Conditions: Avian Influenza Influenza Immunisation
Keywords: A/H7N9 Adults AS03 Immunogenicity Influenza Prime-Boost Reactogenicity Safety Vaccine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: yes

Brief summary:
This is a trial designed to assess the safety, reactogenicity and immunogenicity of one or two doses of monovalent inactivated split influenza 2013 and 2017 A/H7N9 virus vaccines administered intramuscularly at different dosages, given with or without AS03 adjuvant, using different vaccination schedules. This trial will enroll up to 180 males and non-pregnant females, 19 to 50 years of age, who are in good health and who are influenza A/H7 naïve. Subjects will be randomly assigned to 1 of 6 treatment arms (30 subjects per arm) to evaluate the interval between the first and second doses and the presence of the adjuvant in the first and second doses. The neuraminidase-specific antibody response and the neuraminidase content of the Inactivated Influenza Virus Vaccine will be determined using tests that are currently under development. Study duration is approximately 22 months with subject participation duration of approximately 18 months. The primary objectives of the study are: 1) to assess the safety and reactogenicity of 2013 and 2017 A/H7N9 IIVs given with or without AS03 adjuvant following receipt of each study vaccine; 2) to assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody responses following receipt of the second study vaccine.

Detailed description:
This is a Phase II trial designed to assess the safety, reactogenicity and immunogenicity of one or two doses of monovalent inactivated split influenza 2013 and 2017 A/H7N9 virus vaccines (2013 and 2017 A/H7N9 IIVs) administered intramuscularly at different dosages (3.75 or 15 mcg of hemagglutinin (HA) per dose), given with or without AS03 adjuvant, using different heterologous and homologous prime-boost vaccination schedules. Phosphate buffered saline (PBS) diluent may be used to achieve targeted dosages. This trial will enroll up to 180 males and non-pregnant females, 19 to 50 years of age, inclusive, who are in good health and meet all eligibility criteria and who are influenza A/H7 vaccine/infection naïve by medical history. Subjects will be randomly assigned to 1 of 6 treatment arms (30 subjects per arm) evaluating the interval between the priming (first) and boosting (second) doses and the presence of the adjuvant in the priming (first) and boosting (second) doses. The neuraminidase-specific antibody response and the neuraminidase content of the Inactivated Influenza Virus Vaccine will be determined using tests that are currently under development. Study duration is approximately 22 months with subject participation duration of approximately 18 months. The primary objectives of the study are: 1) to assess the safety and reactogenicity of 2013 and 2017 A/H7N9 IIVs given with or without AS03 adjuvant following receipt of each study vaccine; 2) to assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody responses following receipt of the second study vaccine. The secondary objectives are: 1) to assess unsolicited non-serious adverse events (AEs) following receipt of each study vaccine; 2) to assess medically-attended adverse events (MAAEs), including new-onset chronic medical conditions (NOCMCs) and potentially immune-mediated medical conditions (PIMMCs), following receipt of each study vaccine; 3) to assess the kinetics and durability of serum HAI and Neut antibody responses following receipt of each study vaccine.

Arms:
arm 1: 3.75 mcg per 0.5 ml dose of 2013 A/H7N9 Inactivated Influenza Virus Vaccine (IIV) + AS03 adjuvant administered intramuscularly on Day 1 and 3.75 mcg per 0.5 ml dose of 2017 A/H7N9 IIV + ASO3 adjuvant administered intramuscularly on Day 22. Phosphate buffered saline (PBS) diluent may be used to achieve targeted dosages. N=30 arm 2: 3.75 mcg per 0.5 ml dose of 2013 A/H7N9 IIV + AS03 adjuvant administered intramuscularly on Day 1 and 3.75 mcg per 0.5 ml dose of 2017 A/H7N9 IIV + ASO3 adjuvant administered intramuscularly on Day 121. PBS diluent may be used to achieve targeted dosages. N=30 arm 3: 3.75 mcg per 0.5 ml dose of 2013 A/H7N9 IIV + AS03 adjuvant administered intramuscularly on Day 1 and 15 mcg per 0.5 ml dose of 2017 A/H7N9 IIV administered intramuscularly on Day 121. PBS diluent may be used to achieve targeted dosages. N=30 arm 4: 3.75 mcg per 0.5 ml dose of 2017 A/H7N9 IIV + AS03 adjuvant administered intramuscularly on Day 1 and Day 22. PBS diluent may be used to achieve targeted dosages. N=30 arm 5: 3.75 mcg per 0.5 ml dose of 2017 A/H7N9 IIV + AS03 adjuvant administered intramuscularly on Day 1 and Day 121. PBS diluent may be used to achieve targeted dosages. N=30 arm 6: 3.75 mcg per 0.5 ml dose of 2017 A/H7N9 IIV + AS03 Adjuvant administered intramuscularly on Day 1 and 15 mcg per 0.5 ml dose of 2017 A/H7N9 IIV administered intramuscularly on Day 121. PBS diluent may be used to achieve targeted dosages. N=30

Interventions: intervention 1: A/H7N9 intervention 2: AS03 intervention 3: Influenza Virus Vaccine, Monovalent A/H7N9 A/Shanghai/2/2013 intervention 4: Phosphate Buffered Saline (PBS) diluent
Intervention descriptions: intervention 1: Monovalent split 2017 A/H7N9 Inictivated Influenza Virus vaccine containing the HA and NA from low pathogenic avian influenza A/Hong Kong/125/2017 (H7N9) and the PB2, PB1, PA, NP, M and NS from A/Puerto Rico/8/1934 (H1N1). intervention 2: AS03 oil-in-water emulsion adjuvant. intervention 3: Monovalent split 2013 A/H7N9 Inavtivated Influenza Virus vaccine containing the HA and NA from avian influenza A/Shanghai/2/2013 (H7N9) and the PB2, PB1, PA, NP, M and NS from A/Puerto Rico/8/1934 (H1N1). intervention 4: Diluent for Influenza Virus Vaccine.

Protocol document:
Prot_000.pdf: 
 
A Phase II Study to Assess the Safety, Reactogenicity and Immunogenicity of 
Different Prime-Boost Vaccination Schedules of 2013 and 2017 A/H7N9 
Inactivated Influenza Vaccines Administered Intramuscularly with or without 
AS03 Adjuvant in Healthy Adults 19-50 Years of Age 
 
DMID Protocol Number: 17-0078 
 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
 
Pharmaceutical Support: 
Sanofi Pasteur 
GlaxoSmithKline Biologicals 
 
IND Sponsor: Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National Institutes of Health 
 
Lead Principal Investigator: Evan J. Anderson, MD 
DMID Clinical Project Manager: Wendy Buchanan, RN, MS 
DMID Medical Monitor: Mohamed Elsafy, MD 
DMID Medical Officer:  Francisco Leyva, MD, PhD, ScM 
DMID Scientific Lead: Chris Roberts, PhD 
 
Version: 4.0 
December 18, 2019 
 
 


DMID Protocol 17-0078 
Version 4.0 
2013/2017 H7N9 Prime-Boost Interval 
December 18, 2019 
 
i 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application), 21 CFR 812 (Investigational 
Device Exemptions) 
• 
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use E6(R2) Good Clinical Practice (ICH E6 GCP): 
Integrated Addendum to ICH E6(R1) Guidance for Industry, published in the Federal 
Register (83 Federal Register 8882 (2018)), including the latest finalized revision 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, 
as applicable 
• 
Applicable Federal, State and Local Regulations and Guidance 
 


DMID Protocol 17-0078 
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December 18, 2019 
 
ii 
SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 GCP guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and Institutional Review Board 
(IRB)/Institutional Ethics Committee (IEC) approval, except when necessary to protect the 
safety, rights or welfare of subjects. 
Site Principal Investigator: 
 
Signed: 
 
 
Date: 
 
 
Name 
Title 
 
 
 
 


DMID Protocol 17-0078 
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December 18, 2019 
 
iii 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................................. i 
SIGNATURE PAGE ...................................................................................................................... ii 
TABLE OF CONTENTS ............................................................................................................... iii 
LIST OF TABLES ........................................................................................................................ vii 
LIST OF FIGURES ..................................................................................................................... viii 
LIST OF ABBREVIATIONS ........................................................................................................ ix 
PROTOCOL SUMMARY ........................................................................................................... xiii 
1 
Key Roles ................................................................................................................................1 
2 
Background Information and Scientific Rationale .................................................................3 
2.1 
Background Information .............................................................................................3 
2.1.1 Public Readiness and Emergency Preparedness Act ......................................6 
2.2 
Scientific Rationale .....................................................................................................7 
2.3 
Potential Risks and Benefits .......................................................................................9 
2.3.1 Potential Risks ................................................................................................9 
2.3.2 Known Potential Benefits .............................................................................16 
3 
Study Objectives and Outcome Measures ............................................................................18 
3.1 
Study Objectives .......................................................................................................18 
3.1.1 Primary ..........................................................................................................18 
3.1.2 Secondary ......................................................................................................18 
3.1.3 Exploratory ...................................................................................................18 
3.2 
Study Outcome Measures .........................................................................................19 
3.2.1 Primary ..........................................................................................................19 
3.2.2 Secondary ......................................................................................................20 
3.2.3 Exploratory ...................................................................................................21 
4 
Study Design .........................................................................................................................23 
5 
Study Enrollment and Withdrawal........................................................................................25 
5.1 
Eligibility Criteria .....................................................................................................25 
5.1.1 Subject Inclusion Criteria .............................................................................25 
5.1.2 Subject Exclusion Criteria ............................................................................26 
5.2 
Treatment Assignment Procedures ...........................................................................29 
5.2.1 Enrollment and Randomization Procedures..................................................29 
5.2.2 Masking Procedures ......................................................................................30 
5.2.3 Reasons for Withdrawals and Discontinuation of Study Product 
Administration ..............................................................................................30 
5.2.4 Handling of Withdrawals and Discontinuation of Study Product 
Administration ..............................................................................................33 
5.2.5 Subject Replacement .....................................................................................33 


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5.2.6 Termination of Study ....................................................................................34 
6 
Study Intervention/Investigational Product ..........................................................................35 
6.1 
Study Product Description ........................................................................................35 
6.1.1 Acquisition ....................................................................................................36 
6.1.2 Formulation, Storage, Packaging, and Labeling ...........................................36 
6.1.3 Study Product Storage and Stability Procedures ..........................................38 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ......................................................................................................................39 
6.3 
Modification of Study Intervention/Investigational Product for a Subject ...............41 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product .......41 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational Product
...................................................................................................................................42 
6.6 
Concomitant Medications/Treatments ......................................................................42 
7 
Study Procedures/Evaluations ..............................................................................................43 
7.1 
Clinical Evaluations ..................................................................................................43 
7.2 
Laboratory Evaluations .............................................................................................44 
7.2.1 Clinical Laboratory Evaluations ...................................................................44 
7.2.2 Special Assays or Procedures .......................................................................45 
7.2.3 Specimen Preparation, Handling and Shipping ............................................49 
8 
Study Schedule......................................................................................................................50 
8.1 
Screening (Optional) and Enrollment Visits .............................................................50 
8.1.1 Visit 00, Screening (Day -28 to -1), Clinic Visit, All Treatment Arms, 
Optional.........................................................................................................50 
8.1.2 Visit 01, Day 1, Enrollment (for subjects previously screened at Day -28 to -
1) and First Study Vaccination (Dose 1), Clinic Visit, All Treatment Arms51 
8.1.3 Visit 01, Day 1, Enrollment/Baseline (for subjects not previously screened 
at Day -28 to -1) and First Study Vaccination (Dose 1), Clinic Visit, All 
Treatment Arms ............................................................................................53 
8.2 
Follow-up Visits........................................................................................................55 
8.2.1 Visit 02, Day 2, Clinic Visit, All Treatment Arms .......................................56 
8.2.2 Visit 03, Day 4, Clinic Visit, All Treatment Arms .......................................56 
8.2.3 Visit 04, Day 8, Clinic Visit, All Treatment Arms .......................................57 
8.2.4 Visit 05, Day 15, Clinic Visit, All Treatment Arms .....................................58 
8.2.5 Clinic Visit, Treatment Arms 2, 3, 5, and 6 ..................................................58 
8.2.6 Safety Follow-up, Phone Call, Treatment Arms 2, 3, 5, and 6 .....................59 
8.2.7 Second Study Vaccination (Dose 2), Clinic Visit, All Treatment Arms ......59 
8.2.8 Clinic Visit, All Treatment Arms..................................................................61 
8.2.9 Clinic Visit, All Treatment Arms..................................................................62 
8.2.10 Clinic Visit, All Treatment Arms..................................................................63 
8.2.11 Clinic Visit, All Treatment Arms..................................................................64 


