralizing antibody levels 
in serum following 2 IM doses 
of AZD1222 or saline placebo
(Substudy and Illness Visits 
only)
a) Post-treatment GMTs and GMFRs 
from day of dosing baseline value 
to 28 days post each dose in 
SARS-CoV-2 neutralizing 
antibodies (wild-type assay or 
pseudo-neutralization assay)
a) Post-treatment GMTs and GMFRs from day of dosing baseline 
value to 28 days post each dose in SARS-CoV-2 neutralizing 
antibodies (wild-type assay or pseudo-neutralization assay)
b) Proportion of participants who 
have a post-treatment seroresponse 
(≥4-fold rise in titers from day of 
dosing baseline value to 28 days 
post each dose) to AZD1222 as 
measured by SARS-CoV-2
neutralizing antibodies (wild-type
assay or pseudo-neutralization 
assay)
b) Post-treatment seroresponse (≥4-fold rise in titers from day of 
dosing baseline value to 28 days post each dose) to AZD1222 as 
measured by SARS-CoV-2 neutralizing antibodies (wild-type
assay or pseudo-neutralization assay)

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Table 15
Overview of Primary and Secondary Efficacy Objectives, Endpoints, and Associated Case Definitions
Objective
Endpoint
Case Definition
Secondary
To estimate the efficacy of 
AZD1222 compared to saline 
placebo for the prevention of 
COVID-19 following the first 
dose
The incidence of SARS-CoV-2 RT-
PCR-positive symptomatic illness 
occurring post first dose of study 
intervention
Participant must have RT-PCR-confirmed SARS-CoV-2 and meet 
the following criteria at any point from their initial illness visit at the 
site (Day 1) through their second illness visit (Day 14):
1
One or more Category A findings 
OR
2
Two or more Category B findings
Category A:
•
Pneumonia diagnosed by chest x-ray, or computed tomography
scan
•
Oxygen saturation of ≤ 94% on room air or requiring either 
new initiation or escalation in supplemental O2
•
New or worsening dyspnea/shortness of breath
Category B:
•
Fever > 100 °F (> 37.8 °C) or feverishness
•
New or worsening cough
•
Myalgia/muscle pain
•
Fatigue that interferes with activities of daily living
•
Vomiting and/or diarrhea (only one finding to be counted 
toward endpoint definition)
•
Anosmia and/or ageusia (only one finding to be counted toward 
endpoint definition)
CDC = Centers for Disease Control and Prevention; COVID-19 = coronavirus disease 2019; GMFR = geometric mean fold rise; GMT = geometric mean titer; 
IM = intramuscular; MSD = Meso Scale Discovery; S =Spike; RBD = receptor binding domain; RT-PCR = reverse transcriptase polymerase chain reaction; 
SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2.

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Appendix G
Abbreviations
Abbreviation or special term
Explanation
ACE2
angiotensin-converting enzyme 2
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-hCG
beta-human chorionic gonadotropin
CDC
Centers for Disease Control and Prevention
ChAdOx1 MERS
chimpanzee adenovirus Ox1 with MERS Spike antigen
ChAdOx1 nCoV-19
name of AZD1222 when initially developed by the University of Oxford
CI
confidence interval
CoV
coronavirus 
COVID-19
coronavirus disease 2019
CRO
contract research organization
CSR
clinical study report
DBL
database lock
DSMB
Data Safety Monitoring Board
E
envelope
eCRF
electronic case report form
EDC
electronic data capture
e-Diary
electronic diary
ELISA
enzyme-linked immunosorbent assay
ELISpot
enzyme-linked immunospot
FIH
first-in-human
GCP
Good Clinical Practice
GMFR
geometric mean fold rise
GMT
geometric mean titer
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgA
immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IM
intramuscular 

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Abbreviation or special term
Explanation
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
M
membrane
MAAE
medically attended adverse event
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
MSD
Meso Scale Discovery
NHP
non-human primate
PBMC
peripheral blood mononuclear cell
PSRT
Protocol Safety Review Team
RBD
receptor binding domain
RRR
relative risk reduction
RT-PCR
reverse transcriptase polymerase chain reaction
S
Spike
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV
severe acute respiratory syndrome-coronavirus
SARS-CoV-2
severe acute respiratory syndrome-coronavirus 2
SoA
Schedule of Activities
TBL
total bilirubin
tPA
tissue plasminogen activator
ULN
upper limit of normal
US FDA
United States Food and Drug Administration
USA
United States of America
VE
vaccine efficacy
vp
viral particles
WHO
World Health Organization
w/v
weight/volume

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Appendix H
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 5 (18 January 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The principal reason for this amendment was to add an extension to the study to permit 
evaluation of safety, immunogenicity, and efficacy of 2 doses of AZD1222 administered 8 to 
12 weeks apart to adults and adolescents. The extended dosing interval is supported by 
enhanced immunogenicity data, as well as a high level of protection (VE 73%) against 
COVID-19 demonstrated from a single dose (COVID-19 Vaccine AstraZeneca SmPC 2021).
