A Phase IV Open-Label, Non-Randomized, Multi-Cohort, Multicenter Study in Previously Unvaccinated Immunocompromised Adults to Determine the Immunogenicity and Safety of AZD1222 Vaccine for the Prevention of COVID-19
Phase: PHASE4
Conditions: COVID-19, SARS-CoV-2
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance 
AZD1222 
Study Number  
D8111C00010 
Edition Number 
4.0 
Date 
31 March 2022 
TITLE PAGE 
A Phase IV Open-Label, Non-Randomized, Multi-Cohort, Multicenter 
Study in Previously Unvaccinated Immunocompromised Adults to 
Determine the Immunogenicity and Safety of AZD1222 Vaccine for the 
Prevention of COVID-19 
Sponsor Name:                                                                  AstraZeneca AB 
Legal Registered Address:                                                  151 85 Södertälje, Sweden 
Regulatory Agency Identifier Number:                         NCT 05057897 
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: 
 
 
 
 
D8111C00010  
 
Amendment Number:  
 
 
 
3 
 
Study Intervention:   
 
 
 
AZD1222 
 
Study Phase:  
 
 
 
 
 
IV 
 
Short Title:  A Phase IV Study of AZD1222, a Vaccine for the Prevention of COVID-19 in 
Immunocompromised Adults 
 
Study Physician Name and Contact Information will be provided separately. 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3, Version 4.0 
31 Mar 2022 
Amendment 2, Version 3.0 
14 Dec 2021 
Amendment 1, Version 2.0 
13 Aug 2021 
Original Protocol (Version 1.0) 
06 Aug 2021 
 
Amendment 3 (31 March 2022) 
Overall Rationale for the Amendment:  
Version 3.0 of the amendment was updated in response to feedback received from the 
European Medicines Agency.  
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Whole document 
References to per-protocol analysis 
set changed to immunogenicity 
analysis set. 
For consistency 
throughout 
document. 
Non-substantial 
Section 1.1 Synopsis  
Section 3 Objectives 
Table 5 Study Objectives and 
Endpoints 
Addition of a secondary 
immunogenicity endpoint to analyse 
the change in titre 
levels/seroresponse between 28 days 
post second dose and 28 days post 
third dose for all participants. 
Secondary 
endpoint added 
in response to 
Health Authority 
request. 
Substantial 
Section 1.1 Synopsis  
Section 3 Objectives 
Table 5 Study Objectives and 
Endpoints 
Exploratory endpoint to characterize 
the immunogenicity after a third dose 
booster vaccination of AZD1222 
moved to secondary immunogenicity 
endpoints. 
Secondary 
endpoint added 
in response to 
Health Authority 
request. 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Section 1.3 Schedule of 
Activities 
Table 2 Schedule of 
Activities: 
Vaccination/Follow-up 
Period for 
Immunocompromised 
Cohorts 
Footnote updated to allow for 
oversampling of participants for 
blood samples to achieve 
15 evaluable participants in each 
cohort and balance in samples across 
groups. 
Clarification of 
sampling 
requirements. 
Non-substantial 
Section 1.3 Schedule of 
Activities  
Table 3 Schedule of 
Activities: 
Vaccination/Follow-up 
Period for Immunocompetent 
Participants 
‘eDiary provided’ added at V9 
(V1+182), and footnote added to 
state that the eDiary is to be returned 
V9 + 7 days. 
eDiary is to be 
provided and 
returned after 
receipt of Dose 
3. 
Non-substantial 
Footnote updated to clarify eligibility 
for the third vaccination dose. 
Clarification 
added to further 
explain the 
eligibility of 
participants for 
Dose 3. 
Non-substantial 
Footnote updated to allow for 
oversampling of participants for 
blood samples to achieve 15 
evaluable participants in each cohort 
and balance in samples across 
groups. 
Clarification of 
sampling 
requirements. 
Non-substantial 
Section 2.3.1 Risk 
Assessment 
Updated the important potential risks 
of AZD1222. 
Addition of new 
potential risks. 
Non-substantial 
Section 1.1 Synopsis 
Section 4.1 Study Design 
Section 4.1.2 Vaccination 
Visits 
Section 4.2.2 Rationale for 
Study Endpoints 
Section 8.3.1 Time Period 
and Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information 
Section 8.3.6 Solicited 
Adverse Events 
Sections updated to state that all 
participants (both immunocompetent 
and immunocompromised) are to 
report solicited AEs after each dose. 
Clarification of 
reporting 
requirements for 
solicited AEs. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Section 4.2.2 Rationale for 
Study Endpoints 
Section 8.3.8 Adverse Events 
of Special Interest 
Section 11 References 
Appendix F Adverse Events 
of Special Interest 
Reference to SPEAC 2020 updated 
to SPEAC 2021 
Inclusion of 
updated 
reference. 
Non-substantial 
Section 5.1.1 All Participants 
Table 6 Highly Effective 
Methods of Contraception 
Updated footnote to specify that 
sexual abstinence is considered a 
highly effective method of 
contraception only if defined as 
refraining from heterosexual 
intercourse from 28 days prior to 
Day 1 through 30 days following the 
administration of the last dose of 
study intervention rather than the 
second dose of study intervention. 
Clarification of 
highly effective 
contraception 
method.  
Non-substantial 
Section 5.2 Exclusion 
Criteria 
Clarified the allowed treatment 
options for patients who contract 
COVID-19.  
Clarification of 
allowable 
treatment 
options. 
Non-substantial 
Exclusion criterion corrected to state 
that patients who have donated 
≥ 450 mL of blood products within 
30 days prior to enrollment, rather 
than randomization, are to be 
excluded. 
Correction. 
Non-substantial 
Section 5.4 Screen Failures 
Section was updated to state that 
only 2 rescreenings per participant 
are allowed in the study.  
Clarification of 
allowable 
rescreenings. 
Non-substantial 
Section 6.1.2 Dosing 
Instructions 
A note has been added in line with 
the footnote presented in the 
Schedule of Activities (Table 2 and 
Table 3) that if the Dose 3 of study 
treatment is administered more than 
28 days after Visit 5 and outside the 
visit window due to regulatory 
authority and/or ethics committee 
approval timelines, no protocol 
deviation will be issued. 
Further 
clarification 
added in line 
with the update 
to the Schedule 
of Activities.  
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Section 6.5.2 Prohibited 
Concomitant Medications 
Section has been updated to clarify 
that participants who use any of the 
listed prohibited medications will not 
require withdrawal from the study 
but may require subsequent 
determination of a participant’s 
eligibility to receive a second or third 
dose of study treatment, or 
evaluability in the immunogenicity 
analysis set. 
The bullet point and subsequent note 
describing the investigational 
products allowed for the treatment of 
SARS-CoV-2 or COVID-19 has 
been clarified to state:  
Licensed or authorized products 
(besides vaccines) are allowed. 
Participants who contract COVID-19 
and receive in-patient or outpatient 
treatment, receipt of licensed or 
authorized treatment options, and/or 
participation in investigational 
treatment studies is permitted. 
Clarification of 
allowable 
treatment options 
in the event that 
participants 
contract 
COVID-19. 
Non-substantial 
Section 8.2.4 COVID-19 
Assessment 
Table 9 COVID-19 
Qualifying Symptoms 
The table has been updated to 
remove the duration for each 
qualifying symptom. 
Clarification that 
symptoms of any 
duration quality 
for COVID-19 
testing. 
Non-substantial 
Section 8.3.13.1 Maternal 
Exposure 
Appendix B2 Definition of 
Serious Adverse Events 
Updated ‘congenital abnormalities’ 
to ‘congenital anomalies/birth 
defects’ 
Minor editorial 
change. 
Non-substantial 
Section 9.4.1 General 
Considerations 
Added clarification that: 
Secondary summaries of the change 
from 28 days post dose 2 to 28 days 
post dose 3 within a cohort will be 
performed using the GMT rise from 
dose 2 and seroresponse (from dose 
2). 
Clarification of 
what summaries 
will be carried 
out. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Added clarification that: 
Immunogenicity data from 
participants who did not receive all 
doses would be excluded from the 
analysis from all time points post 
dose visit window. 
Clarification 
added of how 
data from 
participants who 
missed doses 
will be handled. 
Non-substantial 
Section 9.4.2 
Immunogenicity 
Table 17 Secondary 
Immunogenicity Summaries 
to be Completed (by Cohort, 
Timepoint, Antibody, and 
Endpoint) 
Table 20 Secondary 
Immunogenicity 
Comparisons to be 
Completed at the time of the 
Secondary Analysis (by 
Cohorts Compared, 
Timepoint, Antibody, and 
Endpoint) 
Updated with the required 
comparisons for the added secondary 
immunogenicity endpoint. 
Footnote deleted (Table 17). 
Updated in line 
with the updated 
endpoints. 
Substantial 
Appendix F Adverse Events 
of Special Interest 
Table 24 Adverse Events of 
Special Interest 
Table 25 List of Potential 
Immune-mediated Medical 
Conditions 
The tables have been updated with 
additional AESIs and potential 
immune-mediated medical 
conditions. 
Tables have been 
updated in line 
with relevant 
safety data.  
Non-substantial 
Appendix A7: Data Quality 
Assurance 
Updated document retention period 
from 15 to 25 years. 
Updated in line 
with company 
policy. 
Non-substantial 
Appendix H: Protocol 
Amendment History 
New appendix added. 
Added in line 
with template 
requirements.  
Non-substantial 
Whole document 
Minor typographical updates. 
To improve 
readability. 
Non-substantial 
 
 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................... 3 
TABLE OF CONTENTS .......................................................................................................... 8 
LIST OF TABLES .................................................................................................................. 10 
1 
PROTOCOL SUMMARY ................................................................................... 13 
1.1 
Synopsis ................................................................................................................ 13 
1.2 
Schema .................................................................................................................. 19 
1.3 
Schedule of Activities ........................................................................................... 20 
2 
INTRODUCTION ................................................................................................ 28 
2.1 
Study Rationale ..................................................................................................... 28 
2.2 
Background ........................................................................................................... 29 
2.3 
Benefit/Risk Assessment ...................................................................................... 34 
2.3.1 
Risk Assessment ................................................................................................... 34 
2.3.2 
Benefit Assessment ............................................................................................... 37 
2.3.3 
Overall Benefit: Risk Conclusion ......................................................................... 37 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 37 
4 
STUDY DESIGN ................................................................................................. 42 
4.1 
Overall Design ...................................................................................................... 42 
4.1.1 
Screening Visit ..................................................................................................... 44 
4.1.2 
Vaccination Visits ................................................................................................. 44 
4.1.3 
Follow-Up Visits .................................................................................................. 45 
4.2 
Scientific Rationale for Study Design .................................................................. 45 
4.2.1 
Rationale for Study Design and Participant Population ....................................... 45 
4.2.2 
Rationale for Study Endpoints .............................................................................. 46 
4.3 
Justification of Dose ............................................................................................. 47 
4.4 
End of Study Definition ........................................................................................ 48 
5 
STUDY POPULATION ....................................................................................... 48 
5.1 
Inclusion Criteria .................................................................................................. 48 
5.1.1 
All Participants: .................................................................................................... 48 
5.1.2 
Cohort-Specific Inclusion Criteria ........................................................................ 50 
5.2 
Exclusion Criteria ................................................................................................. 51 
5.3 
Lifestyle Considerations ....................................................................................... 53 
5.4 
Screen Failures ..................................................................................................... 53 
6 
STUDY INTERVENTION .................................................................................. 53 
6.1 
Study Intervention Administered .......................................................................... 53 
6.1.1 
Investigational Product ......................................................................................... 53 
6.1.2 
Dosing Instructions ............................................................................................... 54 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 54 

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6.2.1 
Dose Preparation and Administration ................................................................... 55 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 55 
6.4 
Study Intervention Compliance ............................................................................ 55 
6.5 
Concomitant Therapy ........................................................................................... 55 
6.5.1 
Permitted Concomitant Medications .................................................................... 56 
6.5.2 
Prohibited Concomitant Medications ................................................................... 56 
6.6 
Dose Modification ................................................................................................ 57 
6.7 
Interventional After the End of the Study ............................................................ 57 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................ 57 
7.1 
Discontinuation of Investigational Product .......................................................... 57 
7.2 
Study Suspension or Termination ......................................................................... 58 
7.3 
Participant Withdrawal from the Study ................................................................ 58 
7.4 
Lost to Follow-up ................................................................................................. 59 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................... 59 
8.1 
Efficacy Assessments ........................................................................................... 60 
8.2 
Safety Assessments ............................................................................................... 60 
8.2.1 
Physical Examinations .......................................................................................... 60 
8.2.2 
Vital Signs ............................................................................................................ 60 
8.2.3 
Clinical Safety Laboratory Assessments .............................................................. 60 
8.2.4 
COVID-19 Assessments ....................................................................................... 61 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 62 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information ................................................................................................. 63 
8.3.2 
Follow-up of Adverse Events and Serious Adverse Events ................................. 63 
8.3.3 
Causality Collection ............................................................................................. 64 
8.3.4 
Adverse Events Based on Signs and Symptoms .................................................. 64 
8.3.5 
Adverse Events Based on Examinations and Tests .............................................. 65 
8.3.6 
Solicited Adverse Events ...................................................................................... 65 
8.3.6.1 
Solicited AE eDiary .............................................................................................. 66 
8.3.6.2 
Severity Assessment of Solicited AEs .................................................................. 66 
8.3.7 
Medically Attended Adverse Events .................................................................... 66 
8.3.8 
Adverse Events of Special Interest ....................................................................... 67 
8.3.8.1 
Vascular/Hematologic Adverse Events of Special Interest .................................. 67 
8.3.8.2 
Potential Neurological Adverse Events of Special Interest .................................. 67 
8.3.8.3 
Vaccine-associated Enhanced Disease, Including Vaccine-associated 
Enhanced Respiratory Disease ............................................................................. 70 
8.3.9 
Hy’s Law .............................................................................................................. 70 
8.3.10 
COVID-19 Assessment ........................................................................................ 70 
8.3.11 
COVID-19 Severity .............................................................................................. 71 
8.3.12 
Reporting of Serious Adverse Events ................................................................... 71 
8.3.13 
Pregnancy ............................................................................................................. 72 
8.3.13.1 
Maternal Exposure ................................................................................................ 72 

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8.3.14 
Medication Error ................................................................................................... 73 
8.4 
Overdose ............................................................................................................... 73 
8.5 
Human Biological Samples .................................................................................. 74 
8.5.1 
Pharmacokinetics .................................................................................................. 74 
8.5.2 
Immunogenicity Assessments .............................................................................. 74 
8.5.2.1 
SARS-CoV-2 Serology Assessments ................................................................... 74 
8.5.2.2 
SARS-CoV-2 Neutralizing Antibody Assessments ............................................. 75 
8.5.2.3 
Assessment of Cell-mediated Immune Responses ............................................... 75 
8.5.2.4 
Monitoring for Asymptomatic Infection .............................................................. 75 
8.5.2.5 
Additional Serum Immunogenicity ...................................................................... 75 
8.5.3 
Pharmacodynamics ............................................................................................... 75 
8.6 
Human Biological Sample Biomarkers ................................................................ 76 
8.6.1 
Collection of Mandatory Samples for Biomarker Analysis ................................. 76 
8.6.1.1 
Blood Sample for Targeted Sequencing Analyses ............................................... 76 
8.6.1.2 
Blood Samples for Other Biomarker Analyses .................................................... 76 
8.6.2 
Other Study-Related Biomarker Research............................................................ 76 
8.7 
Optional Genomics Initiative Sample ................................................................... 76 
8.8 
Health Economics ................................................................................................. 77 
9 
STATISTICAL CONSIDERATIONS ................................................................. 77 
9.1 
Statistical Hypotheses ........................................................................................... 77 
9.2 
Sample Size Determination .................................................................................. 77 
9.3 
Populations for Analyses ...................................................................................... 79 
9.4 
Statistical Analyses ............................................................................................... 79 
9.4.1 
General Considerations ......................................................................................... 79 
9.4.2 
Immunogenicity .................................................................................................... 81 
9.4.3 
Safety .................................................................................................................... 90 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 91 
11 
REFERENCES ................................................................................................... 124 
 
LIST OF TABLES 
Table 1 
Schedule of Activities: Screening ............................................................... 20 
Table 2 
Schedule of Activities: Vaccination/Follow-up Period for 
Immunocompromised Cohorts .................................................................... 21 
Table 3 
Schedule of Activities: Vaccination/Follow-up Period for 
Immunocompetent Participants ................................................................... 25 
Table 4 
Risk Assessment .......................................................................................... 35 
Table 5 
Study Objectives and Endpoints ................................................................. 37 
Table 6 
Highly Effective Methods of Contraception ............................................... 49 

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Table 7 
Investigational Product ................................................................................ 53 
Table 8 
Local Laboratory Safety Variables ............................................................. 61 
Table 9 
COVID-19 Qualifying Symptoms .............................................................. 62 
Table 10 
List of Predefined Solicited Adverse Events for Reactogenicity 
Assessment .................................................................................................. 66 
Table 11 
Probability of Detecting One or More Safety Events in AZD1222 ............ 77 
Table 12 
Historic Immunogenicity Responses by Dosing Interval ............................ 78 
Table 13 
Historic Seroresponse Rates by Dosing Interval ......................................... 78 
Table 14 
Estimated Half-width of the 95% CI for GMT Given Alternate Assay 
Variance ...................................................................................................... 78 
Table 15  
Estimated Half-width of the 95% Confidence Interval for Selected 
Seroresponse Proportions ............................................................................ 79 
Table 16  
Primary Immunogenicity Summaries to be Completed (by Cohort, 
Timepoint, Antibody, and Endpoint) .......................................................... 81 
Table 17 
Secondary Immunogenicity Summaries to be Completed (by Cohort, 
Timepoint, Antibody, and Endpoint) .......................................................... 83 
Table 18  
Exploratory Anti-vector Immunogenicity Summaries to be Completed 
(by Cohort, Timepoint, Antibody, and Endpoint) ....................................... 84 
Table 19  
Secondary Immunogenicity Comparisons to be Completed at the time of 
the Primary Analysis (by Cohorts Compared, Timepoint, Antibody, and 
Endpoint) ..................................................................................................... 86 
Table 20 
Secondary Immunogenicity Comparisons to be Completed at the time of 
the Secondary Analysis (by Cohorts Compared, Timepoint, Antibody, 
and Endpoint) .............................................................................................. 88 
Table 21  
Tables for Clinical Abnormalities: Local Reactions to Injectable Product106 
Table 22  
Tables for Clinical Abnormalities: Vital Signs ......................................... 107 
Table 23  
Tables for Clinical Abnormalities: Systemic (General or Illness) ............ 108 
Table 24  
Adverse Events of Special Interest ........................................................... 109 
Table 25  
List of Potential Immune-mediated Medical Conditions .......................... 111 
 
LIST OF FIGURES 
Figure 1  
Study Design for Immunocompromised Participants ................................. 19 
Figure 2  
Study Design for Immunocompetent Participants ...................................... 19 
Figure 3  
Neurology Testing Algorithm ..................................................................... 69 
 

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LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .......................... 92 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................... 98 
Appendix C 
Handling of Human Biological Samples ................................................... 102 
Appendix D 
Actions Required in Cases of any Thrombosis in Combination with 
Thrombocytopenia .................................................................................... 104 
Appendix E 
Toxicity Grading Scales for Solicited Adverse Events ............................. 106 
Appendix F 
Adverse Events of Special Interest ........................................................... 109 
Appendix G 
Abbreviations ............................................................................................ 115 
Appendix H 
Protocol Amendment History ................................................................... 117 
 

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Phase IV Open-Label, Non-Randomized, Multi-Cohort, Multicenter Study 
in Previously Unvaccinated Immunocompromised Adults to Determine the Immunogenicity 
and Safety of AZD1222 Vaccine for the Prevention of COVID-19  
Short Title: Phase IV study of AZD1222, a Vaccine for the Prevention of COVID-19 in 
Immunocompromised Adults. 
Rationale: 
The aim of this study is to assess the immunogenicity and safety of AZD1222 for prevention 
of COVID-19 in immunocompromised adults. Clinical studies supporting the emergency use 
authorizations of AZD1222 have, to date, generally excluded participants with significantly 
compromised immune systems. There remains an unmet need in determining the safety and 
immunogenicity of COVID-19 vaccines in a variety of immunocompromised populations, 
including primary immunocompromised adults. An immunocompetent group of participants 
will also be included. 
Objectives and Endpoints: 
The purpose of this study is to demonstrate the immunogenicity and safety of AZD1222, 
AstraZeneca’s approved ChAdOx1 vector vaccine against SARS-CoV-2, in SARS-CoV-2 
seronegative immunocompromised individuals who are unvaccinated. 
The following table lists the primary and secondary endpoints: 
Primary Immunogenicity Objectives 
• 
To characterize the immunogenicity of a 2-dose primary vaccination with AZD1222, with a 4-week 
dosing interval, in SARS-CoV-2 naïve immunocompromised adults and immunocompetent adults ≥ 
18 years. 
Estimand: 
Endpoints a 
1) SARS-CoV-2 specific titres 
2) Seroresponse of SARS-CoV-2 specific 
titres (≥ 4-fold rise in titres from 
baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoints 
28 days after Dose 1; 28 days after Dose 2 
Population 
Immunogenicity analysis set 
Cohort 
Each of 5 immunocompromised cohorts, pooled 
immunocompromised cohorts, and 
immunocompetent cohort 