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8.2.12 Clinic Visit, All Treatment Arms..................................................................64 
8.2.13 Safety Follow-up, Phone Call, All Treatment Arms.....................................65 
8.2.14 Clinic Visit, All Treatment Arms..................................................................65 
8.2.15 Safety Follow-up, Phone Call, All Treatment Arms.....................................66 
8.2.16 Clinic Visit, All Treatment Arms..................................................................66 
8.3 
Final Visit..................................................................................................................67 
8.3.1 Safety Follow-up, Phone Call, All Treatment Arms.....................................67 
8.4 
Early Termination Visit (if needed) ..........................................................................67 
8.5 
Unscheduled Visit (if needed) ..................................................................................68 
9 
Assessment of Safety ............................................................................................................70 
9.1 
Specification of Safety Parameters ...........................................................................70 
9.2 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters .70 
9.2.1 Adverse Events .............................................................................................70 
9.2.2 Reactogenicity...............................................................................................72 
9.2.3 Additional Adverse Event Severity Grading ................................................74 
9.2.4 Serious Adverse Events ................................................................................76 
9.2.5 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .........................................................77 
9.3 
Reporting Procedures ................................................................................................77 
9.3.1 Serious Adverse Events ................................................................................77 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
.......................................................................................................................78 
9.3.3 Reporting of Pregnancy ................................................................................79 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................79 
9.5 
Halting Rules ............................................................................................................79 
9.6 
Safety Oversight........................................................................................................81 
9.6.1 Independent Safety Monitor (ISM) ...............................................................81 
9.6.2 Data and Safety Monitoring Board (DSMB) ................................................82 
10 
Clinical Monitoring ...............................................................................................................84 
10.1 
Site Monitoring Plan .................................................................................................84 
11 
Statistical Considerations ......................................................................................................85 
11.1 
Introduction ...............................................................................................................85 
11.2 
Study Hypotheses......................................................................................................85 
11.3 
Study Outcome Measures .........................................................................................85 
11.4 
Sample Size Considerations ......................................................................................85 
11.4.1 Study Population ...........................................................................................85 
11.4.2 Subject Enrollment and Follow-up ...............................................................86 
11.4.3 Sample Size ...................................................................................................86 
11.5 
Planned Interim Analyses .........................................................................................88 
11.5.1 Interim Safety Review ..................................................................................89 


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11.5.2 Interim Immunogenicity Review ..................................................................89 
11.6 
Final Analysis Plan ...................................................................................................90 
11.6.1 Analysis Populations .....................................................................................90 
11.6.2 Safety Data ....................................................................................................91 
11.6.3 Immunogenicity Data....................................................................................92 
11.6.4 Missing Values and Outliers .........................................................................93 
12 
Data Collection Forms and Access to Source Data/Documents ...........................................95 
13 
Quality Control and Quality Assurance ................................................................................96 
14 
Ethics/Protection of Human Subjects ...................................................................................97 
14.1 
Ethical Standard ........................................................................................................97 
14.2 
Institutional Review Board (IRB) .............................................................................97 
14.3 
Informed Consent Process ........................................................................................97 
14.4 
Exclusion of Women, Minorities and Children (Special Populations) ...................100 
14.5 
Subject Confidentiality ...........................................................................................101 
14.6 
Study Discontinuation .............................................................................................102 
14.7 
Costs, Subject Compensation and Research Related Injuries .................................102 
14.8 
Future Use of Stored Specimens .............................................................................103 
15 
Data Handling and Record Keeping ...................................................................................106 
15.1 
Data Management Responsibilities.........................................................................106 
15.2 
Data Capture Methods ............................................................................................106 
15.3 
Types of Data ..........................................................................................................107 
15.4 
Timing/Reports .......................................................................................................107 
15.5 
Study Records Retention.........................................................................................108 
15.6 
Protocol Deviations .................................................................................................108 
16 
Publication Policy ...............................................................................................................110 
17 
Literature References ..........................................................................................................111 
Appendices ...................................................................................................................................116 
Appendix A. 
SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS .........117 
Appendix B. 
SCHEDULE OF SPECIAL ASSAYS ........................................................127 
Appendix C. 
LIST OF POTENTIALLY IMMUNE-MEDIATED MEDICAL 
CONDITIONS ....................................................................................................................132 
 
 
 
 


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LIST OF TABLES 
Table 1: Study Design .................................................................................................................. xxi 
 
 
Table 4: Venipuncture Volumes for Treatment Arms 1 and 4 ......................................................47 
Table 5: Venipuncture Volumes for Treatment Arms 2, 3, 5, and 6 .............................................48 
Table 6: Injection Site Reactogenicity Grading .............................................................................73 
Table 7: Injection Site Reactogenicity Measurements ...................................................................73 
Table 8: Subjective Systemic Reactogenicity Grading ..................................................................74 
Table 9: Quantitative Systemic (Oral Temperature) Reactogenicity Grading ...............................74 
Table 10: Pulse and BP Adverse Event Grading ...........................................................................75 
Table 11: Clinical Safety Laboratory Adverse Event Grading ......................................................75 
Table 12: Power (%) to Detect Safety Events ...............................................................................87 
Table 13: Precision of Binomial Confidence Intervals ..................................................................87 
Table 14: Minimum Detectable Difference in Proportion Responders .........................................88 
Table 15: Vaccination Period for Treatment Arms 1 and 4 .........................................................117 
Table 16: Follow-Up Period for Treatment Arms 1 and 4 (Including Early Termination 
and Unscheduled Visits) ...........................................................................................120 
Table 17: Vaccination Period for Treatment Arms 2, 3, 5, and 6 ................................................122 
Table 18: Follow-Up Period for Treatment Arms 2, 3, 5, and 6 (Including Early 
Termination and Unscheduled Visits) ......................................................................125 
Table 19: Special Assays for All Treatment Arms ......................................................................127 
Table 20: Clinical Laboratory Evaluations, Special Assays and Venipuncture Volumes 
for Treatment Arms 1 and 4 ......................................................................................128 
Table 21: Clinical Laboratory Evaluations, Special Assays and Venipuncture Volumes 
for Treatment Arms 2, 3, 5, and 6 .............................................................................130 
 
 
 


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LIST OF FIGURES 
Figure 1: Schematic of Study Design ......................................................................................... xxii 
 


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LIST OF ABBREVIATIONS 
A/H1N1 
Influenza A Virus of the H1N1 Subtype 
A/H1N2v 
Influenza A Virus of the H1N2 Variant Subtype 
A/H2N2 
Influenza A Virus of the H2N2 Subtype 
A/H3N2 
Influenza A Virus of the H3N2 Subtype 
A/H3N2v 
Influenza A Virus of the H3N2 Variant Subtype 
A/H5N1 
Influenza A Virus of the H5N1 Subtype 
A/H5N6 
Influenza A Virus of the H5N6 Subtype 
A/H5N8 
Influenza A Virus of the H5N8 Subtype 
A/H7N1 
Influenza A Virus of the H7N1 Subtype 
A/H7N7 
Influenza A Virus of the H7N7 Subtype 
A/H7N9 
Influenza A Virus of the H7N9 Subtype 
A/H9N2 
Influenza A Virus of the H9N2 Subtype 
AE 
Adverse Event/Adverse Experience 
AESIs 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase 
ANCA 
Anti-Neutrophil Cytoplasmic Antibody 
AS03 
Adjuvant System (03) 
BARDA 
Biomedical Advanced Research and Development Authority 
BLA 
Biologics License Application 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CMS 
Clinical Materials Services 
COI 
Conflict of Interest 
Cr 
Creatinine 
CROMS 
Clinical Research Operations and Management Support 
CSL 
Commonwealth Serum Laboratories 
CSR 
Clinical Study Report 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
D 
Day(s) 
DCF 
Data Collection Form 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 


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DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDCSM 
Electronic Data Capture System 
ELISA 
Enzyme-Linked Immunosorbent Assay 
ELISpot 
Enzyme-Linked Immunosorbent Spot 
ELLA 
Enzyme-Linked Lectin Assay 
ESR 
Erythrocyte Sedimentation Rate 
FACS 
Fluorescence-Activated Cell Sorting 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
g/dL 
Grams per Deciliter 
GBS 
Guillain-Barré Syndrome 
GCP 
Good Clinical Practice 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline Biologicals 
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPAI 
Highly Pathogenic Avian Influenza 
HRSA 
Health Resources and Services Administration 
IATA 
International Air Transport Association 
ICD-10 
10th revision of the International Statistical Classification of 
Diseases and Related Health Problems 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICS 
Intracellular Staining 
IEC 
Institutional Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IIV 
Inactivated Influenza Virus Vaccine 
IIV3 
Trivalent IIV 
IM 
Intramuscular(ly) 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 


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IU/L 
International Unit(s) per Liter 
LLC 
Limited Liability Company 
MAAE 
Medically-Attended Adverse Event 
mcg 
Microgram(s) 
µL 
Microliter(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF59 
MF59C.1 Adjuvant 
mg/dL 
Milligram(s) per Deciliter 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
mmHg 
Millimeters of Mercury 
MOP 
Manual of Procedures 
N 
Number of Subjects 
NA 
Neuraminidase 
NAI 
Neuraminidase Inhibiting or Inhibition 
Neut 
Neutralizing or Neutralization 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health, DHHS 
NK 
Natural Killer 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
NOCMCs 
New-Onset Chronic Medical Conditions 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
OTC 
Over the Counter 
PBMC 
Peripheral Blood Mononuclear Cell 
PBS 
Phosphate Buffered Saline 
pH1N1 
2009 H1N1 Influenza 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PIMMCs 
Potentially Immune-Mediated Medical Conditions 
PLT 
Platelets 
PP 
Per Protocol 
PREP Act 
Public Readiness and Emergency Preparedness Act 
PRN 
As Needed 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 


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SDCC 
Statistical and Data Coordinating Center 
SMA 
Secondary Medical Assessor 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SP 
Sanofi Pasteur 
SRID 
Single Radial Immunodiffusion 
TBD 
To Be Determined 
T. Bili 
Total Bilirubin 
US 
United States 
V 
Visit(s) 
VTEU 
Vaccine and Treatment Evaluation Unit 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 


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PROTOCOL SUMMARY 
Title: 
A Phase II Study to Assess the Safety, Reactogenicity and 
Immunogenicity of Different Prime-Boost Vaccination Schedules 
of 2013 and 2017 A/H7N9 Inactivated Influenza Vaccines 
Administered Intramuscularly with or without AS03 Adjuvant in 
Healthy Adults 19-50 Years of Age 
Phase: 
II 
Population: 
Up to 180 males and non-pregnant females, 19 to 50 years of age, 
inclusive, who are in good health and meet all eligibility criteria 
Number of Sites: 
5 Vaccine and Treatment Evaluation Unit (VTEU) sites (and their 
subcontractors) 
Study Duration: 
Approximately 22 months 
Subject Participation 
Duration: 
Up to 18 months 
Estimated Time to Complete 
Enrollment: 
Approximately 12 weeks 
Description of Agent: 
• Monovalent inactivated split influenza 2013 
(A/H7N9/Shanghai/2/2013) and 2017 (A/H7N9/Hong 
Kong/125/2017) A/H7N9 virus vaccines (2013 and 2017 
A/H7N9 inactivated influenza virus vaccines [IIVs]) 
manufactured by Sanofi Pasteur (SP). 
• AS03 adjuvant manufactured by GlaxoSmithKline 
Biologicals (GSK). 
• Phosphate buffered saline (PBS) diluent manufactured by 
Patheon Manufacturing Services LLC. 
Study Objectives: 
 
Primary: 
Safety: 


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xiv 
• To assess the safety and reactogenicity of 2013 and 2017 
A/H7N9 IIVs given with or without AS03 adjuvant 
following receipt of each study vaccine. 
Immunogenicity: 
• To assess the serum hemagglutination inhibition (HAI) and 
neutralizing (Neut) antibody responses following receipt of 
the second study vaccine. 
Secondary: 
Safety: 
• To assess unsolicited non-serious adverse events (AEs) 
following receipt of each study vaccine. 
• To assess medically-attended adverse events (MAAEs), 
including new-onset chronic medical conditions 
(NOCMCs) and potentially immune-mediated medical 
conditions (PIMMCs), following receipt of each study 
vaccine. 
Immunogenicity: 
• To assess the kinetics and durability of serum HAI and 
Neut antibody responses following receipt of each study 
vaccine. 
Exploratory: 
Immunogenicity: 
• To assess the effects of age, sex, body mass index (BMI), 
and prior receipt of seasonal or non-study pandemic 
influenza vaccine(s) on serum HAI and Neut antibody 
responses following receipt of the second study vaccine. 
• To assess the neuraminidase (NA) content of the 2013 and 
2017 A/H7N9 IIVs and determine, in at least a subset of 
samples, the serum antibody responses to N9 NA. 
• To assess, in at least a subset of samples, HA stem-specific 
antibody responses. 