Adolescents have been added to the study population to generate valuable data on safety and 
immunogenicity in this age group.
Note that the new addition to the study was labeled as Part 2 (and included in a separate 
Appendix G) and the existing main study and its corresponding substudy and immunogenicity 
cohort were relabelled as Part 1.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title Page,
1.1 Synopsis
Added “and Adolescents” to the 
title
To generate evidence to 
lower the indication to 
persons 12 years of age
Substantial
1.1 Synopsis,
2.1 Study Rationale
Added text to the study rationale 
regarding adolescents
1.1 Synopsis,
3 Objectives and 
Endpoints,
Appendix F Overview 
of Primary and 
Secondary Efficacy 
Objectives, 
Endpoints, and 
Associated Case 
Definitions (Table 15)
Removed “in adults ≥ 18 years 
of age” from primary objectives 
1-3
To make the objectives
applicable to both Part 1 
and the newly added 
Part 2
Non-substantial
Specified that primary 
objective 3, secondary 
objectives 7-8, and exploratory 
objectives 6-14 apply to both 
Part 1 and Part 2
Added a second endpoint for 
secondary objective 5 and 
exploratory objectives 3 and 4
To show efficacy after 
1 dose in severe 
COVID-19 illness
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis,
1.2 Schema,
1.3 Schedule of 
Activities
3 Objectives and 
Endpoints,
4.1 Overall Design,
4.2 Scientific 
Rationale for Study 
Design,
4.3 Justification for 
Dose,
5 Study Population,
6.1.2 Dosing 
Instructions,
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding,
7.1 Discontinuation of 
study intervention
8 Study Assessments 
and Procedures,
9 Statistical 
Considerations,
Appendix G Part 2 
Added Appendix G to describe 
the new Part 2 and 
corresponding Part 2 Substudy. 
Added cross-references to 
Appendix G.
To permit evaluation of 
safety, immunogenicity, 
and efficacy of 2 doses 
of AZD1222 
administered 8 to 12 
weeks apart in adults 
and adolescents
Substantial
Relabelled the existing main 
study and its corresponding 
substudy and immunogenicity 
cohort as Part 1
For clarity and 
consistency, given the 
addition of Part 2
Non-substantial
1.1 Synopsis,
9.2 Sample Size 
Determination,
9.4 Statistical 
Analyses
Changed “not seropositive” to 
“seronegative”
Clarification
Non-substantial
3 Objectives and 
Endpoints,
Appendix G Part 2
Added footnote d to Table 5 to 
indicate that exploratory 
endpoint 5 is an exploratory 
endpoint for Part 1, but a 
secondary endpoint for Part 2.
Included exploratory endpoint 5 
for Part 1 as a secondary 
endpoint for Part 2 in 
Appendix G
To support efficacy post 
first dose given the 
extension of the dosing 
interval in Part 2
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix E Adverse 
Events of Special 
Interest (Table 13)
Added additional terms to 
“immunologic” of multisystem 
inflammatory syndrome in 
children and adults and added a 
new category “respiratory” with 
term of acute respiratory distress 
syndrome
To add new Brighton 
Collaboration case 
definitions
Non-substantial
Amendment 4 (14 December 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The principal reason for this amendment was to incorporate revisions based on FDA feedback 
and clarifications of study processes. In addition, an immunogenicity cohort was added to 
expand upon cell-mediated immunity data.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title Page
Corrected EudraCT number
Correction
Non-substantial
1.1 Synopsis,
3 Objectives and 
Endpoints,
9.4.1 General 
Considerations
Added text to indicate that 
participants unblinded to 
treatment assignment prior to 
having met the criteria for the 
primary efficacy endpoint will be 
censored at the date of 
unblinding.