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Secondary Safety Objective 
Objective 
Endpoints 
• 
To characterize the reactogenicity and safety of a 
3-dose primary vaccination series with AZD1222, 
with a 4-week dosing interval, in SARS-CoV-2 
naïve immunocompromised adults ≥ 18 years. 
• 
Reactogenicity: Incidence of local and 
systemic solicited AEs for 7 days after 
each dose of AZD1222 by eDiary. 
• 
Incidence of unsolicited AEs for 28 days 
post dose after each vaccination  
• 
Incidence of SAEs, MAAEs and AESIs 
from Day 1 post treatment to last study 
visit.  
• 
Absolute and change from baseline b for 
safety laboratory measures. 
Secondary Immunogenicity Objectives 
• 
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years 
with a 4-week dosing interval between SARS-CoV-2 naïve participants with solid organ transplant 
compared to immunocompetent participants. 
Estimand: 
Endpoints a 
1) Ratio of SARS-CoV-2 specific GMT 
titres 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
rise in titres from baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Solid organ transplant 
Reference Cohort 
Immunocompetent 
• 
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years 
with a 4-week dosing interval between SARS-CoV-2 naïve participants with hematopoietic stem cell 
transplant compared to immunocompetent participants. 
Estimand: 
Endpoints a 
1) Ratio of SARS-CoV-2 specific GMT 
titres 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
rise in titres from baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Hematological stem cell transplant 
Reference Cohort 
Immunocompetent 

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• 
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years 
with a 4-week dosing interval between SARS-CoV-2 naïve participants with solid organ cancer 
patients receiving cytotoxic chemotherapy compared to immunocompetent participants. 
Estimand: 
Endpoints 
1) Ratio of SARS-CoV-2 specific GMT 
titres 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
rise in titres from baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Solid organ cancer patients receiving cytotoxic 
chemotherapy 
Reference Cohort 
Immunocompetent 
• 
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years 
with a 4-week dosing interval between SARS-CoV-2 naïve participants with chronic inflammatory 
disorders compared to immunocompetent participants. 
Estimand: 
Endpoints a 
1) Ratio of SARS-CoV-2 specific GMT 
titres 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
rise in titres from baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Chronic inflammatory disorders 
Reference Cohort 
Immunocompetent 
• 
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years 
with a 4-week dosing interval between SARS-CoV-2 naïve participants with primary 
immunodeficiency compared to immunocompetent participants. 
Estimand: 
Endpoints a 
1) Ratio of SARS-CoV-2 specific GMT 
titres 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
rise in titres from baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Primary immunodeficiency 
Reference Cohort 
Immunocompetent 

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• 
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years 
with a 4-week dosing interval between SARS-CoV-2 naïve participants with any 
immunocompromised condition compared to immunocompetent participants. 
Estimand: 
Endpoints a 
1) Ratio of SARS-CoV-2 specific GMT 
titres 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
rise in titres from baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Pooled immunocompromised 
Reference Cohort 
Immunocompetent 
• 
To characterize the immunogenicity after a 3rd-dose in a 3 dose primary vaccination series with 
AZD1222 in immunocompromised adults ≥ 18 years. 
Estimand: 
Endpoints a 
1) SARS-CoV-2 specific titres 
2) Seroresponse of SARS-CoV-2 specific 
titres (≥ 4-fold rise in titres from 
baseline b) 
 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 3 
Population 
Immunogenicity analysis set 
Cohort 
Each of 5 immunocompromised cohorts and 
pooled immunocompromised cohorts 
• 
To describe the immunogenicity after the 3rd dose in a 3-dose primary vaccination series with 
AZD1222 in adults ≥ 18 years between SARS-CoV-2 naïve immunocompromised participants 
compared to immunocompetent participants after a 2-dose primary vaccination.  
Estimand: 
Endpoints a 
1) Ratio of SARS-CoV-2 specific GMT 
titres 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
rise in titres from baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 3 (28 Days after Dose 2 for 
reference cohort) 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Each of 5 immunocompromised cohorts and 
pooled immunocompromised cohorts 
Reference Cohort 
Immunocompetent 

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• 
To describe the immunogenicity of the AZD1222 vaccination between 28 days post second dose 
compared to 28 days post third dose, in adults ≥ 18 years between SARS-CoV-2 naïve 
immunocompromised and immunocompetent participants. 
Endpoints a 
1) Ratio of SARS-CoV-2 specific GMT 
titres. 
2) Difference in seroresponse rates of 
SARS-CoV-2 specific titres (≥ 4-fold 
increase in titres from 28 days post 
dose 2 to 28 days post dose 3) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2; 28 days after Dose 3 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Each of 5 immunocompromised cohorts, pooled 
immunocompromised cohorts, and 
immunocompetent cohort. 
Reference Cohort 
Not applicable 
• 
To characterize the immunogenicity after a third-dose booster vaccination of AZD1222, administered 
6 months after dose 1 of a 2-dose primary vaccination with AZD1222, in immunocompetent adults 
≥ 18 years. 
Estimand: 
Endpoints a 
1) SARS-CoV-2 specific titres 
2) Seroresponse of SARS-CoV-2 specific 
titres (≥ 4-fold rise in titres from 
baseline b) 
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 3 
Population 
Immunogenicity analysis set 
Cohort 
Immunocompetent cohort 
a  Immunogenicity endpoints will be analysed for both binding (anti-S) and pseudo-neutralization titres. 
b  Baseline is defined as the last collection prior to the first dose. 
AE = adverse event; AESI = adverse event of special interest; GMT = geometric mean titre; MAAE = medically 
attended adverse event; S = spike; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory 
syndrome-coronavirus-2  

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Overall Design: This study is a Phase IV, open-label, non-randomized, multi-cohort, 
multicenter study of the immunogenicity and safety of AZD1222 for the prevention of 
COVID-19 in previously unvaccinated immunocompromised adults ≥18 years. 
Immunocompromised participants will receive primary vaccination with 3 IM doses of 
AZD1222 separated by 4 weeks and will continue to be followed to the end of the study.  
Immunocompetent participants will receive a third dose booster 6 months after dose 1 and will 
continue to be followed to the end of the study.  
Disclosure Statement: This is an open-label preventive treatment study with 6 cohorts that is 
non-randomized. 
Number of Participants: Approximately 360 SARS-CoV-2 spike and nucleocapsid 
seronegative participants will be enrolled to support the primary and secondary objectives of 
this study. 
Intervention Groups and Duration: Participants will include adults ≥ 18 years with stable 
immunocompromising conditions, or on stable doses of immunocompromising therapeutics, 
and will be enrolled in the following 5 disease cohorts of approximately 60 participants each: 
(1) solid organ transplant; (2) hematopoietic stem cell transplant; (3) solid organ cancer 
patients receiving cytotoxic chemotherapy; (4) chronic inflammatory disorders; and (5) 
primary immunodeficiency. A sixth cohort of immunocompetent individuals will also be 
recruited.  Participants will be allocated to the immunocompromised cohorts according to the 
underlying aetiology of their immunocompromised status. 
Data Monitoring Committee: Not applicable. 
Statistical Methods: 
A sample size of 60 participants per cohort was determined mainly based on feasibility, with 
consideration for acceptable precision around the GMT and seroresponse rates for a single 
cohort.  For secondary analyses, assuming a common standard deviation on the natural log 
scale of 1.2 and a 2-sided α=0.05, a sample size of 60 per cohort gives 88.0%/63.8%/36.6% 
power (i.e., probability) to demonstrate that the observed GMT ratio is greater than 0.5/0.6/0.7 
when there is assumed to be no difference (GMT ratio =1).   
The analysis sets will be: 
• All participants analysis set (including all screened participants) 
• Full analysis set (including all enrolled participants) 
• Safety analysis set (including all participants who have received at least one dose of 
AZD1222) 
• Immunogenicity analysis set (including 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) 
 

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The primary analysis will occur when all participants within a cohort have completed visit 8 
(i.e., 28 days after the second dose; see Table 2 and Table 3). Secondary analyses of a third 
dose (primary series) will occur when all participants within an immunocompromised cohort 
have completed visit 10 (i.e., 28 days after the third dose; see Table 2).  The final analysis will 
occur when data from all vaccinated participants are available through completion of the last 
study visit (see Table 2 and Table 3). 
For the primary objective, without a prespecified directional hypothesis, 2-sided 95% 
confidence intervals will be calculated as descriptive measures for each immunogenicity 
endpoint.  Descriptive comparisons between groups will be included in secondary analyses. 
1.2 
Schema 
Figure 1  
Study Design for Immunocompromised Participants 
 
 
Figure 2  
Study Design for Immunocompetent Participants 
 
 

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1.3 
Schedule of Activities 
The Schedule of Activities are shown in Table 1, Table 2 and Table 3. 
Table 1 
Schedule of Activities: Screening 
Study Procedure 
Day -7 to Day 1a 
For Details See 
Section 
Informed consent 
X 
5.1, Appendix A 1 
Demography 
X 
- 
Medical and surgical history  
X 
- 
Prior and concomitant medications 
X 
6.5 
Complete physical examination 
X 
8.2.1 
Vital signs 
X 
8.2.2 
Urine pregnancy test (for women of childbearing potential only)  
X 
8.2.3 
HIV Testing (local laboratory) 
X 
- 
Clinical safety laboratory assessments 
X 
8.2.3 
Serious Adverse Events (SAEs) 
X 
8.3, Appendix B 
Assessment of SARS-CoV-2 infection b  
X 
8.2.4 
Test for antibody against SARS-CoV-2 (lateral flow test) 
X 
8.5.2 
Verify eligibility criteria 
X 
5.1, 5.2 
a   
Screening activities can occur up to 7 days prior to Visit 1. Screening activities can occur on the same day 
as initial vaccination (Day 1, see Table 2 and Table 3) only if laboratory results for HIV, urine 
pregnancy test, complete blood count, and SARS-CoV-2 assessments are obtained prior to 
vaccination. Vaccine administration cannot occur until screening safety lab results are available and 
verification of participant eligibility is confirmed. 
b 
Local assessment of SARS-CoV-2 infection should be conducted using a nucleic acid amplification test 
(e.g., RT-PCR) and is required prior to vaccine administration (Day 1, see Table 2 and Table 3) in order to 
confirm participant eligibility (Section 8.2.4).  
 

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Table 2 
Schedule of Activities: Vaccination/Follow-up Period for Immunocompromised Cohorts 
Study procedure 
Vaccination/Follow-up  
For Details 
see Section 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 a 
V9 
V10 
V11 
V12 b 
 
Timeline (days) 
1 
V1+7  
V1+14 
V1+21  
V1+28  
V5+7 
V5+14  
V5+28  
V8+7  
V8+28  
V1+ 
182  
V1+ 
364  
 
Time window (days) 
- 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 14 
± 30 
 
General Procedures 
Verify eligibility criteria 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
4.1.1, 5 
Medical and surgical 
history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Urine pregnancy test 
(WOCBP only) 
X c 
- 
- 
- 
X c 
- 
- 
X c 
- 
- 
- 
- 
8.2.3 
Prior/concomitant 
medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6.5 
Vaccine administration 
(after screening 
activities, the activities 
listed above, and the pre-
doses sampling activities 
listed below are 
completed) 
X 
- 
- 
- 
X 
- 
- 
X a  
- 
- 
- 
- 
6 
eDiary provided  
X 
- 
- 
- 
X 
- 
- 
X  
- 
- 
- 
- 
8.3.6.1 
eDiary with solicited 
AEs returned 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
- 
8.3.6.1 

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Table 2 
Schedule of Activities: Vaccination/Follow-up Period for Immunocompromised Cohorts 
Study procedure 
Vaccination/Follow-up  
For Details 
see Section 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 a 
V9 
V10 
V11 
V12 b 
 
Timeline (days) 
1 
V1+7  
V1+14 
V1+21  
V1+28  
V5+7 
V5+14  
V5+28  
V8+7  
V8+28  
V1+ 
182  
V1+ 
364  
 
Time window (days) 
- 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 14 
± 30 
 
Safety Assessments 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.2 
Targeted physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.1 
Unsolicited AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
8.3 
SAEs, AESIs and 
MAAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X b  
8.3, 
Appendix B 
Clinical safety laboratory 
assessments (local 
assessments) 
X c 
X 
X f 
X f 
X c 
X 
X f 
X c 
X 
X f 
- 
- 
8.2.3 
Serum sample for Anti-
PF4 ELISA  
X c 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Appendix D 
Immunogenicity Assessments 
Symptomatic assessment 
of SARS-CoV-2 
infection d    
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.4 
Serum sample for SARS-
CoV-2 serology/nAb 
assessments 
X c 
- 
X 
- 
X c 
- 
X 
X c 
- 
X 
X 
X 
8.5.2 

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Table 2 
Schedule of Activities: Vaccination/Follow-up Period for Immunocompromised Cohorts 
Study procedure 
Vaccination/Follow-up  
For Details 
see Section 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 a 
V9 
V10 
V11 
V12 b 
 
Timeline (days) 
1 
V1+7  
V1+14 
V1+21  
V1+28  
V5+7 
V5+14  
V5+28  
V8+7  
V8+28  
V1+ 
182  
V1+ 
364  
 
Time window (days) 
- 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 14 
± 30 
 
Serum sample for 
additional 
immunogenicity assays  
X c 
- 
X 
- 
X c  
- 
X 
X c 
- 
X 
X 
X 
8.5.2 
Blood sample for PBMC 
isolation (assessment of 
B-cell and T-cell 
responses) e 
X c 
- 
X 
- 
X c 
- 
X 
X c 
- 
X 
X 
- 
8.5.2.3 
Whole blood sample for 
BCR and TCR 
sequencing e 
X c 
- 
X 
- 
X c 
- 
X 
X c 
- 
X 
X 
- 
8.6 
Other Laboratory Assessments 
Serum for biomarker 
analyses 
X c 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
8.6.1.2 
Plasma for biomarker 
analyses 
X c 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
8.6.1.2 
Whole blood sample for 
targeted sequencing 
analyses 
X c 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
8.6.1.1 
a 
Immunocompromised participants will receive a third dose of AZD1222 (i.e., cohorts 1 through 5). Participants in cohorts 1 through 5 that complete V8 
prior to implementation of protocol amendment 3 will still be eligible to receive a third dose (primary series). In this case, a repeat V8 should be completed 
when the third dose is administered. V9 and V10 should be based on the date of the third dose visit (i.e., V9 is 7 days after V8, V10 is 28 days after V8).  If, 
the third dose is administered more than 28 days after visit 5, and outside the visit window due to regulatory authority and/or ethics committee approval 
timelines, no protocol deviation will be issued. 

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b  
The last study visit will be the later of the following dates: Day 365 or 6 months after the administration of the 3rd dose (primary series). SAEs, MAAEs and 
 
AESIs will be collected up to the last study visit. 
c  
These samples are collected pre-dose only. 
d  
Participants who become symptomatic after vaccine administration (i.e., during follow-up through last study visit) should be assessed for COVID-19 
infection as defined in Section 8.2.4.  
e 
These samples are to be collected for the first 15 participants in each cohort, at a minimum, and oversampling is allowed to achieve 15 evaluable 
 
participants in each cohort and balance in samples across groups. 
f 
Only the hematology/hemostasis assessments (i.e., complete blood count) will be performed at these visits (Section 8.2.3). 
AE = adverse event; AESI = adverse event of special interest; BCR = B-cell receptor; ELISA = enzyme-linked immunosorbent assay; MAAE = medically 
attended adverse events; nAb = neutralizing antibody; PBMC = peripheral blood mononuclear cell; PF4 = platelet factor 4; RT-PCR = reverse transcriptase 
polymerase chain reaction; SAE = serious adverse event; SARS-CoV-2 =severe acute respiratory syndrome-coronavirus-2; TCR = T-cell receptor; WOCBP = 
women of childbearing potential 
 
 

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Table 3 
Schedule of Activities: Vaccination/Follow-up Period for Immunocompetent Participants 
Study procedure 
Vaccination/Follow-up 
For Details 
see Section 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8  
V9 a 
V10 
V11 
 
Timeline (days) 
1 
V1+7 
V1+14 
V1+21 
V1+28 
V5+7 
V5+14 
V5+28 
V1+182 
V9+28 
V1+364 
 
Time window (days) 
- 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 30 
 
General Procedures 
Verify eligibility criteria 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
4.1.1, 5 
Medical and surgical history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Urine pregnancy test (WOCBP 
only) 
X b 
- 
- 
- 
X b 
- 
- 
- 
X b 
- 
- 
8.2.3 
Prior/concomitant 
medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6.5 
Vaccine administration (after 
screening activities, the 
activities listed above, and the 
pre-doses sampling activities 
listed below are completed) 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
6 
eDiary provided  
X 
- 
- 
- 
X 
- 
- 
 - 
X 
- 
- 
8.3.6.1 
eDiary with solicited AEs 
returned f 
- 
X 
- 
- 
- 
X 
- 
- 
- 
- 
- 
8.3.6.1 
Safety Assessments 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.2 
Targeted physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.1 
Unsolicited AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
8.3 
SAEs, AESIs and MAAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.3, 
Appendix B 

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Table 3 
Schedule of Activities: Vaccination/Follow-up Period for Immunocompetent Participants 
Study procedure 
Vaccination/Follow-up 
For Details 
see Section 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8  
V9 a 
V10 
V11 
 
Timeline (days) 
1 
V1+7 
V1+14 
V1+21 
V1+28 
V5+7 
V5+14 
V5+28 
V1+182 
V9+28 
V1+364 
 
Time window (days) 
- 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 30 
 
Clinical safety laboratory 
assessments (local 
assessments) 
X b 
X 
X e 
X e 
X b 
X 
X e 
X e 
- 
- 
- 
8.2.3 
Serum sample for Anti-PF4 
ELISA  
X b 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Appendix D 
Symptomatic assessment of 
SARS-CoV-2 infection c    
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.4 
Serum sample for SARS-CoV-
2 serology/nAb assessments 
X b 
- 
X 
- 
X b 
- 
X 
X 
X b 
X 
X 
8.5.2 
Serum sample for additional 
immunogenicity assays  
X b 
- 
X 
- 
X b  
- 
X 
X 
X b 
X 
X 
8.5.2 
Blood sample for PBMC 
isolation (assessment of B-cell 
and T-cell responses) d 
X b 
- 
X 
- 
X b 
- 
X 
X 
X b 
X 
X 
8.5.2.3 
Whole blood sample for BCR 
and TCR sequencing d 
X b 
- 
X 
- 
X b 
- 
X 
X 
X b 
X 
X 
8.6 
Other Laboratory Assessments 
Serum for biomarker analyses 
X b 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
8.6.1.2 
Plasma for biomarker analyses 
X b 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
8.6.1.2 
Whole blood sample for 
targeted sequencing analyses 
X b 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
8.6.1.1 

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a 
Immunocompetent participants (ie, cohort 6) will receive a third dose booster of AZD1222 6 months after Dose 1. Participants in this cohort that complete 
V9 prior to implementation of protocol amendment 3 will still be eligible to receive a third dose booster. In this case, a repeat V9 should be completed when 
the third dose booster is administered. V10 should be based on the date of the third dose visit (i.e., V10 is 28 days after V9). If the third dose is administered 
more than 6 months after V1, (ie, outside the visit window) due to regulatory authority and/or ethics committee approval timelines, no protocol deviation 
will be issued. 
b 
These samples are collected pre-dose only. 
c  
Participants who become symptomatic after vaccine administration (ie, during follow-up through Day 365) should be assessed for COVID-19 infection as 
defined in Section 8.2.4.  
d 
These samples are to be collected for the first 15 participants in each cohort, at a minimum, and oversampling is allowed to achieve 15 evaluable 
 
participants in each cohort and balance in samples across groups. 
e 
Only the hematology/hemostasis assessments (i.e., complete blood count) will be performed at these visits (Section 8.2.3)  
f 
eDiary provided at V9 to be returned with solicited AEs at V9 + 7 days. 
AE = adverse event; AESI = adverse event of special interest; BCR = B-cell receptor; ELISA = enzyme-linked immunosorbent assay; MAAE = medically 
attended adverse events; nAb = neutralizing antibody; PBMC = peripheral blood mononuclear cell; PF4 = platelet factor 4; RT-PCR = reverse transcriptase 
polymerase chain reaction; SAE = serious adverse event; SARS-CoV-2 =severe acute respiratory syndrome-coronavirus-2; TCR = T-cell receptor; WOCBP = 
women of childbearing potential 
 

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2 
INTRODUCTION 
2.1 
Study Rationale 
AZD1222 has been developed to address a public health need for vaccines that can prevent 
COVID-19. AZD1222 is a recombinant replication-defective chimpanzee adenovirus 
expressing the SARS-CoV-2 spike (S) surface glycoprotein driven by the human 
cytomegalovirus major immediate early promoter that includes intron A with a human tissue 
plasminogen activator leader sequence at the N terminus. Worldwide efforts to develop 
effective vaccines against SARS-CoV-2 are ongoing, with several vaccines approved and 
others currently in clinical development. Given the extent and continued rapid pace of 
infection, severity of the pandemic’s medical and socioeconomic impact, and the supply 
challenges associated with a global vaccination program, multiple vaccines are needed that 
can be offered to individuals regardless of underlying conditions. 
AZD1222 was granted temporary authorization for the active immunization of individuals 
aged ≥ 18 years for the prevention of COVID-19 in the UK on 29 December 2020 and in the 
EU on 29 January 2021. Currently, AZD1222 has been authorized under conditional 
marketing authorizations or emergency use provisions in more than 90 countries and is listed 
for emergency use by the World Health Organization. As of 31 March 2021, the cumulative 
global post-marketing patient exposure (by doses distributed) to AZD1222 has been estimated 
to be approximately 500,000,000 doses. 
Clinical studies supporting the emergency use authorizations of AZD1222 have, to date, 
generally excluded participants with significantly compromised immune systems. While the 
WHO and CDC recommend vaccination of immunocompromised individuals (CDC 2021, 
WHO 2021), a recent preprint article investigating BNT162b2 (the Pfizer COVID-19 vaccine) 
in kidney transplant patients on immunosuppressive medication showed low rates of 
seroresponse and humoral response (Sattler et al 2021). In addition, during post-authorization 
use, very rare events of serious thrombosis in combination with thrombocytopenia (including 
fatal events), have been observed following vaccination with AZD1222 (Greinacher et al 
2021, Schultz et al 2021). 
The aim of this study is to assess the immunogenicity (including both humoral and cellular 
mediated immunogenicity) and safety of AZD1222 for prevention of COVID-19 as a 3-dose 
primary vaccination series in previously unvaccinated immunocompromised adult 
participants. Immunocompetent participants will be eligible to receive a third dose booster 6 
months after dose 1. Data are urgently needed in immunocompromised individuals as 
effective COVID-19 prevention would have significant impact on mortality in these patients, 
who are often multi-morbid. 