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• To assess, in at least a subset of samples, the cross-
reactivity of serum HAI and Neut antibody responses to 
antigenically drifted variants of influenza A/H7 viruses. 
• To assess, in at least a subset of samples, the frequency of 
influenza-specific (A/H7N9 antigens) IgA, IgG and IgM 
memory B cells (MBCs). 
• To assess, in at least a subset of samples, the frequency of 
influenza-specific (A/H7N9 antigens) IgA, IgG and IgM 
plasmablasts (antibody-secreting cells [ASCs]). 
• To assess, in at least a subset of samples, the 
multifunctional cytokine/chemokine profile of influenza 
A/H7N9-specific CD4 and CD8 T cells. 
• To assess, in at least a subset of samples, the 
characterization of circulating T follicular helper (cTFH) 
cells. 
• To assess, in at least a subset of samples, the study 
vaccine-induced changes in populations and/or activation 
status of innate immune cells (monocytes, dendritic cells 
[DCs] and natural killer [NK] cells). 
• To assess, in at least a subset of samples, the study 
vaccine-induced activation status of B cells. 
• To assess, in at least a subset of samples, the B cell 
receptor repertoire and degree of somatic hypermutation 
generated in response to study vaccination. 
Study Outcome Measures: 
 
Primary: 
Safety: 
• Occurrence of all serious adverse events (SAEs) from the 
time of the first study vaccination through approximately 
12 months after the last study vaccination. 
• Occurrence of solicited injection site and systemic 
reactogenicity events from the time of each study 
vaccination through 7 days after each study vaccination. 


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• Occurrence of clinical safety laboratory AEs from the time 
of each study vaccination through approximately 7 days 
after each study vaccination. 
Immunogenicity: 
• For HAI and Neut antibodies, percentage of subjects 
achieving seroconversion against the influenza A/H7N9 
study vaccine viruses (defined as either a pre-vaccination 
titer <1:10 and a post-vaccination titer ≥1:40 or a pre-
vaccination titer ≥1:10 and a minimum four-fold rise in 
post-vaccination antibody titer) approximately 21 days 
after the second study vaccination. 
• For HAI and Neut antibodies, percentage of subjects 
achieving titer ≥1:40 against the influenza A/H7N9 study 
vaccine viruses approximately 21 days after the second 
study vaccination. 
• Geometric mean titers (GMTs) of serum HAI and Neut 
antibodies against the influenza A/H7N9 study vaccine 
viruses approximately 21 days after the second study 
vaccination. 
Secondary: 
Safety: 
• Occurrence of all unsolicited non-serious AEs from the 
time of each study vaccination through approximately 21 
days after each study vaccination. 
• Occurrence of all MAAEs, including NOCMCs and 
PIMMCs, from the time of the first study vaccination 
through approximately 12 months after the last study 
vaccination. 
Immunogenicity: 
• For HAI and Neut antibodies, percentage of subjects 
achieving seroconversion against the influenza A/H7N9 
study vaccine viruses approximately 21 days after the first 
study vaccination as well as immediately prior to and 
approximately 180 days after the second study vaccination. 


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• For HAI and Neut antibodies, percentage of subjects 
achieving titer ≥1:40 against the influenza A/H7N9 study 
vaccine viruses immediately prior to each study 
vaccination, approximately 21 days after the first study 
vaccination and approximately 180 days after the second 
study vaccination. 
• GMTs of serum HAI and Neut antibodies against the 
influenza A/H7N9 study vaccine viruses immediately prior 
to each study vaccination, approximately 21 days after the 
first study vaccination and approximately 180 days after 
the second study vaccination. 
Exploratory: 
Immunogenicity: 
• For HAI and Neut antibodies, GMTs and percentage of 
subjects achieving seroconversion against the influenza 
A/H7N9 study vaccine viruses approximately 21 days after 
the second study vaccination, by age, sex, BMI, and prior 
receipt of seasonal or non-study pandemic influenza 
vaccine(s). 
• GMTs and percentage of subjects achieving 
seroconversion (defined as four-fold change from baseline) 
of serum anti-NA (by enzyme-linked immunosorbent assay 
[ELISA]) or anti-neuraminidase inhibition (NAI) (by 
enzyme-linked lectin assay [ELLA]) antibodies 
immediately prior to and approximately 21 days after each 
study vaccination as well as approximately 180 days after 
the second study vaccination. 
• Correlate the HA and/or NA content of 2013 and 2017 
A/H7N9 IIVs with the elicited HA or N9 NA-specific 
antibody titer approximately 21 days after each study 
vaccination as well as immediately prior to and 
approximately 180 days after the second study vaccination. 
• GMTs of HA stem-specific antibody immediately prior to 
and approximately 21 days after each study vaccination as 
well as approximately 180 days after the second study 
vaccination. 


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• For HAI and Neut antibodies, GMTs and percentage of 
subjects achieving seroconversion against antigenically 
drifted variants of influenza A/H7 viruses approximately 
21 days after the second study vaccination. 
• Percentage of influenza-specific (A/H7N9 antigens) IgA, 
IgG and IgM MBCs at baseline and approximately 90 and 
180 days after the second study vaccination. 
• Frequency of influenza-specific (A/H7N9 antigens) IgA, 
IgG and IgM plasmablasts (ASCs) present in circulation 
approximately 7 days after each study vaccination. 
• Percentage of influenza A/H7N9-specific CD4 and CD8 T 
cells producing cytokines/chemokines immediately prior to 
and approximately 7 days after each study vaccination as 
well as approximately 90 days after the second study 
vaccination. 
• Percentage of cTFH cells producing cytokines/chemokines 
immediately prior to and approximately 3, 7 and 14 days 
after each study vaccination. 
• Percentage and activation status of innate immune cells 
(monocytes, DCs and NK cells) immediately prior to and 
approximately 1, 3, 7 and 14 days after each study 
vaccination. 
• Percentage of activated B cells immediately prior to and 
approximately 1, 3, 7 and 14 days after each study 
vaccination. 
• Evaluation of B cell receptor repertoire and degree of 
somatic hypermutation of anti-HA (H7) and anti-NA (N9) 
antibodies at baseline and approximately 180 days after the 
second study vaccination. 
• Correlation of the above exploratory immunologic 
parameters with HAI and Neut antibodies. 
Description of Study Design: This is a Phase II clinical trial in up to 180 males and non-
pregnant females, 19 to 50 years of age, inclusive, who are in good 
health and meet all eligibility criteria. This clinical trial is 
designed to assess the safety, reactogenicity and immunogenicity 


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of one or two doses of monovalent inactivated split influenza 2013 
and 2017 A/H7N9 virus vaccines (2013 and 2017 A/H7N9 IIVs) 
manufactured by Sanofi Pasteur (SP), administered 
intramuscularly at different dosages (3.75 or 15 mcg of 
hemagglutinin (HA) per dose), given with or without AS03 
adjuvant manufactured by GlaxoSmithKline Biologicals (GSK), 
using different heterologous and homologous prime-boost 
vaccination schedules. Phosphate buffered saline (PBS) diluent 
manufactured by Patheon Manufacturing Services LLC may be 
used to achieve targeted dosages. 
Subjects who are influenza A/H7 vaccine/infection naïve by 
medical history will be randomly assigned to 1 of 6 treatment arms 
to receive one or two doses of the 2013 and 2017 A/H7N9 IIVs in 
different heterologous and homologous prime-boost combinations 
evaluating the interval between the priming (first) and boosting 
(second) doses (21 days vs. 4 months) and the presence of the 
adjuvant in the priming (first) and boosting (second) doses (see 
Table 1). 
Reactogenicity will be measured by the occurrence of solicited 
injection site and systemic reactions from the time of each study 
vaccination through 7 days after each study vaccination. 
Unsolicited non-serious adverse events (AEs) will be collected 
from the time of each study vaccination through approximately 21 
days after each study vaccination. Serious adverse events (SAEs) 
and medically-attended adverse events (MAAEs), including new-
onset chronic medical conditions (NOCMCs) and potentially 
immune-mediated medical conditions (PIMMCs), will be 
collected from the time of the first study vaccination through 
approximately 12 months after the last study vaccination. Clinical 
safety laboratory evaluations (hematology and chemistry) will be 
performed on venous blood collected immediately prior to each 
study vaccination and approximately 7 days after each study 
vaccination. 
Immunogenicity testing will include performing serological assays 
to assess hemagglutination inhibition (HAI), neutralizing (Neut), 
neuraminidase inhibition (NAI), neuraminidase (NA)-specific, and 
HA stem-specific antibody titers at multiple time points following 
each study vaccination. In addition, peripheral blood mononuclear 


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cells (PBMCs) will be used to determine broad immunologic 
responses and to correlate these responses with serological 
antibody responses described above in each of the treatment arms. 
These responses will include longitudinal assessments of the 
kinetics, magnitude, specificity, and/or quality of influenza-
specific B and T cells, circulating T follicular helper (cTFH) cells 
and innate immune cells (monocytes, dendritic cells [DCs] and 
natural killer [NK] cells) as well as the frequency of influenza-
specific IgA, IgG and IgM plasmablasts (antibody-secreting cells 
[ASCs]) and B cell receptor somatic hypermutation and repertoire 
assessments. Venous blood will also be collected at multiple time 
points following each study vaccination for the future research use 
of serum, plasma and PBMCs. 
In addition, we plan to determine the N9 NA-specific antibody 
response to study vaccination as well as assess the NA content of 
the 2013 and 2017 A/H7N9 IIVs using assays that are currently 
under development to determine if the NA content in a dose-
specific manner correlates with the N9 NA-specific antibody 
response. 
 






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KEY ROLES 
Lead Principal Investigator: 
 
Evan J. Anderson, MD 
Emory University School of Medicine 
 
DMID Clinical Project Manager: 
Wendy Buchanan, RN, MS 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Medical Monitor: 
Mohamed Elsafy, MD 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Medical Officer: 
 
Francisco Leyva, MD, PhD, ScM 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Scientific Lead: 
 
Chris Roberts, PhD 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
Site Principal Investigators: 
Robert L. Atmar, MD 
Baylor College of Medicine 
 
Emmanuel “Chip” Walter, MD, MPH 
Duke Vaccine and Trials Unit 
 
Nadine Rouphael, MD 
The Hope Clinic of Emory Vaccine Center 
 
Evan J. Anderson, MD 
Emory Children’s Center 
 
Sharon Frey, MD 
St. Louis University 
 
Jeffery Meier, MD 
University of Iowa Hospitals and Clinics 
 


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Pat Winokur, MD 
University of Iowa Hospitals and Clinics 
 
Safety and Pharmacovigilance: 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
(CROMS) 
 
Statistical and Data Coordinating 
Center: 
The Emmes Company, LLC 
 
Clinical Materials Services: 
Fisher BioServices 
 
Central (Clinical) Laboratory: 
PPD Global Central Laboratories 
 
HAI and Neut Antibody Assays 
Laboratory: 
Southern Research 
 
Cellular Immunology and 
Additional Serological Assays 
Laboratories: 
To Be Determined (TBD) 
 
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
The continued emergence of novel influenza A viruses in humans including subtypes H5N1, 
H5N6, H3N2v, H1N2v, H7N7, H9N2, 2009 H1N1, and most recently H7N9, underscores the 
need for focused efforts to prepare for the next influenza pandemic [1-9]. Four pandemics 
occurred during the last century. It was estimated that during the 1918 influenza A/H1N1 
pandemic as many as 40 million deaths occurred worldwide [10]. Excess mortality, high 
morbidity and social disruption were all noted during the 1957 influenza A/H2N2 and the 1968 
influenza A/H3N2 pandemics [11]. In April 2009, a novel influenza virus (2009 A/H1N1) 
originated in pigs and spread to humans around the world becoming the first pandemic of this 
century. In each of these influenza pandemics, human populations lacked significant levels of 
pre-existing immunity to a highly transmissible form of the virus enabling it to spread rapidly. 
Thus, each emergence of a new strain of influenza virus in the human population has the 
potential to result in a global public health emergency. 
A major cornerstone of pandemic preparedness is the capacity to rapidly produce and deliver 
sufficient quantities of safe and effective strain-specific pandemic influenza vaccines. The threat 
of pandemic influenza in 1976 (swine influenza) and again in 1977 (Russian influenza) resulted 
in inactivated influenza virus vaccine (IIV) development programs that provided important 
insights into variables influencing the immune responses to immunization [12, 13]. Vaccine-
associated factors potentially affecting the immunogenicity of IIVs that were noted during the 
1976 experience and have been refined in subsequent years include the amount of viral 
hemagglutinin (HA) protein in the vaccine, the number and intervals of doses administered, the 
addition of immune stimulating components (i.e., adjuvants), and the manufacturing methods 
used to produce the vaccine (i.e., whole virus, split virus or purified surface antigen). Host-
specific factors, including the recipient’s age, their prior influenza infections and/or vaccinations, 
and the presence of underlying diseases and their treatments, all can influence the immune 
responses elicited by an influenza vaccine. 
Serum antibodies targeting the influenza virus HA and neuraminidase (NA), the major surface 
glycoproteins on influenza viruses, play a key role in protective immunity to influenza virus 
infection [14]. Since protection against infection with seasonal influenza virus strains has been 
shown to correlate with both serum hemagglutination inhibition (HAI) and neutralizing (Neut) 
antibody levels, their measurements are used routinely to assess the immunogenicity of both 
seasonal and pandemic IIVs. Recent data also supports an important role for neuraminidase 
inhibiting (NAI) antibodies in protection against disease [15]. In a recent human influenza 