Clarification
Non-substantial
1.1 Synopsis,
3 Objectives and 
Endpoints, 
9.4.2.2 Secondary 
Endpoints,
Appendix G 
(Table 15)
Revised the first secondary 
endpoint
To permit formal 
statistical comparison and 
inclusion as key 
secondary endpoint
Substantial
Identified the 4 key secondary 
endpoints (added footnote c)
To indicate these are the 
endpoints that are 
multiplicity protected
1.1 Synopsis,
4.1 Overall Design,
8.5.2.3 Assessment of 
Mucosal Responses,
8.5.2.4 Assessment of 
Cell-mediated Immune 
Response
Added an immunogenicity cohort 
of approximately 300 participants
To expand upon cell-
mediated immunity data
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis,
4.1 Overall Design,
9.2 Sample Size 
Determination
Reduced the sample size from 
40 000 back to the original 
number of 30 0000
Based on the efficacy 
already seen in the pooled 
analysis from the Oxford 
studies, and the large 
outbreak in the United 
States has increased the 
attack rate
Substantial
1.1 Synopsis,
9.2 Sample Size 
Determination
Changed attack rate for primary 
analysis from 0.6% to 0.8%
Given the reduction in 
sample size from 40 000 
to 30 000 
Non-substantial
1.3 Schedule of 
Activities (Table 2 and 
Table 3)
Revised Table 2 and Table 3 
captions to include 
“Immunogenicity Cohort”
To address addition of 
immunogenicity cohort to 
study
Non-substantial
Added the collection of PBMCs 
at Day 180 for substudy and 
immunogenicity cohort 
participants to Table 3
To build on data 
regarding durability of 
cell-mediated immunity
Revised footnote f of Table 3 to 
indicate that PBMCs will be 
isolated from up to (instead of 
approximately) 300 participants 
in the substudy and 
approximately 300 participants in 
the immunogenicity cohort
To include the newly 
added immunogenicity 
cohort
In Table 3, indicated that 
assessment of nasal adsorption for 
SARS-CoV-2 mucosal responses 
is optional
Clarification
In Table 3, indicated that local 
and systemic predefined solicited 
AEs apply to the substudy only
Clarification
1.3 Schedule of 
Activities (Table 2 and 
Table 3, footnote c),
6.5.2 Prohibited 
Concomitant 
Medications
Added text to indicate that 
experimental vaccinations, other 
than AZD1222, for prevention of 
SARS-CoV-2 or COVID-19 are 
prohibited. Also, noted that 
participants who choose to 
receive a licensed and/or 
authorized COVID-19 vaccine 
should inform the Investigator so 
it can be properly documented 
and they should be encouraged to 
continue study conduct.
To exclude experimental 
vaccinations other than 
AZD1222 and to allow 
participants access to 
emerging standard of care 
given the rapidly evolving 
COVID-19 vaccines 
landscape
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.3 Schedule of 
Activities,
8.5 Human Biological 
Samples,
8.6.2 Other Study-
related Biomarker 
Research,
8.7 Optional Genomics 
Initiative Sample,
Appendix D
Removed Optional Genomics 
Initiative assessment
Due to kit build issues 
during the COVID-19 
pandemic and lack of 
sample tube availability
Non-substantial
4.1 Overall Design,
8.1.1 Monitoring 
COVID-19 Symptoms
In the COVID-19 Qualifying 
Symptoms table, revised “must be 
present for ≥ 2 days” to “must be 
present for ≥ 2 consecutive days” 
Clarification
Non-substantial
5.1 Inclusion Criteria 
(Table 6)
Under combined hormonal 
methods, changed “injectable” to 
“intravaginal”
Correction
Non-substantial
Revised footnote c to specify that 
sexual abstinence is considered a 
highly effective method only if 
defined as refraining from 
heterosexual intercourse from 28 
days prior to Day 1 through 60 
days following administration of 
the second dose of study 
intervention… (instead of ‘during 
the entire period of the study’)
Clarification
5.2 Exclusion Criteria
Added a note to Exclusion 
Criterion 10 to indicate that the 
AESIs outlined in Appendix F 
should be considered when 
evaluating a participant for this 
exclusion criterion
The presence of these 
AESIs may be a safety 
risk to the participant, 
affect the ability of the 
participant to participate 
in the study, or impair 
interpretation of the study 
data
Non-substantial
6.3.3 Procedures for 
Unblinding
Specified the procedures in the 
event a study participant is 
contacted about receiving a 
licensed and/or authorized 
COVID-19 vaccine
Clarification provided due 
to recent Emergency Use 
Authorizations for 
COVID-19 vaccines
Non-substantial
6.5.2 Prohibited 
Concomitant 
Medications
Clarified that routine vaccinations 
are permitted (as clinically 
indicated) 30 days after the 
second vaccination
Clarification
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
8.1.2 Illness Visits
Added text to indicate that if 