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2.2 
Background 
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, which was named Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) (Zhou et al 2020).  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).  The disease these patients contracted was 
subsequently named Coronavirus Disease 2019 (COVID-19).  COVID-19 is the infectious 
disease caused by SARS-CoV-2. The World Health Organization declared the novel 
coronavirus a pandemic on 11 March 2020.  The COVID-19 pandemic, caused by the novel 
coronavirus SARS-CoV-2, has resulted in significant global morbidity and mortality as well 
as major disruption to healthcare systems.  Measures to change the course of the pandemic 
have included the accelerated development of vaccines against the original Wuhan-Hu-1 
strain. 
Coronaviruses are spherical, enveloped viruses with positive-sense single-stranded RNA 
genomes. SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus, 
and it is the seventh coronavirus known to cause human infections and the third known to 
cause severe disease after SARS-CoV and MERS-CoV. One fourth of the viral genome is 
responsible for coding structural proteins, such as the S glycoprotein, envelope, membrane, 
and nucleocapsid proteins.  Envelope, membrane, and nucleocapsid proteins are mainly 
responsible for virion assembly while the S protein is involved in cellular receptor binding, 
mediating fusion of virus and cell membranes and virus entry into host cells during infection.  
The SARS-CoV-2 S glycoprotein is a type I trimeric, transmembrane protein that is located at 
the surface of the viral envelope forming spike-shaped protrusions.  The S protein’s subunits 
are responsible for cellular receptor angiotensin-converting enzyme 2 binding via the receptor 
binding domain and subsequent fusion of virus and cell membranes, thereby mediating the 
entry of SARS-CoV-2 into the target cells.  The S protein has an essential role in virus entry 
and determines tissue and cell tropism, as well as host range.  The roles of the S protein in 
receptor binding and membrane fusion have made it a desirable target for vaccine and 
antiviral development.  The AstraZeneca vaccine AZD1222 expresses a codon-optimized 
coding sequence for S protein from the SARS-CoV-2 genome sequence accession MN908947 
(i.e., the Wuhan-Hu-1 isolate). 
To date, 5 vaccines that rely upon the expression of the SARS-CoV-2 S glycoprotein to 
stimulate/prime a protective immune response against the virus have demonstrated safety and 
efficacy in phase III clinical trials.  Four of these, AZD1222 (also referred to as ChAdOx1 
nCoV-19, a recombinant replication-defective chimpanzee adenoviral vectored), BNT162b2 
(Pfizer-BioNTech, mRNA), mRNA-1273 (Moderna, mRNA), and Ad26.COV2-S (Janssen, 
adenovirus serotype 26 vectored) have received Emergency Use Authorization or Conditional 
Marketing Approval in the United States and/or the European Union, and elsewhere, and 

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NVX-CoV2373 (Novavax; recombinant 86 protein) has also shown efficacy and is likely to be 
in use in the near future.  These vaccines have been designed based upon the initial reported 
genetic sequence of the S protein from Wuhan in January 2020 (Lu et al 2020). 
AZD1222 was 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 tissue plasminogen activator leader sequence at the 
N terminus. The clinical development program for intramuscular AZD1222 in adults currently 
includes 7 ongoing studies being conducted in: the UK (FIH COV001 [NCT04324606] and 
COV002 [NCT04400838]); Brazil (COV003 [ISRCTN89951424]); Kenya (COV004 
[PACTR202005681895696]); South Africa (COV005 [NCT04444674]); the US and Latin 
America (D8110C00001); and Japan (D8111C00002). Primary pooled efficacy analysis data 
from each of these studies, except for the US and Latin America and the Kenya studies, have 
supported the approval of AZD1222 by several health authorities.  
The immunogenicity and efficacy of AZD1222 has been shown in clinical trials (Ramasamy 
et al 2020, Voysey et al 2021a, Voysey et al 2021b). Available immunogenicity data indicate 
that a single dose of AZD1222 elicits both humoral and cellular immunogenicity responses 
and that antibody responses are boosted after a second dose. In a pooled analysis of the 4 
COV studies conducted in the UK, Brazil, and South Africa (DCO2 database lock 07 
December 2020), the vaccine was highly immunogenic; seroresponse of S binding antibody 
was > 98% after a single dose of AZD1222. Seroresponse of live neutralizing antibody was 
82.4% after 1 dose, which rose to 99.4% after a second dose. Immunogenicity data from the 
Japanese study were similar to those from the pooled COV studies. 
Efficacy analyses of the pooled COV study data demonstrated effective protection of 
AZD1222 against COVID-19 with a vaccine efficacy of 66.7% (95.84% CI: 57.4%, 74.0%) 
(p < 0.001) from 15 days after the second dose in seronegative participants receiving 2 doses. 
The COV study data also demonstrated that AZD1222 (5 x 1010 viral particles) provides 
complete protection against COVID-19 hospital admission ≥ 22 days after the first dose in the 
seronegative analysis set (0 vs 14 cases in the control group, 2 of which were severe, 
including one with a fatal outcome). Vaccine efficacy was similar in participants with pre-
existing comorbidities, being those at greatest risk of severe outcomes of COVID-19, 
compared to that in the general population. Recently available primary analysis data from the 
US and Latin America study (D8110C00001) showed primary endpoint vaccine efficacy of 
76.0% (95% CI: 67.6%, 82.2%; p-value < 0.001) (AstraZeneca 2021). 
See the AZD1222 Investigator’s Brochure, Sections 4 and 5 for additional information on 
nonclinical and clinical studies, respectively, of AZD1222 and related ChAdOx1-vectored 

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vaccines. Detail on the development and chemistry of AZD1222 is provided in the IB, Section 
3. 
The safety profile of AZD1222 in clinical trials indicate that it is well tolerated. Data from the 
pooled clinical studies have shown that the majority of solicited local and systemic adverse 
reactions were mild to moderate in severity and resolved within 1 to 7 days. The most 
commonly reported local, solicited AEs were vaccination site tenderness and pain. The most 
commonly reported systemic solicited AEs were fatigue, headache, malaise and myalgia. A 
summary of the key risks for AZD1222 is presented in Section 2.3.1, and additional safety 
information is detailed in AZD1222 IB Section 5.1. 
Overall, the data from the clinical and nonclinical studies of AZD1222, and the acceptable 
safety and efficacy profile, support further exploration of AZD1222 in other populations. The 
purpose of this Phase IV, open-label, non-randomized, multi-cohort, multicenter study is to 
demonstrate the safety and immunogenicity of AZD1222 when administered as a 3-dose 
homologous primary vaccination series in previously unvaccinated immunocompromised adult 
participants. Immunocompetent participants will be eligible to receive a third dose booster 6 
months after dose 1. 
Immunocompromised patients, including cancer patients on chemotherapy, recipients of 
hematopoietic stem-cell transplantation, and patients with primary immunodeficiency, appear to 
have a higher risk of mortality due to COVID-19 complications than the general population 
(Kuderer et al 2020, Lee et al 2020, Robilotti et al 2020, Sharma et al 2021, 
Shields et al 2020). In addition, since immunosuppressed patients may be sources of prolonged 
viral shedding and development of variants (Aydillo et al 2020, McCarthy et al 2021), effective 
vaccination of these vulnerable patients may provide an additional societal benefit. 
Clinical studies supporting emergency use authorizations of COVID-19 vaccines have, to date, 
generally excluded participants with significantly compromised immune systems. Antibody 
responses to vaccines are generally lower in immunocompromised patients, including those on 
chemotherapy, hematopoietic stem cell transplantation recipients, and patients with primary 
immunodeficiencies (Righi et al 2021). The timing of vaccination relative to 
immunosuppressive treatments, for example, may also play a role 
(Righi et al 2021). 
Recently, an analysis was published of humoral and cellular responses in kidney transplant 
patients following vaccination with BNT162b2, with the abstract noting (Sattler et al 2021): 
“As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4/39 
and 1/39 transplanted individuals showed IgA and IgG seroresponse at day 8 ± 1 after 
booster immunization with minor changes until day 23 ± 5, respectively. Although most 
transplanted patients mounted spike-specific T helper cell responses, frequencies were 

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significantly reduced compared to controls and dialysis patients, accompanied by a broad 
impairment in effector cytokine production, memory differentiation and activation-related 
signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ 
counterparts in healthy controls and hemodialysis patients and almost undetectable in 
transplant patients. Signs of alloreactivity promoted by BNT162b2 were not documented 
within the observation period. In summary, our data strongly suggest revised vaccination 
approaches in immunosuppressed patients, including individual immune monitoring for 
protection of this vulnerable group at risk to develop severe COVID-19.” 
Despite the lack of data on the effectiveness of COVID-19 vaccines in immunocompromised 
patients, treatment guidelines recommend COVID-19 vaccination in this population       
(Desai et al 2021, CDC 2021, MSK 2021). Results from the Cov-Boost trial demonstrated 
that a third dose booster of AZD1222 increased immunity after either mRNA or AZD1222 
vaccine administration (Munro et al 2021). Additional data suggests that the efficacy after a 
third dose in immunocompromised participants ranges from 22 – 89% (Del Bello et al 2021, 
Kamar et al 2021, Karaba et al 2021). As well, certain medication may depress the 
immunoresponse further, as preliminary data from the OCTAVE study suggest that 72% of 
patients receiving rituximab fail to mount an antibody response to the spike protein       
(Kamar et al 2021, Karaba et al 2021, Kearns et al 2021). The common factors associated 
with the low seroresponse reported for some of the studies include degree of 
immunosuppression and age. Dosing intervals for these studies ranged from 4 – 28 weeks and 
the efficacy endpoints measurements varied according to the study.  
These data add to the growing body of evidence that support the use of a third dose booster 
with AZD1222 as part of a homologous or heterologous schedule and confirm its acceptable 
safety profile. Accordingly, there is an unmet medical need to determine whether AZD1222 
provides immunocompromised populations at high risk of COVID-19-related mortality with 
adequate protection against COVID-19. 
There are a variety of conditions leading to, and immunosuppressive or immunomodulating 
therapies contributing to, an immunocompromised/immunosuppressed state. This study will 
include participants representing 5 cohorts of immunocompromised patients, as well as an 
immunocompetent cohort, to broadly reflect the range of underlying conditions and therapies. 
For further details on the rationales for the selections of these specific cohorts, see 
Section 4.2.1. Note that information on the risk of thromboembolic events in each cohort is 
included below due to the recent changes to the AZD1222 prescribing information in respect 
of thromboembolic events and thrombocytopenia. 

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The 5 cohorts included in this study are the following: 
1.
Solid Organ Transplant
Solid organ transplant patients often receive lifelong immunosuppression therapies such as
calcineurin inhibitors, antiproliferative/antimetabolites and corticosteroids. Vaccine efficacy
in such patients appears to be vaccine- and timing-specific (Duchini et al 2003). In a study of
immunogenicity after the first dose of mRNA COVID-19 vaccines among solid organ
transplant recipients, the majority of participants did not mount appreciable anti-spike
antibody responses after a median of 20 days following the first dose (anti-S1 or anti–
receptor-binding domain antibodies were detectable in 76 of 436 participants: 17%; 95% CI,
14%-21%) (Boyarsky et al 2021).
The risk of thromboembolic events is increased in solid organ transplant patients, most 
particularly in the period immediately following transplant (Alvarez-Alvarez et al 2015, 
Kainuma et al 2021, Kahan et al 2007). 
Preliminary results from immunogenicity responses in kidney transplant recipients in the 
OCTAVE study show that Anti-S was detected in 61.8% patients. The results also showed 
that seroconversion in study participants was associated with vaccination occurring more than 
1 year after transplantation, the use of calcineurin inhibitor treatment (ie, monotherapy), and 
receiving BNT162b2 (Prendecki et al 2021). 
2.
Hematopoietic Stem Cell Transplant
A hematopoietic stem cell transplant results in immunosuppression because of the
hematopoietic ablative therapy administered before the transplant, drugs used to prevent or
treat graft-versus-host disease, and in some cases, from the underlying disease process
necessitating transplantation (Tomblyn et al 2009). Inactivated vaccines are generally
recommended to be administered at least 3 to 6 months (depending on the vaccine) after the
transplant to improve antibody response (Ljungman et al 2009, AAP 2009, Desai et al 2021).
The risk of thromboembolic events is increased following hematopoietic stem-cell 
transplantation, most particularly in allogenic transplant patients, and the risk does not appear 
to decrease over time. Microangiopathic hemolytic anaemia is common in allogenic transplant 
patients in the weeks immediately after transplant (Munro et al 2021, Pihusch et al 2002, 
Zahid et al 2016).  
3.
Solid Organ Cancer Patients Receiving Cytotoxic Chemotherapy
Vaccination during cytotoxic chemotherapy is not recommended due to the suppressed
immune system response. An exception is inactivated influenza vaccine. The recommended
waiting period between cessation of therapy and administration of a vaccine is dependent on
both the type of therapy and type of vaccine. For instance, the recommendation for patients on

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chemotherapy with anti-B cell antibodies is 6 months or longer after cessation of therapy 
before being vaccinated with inactivated vaccines (Rubin et al 2014). 
Cancer-associated thrombosis is a major cause of mortality in cancer patients. Cancer cells are 
capable of activating the coagulation cascade and other prothrombotic properties of host cells, 
and chemotherapy and immobilisation contribute to the increased risk (Abdol Razak et al 
2018). 
4.
Chronic Inflammatory Disorders
Corticosteroids are commonly used in inflammatory disorders, including rheumatoid arthritis,
inflammatory bowel disease, lupus, and asthma. Low to moderate chronic use of
corticosteroids does not impact the efficacy of inactivated influenza vaccine (see Section 6.5).
For high-dose corticosteroids and corticosteroid injection, which may reduce the immune
response to vaccines, vaccination is recommended to occur 2 weeks before, or 1 week after,
the injection/high-dose administration (CDC 1993).
The risk of thromboembolic events is increased in users of corticosteroids (Johannesdottir et al 
2013, Lieber et al 2016) and in patients in inflammatory disorders, irrespective of treatment 
(Del Bello et al 2021, Desai et al 2017).  
5.
Primary Immunodeficiency
Primary immunodeficiencies include congenital immunodeficiency diseases such as X-linked
agammaglobulinemia, severe combined immunodeficiency, and chronic granulomatous
disease. The most common group of primary immunodeficiencies is primary antibody
deficiencies. Antibody response to vaccination may be reduced or absent in patients with
primary immunodeficiency (Sobh and Bonilla 2016).
Patients with primary immunodeficiencies (in particular those treated with immunoglobulins) 
are at increased risk of thrombotic events (Kamar et al 2021, Karaba et al 2021, Kearns et al 
2021, Kimmig and Palevsky 2016, Ramirez et al 2014). 
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. 
2.3.1 
Risk Assessment 
The available safety profile of AZD1222 indicate that it is safe and well tolerated. A summary 
of safety events is presented below with additional information presented in AZD1222 IB 
section 5.1. 

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Data from the pooled clinical studies indicates the majority of adverse reactions were mild to 
moderate in severity and resolved within 1 to 7 days. The most commonly reported local, 
solicited AEs were vaccination site pain and tenderness. The most commonly reported 
systemic solicited AEs were fatigue, headache, malaise, and myalgia.  
Post-authorization hypersensitivity reactions, including anaphylaxis and angioedema, have 
occurred following administration of AZD1222 and are considered an identified risk. In 
addition, during post-authorization use a very rare event of thrombosis in combination with 
thrombocytopenia, along with bleeding in some cases, have been observed following 
vaccination with AZD1222 (Greinacher et al 2021, Schultz et al 2021). The majority of the 
events occurred within the first 4 – 21 days following vaccination. The mechanism by which 
AZD1222 may be associated with thromboembolic events or thrombocytopenia is unknown. 
Several hypothetical biologic mechanisms (e.g., vaccine induction of platelet factor 4 
autoantibodies) have been proposed to explain the pathophysiology of thromboembolic events 
or thrombocytopenia following vaccination, however none of these hypotheses have been 
verified. Table 4 is a summary of risks considered relevant to the assessment of the overall 
benefit-risk associated with vaccination of immunocompromised patients with AZD1222.  
Table 4 
Risk Assessment 
Potential risk of clinical 
significance 
Summary of data/ 
rationale for risk 
Mitigation strategy 
Identified risks with AZD1222 
Hypersensitivity reactions 
Post-authorization 
hypersensitivity reactions, 
including anaphylaxis and 
angioedema, have occurred 
following administration of 
AZD1222 and are considered an 
identified risk. 
Study participants are to be 
closely monitored after 
administration of AZD1222. 
Participants will be excluded if 
they have a history of allergy to 
any component of the vaccine 
(Section 5.2). 