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challenge study, serum NAI antibody levels were also identified as an independent correlate of 
protection against influenza illness [16]. In the current study, we plan to assess the NA content of 
the monovalent inactivated split influenza 2013 and 2017 A/H7N9 virus vaccines (2013 and 
2017 A/H7N9 IIVs) and determine the correlation of the NA content at different vaccine dosages 
with the elicited humoral antibody responses to the N9 NA. 
Several approaches have been used to increase the immunogenicity of IIVs. Standard-dose 
seasonal IIVs contain 7.5 to 15 mcg of HA antigen per seasonal influenza vaccine strain for 
children and adults up to 64 years of age. Clinical studies evaluating increased HA-containing 
influenza vaccines performed over the past 35 years have shown dose-related increases in serum 
and mucosal antibody responses [17-25]. Higher HA dosage influenza vaccines can lead to 
enhanced antibody responses in the elderly [26]. In 2009, a high-dose seasonal IIV containing 4 
times the standard HA antigen per seasonal influenza vaccine strain was approved in the United 
States (US) for use in individuals 65 years of age and older. 
In general, clinical studies evaluating vaccines made from novel avian influenza viruses (e.g., 
A/H5N1, A/H7N7, 2013 A/H7N9) suggest that these vaccines are substantially less 
immunogenic than those from other novel subtypes (e.g., 2009 A/H1N1 pandemic virus), even 
when administered at high HA dosages [27, 28]. Due to the poor immunogenicity of A/H5 and 
A/H7 vaccines, the inclusion of adjuvants was evaluated to assess their ability to boost anti-viral 
serum IgG levels. In the US, aluminum salts are licensed as adjuvants in combination with 
several vaccines; however, their use in subvirion influenza A/H5N1 vaccines has shown either 
no effect or a very modest enhancement of immune responses compared to non-aluminum salt 
containing formulations [29-31]. In contrast, the use of oil-in-water emulsion adjuvants, most 
notably proprietary adjuvants AS03 and MF59 produced by GlaxoSmithKline Biologicals (GSK) 
and Novartis (now Seqirus), respectively, has resulted in increased antibody responses to IIVs 
containing novel HAs in numerous clinical trials [32-36]. In an early study, dosage levels 
ranging from 3.75 to 30 mcg of A/H5N1 antigen administered with or without AS03 resulted in 
significant increases in antibody geometric mean titers (GMTs) in subjects who received the 
adjuvanted formulations [34]. These GMTs met the Committee for Medicinal Products for 
Human Use (CHMP) criterion for seroconversion rate (>40%) after a single dose with adjuvant. 
Following the second vaccine dose, all adjuvanted formulations complied with both CHMP and 
US Food and Drug Administration (FDA) criteria for seroconversion and seroprotection rates, 
whereas from the non-adjuvanted treatment arms only the 30 mcg formulation met the CHMP 
criterion for seroconversion [34]. GSK received approval for the registration of a pre-pandemic 
AS03-adjuvanted, monovalent inactivated influenza A/H5N1 virus vaccine by European 
regulatory authorities in 2008 and FDA approval of their Biologics License Applications (BLA) 
for an Influenza A (H5N1) Virus Monovalent Vaccine Adjuvanted (with AS03) in 2013. 


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Following the 2009 emergence of the novel A/H1N1 pandemic virus, the European Commission 
granted marketing authorization of GSK’s egg-derived AS03-adjuvanted monovalent inactivated 
influenza 2009 A/H1N1 virus vaccine (Pandemrix™) and Novartis’ egg-derived MF59-
adjuvanted, monovalent inactivated influenza 2009 A/H1N1 virus vaccine (FOCETRIATM). 
These adjuvanted monovalent inactivated influenza 2009 A/H1N1 virus vaccines were widely 
used throughout Europe and in many other countries, albeit not in the US. 
The inclusion of adjuvants in clinical trials evaluating IIVs has also frequently been associated 
with increased injection site reactogenicity [29]. Additionally, in late 2010, a possible association 
between an increased risk of narcolepsy in children and adolescents who had received the AS03-
containing Pandemrix™ was reported in Finland and Sweden. Some, but not all, countries in 
which retrospective studies were conducted showed a similar association [37-45]. See Section 
2.3.1 for further discussion. 
Because of the substantial increases in antibody responses when these oil-in-water emulsion 
adjuvants were added to otherwise poorly immunogenic, novel HA influenza vaccines, they may 
be a critical component of the public health response to the next influenza pandemic. As part of 
its pandemic preparedness efforts, the US Government maintains stockpiles of unique HA-
containing influenza vaccines, including those against influenza A/H7N9 and A/H5N1 viruses as 
well as AS03 and MF59 adjuvants. The National Institute of Allergy and Infectious Diseases 
(NIAID) has conducted several clinical trials to evaluate A/H7N9 and A/H5N1 vaccines 
administered with and without these adjuvants in healthy adult and elderly populations and found 
that the vaccines co-administered with adjuvants were well-tolerated, exhibited dose-sparing and 
substantially increased the immunogenicity of strain-specific novel HA vaccines compared to 
non-adjuvanted formulations [46-51]. In response to emerging influenza A/H5N8 viruses that 
have caused extensive outbreaks in domestic poultry and wild birds in South East Asia [52, 53], 
NIAID is also conducting two ongoing clinical trials with an A/H5N8 vaccine produced by 
bioCSL (now Seqirus) administered with either AS03 (GSK) or MF59 (Seqirus) adjuvants in 
healthy subjects, 19 to 64 years of age (DMID Protocol 15-0064; NCT02624219 and DMID 
Protocol 15-0066; NCT03014310). 
Since March of 2013 [54], avian influenza A/H7N9 viruses have continued to circulate in China 
causing discrete outbreaks (or waves) in humans with high mortality over the past 5 years. China 
is currently experiencing it’s “sixth wave” of A/H7N9 infections, and as of March 2, 2018, a 
total of 1,567 laboratory-confirmed human infections with avian influenza A/H7N9 viruses have 
been reported by the World Health Organization [55]. Whereas most cases have been centered in 
and around mainland China, there have been several traveler-associated cases, including two in 
travelers reported by Canada who were returning from China in early 2015 [56]. Most of the 
reported human cases have been associated with exposure to infected live poultry or 
contaminated environments, including markets where live poultry are sold. Influenza A/H7N9 


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viruses continue to be detected in poultry and their environments in the areas where human cases 
are occurring. Information to date indicates that these viruses do not transmit easily from human 
to human, with most isolates appearing to have retained their susceptibility to NA inhibitors [56]. 
Laboratory studies have shown that influenza A/H7N9 viruses readily infect cells from human 
respiratory tract tissue samples and can spread from ferret to ferret by droplet transmission, 
thereby increasing the concern about the pandemic potential of these viruses [57, 58]. 
During the “fifth wave” of outbreaks which began in October 2016, more human cases of 
A/H7N9 infection were reported in China than during any prior A/H7N9 epidemic wave [55]. In 
addition, an antigenically distinct lineage of these fifth wave influenza A/H7N9 viruses known as 
the Yangtze River Delta lineage has recently emerged and has been associated with an increasing 
number of human cases [59]. 
The US Department of Health and Human Services (DHHS) recently determined influenza 
A/H7N9 virus as having a significant potential to cause a pandemic, and the greatest risk of 
causing severe disease. As a result, DHHS has supported the production of fifth wave pre-
pandemic A/H7N9 IIVs for the US stockpile and for an assessment of safety and 
immunogenicity in clinical trials. 
2.1.1 
Public Readiness and Emergency Preparedness Act 
For this protocol, the study products (2013 and 2017 A/H7N9 IIVs manufactured by Sanofi 
Pasteur and AS03 adjuvant manufactured by GSK) are covered under the Public Readiness and 
Emergency Preparedness Act (PREP Act). Under the PREP Act, covered persons are immune 
from liability actions brought from the administration or use of a covered countermeasure that is 
the subject of a declaration. The PREP Act provides immunity for covered persons (such as 
manufacturers, distributers, program planners, and other qualified persons who prescribe, 
administer or dispense the 2013 and 2017 A/H7N9 IIVs with or without AS03 adjuvant) from 
tort liability, unless the injury was caused by willful misconduct. 
The PREP Act also established the Countermeasures Injury Compensation Program (CICP) to 
provide compensation for serious injuries that occur as the result of the administration or use of 
certain countermeasures. Any requests for compensation must be filed within one year of 
administration or use of the countermeasure. Requests would go to the Health Resources and 
Services Administration (HRSA) Preparedness Countermeasures Injury Compensation Program 
(http://www.hrsa.gov/cicp/). Compensation may then be available for medical benefits, lost 
wages and death benefits to eligible individuals for specified injuries in accordance with 
regulations published by the Secretary of HRSA. Eligibility for compensation and the injuries for 
which compensation may be available are further defined by regulation. 


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An individual who suffers a serious physical injury or death from administration and use of the 
2013 and 2017 A/H7N9 IIVs with or without AS03 adjuvant may request benefits from the 
CICP. A serious physical injury means an injury that is life-threatening, or results in or requires 
medical or surgical intervention to prevent permanent impairment of a body function or 
permanent damage to body structure. The CICP is the payer of last resort. This means that it only 
covers expenses or provides benefits that other third-party payers, such as health insurance, and 
the Department of Veterans Affairs or Workers’ Compensation programs do not have an 
obligation to pay. 
If no funds have been appropriated to the compensation program, the Secretary of HRSA does 
not make a final determination on the individual’s request within 240 days, or if the individual 
decides not to accept the compensation, the injured individual or his representative may pursue a 
tort claim in the US District Court for the District of Columbia, but only if the claim involves 
willful misconduct, is pled with particularity required under the PREP Act, verified, and 
accompanied by an affidavit by a physician who did not treat the individual and certified medical 
records. Any award is reduced by any public or private insurance or worker’s compensation 
available to the injured individual. Awards for non-economic damages, such as pain, suffering, 
physical impairment, mental anguish, and loss of consortium are also limited. If the individual 
accepts compensation, or if there is no willful misconduct, then the individual does not have a 
tort claim that can be filed in a US Federal or a State court. 
2.2 
Scientific Rationale 
As part of the US Government’s past pandemic preparedness efforts, Sanofi Pasteur under 
contract to the Biomedical Advanced Research and Development Authority (BARDA)/DHHS, 
produced several novel pre-pandemic vaccines that were or are currently being evaluated by 
NIAID’s VTEU sites to assess their safety, reactogenicity and immunogenicity when mixed prior 
to administration with either AS03 or MF59 oil-in-water adjuvants manufactured by GSK and 
Seqirus, respectively. In general, these “mix and match” clinical trials have demonstrated that 
adjuvant use results in a significant dose-sparing effect.  
The large number of human infections starting with the “fifth wave” of outbreaks in late 2016 
has increased the pandemic risk potential of influenza A/H7N9 viruses circulating in China. The 
Yangtze River Delta lineage, a distinct A/H7N9 viral lineage, has now emerged and has been 
associated with many of the fifth wave cases. Fifth wave A/H7N9 viruses have led to a broader 
geographic spread of infected birds and human cases within China than previously reported. 
Further, several influenza A/H7N9 viruses in the Yangtze River Delta lineage have recently 
acquired genetic changes characteristic of highly pathogenic avian influenza (HPAI) viruses and 
have now shown an increased ability to infect and kill poultry [56, 59]. To date, no cases of 
A/H7N9 from the new viral lineage have been identified in birds or people infected outside of 