symptoms persist despite a 
negative test result, Investigators 
should provide appropriate 
clinical follow-up of participants, 
as clinically indicated
PCR test is not 100% 
accurate and Investigators 
need to provide 
appropriate clinical 
follow-up of any ill 
participants
Non-substantial
8.1.3 Severe 
COVID-19
Revised statement to indicate that 
the severity of COVID-19 will be 
evaluated in participants with 
symptoms of COVID-19 (instead 
of participants who test positive 
for SARS-CoV-2 by RT-PCR)
To be consistent with 
CRF completion 
guidelines asking sites to 
complete the endpoint 
CRF regardless of the 
local PCR result
Non-substantial
8.3.9.1 Potential 
Neurological AESIs
Added clarification that the 
Investigator should evaluate the 
participant and refer to a 
neurologist as clinically indicated
Based on Investigator 
feedback
Non-substantial
9.1 Statistical 
Hypotheses,
9.4.2.1 Primary 
Endpoint,
9.4.4 Methods for 
Multiplicity Control
Specified that if the primary 
endpoint results of the interim or 
primary analysis are statistically 
significant, an additional analysis 
with 5% alpha will be performed 
once all participants have 
completed the first year of 
follow-up
To evaluate long-term 
efficacy based on 1 year 
of follow-up before the 
final analysis
Substantial
9.3 Populations for 
Analyses (Table 9)
For Per-protocol analysis set, 
specified that erroneously-treated 
participants who receive one dose 
of active study intervention and 
one dose of placebo, regardless of 
the sequence, will be excluded 
from this analysis set
Clarification
Non-substantial
For the safety analysis set, 
specified that a participant who 
has on one or several occasions 
received active study intervention 
is classified as active for all 
summaries, including summaries 
by dose
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
9.4 Statistical Analyses
Added text to indicate when 
unblinding of personnel involved 
in the analyses of the study may 
occur
Clarification for timing of 
Sponsor unblinding
Non-substantial
9.4.2.1 Primary 
Endpoint,
9.5 Interim Analyses
Changed “not seropositive” to 
“seronegative”
Clarification
Non-substantial
9.4.3.1 Primary 
Endpoints
Clarified that AE analyses will 
include intercurrent events for 
safety due to potential unblinding 
of participants for administration 
of licensed and/or approved 
SARS-CoV-2 or COVID-19
vaccine
Clarification
Non-substantial
9.4.4 Methods for 
Multiplicity Control
Revised to indicate how the 
primary efficacy endpoints and 4 
key secondary endpoints will be 
assessed
To address the Agency’s 
request for having a 
secondary endpoint 
testing strategy
Substantial
Amendment 3 (26 October 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The principal reason for this amendment was to expand AESI evaluation and oversight. Other 
key revisions included updating the AZD1222 safety profile, increasing the sample size, 
extending the beyond-use-date for the study intervention, and specifying that the substudy will 
only be conducted in the USA.  
Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title Page
Added ClinicalTrials.gov and 
EudraCT numbers
To align with updated 
information
Non-substantial
1.1 Synopsis
Updated Objectives and 
Endpoints, Overall Design, 
Number of Participants, Statistical 
Methods
To align with edits in the 
protocol body
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.2 Schema, 
Figure 1 Study 
Design
Noted that the substudy will only 
be conducted in the USA
Due to logistical issues
Non-substantial
1.3 Schedule of 
Activities, 
Table 2 
Extended Day 29 visit window 
from ± 3 days to -3 to + 7 days 
To provide greater 
scheduling flexibility to sites 
and participants
Non-substantial
1.3 Schedule of 
Activities, 
Table 3
a) Noted that the substudy will 
only be conducted in the USA 
b) Extended Day 29 visit window 
from ± 3 days to -3 to + 7 days 
c) For participants who received 
the first dose between 
28 August 2020 and 
06 September 2020, extended 
the window for receiving the 
second dose
a) Due to logistical issues 
b) To provide greater 
scheduling flexibility to 
sites and participants
c) To accommodate receipt 
of the second dose of 
study intervention for 
participants who 
received their first dose 
prior to the clinical hold
Non-substantial 
1.3 Schedule of 
Activities, 
Table 4
a) Broadened optional saliva 
sample collection for viral 
shedding to all non-USA sites
b) Noted that PBMCs will be 
collected from participants 
where operationally feasible
Clarifications due to 
logistical issues
Non-substantial
2.2 Background
Updated information on the 
nonclinical and clinical AZD1222 