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Table 4 
Risk Assessment 
Potential risk of clinical 
significance 
Summary of data/ 
rationale for risk 
Mitigation strategy 
Thrombosis in combination with 
thrombocytopenia  
During post-authorization use, 
very rare events of serious 
thrombosis concurrent with 
thrombocytopenia (including fatal 
events), have been observed 
following vaccination with 
AZD1222 (Section 2.2). 
Investigators will be instructed to 
be alert to the signs and symptoms 
of thromboembolism and 
thrombocytopenia, as well as 
coagulopathies. Vaccinated 
participants will be instructed to 
seek immediate medical attention 
if they develop symptoms such as 
severe or persistent headaches, 
blurred vision, shortness of breath, 
chest pain, leg swelling, persistent 
abdominal pain or unusual skin 
bruising, and/or petechiae a few 
days after vaccination 
(Appendix D). Participants with 
CVST will also be excluded. 
Study-specific risks in immunocompromised participants in this trial 
Venous thromboembolism 
Each of the 5 cohorts of 
immunocompromised patients 
being studied are at an increased 
risk of thrombotic events, 
including in particular venous 
thromboembolism 
Investigators will be instructed to 
be alert to the signs and symptoms 
of venous thromboembolism. 
Vaccinated participants will be 
instructed to seek immediate 
medical attention if they develop 
symptoms such as shortness of 
breath, chest pain, or leg swelling. 
Thrombocytopenia 
Each of the 5 cohorts of 
immunocompromised patients 
being studied are at an increased 
risk of thrombocytopenia 
Participants will be excluded if 
they have thrombocytopenia with 
platelet count ≤ 75,000 x 
109/microliter at screening 
(Section 5.2). Investigators will be 
instructed to be alert to signs and 
symptoms of thrombocytopenia 
such as unusual skin bruising or 
petechiae. 
Infection 
Immunocompromised patients are 
at increased risk of infection 
Participants will be excluded if 
they have significant infection or 
other acute illness at screening 
(Section 5.2). 
Important potential risks with AZD1222 are: 1) cerebrovascular venous and sinus thrombosis 
without thrombocytopenia (Section 8.3.8.1), 2) neurologic events and potential 

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immune-mediated neurologic conditions (see Section 8.3.8.2), and 3) vaccine-associated 
enhanced disease, including vaccine-associated enhanced respiratory disease (Section 8.3.8.3). 
Further information on the potential risks and safety information reported across the 
AZD1222 clinical studies are included in the AZD 1222 IB.  
2.3.2 
Benefit Assessment 
Clinical and real-world studies demonstrate that AZD1222 is efficacious in the general 
population and offers recipients protection from COVID-19. There is a high unmet need for a 
COVID-19 vaccine in immunocompromised individuals, as this population often has multiple 
morbidities and significant mortality risk from COVID-19. While a benefit is not guaranteed, 
as protection from COVID-19 may be reduced in immunocompromised recipients, individual 
participants may obtain protection from COVID-19. Further, information gained from this 
study could inform the use of AZD1222 or other COVID-19 vaccines in this population. 
2.3.3 
Overall Benefit: Risk Conclusion 
For the safety of participants, this protocol incorporates various risk mitigation measures 
including appropriate inclusion and exclusion criteria, close monitoring of participants, and 
stopping criteria.  
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 describes the objectives and endpoints of this study. 
Table 5 
Study Objectives and Endpoints 
Primary Immunogenicity Objective 
•
To characterize the immunogenicity of a 2-dose primary vaccination with AZD1222 with a 4-week
dosing interval in SARS-CoV-2 naïve immunocompromised adults and immunocompetent adults ≥ 18
years.
Estimand: 
Endpoints a 
1)
SARS-CoV-2 specific titres
2)
Seroresponse of SARS-CoV-2 specific
titres (≥ 4-fold rise in titres from
baseline b)
Serotype 
Wuhan-Hu-1 
Timepoints 
28 days after Dose 1; 28 days after Dose 2 
Population 
Immunogenicity analysis set 
Cohort 
Each of 5 immunocompromised cohorts, pooled 
immunocompromised cohorts, and 
immunocompetent cohort 

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Table 5 
Study Objectives and Endpoints 
Secondary Safety Objective 
Objective 
Endpoints 
•
To characterize the reactogenicity and safety of a
3-dose primary vaccination series with AZD1222
with a 4-week dosing interval in SARS-CoV-2
naïve immunocompromised adults ≥ 18 years.
•
Reactogenicity: Incidence of local and
systemic solicited AEs for 7 days after
each dose of AZD1222 by eDiary.
•
Incidence of unsolicited AEs for 28 days
post dose after each vaccination
•
Incidence of SAEs, MAAEs and AESIs
from Day 1 post treatment to the last study
visit.
•
Absolute and change from baseline b for
safety laboratory measures.
Secondary Immunogenicity Objectives 
•
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years
with a 4-week dosing interval between SARS-CoV-2 naïve participants with solid organ transplant
compared to immunocompetent participants.
Estimand: 
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
rise in titres from baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Solid organ transplant 
Reference Cohort 
Immunocompetent 
•
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years
with a 4-week dosing interval between SARS-CoV-2 naïve participants with hematopoietic stem cell
transplant compared to immunocompetent participants.
Estimand: 
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
rise in titres from baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Hematopoietic stem cell transplant 
Reference Cohort 
Immunocompetent 
•
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years
with a 4-week dosing interval between SARS-CoV-2 naïve participants with solid organ cancer
patients receiving cytotoxic chemotherapy compared to immunocompetent participants.
Estimand: 

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Table 5 
Study Objectives and Endpoints 
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
rise in titres from baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Solid organ cancer patients receiving cytotoxic 
chemotherapy 
Reference Cohort 
Immunocompetent 
•
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years
with a 4-week dosing interval between SARS-CoV-2 naïve participants with chronic inflammatory
disorders compared to immunocompetent participants.
Estimand: 
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
rise in titres from baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Chronic inflammatory disorders 
Reference Cohort 
Immunocompetent 
•
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years
with a 4-week dosing interval between SARS-CoV-2 naïve participants with primary
immunodeficiency compared to immunocompetent participants.
Estimand: 
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
rise in titres from baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Primary immunodeficiency 
Reference Cohort 
Immunocompetent 
•
To describe the immunogenicity of a 2-dose primary vaccination with AZD1222 in adults ≥ 18 years
with a 4-week dosing interval between SARS-CoV-2 naïve participants with any
immunocompromised condition compared to immunocompetent participants.
Estimand: 

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Table 5 
Study Objectives and Endpoints 
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
rise in titres from baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 2 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Pooled immunocompromised 
Reference Cohort 
Immunocompetent 
•
To characterize the immunogenicity after a 3rd-dose in a 3 dose primary vaccination series with
AZD1222 in immunocompromised adults ≥ 18 years.
Estimand: 
Endpoints a 
1)
SARS-CoV-2 specific titres
2)
Seroresponse of SARS-CoV-2 specific
titres (≥ 4-fold rise in titres from
baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after the Dose 3 
Population 
Immunogenicity analysis set 
Cohort 
Each of 5 immunocompromised cohorts and 
pooled immunocompromised cohorts 
•
To describe the immunogenicity after the 3rd dose in a 3-dose primary vaccination series with
AZD1222 in adults ≥ 18 years between SARS-CoV-2 naïve immunocompromised participants
compared to immunocompetent participants after a 2-dose primary vaccination.
Estimand: 
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
rise in titres from baseline b)
Serotype 
Wuhan-Hu-1 
Timepoint 
28 days after Dose 3 (28 Days after Dose 2 for 
reference cohort) 
Population 
Immunogenicity analysis set 
Comparator Cohort 
Each of 5 immunocompromised cohorts and 
pooled immunocompromised cohorts 
Reference Cohort 
Immunocompetent 
•
To describe the immunogenicity of the AZD1222 vaccination between 28 days post second dose
compared to 28 days post third dose, in adults ≥ 18 years between SARS-CoV-2 naïve
immunocompromised and immunocompetent participants.
Endpoints a 
1)
Ratio of SARS-CoV-2 specific GMT
titres.

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Table 5 
Study Objectives and Endpoints 
2)
Difference in seroresponse rates of
SARS-CoV-2 specific titres (≥ 4-fold
increase in titres from 28 days post
dose 2 to 28 days post dose 3).
Serotype 
Wuhan-Hu-1. 
Timepoint 
28 days after Dose 2; 28 days after Dose 3. 
Population 
Immunogenicity analysis set. 
Comparator Cohort 
Each of 5 immunocompromised cohorts, pooled 
immunocompromised cohorts, and 
immunocompetent cohort. 
Reference Cohort 
Not applicable. 
•
To characterize the immunogenicity after a third dose booster vaccination of AZD1222, administered
6 months after dose 1 of a 2-dose primary vaccination with AZD1222, in immunocompetent adults
≥ 18 years.
Estimand: 
Endpoints a 
1)
SARS-CoV-2 specific titres.
2)
Seroresponse of SARS-CoV-2 specific
titres (≥ 4-fold rise in titres from
baseline b).
Serotype 
Wuhan-Hu-1. 
Timepoint 
28 days after Dose 3. 
Population 
Immunogenicity analysis set. 
Cohort 
Immunocompetent cohort. 
Exploratory Objectives 
Objective 
Endpoints 
•
To monitor the occurrence of COVID-19 in
immunocompromised adults ≥ 18 years that have
received 2 doses of AZD1222.
•
To further describe humoral and cell mediated
responses to AZD1222 following administration of
AZD1222 in immunocompromised adults
≥ 18 years of age.
•
To explore underlying mechanisms should any
thromboembolic events occur.
•
To explore correlations between anti-S, pseudo-
neutralization, and ChAdOx1 nAb antibody titres.
•
Virologically confirmed (RT-PCR
positive) symptomatic cases of COVID-
19.
•
Hospital/ICU admissions and deaths
associated with COVID-19.
•
Seroresponse against non-Spike
(nucleocapsid) SARS-CoV-2 antigen.
•
Intracellular cytokine staining and flow
cytometry for T-cell responses over time.
•
Breadth and depth of BCR and TCR
repertoire through immunosequencing
over time.
•
Magnitude of ChAdOx1 nAbs over time
(GMTs/GMFRs, Seroresponse rate).
•
Magnitude of SARS-CoV-2 specific
binding (anti-RBD) responses
(GMT/GMFR/Seroresponse) over time.
•
Other exploratory assays for humoral and
cellular immune responses based upon
emerging safety, efficacy, and
immunogenicity data.

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Table 5 
Study Objectives and Endpoints 
•
In the case of thrombosis in combination 
with thrombocytopenia, a series of 
additional in-depth investigations will be 
performed (Appendix D).
•
Pairwise correlations between anti-S, 
pseudo-neutralization, and ChAdOx1 nAb 
antibody titres, 28 days after Dose 1 and 
28 days after Dose 2.
a Immunogenicity endpoints will be analyzed for both binding (anti-S) and pseudo-neutralization titres. 
b Baseline is defined as the last collection prior to the first dose. 
AE = adverse event; AESI = adverse event of special interest; BCR = B-cell receptor; COVID-19 = coronavirus 
disease 2019; GMFR = geometric mean fold rise; GMT = geometric mean titre; IM = intramuscular; MAAE = 
medically attended adverse event; RBD = receptor binding domain; RT-PCR = reverse transcriptase polymerase 
chain reaction; S = spike; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome-
coronavirus-2; TCR = T-cell receptor 
4 
STUDY DESIGN 
4.1 
Overall Design 
This study is a Phase IV, open-label, non-randomized, multi-cohort, multicenter study of the 
immunogenicity and safety of AZD1222 for the prevention of COVID-19 in previously 
unvaccinated immunocompromised adults ≥ 18 years. Immunocompromised participants will 
receive a primary vaccination series with 3 IM doses of AZD1222 separated by 4 weeks and 
will be followed to the end of the study. Immunocompetent participants will receive a third 
dose booster 6 months after dose 1 and will continue to be followed to the end of the study. 
A total of approximately 360 SARS-CoV-2 nucleocapsid seronegative participants that have 
been screened and judged to be eligible for the study will be enrolled. The study will include 
adults ≥ 18 years with stable immunocompromising conditions or on stable doses of 
immunocompromising therapeutics, enrolled in 5 disease cohorts of approximately 60 
participants each:  
1. Solid organ transplant
2. Hematopoietic stem cell transplant
3. Solid organ cancer patients receiving cytotoxic chemotherapy
4. Chronic inflammatory disorders
5. Primary immunodeficiency
A sixth cohort of immunocompetent individuals will also be recruited. Participants will be 
allocated to the immunocompromised cohorts according to the underlying aetiology of their 
immunocompromised status (Section 5.1.2). The Sponsor will monitor recruitment status 

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across all cohorts (including the immunocompetent cohort) on an ongoing basis in order to 
ensure balanced geographic and age representation. 
All participants will receive 2 intramuscular doses of AZD1222 (5 ×1010 viral particles), 
separated by 4 weeks, on Day 1 and Day 29, and followed to the last study visit (see Table 2 
and Table 3). Immunocompromised participants will receive a third dose (primary vaccination 
series) 4 weeks or more after dose 2 with AZD1222 and will continue to be followed to the 
end of the study. Immunocompetent participants will be eligible to receive a third dose booster 
6 months after dose 1 and will continue to be followed to the end of the study. All participants 
who have received at least one dose of AZD1222 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. There will be no follow-up on participants who have not received 
AZD1222, regardless of reason. 
Immunogenicity (i.e., anti-S and immune responses including S-binding antibody titres and 
neutralizing antibody levels [pseudo-neutralization]), will be assessed in serum samples 
collected pre-dose on the day of each vaccination (baseline levels before vaccination), 14 days 
after doses 1 and 2, 28 days after dose 3, and as per the Schedule of Activities (see Section 
1.3). 
All participants will be given a thermometer, tape measure, and a proprietary eDiary 
application designed for use with a smart device with instructions for use.  Follow-up visits 
will take place as per the Schedule of Activities (Section 1.3).  All participants will be 
assessed for local and systemic AEs, physical examination, review of eDiaries, and use of 
concomitant medications according to the time points as detailed in the Schedule of Activities 
(Section 1.3).  Blood will also be taken for safety and immunological assessments. 
Safety will be assessed for the duration of the study. Participants will be asked to report on 
solicited AE signs and symptoms for 7 days following each vaccination.  An eDiary will be 
used to collect information on the timing and severity of the solicited signs and symptoms. 
Unsolicited AEs will be recorded for 28 days post dose after each vaccination. SAEs, 
MAAEs, and AESIs will be recorded through to the final study visit. Occurrence of 
COVID-19 in the trial will be reported as a safety event, including monitoring of the potential 
risk of vaccine-induced enhanced disease as an AE of special interest (see Appendix F).  
Detailed information will be collected in a standard way and reported on a specific case report 
form. COVID-19 will be diagnosed and treated as per standard medical practice.  
Experimental treatments for COVID-19 are permitted. Symptomatic participants may be 
regularly contacted over the phone for safety monitoring until symptom resolution. 

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4.1.1 
Screening Visit 
All potential participants will be screened, which may take place up to 7 days prior to Day 1 
(see Section 1.3). Screening activities can occur on the same day as vaccination only if 
laboratory results for HIV, urine pregnancy test, complete blood count, and SARS-CoV-2 
assessments are obtained.  Vaccine administration cannot occur until screening safety lab 
results are available.  
Informed consent will be obtained before screening/enrollment. If written consent is obtained, 
the procedures specified in the Schedule of Activities (see Section 1.3) will be undertaken 
including a medical history, physical examination, height and weight, and concomitant 
medications, and clinical safety laboratory assessments (biochemistry and hematology).  
For women of childbearing potential, it will be recorded that they verbally confirmed use of 
one highly effective form of birth control for at least 28 days prior to the planned vaccination 
and a urine pregnancy test will be performed that must be negative for the participant to be 
enrolled. (Note: Women with urine pregnancy test results that are positive or undetermined 
will not be enrolled and should be advised to seek medical attendance outside the context of 
the trial if pregnancy is suspected).  
The eligibility of the participants will be reviewed at the screening visit and again when all 
results from the screening visit have been received. Decisions to exclude the participant from 
enrollment or to withdraw a participant from the study will be at the discretion of the 
Investigator.  
4.1.2 
Vaccination Visits 
Participants will be considered enrolled upon administration of the investigational product. 
Before vaccination, the eligibility of the participant will be reviewed. Body temperature will 
be observed, and a medical history and physical examination will be undertaken before the 
first vaccination to determine need to postpone vaccination or screen fail the participant. A 
negative urine pregnancy test will need to be obtained from WOCBP before vaccination. 
Baseline blood samples will be obtained before the first vaccination. 
Participants will receive one dose of AZD1222 with 5 × 1010 viral particles (nominal)1 
administered by intramuscular injection on 3 occasions (see Section 6.2.1 for details on 
administration). 
 
1 Corresponding to not less than 2.5 × 108 infectious units  

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All participants will be given an axillary thermometer, tape measure, and a proprietary eDiary 
application with instructions for use to report on solicited signs and symptoms for 7 days 
following vaccination.  
4.1.3 
Follow-Up Visits 
Follow-up visits will take place as specified in the Schedule of Activities (Section 1.3). All 
participants will be assessed for local and systemic AE, physical examination, review of 
eDiary and blood tests at these time points as detailed in the Schedule of Activities (Section 
1.3). Blood will also be taken for immunogenicity assessments. 
For participants who cannot make scheduled visits after the vaccinations, the follow-up should 
be made as much as possible using telephone call and/or other appropriate method until the 
last study visit in order to collect information on any SAEs/MAAEs/AESIs and event of 
SARS-CoV-2 infection, which includes: 1) hospital admissions associated with COVID-19; 2) 
intensive care unit admissions associated with COVID-19; and 3) deaths associated with 
COVID-19. 
4.2 
Scientific Rationale for Study Design 
4.2.1 
Rationale for Study Design and Participant Population 
The participant population includes adults ≥ 18 years that are immunocompromised. 
Participants are allowed to be on stable immunosuppressive or immunomodulating 
medications in order to provide real-world evidence in this group.  
There are a variety of conditions leading to, and immunosuppressive or immunomodulating 
therapies contributing to, an immunocompromised/immunosuppressed state. Due to possible 
variation in the immune response to AZD1222 and safety considerations relevant to specific 
conditions/therapies, participants representing 5 cohorts of immunocompromised patients, as 
well as a sixth cohort of immunocompetent individuals, were chosen for this study. Patients 
with HIV are not included in this study as they were included in prior studies of AZD1222 and 
other COVID-19 vaccines. To date there are preliminary data available on immune responses 
in these cohorts.  
The 5 immunosuppressed cohorts are described in Section 5.1.2. The solid cancer on cytotoxic 
chemotherapy, hemopoietic stem-cell transplantation, and solid organ transplant cohorts were 
chosen to provide results applicable to large real-world populations. The mixed cohort of 
patients with chronic inflammatory conditions was chosen to reflect the variation in treatments 
that can lead to an immunocompromised state. For this cohort, enrollment of a proportion of 
participants that are receiving biological immunosuppressing medications is planned. The fifth 
cohort of participants are those with primary immune deficiency. Primary immune deficiency 
diseases, while rare, are increasing in incidence and are an understudied population.  

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The sixth cohort includes immunocompetent individuals. Consistent with the study 
populations included in the US and Latin America (D8110C00001) study and the University 
of Oxford sponsored COV studies, participants included in this cohort cannot be 
immunosuppressed/immunodeficient or have severe/uncontrolled comorbidities 
(mild/moderate well-controlled comorbidities are allowed). To reflect the real world and 
improve feasibility, no upper age limit was applied to any of the cohorts. 
For the primary and secondary objectives, those enrolled in the study must test negative for 
SARS-CoV-2 nucleocapsid protein antibody during screening.  Pregnant/breastfeeding 
women will be excluded from participation in the study. Persons who have previously 
received any other investigational product for the prevention of COVID-19 will be excluded 
from participation in this study. 
4.2.2 
Rationale for Study Endpoints 
There is no statistical hypothesis testing planned for this study.  Descriptive statistics will 
support evaluation of safety and immunogenicity. 
The primary analysis will occur when all participants within a cohort have completed visit 8 
(i.e., 28 days after the second dose; see Table 2 and Table 3). Secondary analyses of third dose 
(primary series) will occur when all participants within an immunocompromised cohort have 
completed visit 10 (i.e., 28 days after the third dose; see Table 2). The final analysis will occur 
when data from all vaccinated participants are available through completion of the last study 
visit (see Table 2 and Table 3). 
For the primary objective, without a prespecified directional hypothesis, 2-sided 95% 
confidence intervals will be calculated as descriptive measures for each immunogenicity 
endpoint. 
The primary immunogenicity endpoints in this study are analogous to those used for 
evaluating the immunogenicity of AZD1222 in a pivotal Phase 3 efficacy study. Given that an 
immunological correlate of protection has yet to be defined, the assessment of humoral 
immunogenicity through (1) binding antibodies to SARS-CoV-2 (spike, receptor binding 
domain), and (2) neutralizing antibodies (pseudo-neutralization assay) are considered the best 
predictors of immune response to vaccination.  
The primary immunogenicity endpoints of interest in this study are:  
• Antibody titre 
• Seroresponse, defined as ≥ 4-fold increase in the antibody titre from baseline (pre-dose 
1) 

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Geometric mean titre ratios and differences in seroresponses with 95% confidence intervals 
will be presented to support selected comparisons of immunogenicity across groups of 
interest. Geometric mean fold rise over baseline values (GMFR) will be reported along with 
all GMT analyses. 
Additionally, cell mediated immunogenicity assessments including intracellular cytokine 
staining to investigate the induction of cluster of differentiation 4 and 8 (CD4/CD8) cells 
specific to the S protein (and T helper 1 and 2 [Th1/Th2] balance of these cells) will be 
measured. To understand if immunocompromising conditions can affect the B cell receptor 
and T cell receptor repertoire (a measurement of the breadth and depth of the cellular immune 
response), immunosequencing will be conducted in an exploratory endpoint. 
The secondary safety endpoints include: 
•
Incidence of local and systemic solicited AEs for 7 days after each dose of AZD1222 by
eDiary
•
Incidence of unsolicited AEs for 28 days post dose after each vaccination
•
Incidence of SAEs, MAAEs and AESIs from Day 1 post treatment to last study visit (see
Table 2 and Table 3)
Solicited AEs will be collected for 7 days after each dose of AZD1222 for all participants, a 
period that has proven adequate to describe reactogenicity events in previous vaccine studies. 
Other safety endpoints to be collected include unsolicited AEs, SAEs, MAAEs, AESIs and 
clinical safety laboratory assessments. AESIs were selected to include terms identified by the 
Brighton Collaboration involving events associated with vaccination in general (SPEAC 2021). 
The study is not powered to demonstrate differences in SARS-CoV-2 infections and COVID-19 
between cohorts. 
Assessment of AZD1222 immunogenicity and safety will begin immediately after Dose 1. To 
align with other studies in the development plan, immunogenicity will be assessed ≥ 15 days 
after the second dose of study intervention (as this time period is still considered necessary for 
the vaccine to induce protective immune responses in this population). 
4.3 
Justification of Dose 
The approved dose and regimen of AZD1222 will be used in this trial. The AZD1222 dose of 
5 × 1010 viral particles was selected based on accumulated clinical experience with this 
vaccine in ongoing clinical studies sponsored by the University of Oxford. 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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4.4 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities 
(Section 1.3). 
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (Section 1.3) for the last participant in the study globally. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, are not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
5.1.1 
All Participants: 
Age 
1. Adult, ≥ 18 years at the time of signing the informed consent.
Type of Participant 
2. Able to understand and comply with study requirements/procedures based on the
assessment of the investigator.
3. Signed informed consent obtained before conducting any study-related procedures.
Reproduction 
4. Contraceptive use by women should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.
Female participants: 
a)
Women of childbearing potential must:
•
Have a negative pregnancy test on the day of screening and on 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 last dose of
AZD1222. A highly effective method of contraception is defined as one