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China; however, a few cases have been identified in Hong Kong and Taiwan in infected travelers 
returning from China. Importantly, antigenic analysis of the fifth wave influenza A/H7N9 viruses 
and serological studies indicate that the stockpiled 2013 A/H7N9 IIV manufactured several years 
ago does not induce protective HAI or Neut antibodies against the Yangtze River Delta lineage. 
Hence, there is broad consensus across DHHS and interagency leadership that a new vaccine 
should be developed that would be effective against the currently predominating influenza 
A/H7N9 viruses. 
Several candidate vaccine viruses are under evaluation by the Centers for Disease Control and 
Prevention (CDC) and the World Health Organization (WHO) H5 Reference Laboratories 
Network. Under contract to BARDA/DHHS, Sanofi Pasteur has produced monovalent 
inactivated split influenza 2013 and 2017 A/H7N9 virus vaccines (2013 and 2017 A/H7N9 IIVs) 
using largely the same manufacturing process as its licensed, seasonal trivalent IIV (IIV3). The 
availability of the US Government-stockpiled AS03 (GSK) oil-in-water adjuvant provides an 
opportunity to determine if dose-sparing effects occur when mixing the Sanofi Pasteur 2013 and 
2017 A/H7N9 IIVs with the GSK AS03 adjuvant. See Sections 2.3.1 and 6.1 for additional 
details on the 2013 and 2017 A/H7N9 IIVs. 
Heterologous prime-boost vaccination regimens have shown considerable promise in expanding 
the breadth and durability of cross-clade antibody responses [60, 61]. In addition, the use of 
adjuvants and extending the interval between the priming (first) and boosting (second) doses of 
vaccine have also led to more robust cross-clade antibody responses [60-63]. 
The goal of this clinical trial is to assess in healthy adults, 19 to 50 years of age, the safety, 
reactogenicity and immunogenicity of one or two doses 2013 and 2017 A/H7N9 IIVs, 
administered intramuscularly at different dosages (3.75 or 15 mcg of hemagglutinin (HA) per 
dose), given with or without AS03 adjuvant, using different heterologous and homologous 
prime-boost vaccination schedules to evaluate the study vaccine dosage, dose-sparing potential 
of the adjuvant, optimal prime-boost interval for immunogenicity (two doses administered 21 
days vs. 4 months apart), and priming effects of different A/H7N9 IIVs. In addition to assessing 
antigen-sparing strategies, another goal of this study is to assess in at least a subset of samples, if 
serum immunoglobulin elicited by the 2013 and 2017 A/H7N9 IIVs recognize antigenically 
drifted variants of influenza A/H7 viruses. Since antibodies targeting the NA may represent an 
independent correlate of protection against influenza infection [15, 16], we plan to assess the NA 
content of the 2013 and 2017 A/H7N9 IIVs and determine if there is a dose-specific correlation 
of the NA content with the elicited humoral antibody responses to the N9 NA. 
This clinical trial will also investigate novel methods for identifying and assessing alternative 
cellular correlates of protection against influenza infection. These will include longitudinal 
assessments of: 1) the kinetics, magnitude, specificity, and/or quality of influenza-specific B and 
T cells, cTFH cells and innate immune cells (monocytes, DCs and NK cells); 2) the frequency of 


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influenza-specific IgA, IgG and IgM plasmablasts (ASCs); and 3) B cell receptor somatic 
hypermutation and repertoire assessments. 
Based on previously conducted studies with a 2013 A/H7N9 IIV manufactured by Sanofi Pasteur 
administered with or without AS03, we anticipate that two doses of the 2013 and 2017 A/H7N9 
IIVs administered IM at different dosages with or without AS03 adjuvant using different prime-
boost vaccination schedules will be well-tolerated and more immunogenic compared to the non-
adjuvanted study vaccine in healthy adults. 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
The potential risks of participating in this trial are those associated with having blood drawn, the 
intramuscular (IM) injection, possible reactions to the 2013 and 2017 H7N9 IIVs, with or 
without PBS diluent, and/or AS03 adjuvant, and breach of confidentiality. 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down and elevate his/her legs. Bruising at the blood draw site 
may occur, but can be prevented or lessened by applying pressure to the blood draw site for a 
few minutes after the blood is taken. IM injection may also cause transient discomfort and 
fainting. Drawing blood and IM injection may cause infection. The use of aseptic (sterile) 
technique will make infection at the site where blood will be drawn or where the study 
vaccination will be given extremely unlikely. 
There is a small amount of risk to subjects who report that they are in good health but who have 
an unknown health problem at the time of screening. This trial will screen by physical exam, 
history, vital signs and erythrocyte sedimentation rate (ESR). Clinical safety labs for white blood 
cells (WBC), hemoglobin (Hgb), platelets (PLT), alanine aminotransferase (ALT), total bilirubin 
(T. Bili), and creatinine (Cr) will be drawn prior to each study vaccination, but results will not be 
reviewed until after each study vaccination. To minimize the risk, subjects will not receive the 
second study vaccination unless, the most recently evaluated clinical safety laboratory values 
obtained prior to the second study vaccination are Grade 2 or less and the subject does not meet 
any of the other criteria listed in Section 5.2.3. 
There is potential for AEs to occur more frequently in the adjuvanted vaccine treatment arms 
[64] than in the non-adjuvanted treatment arms and there is potentially a higher risk for AEs to 
occur more frequently in the higher dose influenza antigen treatment arms than in the lower dose 
influenza antigen treatment arms. 


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The 2017 A/H7N9 IIV to be used in this clinical trial has not been tested for safety in animals; 
however, it is currently being evaluated in humans. The Division of Microbiology and Infectious 
Diseases (DMID), NIAID is sponsoring two Phase II clinical trials in healthy subjects to assess 
the safety, reactogenicity and immunogenicity of IM doses of the 2017 A/H7N9 IIV produced by 
Sanofi Pasteur, Swiftwater, PA, administered with or without the AS03 adjuvant produced by 
GSK and co-administered sequentially or simultaneously with licensed, seasonal influenza 
vaccine (Fluzone® Quadrivalent Influenza Vaccine) produced by Sanofi Pasteur, Swiftwater, PA 
(DMID Protocols: 17-0075; NCT03312231, 17-0077; NCT03318315). 
The 2013 A/H7N9 IIV to be used in this clinical trial is currently being tested for safety in 
animals. In addition, DMID, NIAID has sponsored at least five Phase II clinical trials to assess 
the safety, reactogenicity and immunogenicity of IM doses of the 2013 A/H7N9 IIV produced by 
Sanofi Pasteur, Swiftwater, PA, administered with or without either AS03 (GSK) or MF59 
(Seqirus) adjuvants in healthy subjects (DMID Protocols: 13-0032; NCT01938742, 13-0033; 
NCT01942265, 13-0034; NCT02213354, 13-0044; NCT02586792, and 14-0015; NCT02921997). 
Overall, the study products administered in these clinical trials were generally safe and well-
tolerated. 
For DMID Protocol 13-0032, nine SAEs were reported. All were assessed as being not related 
to study product. Two cases of Autoimmune thyroiditis (Hashimoto’s disease/Hashimoto’s 
thyroiditis), classified as Adverse Events of Special Interest (AESIs), were reported in this 
clinical trial: one case was assessed as not related to study product (due to preexisting Thyroid 
Peroxidase Antibodies) whereas the other case was assessed as related to study product (no 
preexisting Thyroid Peroxidase Antibodies). 
For DMID Protocol 13-0033, sixteen SAEs were reported. Fifteen of these SAEs were assessed 
as being not related to study product. One SAE was considered to be related: acute inferior 
myocardial infarction. Two AESIs were reported in this clinical trial: psoriasiform dermatitis and 
celiac disease; both assessed as not related to study product, because both disorders pre-existed 
to study vaccination, but both disorders received the diagnosis after study vaccination. 
For DMID Protocol 13-0034, seventy-five SAEs were reported. All were assessed as being not 
related to study product. Two AESIs were reported in this clinical trial: guttate psoriasis vulgaris 
and lichen planus; both were assessed as related to study product. 
For DMID Protocol 13-0044, no SAEs were reported. No AESIs were reported, since this 
clinical trial tested the unadjuvanted 2013 A/H7N9 IIV. 
For DMID Protocol 14-0015, one SAE was reported. It was assessed as not related to study 
product. No AESIs were reported in this clinical trial. 


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The monovalent split 2013 A/H7N9 IIV to be used in this clinical trial was derived from the 
influenza virus A/Shanghai/2/2013 (H7N9). The monovalent split 2017 A/H7N9 IIV to be used 
in this clinical trial was derived from the influenza virus A/Hong Kong/125/2017 (H7N9). The 
manufacturing process for the production of these investigational A/H7N9 vaccines is similar 
to the process used to produce the licensed, Influenza Virus Vaccine Fluzone® family of 
products, except for a minor modification in the PBS diluent in the formulation step of the 
2013 A/H7N9 IIV that was made according to previous experiences of manufacturing of 
monovalent pandemic vaccines. As such, the safety profile of the candidate A/H7N9 vaccines 
should be similar to the current Fluzone® vaccine. 
 
 
 
 
 
 
 
 
 
The potential risks to subjects are anticipated to be similar to those observed for Sanofi Pasteur’s 
unadjuvanted licensed, inter-pandemic (seasonal) IIVs (Fluzone® and Fluzone® High-Dose), their 
unadjuvanted licensed, 2009 A/H1N1 and A/H5N1 monovalent IIVs, and their monovalent split 
2013 A/H7N9 IIV administered with or without AS03 or MF59 (see the Sanofi Pasteur 
Investigator’s Brochure Investigational Pandemic Influenza Virus vaccines, Monovalent 
A/Shanghai/2/2013 (H7N9) product code 504, Monovalent A/Hong Kong/125/2017 (H7N9) 
product code 504, Monovalent A/Indonesia/05/2005 (H5N1) product code 458, Monovalent 
A/Vietnam/1203/2004 (H5N1) product code 399, Monovalent A/Bar-Headed Goose/Qinghai 
Lake/1A/2005 (H5N1) product code 458, Version Number 1.0, January 2018). 
Occasionally, adult recipients of unadjuvanted licensed, IIVs may develop influenza-like 
reactions, such as fever, feverishness (chills/shivering/sweating), fatigue (tiredness), malaise 
(general unwell feeling), myalgia (body aches/muscular pain), arthralgia (joint pain), headache, 
and/or nausea. Some subjects may develop reactions at the injection site, including pruritus 
(itching), ecchymosis (bruising), erythema (redness), induration (hardness), edema (swelling), 
pain, and/or tenderness. Most of these reactions peak in intensity in the first 24 hours after 
vaccination and disappear without treatment within 1 or 2 days. Analgesics (e.g., acetaminophen, 


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ibuprofen or similar non-steroidal anti-inflammatory drugs [NSAIDs]) and rest may generally 
relieve or lessen these reactions. Bruising can sometimes occur due to the vaccination procedure. 
In addition, post-marketing surveillance indicates autoimmune disorders as potential risks for 
pandemic vaccines based on those identified for the seasonal IIVs; these may also include, but 
are not limited to, neuritis, convulsions, severe allergic reactions, syncope, encephalitis, 
thrombocytopenia, vasculitis, and Guillain-Barré syndrome (GBS). Reports of these reactions 
were rare; however, exact incidence rates cannot be precisely calculated. 
Acute and potentially life-threatening allergic reactions (i.e., anaphylaxis) are also possible. 
These reactions occur in about 1 in 4 million people given a vaccination. These reactions can 
manifest as skin rash (hives), swelling around the mouth, throat or eyes (angioedema), difficulty 
breathing (bronchospasm), a fast pulse (tachycardia), or decrease in blood pressure 
(hypotension). If these reactions occur, they can usually be stopped by the administration of 
emergency medications by the study personnel. As with any vaccine or medication, there is a 
very small chance of a death, although researchers do not expect this to occur. 
During the swine influenza (A/H1N1) vaccine campaign of 1976, some recipients developed a 
paralytic illness called GBS. GBS is an acute inflammatory neuropathy characterized by 
weakness, hyporeflexia or areflexia, and elevated protein concentrations in cerebrospinal fluid. 
The rate of GBS was significantly increased in individuals receiving the 1976 swine influenza 
(A/H1N1) vaccine at about 1 per 100,000 vaccine recipients. This syndrome has not been seen 
consistently with other influenza vaccines. Most persons who develop GBS recover completely, 
although the recovery period may be as little as a few weeks or as long as a few years. About 
30% of those with GBS still have residual weakness after 3 years and about 3% may suffer a 
relapse of muscle weakness and tingling sensations many years after the initial attack. Intensive 
surveillance of GBS after administration of IIVs since 1976 has shown a slight increase in risk 
over background cases (more than one additional case of GBS per million persons) following 
vaccination, typically with onset within 6 weeks after vaccination [65]. Interestingly, although 
vaccination rates have increased in the last 10 years, the numbers of reported cases of vaccine-
associated GBS have declined [66]. A recent study in Canada showed that the 2009 A/H1N1 
vaccine was associated with a small but significant risk of GBS in persons 50 years of age and 
older [67]. An active, population-based surveillance study conducted in the US during the 2009-
2010 influenza season found less than 1 excess GBS case per million doses of 2009 A/H1N1 
vaccine administered – a rate similar to that associated with some previously administered 
annual influenza vaccines [68-70]. Another study using the Medicare system showed an elevated 
risk of GBS with monovalent 2009 A/H1N1 vaccination (incidence rate ratio = 2.41, 95% 
confidence interval (CI): 1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% 
CI: 0.21, 5.48) [71]. An international collaboration study also supported a conclusion of an 
association between 2009 A/H1N1 vaccination and GBS [72]. It is unknown if the administration 