development program
To align with information in 
the updated AZD1222 IB
Non-substantial
2.3.1 Risk 
Assessment
Revised important potential risks
Substantial
3 Objectives and 
Endpoints, 
Table 5
a) Revised estimand description 
for the primary efficacy 
endpoint to be conducted in the 
fully vaccinated analysis set, 
and added a secondary 
objective to estimate efficacy 
in all participants regardless of 
prior SARS-CoV-2 infection 
b) Noted that the substudy will 
only be conducted in the USA
a) To align with the 
statistical plan 
b) Due to logistical issues 
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
4.1 Overall 
Design
a) Increased the sample size from 
30 000 to 40 000 participants
b) For participants who received 
the first dose between 
28 August 2020 and 
06 September 2020, extended 
the window for receiving the 
second dose 
c) Noted that the substudy will be 
conducted only in the USA
d) Added a description of the 
independent Neurological AESI 
Expert Committee
a) Increased based on 
updated attack rates and 
public health emergency
b) To accommodate receipt 
of the second dose of 
study intervention for 
participants who 
received their first dose 
prior to the clinical hold
c) Due to logistical issues
d) New committee to 
provide advice on 
selected neurological 
AESIs
a) Substantial
b) Non-substantial
c) Non-substantial
d) Substantial
4.2.1 Rationale 
for Study Design 
and Participant 
Population
Revised enrollment status for 
Study COV002
Aligned with updated study 
status 
Non-substantial
6.2.1.1 AZD1222,
6.2.1.2 Placebo
Extended the beyond-use-date 
from 4 hours to 6 hours
To align with revised use 
hold times based on recent 
microbial challenge study 
data
Non-substantial
8.3.9 Adverse 
Events of Special 
Interest
Expanded the AESI list and 
specified that AESIs will be 
reported to the Sponsor within one 
day of becoming aware of the 
event
To permit close monitoring 
and rapid communication of 
safety information, and 
further understanding of the
AZD1222 safety profile
Substantial
8.3.9.1 Potential 
Neurological 
AESIs
New section for evaluation of 
potential neurological AESIs
For additional safety 
monitoring
Substantial
8.5.2.4 
Assessment of 
Cell-mediated 
Immune 
Responses
Noted that PBMCs will be
collected from participants where 
operationally feasible
Clarifications due to 
logistical issues
Non-substantial
8.6.1.2 
Assessment of 
Viral Shedding
Broadened optional saliva sample 
collection for viral shedding to all 
non-USA sites
9.2 Sample Size 
Determination
Updated to incorporate the 
increased sample size from 30 000 
to 40 000 participants as well as 
the underlying assumptions
Increased based on updated 
attack rates and public 
health emergency
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
9.3 Populations 
for Analyses
Added a fully vaccinated analysis 
set and revised the per-protocol 
analysis set to be based on 
participants in the fully vaccinated 
analysis set
To align with the revised 
statistical analyses for the 
primary endpoint
Non-substantial
9.4.1 General 
Considerations
9.4.2.1 Primary 
Endpoint
9.4.2.2 Secondary 
Endpoints
Revised analyses
To align with the current 
analysis plan
Non-substantial
Appendix A5 
Committee 
Structure
Added a description of the 
independent Neurological AESI 
Expert Committee
New committee to provide 
advice on selected 
neurological AESIs
Substantial
Appendix F 
Adverse Events of 
Special Interest 
a) Expanded the AESI list and 
provided a description of the 
events
b) Added new table listing 
potential immune-mediated 
conditions to provide more 
detail on this new AESI 
To permit close monitoring 
and rapid communication of 
safety information and 
further understand the 
AZD1222 safety profile
Substantial
Appendix G
a) Primary endpoint: Revised to 
note that the statistical analysis 
will be conducted in
participants with negative 
serostatus at baseline
b) Secondary endpoint evaluating 
symptomatic COVID-19 per 
CDC criteria: Revised the case 
definition to remove a 
minimum duration for any of 
the symptoms
c) Added a secondary objective to 
estimate efficacy in all 
participants regardless of prior 
SARS-CoV-2 infection
To align with statistical 
analyses
Non-substantial

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Amendment 2 (17 September 2020)
Overall Rationale for the Amendment:
The principal reason for this amendment was to address US FDA feedback to the 
Investigational New Drug application. Additional changes included statistical revisions per 
DSMB request and other revisions to provide clarity or correct inadvertent errors. All the 
changes were considered non-substantial.   