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

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Informed Consent 
5. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form and in the protocol.
5.1.2 
Cohort-Specific Inclusion Criteria 
If a participant meets the inclusion criteria for more than one cohort then the Sponsor should 
be contacted to determine enrollment as soon as possible.  
Solid organ transplant 
−
Participants with heart, lung, kidney, or liver transplant, and are stable on
immunosuppressants (defined as no change in dose in the previous 4 weeks).
Transplant of more than one organ is acceptable.
Hematopoietic stem cell transplant 
−
Participants with autologous (up to 6 months after transplantation) or allogeneic stem
cell transplant who are immunosuppressed, with no evidence of active graft-versus-
host disease, at least one month after the procedure.
Cancer patients on chemotherapy 
−
Participants with solid tumors (except breast cancer), histologically diagnosed, who
were undergoing intravenous cytotoxic chemotherapy within the last 6 months, who
received at least 1 cycle prior to cytotoxic chemotherapy, and have a life expectancy
of longer than 3 months.
  Chronic inflammatory conditions 
−
Participants with chronic inflammatory conditions, including those on
immunosuppressant medications, can be recruited such as the following: rheumatoid
arthritis, systemic sclerosis, mixed connective tissue disorder, systemic lupus
erythematosus, or inflammatory bowel disease. The following conditions are
specifically excluded: multiple sclerosis and peripheral demyelinating disease.
Primary immune deficiency 
−
Examples include combined granulomatous disorder, SCID, common variable
immunodeficiency.
Immunocompetent: 
−
No confirmed or suspected immunosuppressive or immunodeficient state.
−
No use of immunosuppressant medication within the past 1 month (≥ 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 AZD1222). The following exceptions are

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permitted: topical/inhaled steroids or short-term oral steroids (course lasting ≤ 14 
days).  
−
No receipt of immunoglobulins and/or any blood products within 3 months prior to
administration of AZD1222 or expected receipt during the period of study follow up.
−
No 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 such as diabetes mellitus, hypertension, asthma, and
chronic obstructive pulmonary disease).
The Sponsor reserves the right to reposition the primary cohort group of any participant, in 
discussion with the Investigator. 
5.2 
Exclusion Criteria 
 Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1.
History of allergic disease or reactions likely to be exacerbated by any component of
AZD1222.
a)
Active infection with SARS-CoV-2 as confirmed locally by nucleic acid
amplification test (e.g., RT-PCR).
b)
Known current or past laboratory-confirmed SARS-CoV-2 infection.
c)
Significant infection or other acute illness, including fever (temperature > 37.8°C) on
the day prior to or day of first dosing.
d)
Thrombocytopenia with platelet count ≤ 75,000 x 109/microliter based on complete
blood count test at screening visit.
e)
HIV-positive participants based on a positive ELISA test performed at screening
visit.
f)
Apart from participants in cohort 2, 3 below (cancer patients), history of primary
malignancy except for:
g)
Malignancy with low potential risk for recurrence after curative treatment (for
example, history of childhood leukemia) or metastasis (for example, indolent prostate
cancer) in the opinion of the site investigator.
a.
Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
b. Adequately treated uterine cervical carcinoma in situ without evidence of
disease
c.
Localized prostate cancer

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h)
Clinically significant bleeding disorder (e.g., factor deficiency, coagulopathy, or
platelet disorder), or prior history of significant bleeding or bruising following
intramuscular injections or venipuncture, according to Investigator’s judgement.
i)
History of cerebral venous sinus thrombosis (CVST).
j)
History of Guillain-Barré syndrome, any demyelinating disease, or any other
neuroimmunological disease.
k)
Any other significant disease, disorder, or finding that may significantly increase the
risk to the participant, affect the ability of the participant to participate in the study,
or impair interpretation of the study data.
Prior Concomitant Therapy 
l)
Receipt of, or planned receipt of, licensed or unlicensed SARS-CoV-2 or COVID-19
vaccine, or investigational product. Note: For participants in the study who contract
COVID-19 and receive treatment (either inpatient or outpatient), receipt of licensed
treatment options and/or participation in investigational treatment studies is
permitted.
m) Receipt of any other vaccine (licensed or investigational) 30 days prior to and after
administration of AZD1222. Thirty (30) days after the last vaccination, other routine
vaccinations are permitted, as clinically indicated.
Other Exclusions 
n)
Involvement in the planning and/or conduct of the study (applies to both Sponsor
staff and/or staff at the study site).
o)
Women who are currently pregnant (confirmed with positive pregnancy test),
breastfeeding, having given birth less than 3 months before or planning pregnancy
during the study.
p)
Judgment by the investigator that the participant should not participate in the study if
the participant is unlikely to comply with study procedures, restrictions, and
requirements or if vaccination would interfere with the participant’s ongoing
treatment.
q)
Previous enrollment in the present study.
r)
Has donated ≥ 450 mL of blood products within 30 days prior to enrollment or
expects to donate blood within 90 days of administration of second dose of study
intervention
s)
Participants with a history of chronic alcohol or drug abuse or any condition
associated with poor compliance.

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5.3 
Lifestyle Considerations 
Participants must follow the contraception requirements outlined in Section 5.1. 
Restrictions relating to concomitant medications are described in Section 6.5. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. 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 (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Only 2 rescreenings per participant are 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 
6.1 
Study Intervention Administered 
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. 
6.1.1 
Investigational Product 
The investigational product is described in Table 7. 
Table 7 
Investigational Product 
Intervention Name 
AZD1222 
Type 
Vaccine 
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 
Unit dose strength(s) 
≥ 0.7 × 1011 viral particles/mL 
≥ 2.0 × 108 infectious units/mL 
Dosage level(s) 
5 × 1010 viral particles (nominal, ± 1.5 × 1010 viral particles) 
≥ 1.0 × 108 infectious units 
Route of administration 
Intramuscular 
Use 
Experimental 

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IMP and NIMP 
IMP 
Sourcing 
Provided centrally by the Sponsor 
Packaging and labelling 
Will be provided in vials within a carton.  
Each carton and vial will be labelled as required per country requirement 
Current/Former name or alias 
Previous clinical documentation: ChAdOx1 nCoV-19 
Current trade name: Vaxzevria 
 IMP = Investigational medical product; NIMP = non-investigational medical product; w/v = weight/volume 
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 and can provide up to ten 0.5mL doses.  
Unopened vials of AZD1222 vials must be stored at 2 to 8°C (36 to 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. 
6.1.2 
Dosing Instructions 
Each participant will receive 3 doses of AZD1222 with the first dose administered on Day 1, 
the second dose administered 28 days after dose 1, and the third dose administered 28 days 
after dose 2 for the immunocompromised participants (see Table 2). Immunocompetent 
participants will receive a third dose booster 6 months after dose 1 (see Table 3). 
Note: If the third dose of AZD1222 is administered more than 28 days after Visit 5, and 
outside the visit window due to regulatory authority and/or ethics committee approval 
timelines, no protocol deviation will be issued.  
It is recommended that AZD1222 is administered as an IM injection into the deltoid of the 
nondominant 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
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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 (i.e., receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study
interventions are provided in the Pharmacy Manual or specified handling instructions.
6.2.1 
Dose Preparation and Administration 
Doses of AZD1222 must be prepared by the Investigator’s or site’s designated investigational 
product manager 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 at 2-25°C (36-77°F) 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 6-hour beyond-use-date of the vial, otherwise a new dose must be 
prepared from a new vial.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. 
6.4 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic 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(s) or vaccines taken from signed informed consent through post-study follow-
up (including over the counter or prescription medicines) that the participant is receiving at 
the time of enrollment or receives during the period specified in the Schedule of Activities 
(see Section 1.3) must be recorded in the eCRF along with the information listed below. All 
non-study COVID vaccinations received should be recorded. Study drug, vitamins and/or 
herbal supplements should not be recorded. 

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•
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 AZD1222 should be treated with 
licensed medications and interventions according to standard of care. This should be 
recorded as an AE/SAE (Section 8.3). All routine vaccinations are permitted beginning > 
30 days after last dose of AZD1222. Non-study vaccines are to be recorded in eCRF.
Given the study population, the following medications are expected to be prescribed in some 
cohorts: 
•
Glucocorticoids at any dose
•
Other systemically administered drugs with significant immunosuppressive activity,
including, but not limited to: azathioprine, tacrolimus, cyclosporine, methotrexate,
sulfasalazine, rituximab or cytotoxic chemotherapy
•
Immunoglobulins and/or any blood product
•
Anticoagulants
6.5.2
Prohibited Concomitant Medications 
The following medications are prohibited, and the Sponsor must be notified if a participant 
receives any of these prohibited medications. The use of the following concomitant 
medications and/or vaccines, however, will not require withdrawal from the study, but may 
require subsequent determination of a participant’s eligibility to receive a second or third dose 
or evaluability in the immunogenicity analysis set.  
•
Licensed or authorized products (besides vaccines) indicated for the treatment of
SARS-CoV-2 or COVID-19
Note: For participants who contract COVID-19 and receive in-patient or outpatient 
treatment, receipt of licensed or authorized treatment options, and/or participation 
in investigational treatment studies is permitted. 

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•
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 in the study to be followed for safety 
reporting and all assessments.  Non-study vaccines are to be recorded in eCRF  
•
Receipt of any vaccine (licensed or investigational) within 30 days prior to and after
administration of AZD1222 (e.g., Dose 1, Dose 2, Dose 3). Thirty (30) days after the third
vaccination, other routine vaccinations are permitted as clinically indicated.
If a participant receives a prohibited concomitant medication, the Investigator should, in 
consultation with the Sponsor, evaluate any potential impact on receipt of AZD1222 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. 
6.6 
Dose Modification 
Study intervention will be administered as described in Section 6.1.  Dose modification is 
not permitted.  
6.7 
Interventional After the End of the Study 
There is no intervention after the end of the study (see definition in Section 4.4). 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Investigational Product 
Participants will receive 3 doses of open-label AZD1222 in this study. A participant must not 
receive the first, second or third dose of AZD1222 if any of the following has occurred: 
•
Withdrawal of consent after signing informed consent
•
Participant meets one or more of the exclusion criteria or fails to meet all inclusion criteria
for study participation
•
Laboratory-confirmed SARS-CoV-2 infection or HIV infection
•
Participant is pregnant or nursing
•
Any allergic reaction including anaphylaxis that is assessed as related to AZD1222
•
Any SAE assessed as related to AZD1222

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•
Any AE that, in the judgment of the site investigator, is related to AZD1222 and may
jeopardize the safety of the study participant (e.g., a thrombotic event after Dose 1).
•
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 AZD1222 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 AZD1222, regardless of 
reason, will not be followed. 
In the event that a study participant receives a licensed and/or authorized COVID-19 vaccine, 
the Sponsor needs to be notified within 24 hours and this should be documented in the site 
source documents. Participants who have received study intervention, regardless of reason, 
will be followed for the full study period. 
7.2 
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 AZD1222 that in the opinion 
of the Sponsor may preclude further administration of AZD1222. 
Inability to recruit for the study if insufficient participants are able to be enrolled. 
7.3 
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, behavioural, compliance, 
or administrative reasons. 
A participant who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (e.g., 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 

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the decision on use of existing samples in the site study records and inform the Sponsor Study 
Team. If the participant does not specifically request withdrawal of consent for use of 
samples, then the samples collected prior to the consent withdrawal will be destroyed once per 
protocol-specified analysis is complete. 
7.4 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/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 described 
in  Appendix A. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
•
Study procedures and their timing are summarized in the Schedule of Activities (Section 
1.3). Protocol or exemptions are not allowed.
•
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3) is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline

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purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities. 
8.1 
Efficacy Assessments 
Not applicable. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.2.1 
Physical Examinations 
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the Schedule of Activities (Section 1.3). 
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems. Each clinically significant 
abnormal finding at screening will be recorded in the medical history. 
A targeted physical examination will include areas suggested by the medical history and, e.g., 
signs of thrombosis or thrombocytopaenia. Each clinically significant abnormal finding 
following vaccination will be recorded as an AE. 
All physical examinations will be performed by a licensed healthcare provider 
(e.g., physician, physician assistant, or licensed nurse practitioner). 
8.2.2 
Vital Signs 
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the Schedule of Activities (Section 1.3). The participant should be 
resting prior to the collection of vital signs. 
Situations in which vital sign results should be reported as AEs are described in Section 8.3. 
8.2.3 
Clinical Safety Laboratory Assessments 
Blood samples for determination of clinical chemistry and hematology will be taken at the 
visits indicated in the Schedule of Activities (Section 1.3). Additional unscheduled safety 
samples may be collected if clinically indicated at the discretion of the Investigator, with 
the date and time of collection recorded in the appropriate eCRF. See Appendix D, and 
Section 8.3.8.1for information on decrease in platelets from baseline.  

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The standard clinical chemistry and hematology analysis will be performed at a local 
laboratory at or near to the Investigator’s site. Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site. 
The laboratory safety variables in Table 8 will be assessed. 
Table 8 
Local Laboratory Safety Variables 
Hematology/Hemostasis (blood) 
Clinical Chemistry (serum/plasma) 
Hemoglobin 
Creatinine 
Leukocyte count 
Bilirubin, total 
Leukocyte differential count (absolute count) 
Alkaline phosphatase (ALP) 
Platelet count 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Clotting (serum/plasma) 
Activated partial thromboplastin time 
Prothrombin time 
Fibrinogen 
D-dimer
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected and a urine pregnancy test will be performed at screening, and a negative test result 
must be confirmed, before each vaccination. Urine pregnancy tests for β-human chorionic 
gonadotropin may be performed at the site using a licensed test (dipstick).  
See Appendix D for additional investigations to be performed if a venous thromboembolic and 
thrombocytopenia event occurs. 
8.2.4 
COVID-19 Assessments 
Participants should be tested for SARS-CoV-2 infection at the screening visit using a nucleic 
acid amplification test (e.g., RT-PCR). After vaccine administration, participants who 
become symptomatic with at least one of the qualifying symptoms listed below (Table 9) 
during follow-up (i.e., through the last study visit; see Table 2 and Table 3) will be instructed 
to call the trial staff who will then advise on how to proceed with clinical testing for 
COVID-19. When participants are suspected of being infected with SARS-CoV-2, based on 
their symptoms and a positive nucleic acid amplification test (e.g., RT-PCR), they will be 
advised to contact hospitals/clinics designated for treatment of COVID-19 as per local 
guidance. 

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Table 9 
COVID-19 Qualifying Symptoms 
Participant must present with at least one of the following symptoms to qualify for clinical COVID-19 
testing 
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 
Diarrhoea 
Adapted from (CDC 2020) 
8.3 
Adverse Events and Serious Adverse Events 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in an eDiary (Section 8.3.6) and will be assessed separately 
from the (unsolicited) AEs collected during the study. General information for AEs in this 
protocol excludes the reporting of solicited AEs via eDiary unless otherwise noted. 
All other AEs are considered to be unsolicited AEs (collected by ‘open question’ at study 
visits). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative).  

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The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
Solicited AEs will be recorded for 7 days after each study vaccination for all participants (see 
Table 2 and Table 3). 
If a solicited AE is not resolved within the eDiary reporting period, the event will be reported 
as a non-solicited adverse event in the eCRF, with a start date of when started and the actual 
stop date. 
Unsolicited AEs will be recorded for 28 days after each study vaccination (see Table 2 and 
Table 3).  
SAEs will be recorded from the time of signature of the informed consent form through the 
last participant contact. 
Medically-attended AEs and AEs of special interest will be recorded from Day 1 through the 
last participant contact.  
All participants will be followed up after the administration of the first dose of study vaccine.  
SAEs, MAAEs and AESIs will be collected up to the last study visit. See the Schedule of 
Activities for the scheduled timepoints (Section 1.3). 
If the Investigator becomes aware of an SAE with a suspected causal relationship to the IP 
that occurs after the end of the clinical study in a participant treated by him or her, the 
Investigator shall, without undue delay, report the SAE to the Sponsor. 
8.3.2 
Follow-up of Adverse Events and Serious Adverse Events 
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
AE variables 
The following variables will be collected for each AE: 
•
AE (verbatim)
•
Date when the AE started and stopped
•
Severity grade/maximum severity grade/changes in severity grade
•
Whether the AE is serious or not

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•
Investigator causality rating against the IP (yes or no)
•
Action taken with regard to IP
•
AE caused participant’s withdrawal from study (yes or no)
•
Outcome
In addition, the following variables will be collected for SAEs: 
•
Date AE met criteria for SAE
•
Date investigator became aware of SAE
•
AE is serious due to
•
Date of hospitalization
•
Date of discharge
•
Probable cause of death
•
Date of death
•
Autopsy performed
•
Causality assessment in relation to study procedure(s)
•
Causality assessment to other medication
A revised toxicity grading scale from US FDA guidance for healthy volunteers enrolled in 
a preventive vaccine clinical study (FDA 2007) will be used for all unsolicited events with 
an assigned severity grading including Grade 5.  
8.3.3 
Causality Collection 
The investigator should assess causal relationship between IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the investigational product?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes.’ 
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 
Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff, ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation, will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 

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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 
Results from Clinical Study Protocol-mandated vital signs and laboratory safety assessments 
will be summarised in the Clinical Study Report.  
Deterioration compared with baseline in protocol-mandated vital signs and laboratory 
assessments should therefore only be reported as AEs if they fulfill any of the SAE or 
medically-attended AE (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. Wherever possible the reporting investigator uses the 
clinical rather than the laboratory term (e.g., anaemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 
Solicited Adverse Events 
Local and systemic predefined solicited AEs for reactogenicity assessment (Table 10) will be 
collected in a Solicited AE eDiary for 7 days following administration of AZD1222 (see 
Table 2 and Table 3):   
For all participants, solicited AEs will be recorded for 7 days after each dose of AZD1222.  
If a solicited AE is not resolved within the eDiary reporting period, the event will be also 
reported as a non-solicited adverse event in the eCRF, with a start date of when started and the 
actual stop date. 
Solicited AEs should not be reported as unsolicited AEs. However, solicited AEs should be 
reported as SAEs if they fulfil the criteria. 

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Table 10 
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 cut-off 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 centimetres) in diameter. 
8.3.6.1 
Solicited AE eDiary 
On Day 1, participants (or, if applicable, their caregiver, surrogate, or legally authorized 
representative) will be given an oral thermometer, tape measure, and access to the Solicited 
AE eDiary, 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 
AZD1222, the timing and severity of local and systemic solicited AEs, if applicable, and 
whether medication was taken to relieve the symptoms.  
8.3.6.2 
Severity Assessment of Solicited AEs 
Severity will be assessed for solicited AEs by the participant (or, if applicable, their caregiver, 
surrogate, or legally authorised representative) according to toxicity grading scales modified 
and abridged from the US FDA guidance (FDA 2007) as defined in Appendix E. Because 
solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to AZD1222. 
8.3.7 
Medically Attended Adverse Events 
Medically-attended AEs (MAAEs) will be collected according to the timepoints specified in 
the Schedule of Activities (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, 

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including abnormal vital signs, identified on a routine study visit will not be considered 
MAAEs. 
8.3.8 
Adverse Events of Special Interest 
AEs of special interest (AESIs) will be collected according to the timepoints specified in the 
Schedule of Activities (Section 1.3). 
AESIs are events of scientific and medical interest specific to the further understanding of the 
AZD1222 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 2021), clinical experience, and scientific interest. A list of events is 
provided in Appendix F. 
An AESI can be serious or nonserious. 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 (i.e., immediately but no later than 
24 hours) of when he or she becomes aware of it. 
8.3.8.1 
Vascular/Hematologic Adverse Events of Special Interest 
Thrombotic, thromboembolic, and thrombocytopenia events are considered to be adverse 
events of special interest. The Investigator should remain vigilant for the occurrence of 
thrombotic events with thrombocytopenia and/or bleeding. If a participant experiences new 
onset thromboembolic events with thrombocytopenia, there should be prompt evaluation with 
a thorough hematological investigation. COVID-19 testing, including PCR and serology 
(nucleoprotein antibodies), should also be performed. See Appendix D for further guidance on 
investigation and management of suspected events. 
In the event of such a case of thrombosis and in accordance with local laws and ethical 
procedures, one blood sample may be taken from the participant and targeted genome 
sequencing performed in order to enable investigations into the possible role of genetic 
polymorphisms as risk factors for these events. 
An independent Hematology Expert Panel will be available to review and provide advice on 
requests about the diagnosis and causality assessment of selected thrombosis with 
thrombocytopenia AESIs occurring in the AZD1222 clinical development program. Details on 
the composition and operation of this committee are described in the Hematology Expert 
Panel Charter (see Appendix A 5). 
8.3.8.2 
Potential Neurological Adverse Events of Special Interest 
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(e.g., weakness, numbness, paraesthesia, hypoesthesia, hyperesthesia, dysesthesias), 

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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 (e.g., electromyography). In cases of concern for spinal cord 
disease, see Figure 3 for a recommended testing algorithm. 
An independent Neurology Expert Committee for AESIs will review and provide advice on 
their diagnosis and causality assessment of selected neurological AEs of special interest 
occurring in the AZD1222 clinical development program (see Appendix A 5). 