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of the 2013 and 2017 A/H7N9 IIVs to be used in this clinical trial will result in an increased 
incidence of GBS as the mechanism leading to this AE has not been completely elucidated. 
As of November 22, 2015 (per the GSK AS03 Adjuvant Investigator’s Brochure dated February 
2016), data are available for 56 GSK-sponsored clinical trials of AS03-adjuvanted monovalent 
pandemic vaccines manufactured by GSK. More than 18,000 adult (age ≥18 years) and 6,900 
pediatric (6 months to 17 years old) clinical trial participants have received at least one dose of a 
GSK-manufactured, AS03-adjuvanted monovalent pandemic influenza vaccine. Clinical data 
collected by GSK as of November 22, 2015, suggest that inactivated monovalent (pre)pandemic 
influenza virus antigens adjuvanted with AS03 have generally acceptable safety and benefit/risk 
profiles, though the incidence rates of solicited injection site and systemic AEs are higher with 
AS03-adjuvanted antigens than with antigen alone, a licensed IIV3 or placebo. Some unsolicited 
AEs (e.g., insomnia, dizziness, cystitis) were associated with a higher relative risk among AS03-
adjuvanted H5N1 recipients in contrast to Fluarix® or placebo recipients. 
The information and guidance that follow are based on pre-clinical and clinical study results for 
GSK-manufactured AS03-adjuvanted monovalent pandemic vaccines, post-marketing safety 
surveillance data seen with unadjuvanted, IIV3s and (in the case of the A/H1N1 vaccines) post-
marketing safety surveillance data seen to date for both Pandemrix™ and Arepanrix™ H1N1 
vaccines. 
The reactogenicity profile in humans of GSK-manufactured AS03-adjuvanted vaccines is 
primarily associated with the adjuvant. The incidence and severity of injection site redness, 
swelling and pain at the injection site in recipients of AS03-adjuvanted vaccines are increased 
relative to monovalent pandemic influenza antigen alone, a licensed IIV3 or placebo. There is no 
increase in injection site and systemic reactogenicity events in recipients of AS03-adjuvanted 
vaccines after a second dose of vaccine relative to the first when given 21 days apart. In young 
children (6 months to 6 years old), increased frequency of fever has been observed following a 
heterologous booster dose of adjuvanted vaccine administered 6 months after the primary series. 
As of November 22, 2015, there has been no evidence in clinical trials to support a conclusion 
that any potential immune-mediated disease or group of diseases was causally related to an AS03-
adjuvanted vaccine. There have been no deaths in GSK clinical trials of AS03-adjuvanted 
pandemic influenza vaccines assessed as related to study vaccine. A total of 1,428 non-fatal SAEs 
have been reported for adult subjects as of November 22, 2015. Fifteen of these events were 
deemed related to vaccination by the Investigator or GSK. Of these, six occurred in recipients of 
an adjuvanted H1N1 vaccine: asthma, herpes zoster, hepatic enzyme increased, and pain in 
extremity, polymyalgia rheumatic, and thrombocytopenia. Three occurred in recipients of 
unadjuvanted H1N1 vaccine: alanine aminotransferase increased, hypersensitivity, and multiple 
sclerosis. One SAE classified as related (myalgia) occurred in a subject who received a control 
product. Four SAEs classified as related occurred in recipients of an adjuvanted H5N1 vaccine: 


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autoimmune hepatitis, angina pectoris, pulmonary embolism, and non-Hodgkin’s lymphoma. One 
SAE classified as related (lobar pneumonia) occurred in a recipient of an unadjuvanted H5N1 
vaccine. Overall, the reactogenicity and safety profile of AS03-adjuvanted pandemic vaccines is 
acceptable and no safety concerns have been identified in clinical trials. 
Narcolepsy is a chronic sleep disorder with a background incidence rate, based on US data, of 
approximately 1.37 per 100,000 per year, with a peak onset between 10 and 19 years of age in 
some datasets. Narcolepsy, when associated with cataplexy is seen almost exclusively in 
individuals who are HLA DQB1*0602 allele carriers [73]. An autoimmune etiology has been 
proposed. In the post-marketing period for adjuvanted H1N1 pandemic vaccines, several 
epidemiological studies conducted in several countries independently of GSK reported an 
increased risk of narcolepsy with or without cataplexy in subjects who were vaccinated with 
Dresden-manufactured H1N1 (Pandemrix™ H1N1) vaccine during the 2009-2010 season. These 
studies have described an absolute risk increase of narcolepsy of approximately 1.4 to 8 additional 
cases per 100,000 vaccinated children/adolescents, and approximately one additional case per 
100,000 vaccinated adults compared to background rates of 0.12 to 0.79 per 100,000 
children/adolescents per year and 0.67 to 1.10 per 100,000 adults per year. The observed temporal 
association between narcolepsy and vaccination with Pandemrix™ H1N1 is not fully understood, 
and further research to evaluate the association between narcolepsy and Pandemrix™ H1N1, and 
other possible contributory factors to the development of narcolepsy during the 2009-2010 
pandemic, such as genetic and environmental factors, is being conducted. A GSK-supported 
study was conducted in Quebec, Canada, to assess the risk of narcolepsy associated with 
Arepanrix H1N1, using various index dates, risk periods, observation periods, and 
epidemiological designs. Overall, GSK considers that there is no strong evidence of an 
association between Q-Pan-H1N1 and narcolepsy in Quebec. Recently, the CDC conducted a 
study to assess trends in narcolepsy incidence rates before and after 2009 H1N1 influenza 
(pH1N1) vaccination campaigns and to evaluate the risk of narcolepsy following adjuvanted 
pH1N1 vaccines. Results of the incidence rates analysis indicated no change in narcolepsy rates 
between the period before wild-type pH1N1 virus circulation and the period after the start of 
pH1N1vaccination campaigns in any countries except Sweden, the first signaling country, and 
Taiwan, where incidence began to increase upon wild-type pH1N1 virus circulation. In the case-
control analysis, no association was observed for AS03-adjuvanted pH1N1 vaccine and 
narcolepsy in children or adults, and in the case-coverage analysis no association was observed 
for narcolepsy in children, the only age groups studied. However, the data for the AS03-
adjuvanted pH1N1 vaccine, Pandemrix™, were limited (20th Annual Conference on Vaccine 
Research, April 24-26th, 2017, Abstract S6-1). 
No post-marketing data are available for AS03 administered in combination with any GSK-
manufactured H5N1, H7N1, H7N9, or H9N2 antigen. However, millions of doses of GSK-
manufactured H1N1 antigens, combined with AS03, were administered in the context of the 


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2009/10 pandemic response. In addition to the adverse reactions reported in clinical trials, the 
following have been reported during post-marketing experience with Pandemrix™ (H1N1) and 
Arepanrix™ (H1N1): 
• Immune system disorders 
o Rare: anaphylaxis, allergic reactions 
• Nervous system disorders 
o Rare: febrile convulsions (in subjects below 20 years of age), somnolence**, 
Guillain-Barré syndrome* 
*Spontaneous reports of Guillain-Barré syndrome have been received following 
vaccination with Arepanrix™ (H1N1); however, a causal association between 
vaccination and Guillain-Barré syndrome has not been established. Data from a post-
marketing epidemiological study in Canada indicate a small but significant increased 
relative risk of Guillain-Barré syndrome of 1.80 (95% CI, 1.63-4.62) in the 56-day 
period following vaccination with Arepanrix™ (H1N1, in persons 50 years of age 
and older). The number of GBS cases attributable to vaccination was approximately 
2 per 1 million doses. 
**reported in patients with narcolepsy and as a temporary event following 
vaccination 
o Very rare1: narcolepsy with or without cataplexy 
1Frequency based on estimated attributable risk from epidemiological studies in 
several European countries. 
• Skin and subcutaneous tissue disorders 
o Rare: angioedema, generalized skin reactions, urticaria 
• General disorders and administration site conditions 
o Rare: injection site reactions (such as inflammation, mass, ecchymosis) 
From post-marketing surveillance with inter-pandemic (seasonal) trivalent vaccines, the 
following additional AEs have been reported: 
• Blood and lymphatic system disorders 


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o Transient thrombocytopenia 
• Nervous system disorders 
o Neuralgia, convulsions 
o Neurological disorders, such as encephalomyelitis, neuritis, and Guillain-Barré 
syndrome 
• Vascular disorders 
o Vasculitis with transient renal involvement 
As of November 22, 2015, the available data for women who become pregnant during clinical 
trials of AS03-adjuvanted (pre) pandemic influenza vaccines do not suggest any causal 
relationship between adverse pregnancy outcomes and receipt of an AS03-adjuvanted vaccine. 
However, there are no available data related to the risks of exposure to A/H7N9 IIVs 
administered with or without AS03 upon pregnancy and pregnancy outcomes. 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating VTEU sites. Electronic files will be 
password-protected. Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this trial will be allowed access to the PHI that is collected. Any publications from 
this trial will not use information that will identify subjects by name. Organizations that may 
inspect and/or copy research records maintained at the participating VTEU sites for quality 
assurance and data analysis include groups such as the IRB, NIAID and the FDA. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law. This web site will not include information that can identify subjects. 
There may be other risks, discomforts or side effects that are unknown at this time. 
2.3.2 
Known Potential Benefits 
There are no known benefits attributable to the receipt of the 2013 and 2017 A/H7N9 IIVs with 
or without AS03 adjuvant. Vaccination using the 2013 and 2017 A/H7N9 IIVs with or without 
AS03 adjuvant may or may not provide protection against a serious disease with the influenza 
2013 and 2017 A/H7N9 viruses, should the subject be exposed. The duration of any such 
protection is currently unknown. The 2013 and 2017 A/H7N9 IIVs with or without AS03 


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adjuvant are not expected to offer protection against circulating seasonal influenza viruses. There 
may be pandemic preparedness benefits to society in the future if the vaccine and adjuvants 
being evaluated in this clinical trial prove to be sufficiently safe and immunogenic and can be 
employed if a need for widespread influenza 2013 or 2017 A/H7N9 vaccination occurs. 
 


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3 
STUDY OBJECTIVES AND OUTCOME MEASURES 
3.1 
Study Objectives 
3.1.1 
Primary 
Safety: 
• To assess the safety and reactogenicity of 2013 and 2017 A/H7N9 IIVs given with or 
without AS03 adjuvant following receipt of each study vaccine. 
Immunogenicity: 
• To assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody 
responses following receipt of the second study vaccine. 
3.1.2 
Secondary 
Safety: 
• To assess unsolicited non-serious adverse events (AEs) following receipt of each study 
vaccine. 
• To assess medically-attended adverse events (MAAEs), including new-onset chronic 
medical conditions (NOCMCs) and potentially immune-mediated medical conditions 
(PIMMCs), following receipt of each study vaccine. 
Immunogenicity: 
• To assess the kinetics and durability of serum HAI and Neut antibody responses 
following receipt of each study vaccine. 
3.1.3 
Exploratory 
Immunogenicity: 
• To assess the effects of age, sex, body mass index (BMI), and prior receipt of seasonal or 
non-study pandemic influenza vaccine(s) on serum HAI and Neut antibody responses 
following receipt of the second study vaccine. 


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• To assess the neuraminidase (NA) content of the 2013 and 2017 A/H7N9 IIVs and 
determine, in at least a subset of samples, the serum antibody responses to N9 NA. 
• To assess, in at least a subset of samples, HA stem-specific antibody responses. 
• To assess, in at least a subset of samples, the cross-reactivity of serum HAI and Neut 
antibody responses to antigenically drifted variants of influenza A/H7 viruses. 
• To assess, in at least a subset of samples, the frequency of influenza-specific (A/H7N9 
antigens) IgA, IgG and IgM memory B cells (MBCs). 
• To assess, in at least a subset of samples, the frequency of influenza-specific (A/H7N9 
antigens) IgA, IgG and IgM plasmablasts (antibody-secreting cells [ASCs]). 
• To assess, in at least a subset of samples, the multifunctional cytokine/chemokine profile 
of influenza A/H7N9-specific CD4 and CD8 T cells. 
• To assess, in at least a subset of samples, the characterization of circulating T follicular 
helper (cTFH) cells. 
• To assess, in at least a subset of samples, the study vaccine-induced changes in 
populations and/or activation status of innate immune cells (monocytes, dendritic cells 
[DCs] and natural killer [NK] cells). 
• To assess, in at least a subset of samples, the study vaccine-induced activation status of B 
cells. 
• To assess, in at least a subset of samples, the B cell receptor repertoire and degree of 
somatic hypermutation generated in response to study vaccination. 
3.2 
Study Outcome Measures 
3.2.1 
Primary 
Safety: 
• Occurrence of all serious adverse events (SAEs) from the time of the first study 
vaccination through approximately 12 months after the last study vaccination. 
• Occurrence of solicited injection site and systemic reactogenicity events from the time of 
each study vaccination through 7 days after each study vaccination. 