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis
Updated Objectives and 
Endpoints, Overall Design, 
Statistical Methods
To align with edits in the 
protocol body
Non-substantial
1.3 Schedule of 
Activities, Table 3
Removed ‘at least’ to clarify that 
PBMCs will be isolated from 
approximately 300 participants 
Clarification
Non-substantial
1.3 Schedule of 
Activities, Table 4
a) Added new footnote ‘b’ to 
indicate that collection of saliva 
sample for viral shedding 
assessment is optional in 
Chile/Peru and may occur after 
a feasibility assessment has 
been completed
b) Footnote ‘c’: removed the 
requirement for the RT-PCR 
test to be a rapid test
a) Feasibility of collection 
of saliva samples in 
Chile/Peru is underway
b) Not a requirement per 
protocol and provides 
more flexibility to the 
sites
Non-substantial
3 Objectives and 
Endpoints, Table 5
a) Revised definition of 
intercurrent event 
b) Revised secondary objective 1 
to assess for all SARS-COV-2 
infection
c) Added an exploratory objective 
to estimate the efficacy of 2 IM 
doses of AZD1222 compared 
to placebo for COVID-19-
related deaths
d) Added an exploratory objective 
to estimate the efficacy of 
AZD1222 compared to placebo 
for the prevention of COVID-
19 following the first dose
e) Renumbered exploratory 
objective 12: removed ‘serum’ 
prior to B- and T-cell responses
a) To align with changes 
in the primary analysis
b) To align with analyses
c) Per US FDA request
d) Per DSMB request
e) To correct a 
misstatement
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
4.1 Overall Design
Removed requirement to limit 
initial enrollment to participants 
18 to 55 years of age
The US FDA reviewed the 
accrued data from the 
ongoing University of 
Oxford studies and 
approved enrollment in all 
age groups prior to 
enrollment of the first 
subject.
Non-substantial
6.2.1 Dose Preparation 
and Administration
Clarified description for use of 
AZD1222 and placebo within the 
beyond-use-date 
To avoid confusion in the 
time period from the first 
needle puncture of the 
AZD1222 vial or placebo 
vial/IV bag to dose 
administration
Non-substantial
6.2.1.1 AZD1222
(Additional change)
Removed specification for a 1 mL 
syringe to be used for AZD1222 
dose preparation 
To provide flexibility in 
dose administration
Non-substantial
6.5 Concomitant 
Therapy
Specified that all concomitant 
medication must be recorded in 
the eCRF
Per US FDA request
Non-substantial
6.5.1 Permitted 
Concomitant 
Medications
Clarified the concomitant 
medications permitted for the 
treatment of COVID-19 after 
receiving study intervention
Per US FDA request
Non-substantial
6.5.2 Prohibited 
Concomitant 
Medications
a) For participants who received a 
prohibited concomitant 
medication, described the 
potential impact on 
participation in the study, 
including study withdrawal, 
discontinuation of study 
intervention, or evaluability in 
analysis data sets
b) Added immunoglobulins and/or 
blood product
a) Per US FDA request
b) For alignment with 
exclusion criterion 13
Non-substantial
7.1 Discontinuation of 
Study Intervention
a) Added new criterion for 
laboratory-confirmed SARS-
CoV-2 infection
b) Revised criterion that any 
allergic reaction related to 
study intervention, regardless 
of severity grade, will result in 
study discontinuation
a) Clarification
b) Per US FDA request
c) Per US FDA request
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
c) Added new criterion for receipt 
of prohibited concomitant 
medication that may jeopardize 
the safety of the participant or 
interpretation of the data
8.1.2 Illness Visits
Clarified that home collection 
requirements include digital health 
device and Illness e-Diary 
recordings, and saliva samples
Per US FDA request
Non-substantial
8.1.2.2 Digital Health 
Device
Described the monitoring 
protocols for triage and follow-up 
of alerts from the digital health 
device
Per US FDA request
Non-substantial
8.5.2.4 Assessment of 
Cell-mediated Immune 
Responses
Clarified the number of 
participants who will provide 
PBMC samples, ie, approximately 
300 in the substudy and from up to 