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

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8.3.8.3 
Vaccine-associated Enhanced Disease, Including Vaccine-associated 
Enhanced Respiratory Disease 
The pathogenesis of vaccine-associated enhanced disease (VAED) in the context of SARS-
CoV-2 is unclear, and there are no consistent mechanisms or immune markers of disease 
enhancement from nonclinical studies. Vaccine-associated enhanced respiratory disease 
(VAERD) refers to the predominantly lower respiratory tract presentation of VAED. The 
mechanism of the pathogenesis of VAERD may be specific to the lower respiratory tract or 
may be part of a systemic process. 
There is a theoretical concern that vaccination against SARS-CoV-2 may be associated with 
enhanced severity of COVID-19 episodes, which would manifest as VAED/VAERD. 
Vaccine-associated enhanced disease was observed in children given formalin-inactivated 
whole-virus vaccines against respiratory syncytial virus and measles virus in the 1960s 
(Haynes 2020), and findings from experimental models of SARS-CoV and MERS-CoV 
infection suggest that VAED may be possible in certain conditions (FDA 2020).     
8.3.9 
Hy’s Law 
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation. This evaluation will be conducted at the local laboratory.  
Hy’s Law criteria: AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN, where no 
other reason, other than the study intervention, can be found to explain the combination of 
increases, e.g., elevated ALP indicating cholestasis, viral hepatitis, another drug. The 
elevation in transaminases must precede or be coincident with (i.e., on the same day) the 
elevation in total bilirubin, but there is no specified timeframe within which the elevations in 
transaminases and total bilirubin must occur. 
Any occurrences of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥ 3 × upper limit of normal together with total bilirubin ≥ 2 × upper limit of normal at any 
point during the study following the administration of study medication and confirmed as 
Hy’s Law should be reported to the Sponsor as an SAE within 1 day with a serious criteria of 
‘Important medical event’.  
The study physician will contact the Investigator to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and 
the continuous review of data.  
8.3.10 
COVID-19 Assessment 
This study will describe the incidence of COVID-19 adverse events reported from Day 1 to 
last study visit (see Table 2 and Table 3). 

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COVID-19 is defined as a positive symptomatic illness that is confirmed by a nucleic acid 
amplification test (e.g., RT-PCR). At all clinic visits following the initial vaccination, 
participants will be asked if they have had a diagnosis of COVID-19 since their last clinic 
visit (see Schedule of Activities in Section 1.3). Medical records will be obtained for 
confirmation of a participant-reported diagnosis of COVID-19. 
Qualifying symptoms are fever, shortness of breath, difficulty breathing, chills, cough, fatigue, 
muscle/body aches, headache, new loss of taste or smell, sore throat, congestion, runny nose, 
nausea, vomiting, or diarrhoea (see Section 8.2.4). Events will be reported as AEs/SAEs. 
If a participant presents at clinic visit with COVID symptoms, diagnosis will be confirmed as 
described in Section 8.2.4. 
8.3.11 
COVID-19 Severity 
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 local 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, non-invasive 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
8.3.12 
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, 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 (i.e., 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 Sponsor Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 

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For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
Sponsor representatives of any follow-up information on a previously reported SAE within 1 
calendar day (i.e., 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 Electronic Data 
Capture system, an automated email alert is sent to the designated Sponsor representative.  
If the Electronic Data Capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate Sponsor representative by telephone or other method 
and the event is entered into the Electronic Data Capture system when available. 
The Sponsor representative will advise the investigator/study site staff how to proceed.  
For further guidance on the definition of a SAE, see Appendix B. 
The reference document for definition of expectedness is the AZD1222 Investigator Brochure, 
Section 5.6. 
8.3.13 
Pregnancy 
All pregnancies and outcomes of pregnancy with conception dates following administration of 
study intervention should be reported to the Sponsor except for: 
•
If the pregnancy is discovered before the study participant has received any study
intervention
•
Pregnancies in the partner of male participants
8.3.13.1 
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 (Section 5.2). Pregnancy itself is not 
regarded as an AE unless there is a suspicion that AZD1222 may have interfered with the 
effectiveness of a contraceptive medication. Congenital anomalies/birth defects and 
spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital anomaly/
birth defect) 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 (i.e., immediately but no later 
than 24 hours) of when he or she becomes aware of it. 

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The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (Section 8.3.12) and within 30 days for all other pregnancies that are not 
associated with 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. 
8.3.14 
Medication Error 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate Sponsor representatives within 1 day (i.e., 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 (Section 8.3.12) and within 30 days for all other 
medication errors. 
The definition of a Medication Error can be found in Appendix B 4.  
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 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 one or 

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5 calendar days for overdoses associated with an SAE (Section 8.3.12) 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. For further details on Handling of Human Biological 
Samples, see Appendix C. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
Remaining biological sample aliquots will be retained at the Sponsor or its designee for a 
maximum of 15 years following issue of the Clinical Study Report. Additional use excludes 
genetic analysis and includes but is not limited to, analysis of COVID-19 and other 
coronavirus-related diseases or vaccine-related responses (e.g., exploratory immunology), 
such as systems serology and profiling of B- and T-cell repertoire. The results from further 
analysis may be reported in an appendix of the Clinical Study Report. 
8.5.1 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.5.2 
Immunogenicity Assessments 
Serum and blood samples for immunogenicity assessments will be collected according to the 
Schedule of Activities (Section 1.3).   Samples will be collected, labelled, stored, and shipped 
as detailed in the Laboratory Manual. Results for exploratory immunogenicity analyses may 
be reported separately from the Clinical Study Report. 
8.5.2.1 
SARS-CoV-2 Serology Assessments 
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels 
from all participants according to the Schedule of Activities (Section 1.3). Authorized 
laboratories will assess serologic responses to AZD1222 using validated (or qualified, where 
appropriate) assays. Serologic assessment to S, RBD, and Nucleocapsid antigens will be 
assessed quantitatively using a validated multiplexed electrochemiluminescence based 
immunoassay. Additionally, seroresponse will be assessed for each antigen over time. 
Exploratory assessments will be performed by utilizing the rate of seroresponse to the 
Nucleocapsid antigen on a multiplexed electrochemiluminescence based immunoassay. The 
rate of asymptomatic SARS-CoV-2 infection in participants receiving AZD1222 will be 
determined 

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by seroresponse in a SARS-CoV-2 Nucleocapsid assay operated by an authorized laboratory. 
Serologic assessment to S, RBD, and Nucleocapsid antigens will be assessed quantitatively 
using a validated multiplexed ECL based 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 according to the timepoints specified in the Schedule of Activities (Section 1.3). 
Authorized laboratories will measure neutralizing antibodies to SARS-CoV-2 using validated 
wild-type neutralization assay and/or pseudo-neutralization assays.  Neutralizing antibody 
assessments to emerging variants may also be investigated. 
8.5.2.3 
Assessment of Cell-mediated Immune Responses 
Cell-mediated immune responses (i.e., B-cell and T-cell responses) will be assessed by 
characterizing peripheral blood mononuclear cells 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. Samples will be collected at 
timepoints specified in the Schedule of Activities (Section 1.3). 
Additionally, plasma may be isolated from the whole blood samples collected to isolate 
peripheral blood mononuclear cells, which can be utilized for exploratory immunogenicity 
and biomarker analyses (see Table 2 and Table 3).  
8.5.2.4 
Monitoring for Asymptomatic Infection 
Blood samples will be collected according to the Schedule of Activities (Section 1.3) for 
SARS-CoV-2 serology testing to determine if participants have had an asymptomatic 
infection.  
8.5.2.5 
Additional Serum Immunogenicity 
Additional serum samples for exploratory immunogenicity evaluation will be obtained 
according to the Schedule of Activities (Section 1.3). Serologic assessment to anti-vector 
immune responses (i.e., 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 
based upon emerging safety, efficacy, immunogenicity data. 
8.5.3 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 

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8.6 
Human Biological Sample Biomarkers 
8.6.1 
Collection of Mandatory Samples for Biomarker Analysis 
Samples for biomarker research are required and will be collected from all participants. 
Details for sample collection, processing, and testing will be provided in the Laboratory 
Manual. 
8.6.1.1 
Blood Sample for Targeted Sequencing Analyses 
A blood sample for targeted sequencing analyses will be collected on Day 1 in accordance 
with the Schedule of Activities (Section 1.3) and will be tested to investigate predictive 
markers of safety per Appendix D. If, for any reason, the blood sample is not drawn on Day 
1, it may be taken at any time up until the last study visit.  
8.6.1.2 
Blood Samples for Other Biomarker Analyses 
Biomarkers will be tested in blood samples for exploratory objectives to investigate predictive 
markers of response and safety. These samples will be used to assess AZD1222-related 
activity, which may include but are not limited to cytokines, autoimmune-related testing and 
platelet immunologic testing. 
The following samples for biomarker research are required from all participants in this study: 
•
Plasma sample:  whole blood sample will be taken at Day 1, for the isolation of 
plasma, and will be tested to investigate predictive markers of safety Appendix D.
•
Serum sample:  whole blood sample will be taken at Day 1, for the isolation of serum, 
and will be tested to investigate predictive markers of safety per Appendix D.
Details for sample collection, processing, and testing will be provided in the Laboratory 
Manual. 
Any results from such analyses may be reported in an addendum of the Clinical Study Report. 
8.6.2 
Other Study-Related Biomarker Research 
To further characterise the safety profile of AZD1222, already collected samples may be 
analysed for different biomarkers including, but not limited to, serum, plasma, or cytokines, 
quantification of RNA, micro-RNA, and/or non-coding RNA using quantitative RT-PCR, 
microarray, sequencing, or other technology in blood, peripheral blood mononuclear cells, or 
other specimens to evaluate their association with AZD1222. 
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 in this study. 

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8.8 
Health Economics 
Not applicable.  
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
There is no formal statistical hypothesis testing planned for this study. Descriptive analyses 
will support evaluation of safety and immunogenicity and qualitative comparison between 
groups. 
9.2 
Sample Size Determination 
The sample size (approximately 60 participants in each immunocompromised cohort) was 
determined mainly for feasibility purposes, with consideration for acceptable precision around 
the GMT and seroresponse rates for a single cohort. Since correlates of protection are not 
available, a descriptive approach is proposed for primary analyses. For secondary and 
exploratory analyses, assuming a common standard deviation on the natural log scale of 1.2 
and a 2-sided α=0.05, a sample size of 60 per cohort gives 88.0%/63.8%/36.6% power (i.e. 
probability) to demonstrate that the observed GMT ratio is greater than 0.5/0.6/0.7 when there 
is assumed to be no difference (GMT ratio =1).  
Table 11 indicates the probability of observing one or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a 
particular type for participants in each cohort. With the sample size of 60 participants per 
cohort, at least 1 participant with an AE of incidence rate of 1% can be detected with 
probability of about 45%. 
Table 11 
Probability of Detecting One or More Safety Events in AZD1222  
 Event Frequency 
Probability (> 1 event) 
 
N=60 
N=300 
≥ 10% (Very Common) 
> 99% 
> 99% 
≥ 1% (Common) 
45.3% 
95.1% 
≥ 0.1% (Uncommon) 
5.8% 
25.9% 
≥ 0.01% (Rare) 
0.6% 
3.0% 
 
The primary objective of this study is to characterize anti-SARS-CoV-2 antibody (specific 
binding (anti-S) and pseudo-neutralization) levels in serum following 2 IM doses of AZD1222 
administered 28 days apart in immunocompromised individuals. 
Historical data were available on the immunogenicity responses from the pooled 
COV001/002/003/005 studies. Table 12 presents the natural log transformed immunogenicity 

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responses by assay. These results indicate that the pseudo-neutralizing antibodies exhibited 
the largest variation (SD = 1.20), while live-neutralizing had the lowest (SD = 0.72). 
Table 12 
Historic Immunogenicity Responses by Dosing Interval 
GMT 
Post 1st Dose 
4 weeks a 
N 
Mean 
SD 
N 
Mean 
SD 
Pseudo 
476 
4.3 
1.34 
166 
5.3 
1.20 
Live 
51 
4.9 
1.15 
42 
6.2 
0.72 
Anti-S 
1139 
9.1 
1.14 
293 
10.1 
0.96 
  
Estimates from COV001/2/3/5 using 2- to 6-week interval between doses 
 
Table 13 presents the seroresponse (≥ 4-fold change from baseline) by assay. These results 
indicate that the pseudo-neutralizing antibodies exhibited the lowest proportion of 
seroresponse (59.7%), while both live-neutralizing and spike-binding seroresponse rates 
exceeded 95%. 
Table 13 
Historic Seroresponse Rates by Dosing Interval 
SeroConv 
Post 1st Dose 
4 weeks a 
N 
Proportion 
N 
Proportion 
Pseudo 
499 
32% 
382 
59.7% 
Live 
96 
75% 
95 
96.8% 
Anti-S 
940 
96.6% 
636 
95.9% 
  
Estimates from COV001/2/3/5 using 2- to 6-week interval between doses 
 
Under the assumption that the variance associated with each antibody assay will be similar to 
the adult data from the pooled COV001/002/003/005 studies (Table 12), 60 participants will 
provide a 95% confidence interval half-width between 0.182 and 0.304 (Table 14). 
Table 14 
Estimated Half-width of the 95% CI for GMT Given Alternate Assay 
Variance 
Standard deviation 
Estimated half-width of the 95% confidence interval (natural log scale) 
N=60 
N=300 
0.72 
0.182 
0.081 
0.83 
0.210 
0.094 
0.96 
0.243 
0.109 
1.1 
0.278 
0.124 
1.2 
0.304 
0.136 
 
Under the assumption that the seroresponse rates associated with immunocompromised 
cohorts will be similar to the adult data from the pooled COV001/002/003/005 studies 

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(Table 13), 60 participants will provide a 95% confidence interval half-width between 2.1% 
and 12.4% (Table 15). 
Table 15  
Estimated Half-width of the 95% Confidence Interval for Selected 
Seroresponse Proportions 
Observed 
seroresponse rate 
Estimated half-width of the 95% confidence interval 
 
N=60 
N=300 
30.0% 
11.6% 
5.2% 
40.0% 
12.4% 
5.5% 
50.0% 
12.7% 
5.7% 
59.7% 
12.4% 
5.6% 
85.5% 
8.9% 
4.0% 
95.9% 
5.0% 
2.2% 
 
9.3 
Populations for Analyses 
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 enrolled participants, i.e., those participants who meet screening eligibility 
criteria. Participants who withdraw consent to participate in the study will be 
included up to the date of their study withdrawal. 
Safety analysis set 
The safety analysis set consists of all participants who have received at least 
one dose of AZD1222. A participant who has on one or several occasions 
received active study intervention is classified as active for all summaries, 
including summaries by dose. This will be the primary analysis set for all 
safety analyses. 
Immunogenicity analysis set 
The immunogenicity analysis set 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 such protocol violations will be documented in the Statistical 
Analysis Plan. This will be the primary analysis set for all immunogenicity 
analyses. 
 
9.4 
Statistical Analyses 
9.4.1 
General Considerations 
This section provides a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints. A more technical and detailed 
description of the statistical analyses will be described in the Statistical Analysis Plan, and an 
approved version will be finalized prior to any primary analyses.  

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The primary analysis will occur when all participants within a cohort have completed visit 8 
(i.e., 28 days after the second dose; see Table 2 and Table 3).  Analyses of pooled 
immunocompromised cohorts will be performed only after all immunocompromised cohorts 
have completed visit 8 (i.e., 28 days after the second dose; see Table 2) for this analysis. 
Secondary analyses of third dose (primary series) will occur when all participants within an 
immunocompromised cohort have completed visit 10 (i.e., 28 days after the third dose; see 
Table 2). Analyses of pooled immunocompromised cohorts will be performed only after all 
immunocompromised cohorts have completed their visit 10 (i.e., 28 days after the third dose; 
see Table 2) for this analysis. 
The final analysis will occur when data from all vaccinated participants are available through 
completion of the last study visit (see Table 2 and Table 3). 
Exploratory analyses may not be reported in the Clinical Study Report, but in an addendum to 
the Clinical Study Report. 
Data will be provided in data listings sorted by cohort and participant number. Tabular 
summaries will be presented by cohort. Categorical data will be summarized by the number 
and percentage of participants in each category. 
Continuous variables will be summarised with descriptive statistics, including number of 
available observations, mean, standard deviation, median, minimum and maximum, and 
quartiles where more appropriate.  Data may be log-transformed, as appropriate. 
All point estimates will be presented together with a 95% CI, unless otherwise stated. 
Demography and baseline characteristics will be summarised by cohort. 
All secondary comparisons between individual or pooled immunocompromised cohorts and 
the immunocompetent cohort will be done using GMT ratios and differences in seroresponse 
rates, with 95% CI. Given the descriptive nature of these analyses, no p-values will be 
reported. 
Secondary summaries of the change from 28 days post dose 2 to 28 days post dose 3 within a 
cohort will be done using GMT fold rise from dose 2 (day 28 post dose 3 titre/day 28 post 
dose 2 titre) and seroresponse (from dose 2), defined as a ≥ 4-fold increase in titres from 
28 days post dose 2 to 28 days post dose 3, with 95% CI. 
All participants will be analysed according to the cohort in which they are enrolled, regardless 
of meeting criteria for multiple cohorts. Sensitivity analyses to account for participants 
meeting multiple cohort criteria may be defined in the SAP. 

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For primary and secondary immunogenicity analyses, participants who do not receive the 
second dose of study intervention will be excluded from all time points post the dose 2 visit 
window. Participants who do not receive the third dose of study intervention will be excluded 
from all time points post the dose 3 visit window. 
9.4.2 
Immunogenicity 
The immunogenicity endpoints of interest in this study are: 
• Antibody titre 
• Seroresponse, defined as ≥ 4-fold increase in the antibody titre from baseline 
(pre-dose 1) 
 
For the primary objective (to characterize the immunogenicity of a 2-dose primary vaccination 
series with AZD1222), without a prespecified directional hypothesis, 2-sided 95% CIs will be 
calculated as descriptive measures for each immunogenicity endpoint. 
The geometric mean titre and seroresponse rate will be summarised descriptively by cohort, 
timepoint and antibody for the immunogenicity population (Table 16). GMFR will be reported 
along with all GMT analyses. 
Table 16  
Primary Immunogenicity Summaries to be Completed (by Cohort, 
Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Organ Transplant 
28 post 1st dosea 
Pseudo 
GMT 
1 
Seroresponse 
2 
Anti-S 
GMT 
3 
Seroresponse 
4 
28 post 2nd dosea 
Pseudo 
GMT 
5 
Seroresponse 
6 
Anti-S 
GMT 
7 
Seroresponse 
8 
Hemopoietic Stem Cell 
Transplantation 
28 post 1st dosea 
Pseudo 
GMT 
9 
Seroresponse 
10 
Anti-S 
GMT 
11 
Seroresponse 
12 
28 post 2nd dosea 
Pseudo 
GMT 
13 
Seroresponse 
14 
Anti-S 
GMT 
15 
Seroresponse 
16 

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Table 16  
Primary Immunogenicity Summaries to be Completed (by Cohort, 
Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Solid organ cancer on 
chemotherapy 
28 post 1st dosea 
Pseudo 
GMT 
17 
Seroresponse 
18 
Anti-S 
GMT 
19 
Seroresponse 
20 
28 post 2nd dosea 
Pseudo 
GMT 
21 
Seroresponse 
22 
Anti-S 
GMT 
23 
Seroresponse 
24 
Inflammatory 
28 post 1st dosea 
Pseudo 
GMT 
25 
Seroresponse 
26 
Anti-S 
GMT 
27 
Seroresponse 
28 
28 post 2nd dosea 
Pseudo 
GMT 
29 
Seroresponse 
30 
Anti-S 
GMT 
31 
Seroresponse 
32 
Primary Immunodeficiency 
28 post 1st dosea 
Pseudo 
GMT 
33 
Seroresponse 
34 
Anti-S 
GMT 
35 
Seroresponse 
36 
28 post 2nd dosea 
Pseudo 
GMT 
37 
Seroresponse 
38 
Anti-S 
GMT 
39 
Seroresponse 
40 
Pooled Immunocompromised 
28 post 1st dosea 
Pseudo 
GMT 
41 
Seroresponse 
42 
Anti-S 
GMT 
43 
Seroresponse 
44 
28 post 2nd dosea 
Pseudo 
GMT 
45 
Seroresponse 
46 
Anti-S 
GMT 
47 
Seroresponse 
48 

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Table 16  
Primary Immunogenicity Summaries to be Completed (by Cohort, 
Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Healthy (Immunocompetent) 
28 post 1st dosea 
Pseudo 
GMT 
49 
Seroresponse 
50 
Anti-S 
GMT 
51 
Seroresponse 
52 
28 post 2nd dosea 
Pseudo 
GMT 
53 
Seroresponse 
54 
Anti-S 
GMT 
55 
Seroresponse 
56 
a 
Samples collected for the Day 28 post 1st dose must be collected on or before the date of 2nd dose to be 
included in analyses. Similarly, samples collected for the Day 28 post 2nd dose must be collected on or 
before the date of 3rd dose to be included in analyses. 
 