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• Occurrence of clinical safety laboratory AEs from the time of each study vaccination 
through approximately 7 days after each study vaccination. 
Immunogenicity: 
• For HAI and Neut antibodies, percentage of subjects achieving seroconversion against 
the influenza A/H7N9 study vaccine viruses (defined as either a pre-vaccination titer 
<1:10 and a post-vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and a minimum 
four-fold rise in post-vaccination antibody titer) approximately 21 days after the second 
study vaccination. 
• For HAI and Neut antibodies, percentage of subjects achieving titer ≥1:40 against the 
influenza A/H7N9 study vaccine viruses approximately 21 days after the second study 
vaccination. 
• Geometric mean titers (GMTs) of serum HAI and Neut antibodies against the influenza 
A/H7N9 study vaccine viruses approximately 21 days after the second study vaccination. 
3.2.2 
Secondary 
Safety: 
• Occurrence of all unsolicited non-serious AEs from the time of each study vaccination 
through approximately 21 days after each study vaccination. 
• Occurrence of all MAAEs, including NOCMCs and PIMMCs, from the time of the first 
study vaccination through approximately 12 months after the last study vaccination. 
Immunogenicity: 
• For HAI and Neut antibodies, percentage of subjects achieving seroconversion against 
the influenza A/H7N9 study vaccine viruses approximately 21 days after the first study 
vaccination as well as immediately prior to and approximately 180 days after the second 
study vaccination. 
• For HAI and Neut antibodies, percentage of subjects achieving titer ≥1:40 against the 
influenza A/H7N9 study vaccine viruses immediately prior to each study vaccination, 
approximately 21 days after the first study vaccination and approximately 180 days after 
the second study vaccination. 


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• GMTs of serum HAI and Neut antibodies against the influenza A/H7N9 study vaccine 
viruses immediately prior to each study vaccination, approximately 21 days after the first 
study vaccination and approximately 180 days after the second study vaccination. 
3.2.3 
Exploratory 
Immunogenicity: 
• For HAI and Neut antibodies, GMTs and percentage of subjects achieving 
seroconversion against the influenza A/H7N9 study vaccine viruses approximately 21 
days after the second study vaccination, by age, sex, BMI, and prior receipt of seasonal or 
non-study pandemic influenza vaccine(s). 
• GMTs and percentage of subjects achieving seroconversion (defined as four-fold change 
from baseline) of serum anti-NA (by enzyme-linked immunosorbent assay [ELISA]) or 
anti-neuraminidase inhibition (NAI) (by enzyme-linked lectin assay [ELLA]) antibodies 
immediately prior to and approximately 21 days after each study vaccination as well as 
approximately 180 days after the second study vaccination. 
• Correlate the HA and/or NA content of 2013 and 2017 A/H7N9 IIVs with the elicited HA 
or N9 NA-specific antibody titer approximately 21 days after each study vaccination as 
well as immediately prior to and approximately 180 days after the second study 
vaccination. 
• GMTs of HA stem-specific antibody immediately prior to and approximately 21 days 
after each study vaccination as well as approximately 180 days after the second study 
vaccination. 
• For HAI and Neut antibodies, GMTs and percentage of subjects achieving 
seroconversion against antigenically drifted variants of influenza A/H7 viruses 
approximately 21 days after the second study vaccination. 
• Percentage of influenza-specific (A/H7N9 antigens) IgA, IgG and IgM MBCs at baseline 
and approximately 90 and 180 days after the second study vaccination. 
• Frequency of influenza-specific (A/H7N9 antigens) IgA, IgG and IgM plasmablasts 
(ASCs) present in circulation approximately 7 days after each study vaccination. 
• Percentage of influenza A/H7N9-specific CD4 and CD8 T cells producing 
cytokines/chemokines immediately prior to and approximately 7 days after each study 
vaccination as well as approximately 90 days after the second study vaccination. 


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• Percentage of cTFH cells producing cytokines/chemokines immediately prior to and 
approximately 3, 7 and 14 days after each study vaccination. 
• Percentage and activation status of innate immune cells (monocytes, DCs and NK cells) 
immediately prior to and approximately 1, 3, 7 and 14 days after each study vaccination. 
• Percentage of activated B cells immediately prior to and approximately 1, 3, 7 and 14 
days after each study vaccination. 
• Evaluation of B cell receptor repertoire and degree of somatic hypermutation of anti-HA 
(H7) and anti-NA (N9) antibodies at baseline and approximately 180 days after the 
second study vaccination. 
• Correlation of the above exploratory immunologic parameters with HAI and Neut 
antibodies. 
 


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4 
STUDY DESIGN 
This is a Phase II clinical trial in up to 180 males and non-pregnant females, 19 to 50 years of 
age, inclusive, who are in good health and meet all eligibility criteria. This clinical trial is 
designed to assess the safety, reactogenicity and immunogenicity of one or two doses of 
monovalent inactivated split influenza 2013 and 2017 A/H7N9 virus vaccines (2013 and 2017 
A/H7N9 IIVs) manufactured by Sanofi Pasteur (SP), administered intramuscularly at different 
dosages (3.75 or 15 mcg of hemagglutinin (HA) per dose), given with or without AS03 adjuvant 
manufactured by GlaxoSmithKline Biologicals (GSK), using different heterologous and 
homologous prime-boost vaccination schedules. Phosphate buffered saline (PBS) diluent 
manufactured by Patheon Manufacturing Services LLC may be used to achieve targeted dosages. 
Subjects who are influenza A/H7 vaccine/infection naïve by medical history will be randomly 
assigned to 1 of 6 treatment arms to receive one or two doses of the 2013 and 2017 A/H7N9 IIVs 
in different heterologous and homologous prime-boost combinations evaluating the interval 
between the priming (first) and boosting (second) doses (21 days vs. 4 months) and the presence 
of the adjuvant in the priming (first) and boosting (second) doses (see Table 1). 
Reactogenicity will be measured by the occurrence of solicited injection site and systemic 
reactions from the time of each study vaccination through 7 days after each study vaccination. 
Unsolicited non-serious adverse events (AEs) will be collected from the time of each study 
vaccination through approximately 21 days after each study vaccination. Serious adverse events 
(SAEs) and medically-attended adverse events (MAAEs), including new-onset chronic medical 
conditions (NOCMCs) and potentially immune-mediated medical conditions (PIMMCs), will be 
collected from the time of the first study vaccination through approximately 12 months after the 
last study vaccination. Clinical safety laboratory evaluations (hematology and chemistry) will be 
performed on venous blood collected immediately prior to each study vaccination and 
approximately 7 days after each study vaccination. 
Immunogenicity testing will include performing serological assays to assess hemagglutination 
inhibition (HAI), neutralizing (Neut), neuraminidase inhibition (NAI), neuraminidase (NA)-
specific, and HA stem-specific antibody titers at multiple time points following each study 
vaccination. In addition, peripheral blood mononuclear cells (PBMCs) will be used to determine 
broad immunologic responses and to correlate these responses with serological antibody 
responses described above in each of the treatment arms. These responses will include 
longitudinal assessments of the kinetics, magnitude, specificity, and/or quality of influenza-
specific B and T cells, circulating T follicular helper (cTFH) cells and innate immune cells 
(monocytes, dendritic cells [DCs] and natural killer [NK] cells) as well as the frequency of 
influenza-specific IgA, IgG and IgM plasmablasts (antibody-secreting cells [ASCs]) and B cell 
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at multiple time points following each study vaccination for the future research use of serum, 
plasma and PBMCs. 
In addition, we plan to determine the N9 NA-specific antibody response to study vaccination as 
well as assess the NA content of the 2013 and 2017 A/H7N9 IIVs using assays that are currently 
under development to determine if the NA content in a dose-specific manner correlates with the 
N9 NA-specific antibody response. 
For additional details on study procedures and evaluations and study schedule by study 
visits/days, see Sections 7 and 8 as well as Appendix A: Schedule of Study Procedures and 
Evaluations and Appendix B: Schedule of Special Assays. 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Up to 180 males and non-pregnant females, 19 to 50 years of age, inclusive, who are in good 
health and meet all eligibility criteria will be enrolled at up to 5 VTEU sites (and their 
subcontractors) participating in this trial. The target population should reflect the community at 
large at each of the participating VTEU sites. Estimated time to complete enrollment in this trial 
is approximately 12 weeks. Information regarding this trial may be provided to potential subjects 
who have previously participated in vaccine trials conducted at each of the participating VTEU 
sites. Other forms and/or mechanisms of recruitment may also be used. The IRB will approve all 
materials prior to use. 
Subject Inclusion and Exclusion Criteria must be assessed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator (PI) or sub-
investigator. 
No exemptions are granted on Subject Inclusion or Exclusion Criteria in DMID-sponsored 
studies. Questions about eligibility should be directed toward the DMID Medical Officer. 
5.1 
Eligibility Criteria 
5.1.1 
Subject Inclusion Criteria 
Subjects eligible to participate in this trial must meet all of the following inclusion criteria: 
1. Provide written informed consent prior to initiation of any study procedures. 
2. Are able to understand and comply with planned study procedures and be available for all 
study visits. 
3. Must agree to the collection of venous blood per protocol. 
4. Must agree to have residual specimens and samples/specimens collected during this trial 
specifically for the purpose of future research stored for future research use. 
5. Are males or non-pregnant females, 19 to 50 years of age, inclusive. 
6. Are in good health1. 
1As determined by medical history and physical examination to evaluate acute or currently ongoing chronic medical 
diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the assessment 
of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions should 
be stable for the last 60 days (no hospitalizations, emergency room or urgent care for condition and no adverse 


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symptoms that need medical intervention such as medication change/supplemental oxygen). This includes no change in 
chronic prescription medication, dose or frequency as a result of deterioration of the chronic medical diagnosis or 
condition in the 60 days prior to enrollment. Any prescription change that is due to change of health care provider, 
insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be 
considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a 
disease outcome, as determined by the site PI or appropriate sub-investigator, will not be considered a deviation of this 
inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site PI or 
appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and 
immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes 
subsequent to enrollment and study vaccination are acceptable provided there was no deterioration in the subject’s 
chronic medical condition that necessitated a medication change, and there is no additional risk to the subject or 
interference with the evaluation of responses to study vaccination. Note: Topical, nasal and inhaled medications 
(except inhaled corticosteroids as outlined in the Subject Exclusion Criteria (see Section 5.1.2)) as well as herbals, 
vitamins and supplements are permitted. 
7. Oral temperature is less than 100.0°F. 
8. Pulse is 47 to 100 beats per minute, inclusive. 
9. Systolic blood pressure is 85 to 150 mmHg, inclusive. 
10. Diastolic blood pressure is 55 to 95 mmHg, inclusive. 
11. ESR is less than 30 mm per hour. 
12. Women of childbearing potential2 must use an acceptable contraception method3 from 30 
days before first study vaccination until 60 days after last study vaccination. 
2Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure® 
placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at 
least 90 days after the procedure, and still menstruating or <1 year has passed since the last menses if menopausal. 
3Includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous 
relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving 
the first study vaccination, barrier methods such as condoms or diaphragms/cervical cap with spermicide, effective 
intrauterine devices, NuvaRing®, and licensed hormonal methods such as implants, injectables or oral contraceptives 
(“the pill”). 
13. Women of childbearing potential must have a negative urine or serum pregnancy test 
within 24 hours prior to study vaccination. 
5.1.2 
Subject Exclusion Criteria 
Subjects eligible to participate in this trial must not meet any of the following exclusion criteria: 
1. Have an acute illness4, as determined by the site PI or appropriate sub-investigator, 
within 72 hours prior to study vaccination. 


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4An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion 
of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety 
parameters as required by the protocol. 
2. Have any medical disease or condition that, in the opinion of the site PI or appropriate 
sub-investigator, is a contraindication to study participation5. 
5Including acute or chronic medical disease or condition, defined as persisting for at least 90 days, that would place 
the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may 
interfere with the evaluation of responses or the subject’s successful completion of this trial. 
3. Have immunosuppression as a result of an underlying illness or treatment, a recent 
history or current use of immunosuppressive or immunomodulating disease therapy. 
4. Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to 
study vaccination. 
5. Have known active neoplastic disease or a history of any hematologic malignancy. Non-
melanoma, treated, skin cancers are permitted. 
6. Have known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. 
7. Have known hypersensitivity or allergy to eggs, egg or chicken protein, squalene-based 
adjuvants, or other components of the study vaccine. 
8. Have a history of severe reactions following previous immunization with licensed or 
unlicensed influenza vaccines. 
9. Have a personal or family history of narcolepsy. 
10. Have a history of GBS. 
11. Have a history of convulsions or encephalomyelitis within 90 days prior to study 
vaccination. 
12. Have a history of PIMMCs6 
6Refer to Appendix C: List of Potentially Immune-Mediated Medical Conditions. 
13. Have a history of alcohol or drug abuse within 5 years prior to study vaccination. 
14. Have any diagnosis, current or past, of schizophrenia, bipolar disease or other psychiatric 
diagnosis that may interfere7 with subject compliance or safety evaluations. 
7As determined by the site PI or appropriate sub-investigator. 