approximately the first 3 000 
during the Day 1 illness visit
To align with the SoA 
Table 3 and Table 4
Non-substantial
8.6.1.1 Virologic 
Assessments
(additional change)
Clarified that a validated 
multiplexed respiratory panel may 
be utilized to assess the presence 
of respiratory pathogens 
Multiplexed respiratory 
panel testing is not an 
absolute requirement
Non-substantial
8.6.1.2 Assessment of 
Viral Shedding
a) Clarified that saliva collection 
is performed utilizing a 
Spectrum DNA (SDNA-1000) 
collection kit
b) Removed ‘qualitative’ to 
describe the type of shedding 
assessment
c)  Added information that 
collection of saliva sample for 
viral shedding assessment is 
optional in Chile/Peru and may 
occur after a feasibility 
assessment has been completed
a) Clarification 
b) Updated due to an 
assay improvement
c) Feasibility of 
collection of saliva 
samples in Chile/Peru 
is underway
Non-substantial
9 Statistical 
Considerations
9.1, 9.2, 9.4, 9.4.2.1, 
9.4.4, and 9.5
Amended the testing strategy, 
sample sizing, as well as number 
of events required for the interim 
and primary analyses
Per DSMB request
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
9.3 Populations for 
Analysis, Table 9
Added definition for 
immunogenicity analysis set
To describe the population 
to be used for the 
immunogenicity 
assessments
Non-substantial
9.4.1 General 
Considerations
Revised definition of intercurrent 
event
To align with changes in 
the primary analysis
Non-substantial
9.4.2 Efficacy
a) Added reference to new 
Appendix G (see description 
for Appendix G below)
b) Added description of an 
adjudication committee that 
will review data of potential 
cases for the COVID-19-related 
efficacy endpoints
a) Per US FDA request
b) To provide clarity on 
the process for 
determining cases to 
be included in the 
COVID-19-related 
efficacy evaluations 
Non-substantial
9.4.2.1 Primary 
Endpoint
(additional change)
Clarified a supportive analysis of 
the primary endpoint
Incorrect statement about 
censored observations 
removed
Non-substantial
9.4.2.2 Secondary 
Endpoints
a) Bullet 1: Clarified that the 
endpoint will assess the 
proportion of participants who 
have a post-treatment response 
(negative at baseline to positive 
post treatment with study 
intervention) for SARS-CoV-2 
Nucleocapsid antibodies over 
time
b) Bullet 2: Included the endpoint 
to assess the incidence of 
SARS-CoV-2 RT-PCR positive 
symptomatic illness using the 
CDC criteria
c) Bullet 3: Clarified the 
University of Oxford symptom 
criteria used to assess the 
incidence of SARS-CoV-2 RT-
PCR positive symptomatic 
illness
d) Specified the analyses for the 
incidence endpoints, and added 
a description of the analysis for 
participants positive for SARS-
CoV-2 Nucleocapsid antibodies
a) To align with analyses
b) Corrected an 
inadvertent omission
c) Per US FDA request
d) Clarification
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix A5 
Committee Structure
Added description of an 
adjudication committee that will 
review data of potential cases for 
the COVID-19-related efficacy 
endpoints
To provide clarity on the 
process for determining 
cases to be included in the 
COVID-19-related 
efficacy evaluations
Appendix G Overview 
of Primary and 
Secondary Efficacy 
Objectives, Endpoints, 
and Associated Case 
Definitions
New overview table presenting the 
primary and secondary efficacy 
objectives, endpoints, and 
associated case definitions 
Per US FDA request
Non-substantial
Appendix I Protocol 
Amendment History
Moved summary of changes for 
Protocol Amendment 1 to this new
appendix  
Per protocol template
Non-substantial
CDC = Centers for Disease Control and Prevention; COVID-19 = coronavirus disease 2019; eCRF = 
electronic case report form; DSMB = Data Safety Monitoring Board; e-Diary = electronic diary; IM = 
intramuscular; NP = nasopharyngeal; PBMC = peripheral blood mononuclear cell; RT-PCR = reverse 
transcriptase polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus 2; 
SoA = schedule of activities; US FDA = United States Food and Drug Administration. 