Secondary immunogenicity antibody responses will be performed similarly to the primary 
immunogenicity analyses at 28 days post 3rd dose (Table 17). 
Table 17 
Secondary Immunogenicity Summaries to be Completed (by Cohort, 
Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Organ Transplant 
28 post 3rd dose 
Pseudo 
GMT 
1 
Seroresponse 
2 
Anti-S 
GMT 
3 
Seroresponse 
4 
Hemopoietic Stem Cell 
Transplantation 
28 post 3rd dose 
Pseudo 
GMT 
5 
Seroresponse 
6 
Anti-S 
GMT 
7 
Seroresponse 
8 
Solid organ cancer on 
chemotherapy 
28 post 3rd dose 
Pseudo 
GMT 
9 
Seroresponse 
10 
Anti-S 
GMT 
11 
Seroresponse 
12 

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Table 17 
Secondary Immunogenicity Summaries to be Completed (by Cohort, 
Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Inflammatory 
28 post 3rd dose 
Pseudo 
GMT 
13 
Seroresponse 
14 
Anti-S 
GMT 
15 
Seroresponse 
16 
Primary Immunodeficiency 
28 post 3rd dose 
Pseudo 
GMT 
17 
Seroresponse 
18 
Anti-S 
GMT 
19 
Seroresponse 
20 
Pooled Immunocompromised 
28 post 3rd dose 
Pseudo 
GMT 
21 
Seroresponse 
22 
Anti-S 
GMT 
23 
Seroresponse 
24 
Healthy (Immunocompetent) a 
28 post 3rd dose 
Pseudo 
GMT 
25 
Seroresponse 
26 
Anti-S 
GMT 
27 
Seroresponse 
28 
 
Exploratory anti-vector antibody responses will be performed similarly to the primary 
immunogenicity analyses (Table 18). 
Table 18  
Exploratory Anti-vector Immunogenicity Summaries to be 
Completed (by Cohort, Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Organ Transplant 
28 post 1st dosea 
ChAdOx1 nAb 
GMT 
1 
Seroresponse 
2 
28 post 2nd dosea 
ChAdOx1 nAb 
GMT 
3 
Seroresponse 
4 
28 post 3rd dose 
ChAdOx1 nAb 
GMT 
5 
Seroresponse 
6 

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Table 18  
Exploratory Anti-vector Immunogenicity Summaries to be 
Completed (by Cohort, Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Hemopoietic Stem Cell 
Transplantation 
28 post 1st dosea 
ChAdOx1 nAb 
GMT 
7 
Seroresponse 
8 
28 post 2nd dosea 
ChAdOx1 nAb 
GMT 
9 
Seroresponse 
10 
28 post 3rd dose 
ChAdOx1 nAb 
GMT 
11 
Seroresponse 
12 
Solid organ cancer receiving 
chemotherapy 
28 post 1st dosea 
ChAdOx1 nAb 
GMT 
13 
Seroresponse 
14 
28 post 2nd dosea 
ChAdOx1 nAb 
GMT 
15 
Seroresponse 
16 
28 post 3rd dose 
ChAdOx1 nAb 
GMT 
17 
Seroresponse 
18 
Inflammatory 
28 post 1st dosea 
ChAdOx1 nAb 
GMT 
19 
Seroresponse 
20 
28 post 2nd dosea 
ChAdOx1 nAb 
GMT 
21 
Seroresponse 
22 
28 post 3rd dose 
ChAdOx1 nAb 
GMT 
23 
Seroresponse 
24 
Primary Immunodeficiency 
28 post 1st dosea 
ChAdOx1 nAb 
GMT 
25 
Seroresponse 
26 
28 post 2nd dosea 
ChAdOx1 nAb 
GMT 
27 
Seroresponse 
28 
28 post 3rd dose 
ChAdOx1 nAb 
GMT 
29 
Seroresponse 
30 
Pooled Immunocompromised 
28 post 1st dosea 
ChAdOx1 nAb 
GMT 
31 
Seroresponse 
32 
28 post 2nd dosea 
ChAdOx1 nAb 
GMT 
33 
Seroresponse 
34 
28 post 3rd dose 
ChAdOx1 nAb 
GMT 
35 
Seroresponse 
36 

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Table 18  
Exploratory Anti-vector Immunogenicity Summaries to be 
Completed (by Cohort, Timepoint, Antibody, and Endpoint) 
Cohort 
Day 
Antibody 
Endpoint 
Index 
Healthy (Immunocompetent) 
28 post 1st dosea 
ChAdOx1 nAb 
GMT 
37 
Seroresponse 
38 
28 post 2nd dosea 
ChAdOx1 nAb 
GMT 
39 
Seroresponse 
40 
28 post 3rd dose 
ChAdOx1 nAb 
GMT 
41 
Seroresponse 
42 
a  
Samples collected for the Day 28 post 1st dose must be collected on or before the date of 2nd dose to be 
included in analyses. Similarly, samples collected for the Day 28 post 2nd dose must be collected on or before the 
date of 3rd dose to be included in analyses. 
 
For secondary analyses to be completed at the time of primary analysis, immunocompromised 
groups will be compared to the immunocompetent group at 28 days post 2nd dose using both 
geometric mean titre ratios and seroresponse rate differences, with corresponding 2-sided 95% 
CIs (Table 19).  
Table 19  
Secondary Immunogenicity Comparisons to be Completed at the time 
of the Primary Analysis (by Cohorts Compared, Timepoint, Antibody, 
and Endpoint) 
Comparator 
Cohort 
Reference Cohort 
Day 
Antibody 
Endpoint 
Index 
Organ Transplant 
Healthy 
(Immunocompetent) 
28 post 
2nd dose 
Pseudo 
GMT Ratio 
1 
Difference in 
Seroresponse 
2 
Anti-S 
GMT Ratio 
3 
Difference in 
Seroresponse 
4 
Hemopoietic Stem 
Cell 
Transplantation 
Healthy 
(Immunocompetent) 
28 post 
2nd dose 
Pseudo 
GMT Ratio 
5 
Difference in 
Seroresponse 
6 
Anti-S 
GMT Ratio 
7 
Difference in 
Seroresponse 
8 
Solid organ cancer 
on chemotherapy 
Healthy 
(Immunocompetent) 
28 post 
2nd dose 
Pseudo 
GMT Ratio 
9 
Difference in 
Seroresponse 
10 
Anti-S 
GMT Ratio 
11 

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Table 19  
Secondary Immunogenicity Comparisons to be Completed at the time 
of the Primary Analysis (by Cohorts Compared, Timepoint, Antibody, 
and Endpoint) 
Comparator 
Cohort 
Reference Cohort 
Day 
Antibody 
Endpoint 
Index 
Difference in 
Seroresponse 
12 
Inflammatory 
Healthy 
(Immunocompetent) 
28 post 
2nd dose 
Pseudo 
GMT Ratio 
13 
Difference in 
Seroresponse 
14 
Anti-S 
GMT Ratio 
15 
Difference in 
Seroresponse 
16 
Primary 
Immunodeficiency 
Healthy 
(Immunocompetent) 
28 post 
2nd dose 
Pseudo 
GMT Ratio 
17 
Difference in 
Seroresponse 
18 
Anti-S 
GMT Ratio 
19 
Difference in 
Seroresponse 
20 
Pooled 
Immunocompromi
sed 
Healthy 
(Immunocompetent) 
28 post 
2nd dose 
Pseudo 
GMT Ratio 
21 
Difference in 
Seroresponse 
22 
Anti-S 
GMT Ratio 
23 
Difference in 
Seroresponse 
24 
 
For secondary analyses to be completed at the time of the secondary analysis, immunogenicity 
responses at 28 days post 3rd dose in immunocompromised groups will be compared to the 
immunogenicity responses at 28 days post 2nd dose in the immunocompetent group using both 
geometric mean titre ratios and seroresponse rate differences, with corresponding 2-sided 95% 
CIs (Table 20). Immunogenicity responses at 28 days post 3rd dose will be compared to the 
immunogenicity responses at 28 days post 2nd dose within each cohort in the same manner. 

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Table 20 
Secondary Immunogenicity Comparisons to be Completed at the time 
of the Secondary Analysis (by Cohorts Compared, Timepoint, 
Antibody, and Endpoint) 
Comparator Cohort 
Reference 
Cohort 
Day 
Antibody 
Endpoint 
Inde
x 
Organ Transplant 
Healthy 
(Immunocomp
etent) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Ratio 
1 
Difference in 
Seroresponse 
2 
Anti-S 
GMT Ratio 
3 
Difference in 
Seroresponse 
4 
Hemopoietic Stem Cell 
Transplantation 
Healthy 
(Immunocomp
etent) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Ratio 
5 
Difference in 
Seroresponse 
6 
Anti-S 
GMT Ratio 
7 
Difference in 
Seroresponse 
8 
Solid organ cancer on 
chemotherapy 
Healthy 
(Immunocomp
etent) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Ratio 
9 
Difference in 
Seroresponse 
10 
Anti-S 
GMT Ratio 
11 
Difference in 
Seroresponse 
12 
Inflammatory 
Healthy 
(Immunocomp
etent) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Ratio 
13 
Difference in 
Seroresponse 
14 
Anti-S 
GMT Ratio 
15 
Difference in 
Seroresponse 
16 
Primary 
Immunodeficiency 
Healthy 
(Immunocomp
etent) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Ratio 
17 
Difference in 
Seroresponse 
18 
Anti-S 
GMT Ratio 
19 
Difference in 
Seroresponse 
20 

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Table 20 
Secondary Immunogenicity Comparisons to be Completed at the time 
of the Secondary Analysis (by Cohorts Compared, Timepoint, 
Antibody, and Endpoint) 
Comparator Cohort 
Reference 
Cohort 
Day 
Antibody 
Endpoint 
Inde
x 
Pooled 
Immunocompromised 
Healthy 
(Immunocomp
etent) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Ratio 
21 
Difference in 
Seroresponse 
22 
Anti-S 
GMT Ratio 
23 
Difference in 
Seroresponse 
24 
Organ Transplant (28 
days post 3rd dose) 
Organ 
Transplant (28 
days post 2nd 
dose) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Fold Rise 
25 
Seroresponse (from 
2nd dose) a 
26 
Anti-S 
GMT Fold Rise 
27 
Seroresponse (from 
2nd dose) a 
28 
Hemopoietic Stem Cell 
Transplantation (28 days 
post 3rd dose) 
Hemopoietic 
Stem Cell 
Transplantatio
n (28 days 
post 2nd dose) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Fold Rise 
29 
Seroresponse (from 
2nd dose) a 
30 
Anti-S 
GMT Fold Rise 
31 
Seroresponse (from 
2nd dose) a 
32 
Solid organ cancer on 
chemotherapy (28 days 
post 3rd dose) 
Solid organ 
cancer on 
chemotherapy 
(28 days post 
2nd dose) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Fold Rise 
33 
Seroresponse (from 
2nd dose) a 
34 
Anti-S 
GMT Fold Rise 
35 
Seroresponse (from 
2nd dose) a 
36 
Inflammatory (28 days 
post 3rd dose) 
Inflammatory 
(28 days post 
2nd dose) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Fold Rise 
37 
Seroresponse (from 
2nd dose) a 
38 
Anti-S 
GMT Fold Rise 
39 
Seroresponse (from 
2nd dose) a 
40 

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Table 20 
Secondary Immunogenicity Comparisons to be Completed at the time 
of the Secondary Analysis (by Cohorts Compared, Timepoint, 
Antibody, and Endpoint) 
Comparator Cohort 
Reference 
Cohort 
Day 
Antibody 
Endpoint 
Inde
x 
Primary 
Immunodeficiency (28 
days post 3rd dose) 
Primary 
Immunodefici
ency (28 days 
post 2nd dose) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Fold Rise 
41 
Seroresponse (from 
2nd dose) a 
42 
Anti-S 
GMT Fold Rise 
43 
Seroresponse (from 
2nd dose) a 
44 
Pooled 
Immunocompromised 
(28 days post 3rd dose) 
Pooled 
Immunocompr
omised (28 
days post 2nd 
dose) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Fold Rise 
45 
Seroresponse (from 
2nd dose) a 
46 
Anti-S 
GMT Fold Rise 
47 
Seroresponse (from 
2nd dose) a 
48 
Healthy 
(Immunocompetent) (28 
days post 3rd dose) 
Healthy 
(Immunocomp
etent) (28 days 
post 2nd dose) 
Comparator: 28 
post 3rd dose 
Reference: 28 post 
2nd dose 
Pseudo 
GMT Fold Rise 
49 
Seroresponse (from 
2nd dose) a 
50 
Anti-S 
GMT Fold Rise 
51 
Seroresponse (from 
2nd dose) a 
52 
a 
Seroresponse (from 2nd dose) is defined as a ≥ 4-fold increase in titres from 28 days post dose 2 to 28 days 
post dose 3. 
 
Exploratory correlative analyses between ChAdOx1 nAb, anti-S and pseudo-neutralizing 
antibody responses may be performed. 
9.4.3 
Safety 
The safety of AZD1222 will primarily be assessed by: 
• Incidence of unsolicited AEs for 28 days after each dose of AZD1222 
• Incidence of SAEs from Day 1 post treatment through the last study visit 
• Incidence of AESIs from Day 1 post-treatment through the last study visit 
• Incidence of MAAEs from Day 1 post-treatment through the last study visit 
• Incidence of local and systemic solicited AEs for 7 days after each dose of AZD1222 
• Description of safety laboratory assessments, including coagulation and platelet assay 
results 

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AE severity will be graded according to a revised toxicity grading scale from the US FDA 
guidance (FDA 2007) see Appendix F and coded using the most recent version of the Medical 
Dictionary for Regulatory Activities. AEs will be presented for each cohort 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. 
Summaries will present the relationship to IP as assessed by the investigator, maximum 
intensity, seriousness, and death. 
A listing will cover details for each AE. 
Details of all AE analysis, laboratory safety analyses, vital sign analyses will be provided in 
the SAP, which will include descriptive statistics presented for observed and change from 
baseline values for all safety parameters. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Not Applicable. 

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Appendix A Regulatory, Ethical, and Study Oversight Considerations 
A 1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the clinical study protocol (CSP) and with the 
following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., 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 other applicable local regulations. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor of a 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, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 

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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 a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the [Investigator’s Brochure or state other documents] 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 authorised 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 authorised 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 (HIPAA) requirements, where 
applicable, and the IRB/IEC or study centre. 
The 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 authorised 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. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorised 
representative. 
Participants who are rescreened are required to sign a new ICF. 

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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 authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
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 authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
A 5 
Committees Structure 
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with AstraZeneca Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators.  
An independent Neurology Expert Committee for AESIs will be available to review and 
provide advice on request about their 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 Neurology Expert 
Committee for AESIs Charter.  
An independent Hematology Expert Panel will be available to review and provide advice on 
requests about their diagnosis and causality assessment of selected thrombosis with 
thrombocytopenia AESIs occurring in the AZD1222 clinical development program. Details on 
the composition and operation of this committee are described in the Hematology Expert 
Panel Charter. 

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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 (e.g., 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 (e.g., 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 (e.g., Contract 
Research Organizations). 
Study monitors will perform ongoing source data review to confirm that the safety and rights 
of participants are being protected, and that the study is being conducted in accordance with 
the currently approved protocol and any other study agreements, ICH/GCP, and all applicable 
regulatory requirements.  
 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 25 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. 

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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. 
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 

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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 adverse event is the development of any untoward medical occurrence in a patient or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (e.g., 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 serious and non-serious AEs 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 
A serious adverse event is an AE occurring during any study phase (i.e., 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 anomaly or birth defect 
• Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a non-serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy. 

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Life-threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product 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 (e.g., hepatitis that resolved without hepatic failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., 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 jeopardise 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. 
• Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
• Development of drug dependency or drug abuse 
 
Intensity Rating Scale: 
 A revised toxicity grading scale found in the US FDA guidance for healthy volunteers 
enrolled in a preventive vaccine clinical study (FDA 2007) will be utilized for all events with 
an assigned severity grading including Grade 4. 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 

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several hours may be considered severe nausea, but not a 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 a 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 drug. 
• 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 drug? 
• Consistency with known drug profile. Was the AE consistent with the previous knowledge 
of the suspect drug (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 drug? 
• 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 drug 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 recognised feature of overdose of the drug? 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 

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B 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 drug, but rather a human or process related 
failure while the drug 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 drug 
• 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: 
• Drug name confusion 
• Dispensing error e.g., medication prepared incorrectly, even if it was not actually given to 
the participant 
• Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as a 
solid tablet  
• Drug not stored as instructed e.g., kept in the fridge when it should be at room temperature  
• Wrong participant received the medication (excluding IRT/RTSM errors) 
• Wrong drug administered to participant (excluding IRT/RTSM errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error  
• Participant accidentally missed drug dose(s) e.g., forgot to take medication 
• Accidental overdose (will be captured as an overdose) 
• Participant failed to return unused medication or empty packaging 
• 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 centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre 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. 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner. 
C 2 
Withdrawal of Informed Consent for Donated Biological Samples  
The Sponsor ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent form. 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, the Sponsor is not obliged to destroy the results of this research. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
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, the samples are disposed of or repatriated as appropriate, 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, e.g., 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, e.g., 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 Actions Required in Cases of any Thrombosis in 
Combination with Thrombocytopenia 
D 1.1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of thrombosis in combination with thrombocytopenia. It is not intended to be a 
comprehensive guide to the management of all venous thromboembolic events. 
During the course of the study, the Investigator will remain vigilant for occurrence of 
thrombosis in combination with thrombocytopenia. Appropriate investigations (e.g., imaging) 
to diagnose these events should be made on a case-by-case basis. The Investigator is 
responsible for determining whether a patient meets criteria for thrombosis in combination 
with thrombocytopenia at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting criteria for thrombosis in combination with 
thrombocytopenia. The Study Physician contacts the Investigator to provide guidance, discuss, 
and agree an approach for the participant’s follow-up and the continuous review of data. 
Notably, participants should only be treated with heparin if HIT antibodies are negative at the 
last available timepoint. An alternative explanation for thrombocytopenia should be 
considered (e.g., alcohol use, liver cirrhosis, concomitant medications, exposure to toxic 
chemicals, viral infections). 
The Investigator is responsible for recording data pertaining to thrombosis in combination 
with thrombocytopenia and for reporting AEs and SAEs according to the outcome of the 
review and assessment in line with standard safety reporting processes. 
D 1.2 
Tests that Should Be Considered if Thrombosis in Combination with 
Thrombocytopenia Occurs 
The following tests should be considered, but not limited to: 
1. Measurement of platelet levels, prothrombin time (PT), activated partial thromboplastin 
time (aPTT), D-dimer, and fibrinogen levels 
2. Complete blood count, reticulocyte count, blood film, haptoglobins 
3. Anti-PF4 antibodies (by ELISA), 
4. ANA, ANCA, rheumatoid factor, HLA B27, ADAMTS13 activity, anti-cardiolipin 
antibodies IgG + IgM, and anti-B2GPI antibodies IgG + IgM 
5. Complement (e.g., C3, C4, Complement Complex C5b-9, C5a), autoantibodies (e.g., 
antinuclear IgG, anti-double-stranded DNA IgG, anti-Smith IgG, anti-SSA IgG, anti-SSB 
IgG, anti-Jo1 IgG, anti-MPO IgG, anti-PR3 IgG, anti-glomerular basement membrane 
IgG) 

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6. Factor V Leiden, Factor II (prothrombin) variant  
7. Platelet activation markers and functional assays, e.g., sCD40L, soluble glycoproteins, 
degranulation markers (PF4, vWF, P-selectin, annexin V), anti-PF4-plasma-serotonin 
release assay (if anti-PF4 antibody ELISA positive) 
8. Serum inflammatory markers: TNFa, IL-1, IL-4, IL-6, IL-10, IL-13 
9. Cell adhesion markers: VCAM, ICAM, E-Selectin 
10. Adenovirus serology 
11. Additional viral serology: Cytomegalovirus (IgG and IgM), Epstein-Barr virus (IgG and 
IgM), HIV, Parvo virus B19 
12. COVID-19 testing, including PCR and serology 
13. Calculation of an ISTH score for DIC (derived from platelet levels, PT; fibrinogen, and 
D-Dimer) (Toh et al 2007) 
 

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Appendix E  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 21: Clinical Abnormalities, Local Reactions to Injectable Product 
Table 22: Clinical Abnormalities, Vital Signs 
Table 23: Clinical Abnormalities, Systemic (General or Illness) 
Table 21  
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product 
Local Reaction to 
Injectable Product 
Reaction Grade 
Mild  
(Grade 1) 
Moderate 
 (Grade 2) 
Severe  
(Grade 3) 
Life Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/redness a, b 
1-2 inches 
 (2.5–5 cm) 
> 2-4 inches 
 (5.1–10 cm) 
> 4 inches 
 (> 10 cm) 
Necrosis or 
exfoliative 
dermatitis 
Induration/swelling a, b  
1-2 inches 
 (2.5–5 cm) 
> 2-4 inches 
 (5.1–10 cm) 
> 4 inches 
 (> 10 cm) 
Necrosis 
a. 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.  Reactions < 0.25 inches (< 0.6 centimetres) in diameter will not be 
recorded. 
b. Grade 4 erythema or induration is determined by study site with participant input rather than being 
recorded directly in Solicited AE eDiary. 
ER: emergency room. 
 
 

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Table 22  
Tables for Clinical Abnormalities: Vital Signs 
Vital Sign 
Vital Signs Grade 
Mild  
(Grade 1) 
Moderate 
 (Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4)a 
Fever (°C/°F) 
37.9-38.4 
 100.1-101.1 
38.5-38.9 
 101.2-102.0 
39.0-40 
 102.1-104 
> 40 
 > 104 
Tachycardia 
(beats/minute) 
101-115 
116- 130 
> 130 
Emergency room visit 
or hospitalization for 
arrhythmia 
Bradycardia 
(beats/minute) 
50-54 
45-49 
< 45 
Emergency room visit 
or hospitalization for 
arrhythmia 
Hypertension; systolic 
(mm Hg) 
141-150 
151-155 
> 155 
Emergency room visit 
or hospitalization for 
malignant hypertension 
Hypertension; diastolic 
(mm Hg) 
91-95 
96-100 
> 100 
Emergency room visit 
or hospitalization for 
malignant hypertension 
Hypotension; systolic 
(mm Hg) 
85-89 
80-84 
< 80 
Emergency room visit 
or hospitalization for 
hypotensive shock 
Respiratory rate 
(breaths/minute) 
17-20 
21-25 
> 25 
Intubation 
Grade 4 vital signs other than fever are reported as adverse events.  Use clinical judgment when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes. 
 
 
 

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Table 23  
Tables for Clinical Abnormalities: Systemic (General or Illness) 
Systemic 
(General) 
Systemic Grade a 
Mild  
(Grade 1) 
Moderate 
 (Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/ 
 vomiting 
No interference with 
activity or  
1-2 episodes/24 
hours 
Some interference 
with activity or > 2 
episodes/24 hours 
Prevents daily 
activity, required 
outpatient intravenous 
hydration 
Emergency room 
visit or 
hospitalization for 
hypotensive shock 
Chills 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
Emergency room 
visit or 
hospitalization 
Headache 
No interference with 
activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours or some 
interference with 
activity 
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity 
Emergency room 
visit or 
hospitalization 
Fatigue 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
Emergency room 
visit or 
hospitalization 
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
Emergency room 
visit or 
hospitalization 
Systemic Illness 
Illness or 
clinical 
adverse event 
(as defined 
according to 
applicable 
regulations) 
No interference with 
activity 
Some interference 
with activity not 
requiring 
intervention 
Prevents daily activity 
and required medical 
intervention 
Emergency room 
visit or 
hospitalization 
 
 

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Appendix F  Adverse Events of Special Interest 
Adverse events of special interest for this study are based on Brighton Collaboration case 
definitions (SPEAC 2021), clinical experience, and scientific interest.  There is no current 
evidence to suggest that AZD1222 is associated with these AEs of special interest. 
Table 24  
Adverse Events of Special Interest 
Category 
Medical Concept 
Neurologic 
Generalized convulsion: episodes of neuronal hyperactivity most commonly resulting 
in sudden, involuntary muscular contractions.  They may also manifest as sensory 
disturbances, autonomic dysfunction and behavioural abnormalities, and impairment 
or loss of consciousness.   
Guillain-Barré syndrome: a peripheral nerve demyelinating disease, which can present 
as temporary ascending paralysis. 
Acute disseminated encephalomyelitis: defined as a uniphasic syndrome of brain 
inflammation and demyelination occurring in temporal association with an antecedent 
immunologic challenge, such as infection or an immunization.  ADEM most 
commonly occurs in the paediatric population. 
Other neurologic events: include new onset event (acute or subacute) motor and 
sensory disturbances (e.g., weakness, numbness, paraesthesia, hypoesthesia, 
hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait impairment, or visual 
disturbance, or any event of myelitis, encephalomyelitis, myelitis transverse, aseptic 
meningitis or other sudden neurological deficit. 
Vascular 
Thrombotic, thromboembolic, and neurovascular events: events that can manifest as 
transient or permanent vision problems, dizziness, trouble understanding, facial droop, 
slurred speech, unilateral weakness, deep vein thrombosis with swollen, warm or 
painful leg, pulmonary embolism with shortness of breath, chest pain or irregular heart 
rate. 
Hematologic 
Thrombocytopenia: a disorder in which there is an abnormally low platelet count; a 
normal platelet count ranges from 150 000 to 450 000 platelets per μL. 
Immunologic 
Vasculitides: a group of related disorders characterized by inflammation of blood 
vessels (vasculitis) leading to tissue or end-organ injury. 
Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement 
that can present as, or rapidly progress to, a severe life-threatening reaction requiring 
immediate medical attention. 
Vaccine-associated enhanced respiratory disease: pathogenicity has been linked to a 
vaccine immune response characterized by induction of non‑neutralizing antibodies, 
and a T-cell response of the Th2 type with hypereosinophilia (Lambert PH, et al 2020).  
VAERD may manifest as a severe form of respiratory disease with prolonged fever, 

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Table 24  
Adverse Events of Special Interest 
Category 
Medical Concept 
and diverse clinical manifestations of disease severity and pathological changes 
marked by increased areas of lung consolidation, broncho-interstitial pneumonia, and 
necrotizing bronchiolitis (Rajão et al 2016). 
Potential immune-mediated conditions: a group of autoimmune inflammatory 
disorders characterized by an alteration in cellular homeostasis, which may or may not 
have an autoimmune aetiology.  A list of events is provided in Table 25. 
Cardiovascular 
system 
Myocarditis and pericarditis. 
Other forms of acute cardiac injury including arrhythmias, heart failure, coronary 
artery disease, myocardial infarction, stress cardiomyopathy. 
Renal 
Acute kidney injury. 
Gastrointestinal 
Acute liver injury. 
Acute pancreatitis. 
Musculoskeletal 
system 
Aseptic arthritis. 
Rhabdomyolysis. 
Skin 
Erythema multiforme. 
Chilblain-like lesions. 
Other system 
Anosmia, ageusia. 
 
 
 

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Table 25  
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 
 
Subacute thyroiditis, 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 

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Table 25  
List of Potential Immune-mediated Medical Conditions 
Category 
Condition 
 
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 
 
Aseptic arthritis 
Neuroinflammatory disorders 
Acute disseminated encephalomyelitis, including site specific variants 
(e.g., non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis) 
 
Cranial nerve disorders, including paralyses/paresis (e.g., 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 
 
Aseptic meningitis 
Skin disorders 
Alopecia areata 
 
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis 

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Table 25  
List of Potential Immune-mediated Medical Conditions 
Category 
Condition 
 
Cutaneous lupus erythematosus 
 
Erythema nodosum 
 
Morphoea 
 
Lichen planus 
 
Psoriasis 
 
Rosacea 
 
Sweet’s syndrome 
 
Vitiligo 
Vasculitides 
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis 
 
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Bechet's 
syndrome, leukocytoclastic vasculitis, single organ cutaneous vasculitis 
Other 
Antiphospholipid syndrome 
 
Autoimmune hemolytic anaemia 
 
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
 
Autoimmune myocarditis/cardiomyopathy 
 
Autoimmune thrombocytopenia 
 
Goodpasture syndrome 

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Table 25  
List of Potential Immune-mediated Medical Conditions 
Category 
Condition 
 
Idiopathic pulmonary fibrosis 
 
Pernicious anaemia 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
 
Sjögren’s syndrome 
 
Stevens-Johnson syndrome 
 
Uveitis 
 
Multisystem inflammatory syndrome 
 

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Appendix G  Abbreviations 
Abbreviation or special term 
Explanation 
AEs 
Adverse events 
AESIs 
Adverse events of special interest 
BCR 
B-cell receptor 
ChAdOx1 nCoV-19 
AZD1222 when initially developed by the University of Oxford 
COVID-19 
Coronavirus disease 2019 
CSP 
Clinical Study Protocol 
CVST 
Cerebral venous sinus thrombosis 
DIC 
Disseminated intravascular coagulation 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
GMFR 
Geometric Mean Fold Rise 
GMT 
Geometric Mean Titre 
HSCT 
Hematopoietic stem-cell transplantation 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH/GCP 
International Council of Harmonisation/Good Clinical Practice 
IM 
Intramuscular 
I(M)P 
Investigational (Medical) Product 
IRB/IEC 
Institutional Review Board/ Independent Ethics Committee 
ISTH 
International Society on Thrombosis and Haemostasis 
MAAEs 
Medically attended adverse event 
MERS 
Middle East respiratory syndrome 
MSD 
Meso Scale Discovery 
nAb 
Neutralizing antibody 
PBMC 
Peripheral blood mononuclear cell 
RBD 
Receptor binding domain 
RT-PCR 
Reverse transcriptase-polymerase chain reaction 
S 
Spike protein 
SAEs 
Serious adverse events 
SARS-CoV-2 
Severe acute respiratory syndrome-coronavirus-2 
SCID 
Severe combined immunodeficiency 
TCR 
T-cell receptor 
VAED 
Vaccine-associated enhanced disease 
VAERD 
Vaccine-associated enhanced respiratory disease 

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Abbreviation or special term 
Explanation 
WOCBP 
Women of childbearing potential 

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Appendix H Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly below the Table of Contents. 
Amendment 2 (14 December 2021) 
Overall Rationale for the Amendment 
The principal reasons for updating this protocol were to: 
• Add a third dose in the primary vaccination series, four weeks after the second dose, 
for all immunocompromised cohorts and update the study design and schedule of 
activities. 
• Add a third dose booster six months after the first dose for the immunocompetent 
cohort and update the study design and schedule of activities. 
• Update the study objectives, endpoints, and statistical considerations. 
• Additional minor clarifications and corrections. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Section 1.1 Synopsis 
Section 3 Objectives and 
Endpoints 
Added footnote ‘b’ to 
Objectives and Endpoints 
table that baseline is 
collected prior to first dose 
Clarification of baseline 
collection 
Substantial 
Updated Secondary Safety 
Objective and Endpoint to 
characterize reactogenicity 
of a 3-dose primary 
vaccination series, from a 
2-dose series, in 
immunocompromised 
cohorts 
Clarification that a third 
dose will be given to both 
immunocompromised and 
immunocompetent 
participants  
Added a Secondary 
Immunogenicity 
Objectives To characterize 
the immunogenicity after a 
3rd-dose in a 3 dose 
primary vaccination series 
with AZD1222 in 
immunocompromised 
adults ≥ 18 years. 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Added a Secondary 
Immunogenicity Objective 
to describe the 
immunogenicity after the 
3rd dose in a 3-dose 
primary vaccination series 
with AZD1222 in adults ≥ 
18 years between SARS-
CoV-2 naïve 
immunocompromised 
participants compared to 
immunocompetent 
participants after a 2-dose 
primary vaccination.  
Substantial 
Added an Exploratory 
Objective to characterize 
the immunogenicity after a 
3rd-dose booster 
vaccination of AZD1222, 
administered 6 months 
after dose 1 of a 2-dose 
primary vaccination with 
AZD1222, in 
immunocompetent adults 
≥ 18 years. 
Section 1.2 Schema 
Figure 2: Study Design 
for Immunocompetent 
Participants 
Added Figure 2: Study 
Design for 
Immunocompetent 
Participants 
Clarification that this 
group has a different 
study design due to 
different dosing schedule 
Non-substantial 
Section 1.3 Schedule of 
Activities 
Table 2: Schedule of 
Activities: 
Vaccination/Follow-up 
Added Table 3  
Schedule of Activities for 
Immunocompetent cohort 
is different from 
immunocompromised 
cohorts  
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Period for 
Immunocompromised 
Cohorts 
Table 3: Schedule of 
Activities: 
Vaccination/Follow-up 
Period for 
Immunocompetent 
Participants 
Table 2: added third dose 
to the schedule of 
activities, updated the 
“Timeline (days)” to 
include number of days 
after previous visit (e.g. 
V1+7) added footnote ‘a’ 
and ‘b.’ 
Clarified that 
immunocompromised 
participants enrolled 
under protocol v2 that 
have already completed 
their V8 visit will have to 
repeat this visit prior to 
receiving a third dose; 
Clarified that the last 
study visit will be the 
latter of either Day 365 or 
6 months after dose 3 
Substantial 
Section 2 Introduction 
Added that participants are 
eligible to receive a third 
dose, minor corrections in 
Study Rationale, included 
information on COVID-19 
studies that included a 
third dose, updated 
references 
Inclusion of third dose 
and scientific studies 
supporting the inclusion 
of third dose; clarification 
of references  
Non-substantial 
Section 4.1 Overall 
Design 
Added that participants are 
eligible to receive a third 
dose, updated the AE 
follow-up period and final 
study visit 
Clarity of safety follow-
up period and inclusion of 
third dose 
Non-substantial 
Section 4.1.1 Screening 
Visit 
Added the word 
“pregnancy” for urine test 
Clarification that this is 
for a pregnancy test 
Non-substantial 
Section 4.1.2 Vaccination 
visit 
Added “urine” to 
pregnancy test, updated to 
3 intramuscular vaccine 
injections, updated follow 
up period for recording 
AEs 
Clarification that 
pregnancy test is a urine 
test, updated to include a 
third dose 
Non-substantial 
Section 4.1.3 Follow Up 
Visits 
Deleted “Day 365” for last 
study visit 
The last study visit may 
not be Day 365 for 
immunocompromised 
cohorts 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Section 4.2.2 Rationale 
for Study Endpoints 
Updated the primary 
analysis and added a 
secondary analyses for 
third dose; Updated 
“geometric mean titre” to 
“antibody titre;” added 
analysis of geometric 
mean fold rise 
Statistical analyses 
updated to include 
analysis of a third dose 
Non-substantial 
Section 5.1 Inclusion 
Criteria 
Updated to last visit 
instead of Day 365, 
corrected footnote labels 
in Table 6 
Clarification that last 
study visit may not be 
Day 365, clarification of 
bullet headings 
Non-substantial 
Section 5.2 Exclusion 
Criteria 
Updated RT-PCR to 
nucleic acid amplification 
test; Changed from “past 
laboratory confirmed 
SARS-CoV-2 infection” to 
“current or past” 
To expand from just RT-
PCR test to any type of 
nucleic acid amplification 
test for SARS-CoV-2 
Non-substantial 
Section 6.1.2 Dosing 
Instructions 
Section 6.5.2 Prohibited 
Concomitant Medications 
Section 7.1 
Discontinuation of 
Investigational Product 
Added that participants are 
eligible to receive a third 
dose 
Clarification that 
participants will receive a 
third dose 
Non-substantial 
7.2 Study Suspension or 
Termination 
Added sentence that the 
“inability to recruit for the 
study if insufficient 
participant are able to be 
enrolled”  
Clarity that the study can 
be suspended if hard to 
enroll participants 
Non-substantial 
Section 8.2.3 Clinical 
Safety Laboratory 
Assessments 
Updated that negative 
urine pregnancy test is 
required at screening. 
Clarification that this test 
must be performed during 
screening 
Non-substantial 
Section 8.2.4 COVID-19 
Assessments 
Section 8.3.10 COVID-19 
Assessment 
Section 9.4.3 Safety 
Updated “day 365” to “last 
study visit” 
Clarification that last 
study visit may not be 
Day 365 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Section 8.3.1 Time Period 
and Frequency for 
Collecting Adverse Event 
and Serious Adverse 
Event Information 
Section 8.3.6 Solicited 
Adverse Events 
Specified the time period 
for collecting AEs for 
immunocompromised 
cohorts and 
immunocompetent cohort 
Clarification that 
immunocompromised and 
immunocompetent groups 
have different dosing 
scheudled 
Non-substantial 
Section 8.3.9 Hy’s Law 
Added “Hy’s Law 
Criteria” 
Clarified Hy’s Law 
requirement for study 
Non-substantial 
Section 8.5.2.1 SARS-
CoV-2 Serology 
Assessments 
Deleted that the 
seroresponse is a “≥4 fold 
rise from baseline value”; 
changed that SARS-CoV-2 
antigens will be analyzed 
with “MSD” to “ECL 
based” immunoassay. 
Clarified how 
seroresponse is measured 
and testing of SARS-
CoV-2 antigens 
Non-substantial 
Section 8.5.2.2 SARS-
CoV-2 Neutralizing 
Antibody Assessments 
Added that neutralizing 
antibody assessments of 
emerging variants may be 
investigated 
Clarified that testing of 
new SARS-CoV-2 
variants will be allowed 
Non-substantial 
Section 8.5.2.3 
Assessment of Cell 
mediated Immune 
Responses 
Section 8.5.2.4 
Monitoring for 
Asymptomatic Infections 
Minor edits of text 
Clarity 
Non-substantial 
9.2 Sample Size 
Determination 
Added exploratory 
analysis will be conducted 
Clarified that exploratory 
analysis may will be 
performed 
Non-substantial 
Section 9.4.1 General 
Considerations 
Updated the primary 
analysis to include pooled 
immunocompromised 
cohorts and added that a 
secondary analysis will be 
performed. 
Clarified when the 
primary analysis and 
secondary analysis will be 
performed 
Substantial 
Section 9.4.2 
Immunogenicity 
Table 16 Primary 
Immunogenicity 
Added that GMFR will be 
reported with the GMT 
analysis 
Updated this assessment 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Summaries to be 
Completed (by Cohort, 
Timepoint, Antibody, and 
Endpoint) 
Table 17 Secondary 
Immunogenicity 
Summaries to be 
Completed (by Cohort, 
Timepoint, Antibody, and 
Endpoint) 
Table 18 Exploratory 
Anti-vector 
Immunogenicity 
Summaries to be 
Completed (by Cohort, 
Timepoint, Antibody, and 
Endpoint) 
Table 19 Secondary 
Immunogenicity 
Comparisons to be 
Completed at the Time of 
the Primary Analysis (by 
Cohorts Compared, 
Timepoint, Antibody, and 
Endpoint) 
Table 20 Secondary 
Immunogenicity 
Comparisons to be 
Completed at the time of 
the Secondary Analysis 
(by Cohorts Compared, 
Timepoint, Antibody, and 
Endpoint) 
Table 16: updated footnote 
that samples collected on 
Day 28 after dose 2 must 
be collected before third 
dose 
 
Clarification on when the 
analysis will occur 
Substantial 
Table 17: this is a new 
table; added a sentence 
that secondary 
immunogenicity antibody 
responses are performed 
similarly to primary 
immunogenicity analyses 
Required for secondary 
immunogenicity analysis 
Table 18: updated that the 
time when the analysis 
will occur and that 
analysis will occur in the 
pooled 
immunocompromised and 
healthy 
(immunocompetent) 
cohorts 
Clarity 
Table 19: Updated the 
Title for this table to add 
“at the time of the Primary 
Analysis” 
Clarity 
Added sentence clarifying 
when the secondary 
analysis will be performed 
comparing 
immunocompromised and 
immunocompetent groups 
Clarity 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Table 20: this is a new 
table  
Required for secondary 
immunogenicity analysis 
Substantial 
Section 9.4.3 Safety 
Deleted “Day 365” and 
added “the last study 
visit.” 
Clarification 
Non-substantial 
Appendix G 
Abbreviations 
Added GMFR 
Definition 
Non-substantial 
 
Amendment 1 (13 August 2021) 
Overall Rationale for the Amendment 
Version 1 of the protocol was updated based on feedback from internal reviews. The principal 
reasons for this amendment were as follows: 
• The cohort-specific inclusion criteria for the solid organ cancer patients receiving 
cytotoxic chemotherapy cohort in Section 5.1.2 had been updated. 
• The requirement to perform a serum pregnancy test for women of childbearing 
potential at the Screening Visit was removed from Section 8.2.3, to align with the 
Schedule of Activities.  
 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ Non-
substantial 
Section 5.1.2 Cohort 
Specific Inclusion 
Criteria 
Changed the number of 
months, from 3 to 6, that 
cancer patients are 
required to be on 
intravenous cytotoxic 
chemotherapy. 
Ensure the increase in the 
amount of time on 
concomitant medications 
for this cohort. 
Substantial. 
Section 8.2.3 Clinical 
Safety Laboratory 
Assessments 
Deleted “serum test” for 
pregnancy screening. 
The study will use urine 
test for pregnancy 
screening. 
Substantial. 

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