Amendment 1 (10 August 2020)
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis
Updated Objectives and 
Endpoints, Overall Design, and 
Statistical Methods 
To align with edits in main 
body
Non-substantial
1.2 Schema
Revised the footnote to identify 
the number of randomized 
participants in each age group to 
participate in the substudy
To identify by age group the 
3 000 randomized 
participants who will 
participate in the substudy
Non-substantial
1.3 Schedule of 
Activities
Table 2 Treatment and 
Follow-up Period -
Main Study
Added assessment for recording 
any concomitant medication 
administered for the treatment of 
an SAE, MAAE, or AESI from 
Day 90 through Day 730
To support evaluation of 
SAEs, MAAEs, or AESIs
Non-substantial
1.3 Schedule of 
Activities
Table 3 Treatment and 
Follow-up Period -
Substudy
a) Added assessment for 
recording any concomitant 
medication administered for 
the treatment of an SAE, 
MAAE, or AESI from 
Day 90 through Day 730
a) To support evaluation of 
SAEs, MAAEs, or 
AESIs
b) To help ensure PBMCs 
can be collected in 
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
b) Footnote d: identified that ‘at 
least 300’ participants in the 
substudy can have PBMCs 
collected
participants across age 
groups
2.2 Background
a) Corrected the study number 
for the University of Oxford 
South African clinical study
b) Updated preliminary clinical 
data from Study COV001 and 
Study COV002
To align with: 
a) The study number 
correction made by the 
University of Oxford 
b) The updated AZD1222 
IB, Edition 1.1
Non-substantial
2.3.1 Risk Assessment
Updated common solicited AE 
information 
To align with the updated 
AZD1222 IB, Edition 1.1
Non-substantial
3 Objectives and 
Endpoints
a) Clarified that secondary 
objective 6 is performed in 
substudy and illness visits 
only
b) Footnote a: identified the 
number of randomized 
participants in each age group 
to participate in the substudy
a) Humoral responses to 
AZD1222 are not 
required for main study 
participants
b) To identify by age group 
the 3 000 randomized 
participants who will 
participate in the 
substudy
Non-substantial
4.1 Overall Design
a) Clarified that enrollment will 
begin with participants 18 to 
55 years of age, followed by 
older age groups after FDA 
review of accruing clinical 
data
b) Identified the number of 
randomized participants in 
each age group to participate 
in the substudy
a) To provide for review of 
immunogenicity data in 
older subjects prior to 
enrollment’
b) To identify by age group 
the 3 000 randomized 
participants who will 
participate in the 
substudy
Non-substantial
4.2.1 Rationale for 
Study Design and 
Participant Population
Updated the number of
participants 56 to 69 and 
≥70 years of age anticipated to 
have received AZD1222 at time 
of study initiation
To align with updated study 
status
Non-substantial
5.1 Inclusion Criteria
Corrected number formatting to 
separate Criteria 3 and 4
Inclusion criterion 4 was 
erroneously included under 
inclusion criterion 3
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
5.2 Exclusion Criteria
a) Clarified Criterion 2 to 
include participants with any 
other demyelinating condition
b) Clarified Criterion 6 to state 
≥20 mg per day vs 
≥20 mg/kg/day of prednisone
Per NIH request
Correct typographical error
Non-substantial
6.1.2 Dosing 
Instructions
Deleted instructions to cover the 
injection site with a sterile 
dressing
Erroneously included in 
original protocol
Non-substantial
6.2.1 Dose Preparation 
and Administration; 
6.2.1.1 AZD1222
6.2.1.2 Placebo
Clarified that AZD1222 and 
placebo doses drawn into 
syringes for administration must 
be administered according to the 
beyond-use-date of the vial or IV 
bag
To align with the beyond-
use-date of the vial or IV 
bag as AZD1222 and 
placebo do not contain 
preservatives
Non-substantial
7.2 Participant 
Withdrawal from the 
Study
Clarified that all collected 
samples will be destroyed if the 
participant withdraws consent 
for use of existing samples
To align with current 
process
Non-substantial
8.1.1 Monitoring 
COVID-19 Symptoms
Clarified that investigator 
judgement should be used when 
determining which participants 
should initiate illness visits 
during the 7 days following 
administration of each dose of 
study intervention
To help ensure that 
qualifying symptoms for 
illness visits are due to 
potential infection with 
SARS-CoV-2 and not to 
reactogenicity of the study 
intervention 
Non-substantial
8.1.2.2 Digital Health 
Device
Clarified that the monitoring 
team will receive and triage 
alerts associated with 
participants’ digital health 
device data rather than the 
investigator
To align with current 
process
Non-substantial
9.1 Statistical 
Hypotheses
9.4.2.1 Primary 
Endpoint
9.4.4 Methods for 
Multiplicity Control
9.5 Interim Analyses
Clarified the statistical 
significance for determining 
vaccine efficacy 
To add greater detail to the 
statistical analysis approach 
for the primary estimand
Non-substantial
9.4 Statistical 
Analyses
Clarified that the SAP will be 
approved prior to the interim 
analysis vs the primary analysis
Per standard practice
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix A 5 
Committee Structure
Added criteria for pausing the 
study for DSMB review 
To ensure safety oversight 
Non-substantial
Appendix E Toxicity Grading Scales for Solicited Adverse Events 
Table 11 Clinical 
Abnormalities: Vital 
Signs
Revised the temperature range 
for fever
To align with definition of 
fever throughout the main 
body 
Non-substantial
Table 12 Clinical 
Abnormalities: 
Systemic
Added information for assessing 
severity grade of chills and 
deleted diarrhea
To align with solicited 
adverse events being 
collected, which includes 
chills but not diarrhea
Non-substantial
AESI = adverse event of special interest; MAAE = medically attended adverse event; NIH = National 
Institutes of Health; SAE = serious adverse event; SAP = Statistical Analysis Plan. 

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