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15. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement 
for danger to self or others within 10 years prior to study vaccination. 
16. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose within 
30 days prior to study vaccination. 
17. Have taken high-dose inhaled corticosteroids8 within 30 days prior to each study 
vaccination. 
8High-dose defined as per age as using inhaled high-dose per reference chart in the National Heart, Lung and Blood 
Institute Guidelines for the Diagnosis and Management of Asthma (EPR-3) or other lists published in UPTODATE. 
18. Received a licensed, live vaccine within 30 days prior to the first study vaccination, or 
plan to receive a licensed, live vaccine within 30 days before or after each study 
vaccination. 
19. Received or plan to receive a licensed, inactivated vaccine (excluding all licensed, 
seasonal IIVs) within 14 days before or after each study vaccination. 
20. Received or plan to receive a licensed, seasonal IIV within 21 days before or after each 
study vaccination. 
21. Received immunoglobulin or other blood products (except Rho D immunoglobulin) 
within 90 days prior to each study vaccination. 
22. Received an experimental agent9 within 30 days prior to the first study vaccination or 
expect to receive an experimental agent10 during the trial-reporting period11. 
9Including vaccine, drug, biologic, device, blood product, or medication. 
10Other than from participation in this trial. 
11Approximately 12 months after the last study vaccination. 
23. Are participating or plan to participate in another clinical trial with an interventional 
agent12 that will be received during the trial-reporting period13. 
12Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication. 
13Approximately 12 months after the last study vaccination. 
24. Received or plan to receive an influenza A/H7 vaccine14 or have a history of influenza 
A/H7 subtype infection. 
14And assigned to a treatment arm receiving influenza A/H7 vaccine, i.e., does not apply to documented placebo 
recipients. 


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25. Had substantial direct contact15 with live or freshly slaughtered poultry or pigeons while 
in mainland China within the past five years. 
15Substantial direct contact is defined as visited a poultry farm and/or a live poultry market. 
26. Occupational exposure to or substantial direct physical contact16 with birds in the past 
year and through 21 days after the last study vaccination. 
16Exposure to free range chickens in the yard is exclusionary. Casual contact with birds at petting zoos or county or 
state fairs or having pet birds does not exclude subjects from study participation. 
27. Female subjects who are breastfeeding or plan to breastfeed at any given time from the 
first study vaccination until 30 days after the last study vaccination. 
28. Plan to travel outside the US (continental US, Hawaii and Alaska) from the time of each 
study vaccination through 21 days after each study vaccination. 
5.2 
Treatment Assignment Procedures 
5.2.1 
Enrollment and Randomization Procedures 
Per ICH E6 GCP, screening records will be kept at each participating VTEU site to document the 
reason why an individual was screened, but failed trial entry criteria. The reasons why 
individuals failed screening will be recorded in the Statistical and Data Coordinating Center’s 
(SDCC) AdvantageEDCSM (Electronic Data Capture System). 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled and randomly assigned to 1 of 6 treatment arms, stratified by the 
participating VTEU site and prior receipt of licensed, seasonal influenza vaccine (defined as 
receipt of at least one of the 2017-2018 and/or 2018-2019 licensed, seasonal influenza vaccines). 
Subjects will receive two study vaccinations per their randomized treatment assignment (see 
Table 1). 
Enrollment of subjects will be done online using the enrollment module of AdvantageEDCSM. 
The randomization code will be prepared by statisticians at the SDCC and included in the 
enrollment module for this trial. AdvantageEDCSM will assign each subject to a treatment arm 
after the demographic and eligibility data have been entered into the system. A designated 
individual at each participating VTEU site will be provided with a code list for emergency 
unblinding purposes, which will be kept in a secure place. 
Instructions for use of the enrollment module are included in the AdvantageEDCSM User’s 
Guide. Manual back-up procedures and instructions are provided for use in the event that a 


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participating VTEU site temporarily loses access to the Internet or the online enrollment system 
is unavailable. 
5.2.2 
Masking Procedures 
This is a partially-blinded clinical trial. 
Subjects, site investigators and study personnel performing any study-related assessments 
following study vaccine administration to the subject are partially-blinded (blinded to treatment 
assignment and unblinded to treatment interval). Laboratory personnel performing HAI and Neut 
antibody assays will receive serum specimens blinded to subject ID number and specimen visit 
number. 
The randomization scheme will be generated by the SDCC and provided to unblinded study 
personnel (i.e., research pharmacists performing study vaccination preparations and unblinded 
study vaccine administrators) at the participating VTEU sites. 
The unblinded study vaccine administrator is a study personnel member credentialed to 
administer vaccines and may also participate in dose preparation, but will not be involved in 
study-related assessments or have subject contact for data collection following study vaccine 
administration to the subject. 
The Data and Safety Monitoring Board (DSMB) may receive data in aggregate and presented by 
treatment arm. The DSMB may also be provided with expected and observed rates of the 
expected AEs in an unblinded fashion, and may request the treatment assignment be unblinded 
for an individual subject if required for safety assessment. The DSMB will review grouped and 
unblinded data in the closed session only. 
5.2.3 
Reasons for Withdrawals and Discontinuation of Study Product Administration 
Subjects may voluntarily withdraw their consent for trial participation at any time and for any 
reason, without penalty or loss of benefits to which they are otherwise entitled. 
The site PI or appropriate sub-investigator may also withdraw a subject from receiving the study 
vaccine for any reason. 
A subject may withdraw or be withdrawn from this trial for any of the following reasons: 
• Medical disease or condition, or any new clinical finding for which continued 
participation, in the opinion of the site PI or appropriate sub-investigator, would 
compromise the safety of the subject, or would interfere with the subject’s successful 


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completion of this trial, or would interfere with the evaluation of responses (for example, 
has baseline significant laboratory abnormalities). 
• Subject no longer meets eligibility criteria (see Section 5.1). Note: Medication changes in 
the 60 days prior to enrollment, as specified in Subject Inclusion Criterion #4, are 
exclusionary for receipt of the first study vaccination only. 
• Subject withdrawal of consent. 
• Subject lost to follow-up. 
• Termination of this trial. 
• As deemed necessary by the site PI or appropriate sub-investigator for noncompliance or 
other reasons. 
• New information becomes available that makes further participation unsafe. 
The second study vaccination will not be administered to a subject if any of the following 
criteria are met: 
• Medical condition or medication change for which continued participation, in the opinion 
of the site PI or appropriate sub-investigator, would pose a risk to the subject or would be 
likely to confound interpretation of the results. 
• Presence of signs or symptoms that could confound or confuse assessment of study 
vaccine reactogenicity. For subjects with injection site or systemic signs or symptoms, or 
with an acute illness, including an oral temperature greater than or equal to 100°F, the 
second study vaccination should be postponed/deferred until signs, symptoms or acute 
illness have/has resolved, or are/is improving as further specified below, and if within the 
acceptable protocol-specified window for the Dose 2 visit. No exceptions to the protocol-
specified window will be made. Note for afebrile, acute illness only: If a subject is 
afebrile, his/her acute illness is nearly resolved with only minor residual symptoms 
remaining, this occurs within the acceptable protocol-specified window for the Dose 2 
visit, and, in the opinion of the site PI or appropriate sub-investigator, the residual 
symptoms will not interfere with the ability to assess safety parameters as required by the 
protocol, the subject may receive the second study vaccination without further approval 
from the DMID Medical Officer. No exceptions to the protocol-specified window will be 
made. 


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• Grade 3 solicited or unsolicited AE that occurs without alternative etiology in the 8 days 
after the first study vaccination. 
• Grade 3 solicited or unsolicited AE that is ongoing, whether or not it is improved or 
resolving. 
• Any unresolved or ongoing Grade 2 solicited or unsolicited AE that does not decrease to 
Grade 1 or less prior to the second study vaccination. Note: An unresolved or ongoing 
Grade 1 solicited or unsolicited AE is permissible following the documented 
determination by the site PI or appropriate sub-investigator, that it would not render study 
vaccination unsafe or interfere with the evaluation of responses. 
• Grade 3 clinical safety laboratory value (according to the toxicity table, Section 9.2.3) 
that does not decrease to Grade 2 or less prior to the second study vaccination. Note: Any 
clinical safety laboratory parameter may be re-evaluated only once at the central (clinical) 
laboratory in order to assess eligibility prior to the second study vaccination. If the 
clinical safety laboratory value decreases to Grade 2 or less, the subject may receive the 
second study vaccination. The second study vaccination should be scheduled to occur 
within the acceptable protocol-specified window for the Dose 2 visit. No exceptions to 
the protocol-specified window will be made. 
• New onset of illness or condition that meets the Subject Exclusion Criteria (see Section 
5.1.2). 
• Hospitalization that occurs before administration of the second study vaccination. 
• Subject no longer meets eligibility criteria (see Section 5.1). Note: Medication changes 
subsequent to the first study vaccination are not exclusionary for receipt of the second 
study vaccination provided there was no deterioration in the subject’s chronic medical 
condition that necessitated a medication change, and there is no additional risk to the 
subject or interference with the evaluation of responses to study vaccination. 
• Subject refusal of further study vaccination. 
• Subject withdrawal of consent. 
• Subject lost to follow-up. 
• Termination of this trial. 
• As deemed necessary by the site PI or appropriate sub-investigator for noncompliance or 
other reasons. 


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• New information becomes available that makes further participation unsafe. 
5.2.4 
Handling of Withdrawals and Discontinuation of Study Product Administration 
The primary reason for withdrawal from this trial will be recorded on the Study Status data 
collection form (DCF). Subjects will be encouraged to complete the Early Termination Visit. 
The Early Termination Visit procedures are listed in Section 8.4. 
Although subjects are free to withdraw at any time or may be withdrawn by the site PI or 
appropriate sub-investigator at any time (see Section 5.2.3), those subjects who receive only one 
dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments 
(may be conducted by phone call rather than in person) continuing through approximately 12 
months after their last study vaccination. These subjects will also be encouraged to provide a 
venous blood sample for serological assays approximately 21 and 180 days after their last study 
vaccination. See the protocol-specific Manual of Procedures (MOP) for alternate follow-up 
requirements. 
Every attempt will be made to follow all AEs, including solicited injection site and systemic 
reactions, unsolicited non-serious AEs, SAEs, and MAAEs, including NOCMCs and PIMMCs, 
ongoing at the time of early withdrawal through resolution as per applicable collection times 
defined for the specific type of AE. 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort (i.e., 
three documented contact attempts via phone calls made on separate occasions and followed by a 
certified letter) will be made to locate or recall them, or at least to determine their health status. 
These efforts will be documented in the subject’s study records. 
The site PI or appropriate sub-investigator will inform the subject that already collected data will 
be retained and analyzed even if the subject withdraws or is withdrawn from this study. 
5.2.5 
Subject Replacement 
Subjects who withdraw, or are withdrawn or terminated from this trial, or are lost to follow-up 
after signing the informed consent form (ICF), randomization and receipt of study vaccine will 
not be replaced. However, if a subject withdraws after signing the ICF, but before randomization 
and/or receipt of study vaccine, they may be replaced. 


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5.2.6 
Termination of Study 
Although the sponsor has every intention of completing this trial, it reserves the right to 
terminate this trial at any time for clinical or administrative reasons. Reasons for termination 
include, but are not limited to, study closure due to DSMB review and recommendation, and at 
the discretion of DMID. 
If this trial is prematurely terminated by the sponsor, any regulatory authority, the site PI, or 
appropriate sub-investigator for any reason, the site PI or appropriate sub-investigator will 
promptly inform the subjects and assure appropriate therapy or follow-up for the subjects, as 
necessary. The site PI or appropriate sub-investigator will provide a detailed written explanation 
of the termination to the IRB. 
 


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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
6.1 
Study Product Description 
2013 A/H7N9 IIV 
Sanofi Pasteur has developed a monovalent split 2013 A/H7N9 IIV manufactured using a reverse 
genetics-derived reassortant candidate vaccine virus, IDCDC RG32A (H7N9), containing the 
HA and NA from avian influenza A/Shanghai/2/2013 (H7N9) and the PB2, PB1, PA, NP, M and 
NS from A/Puerto Rico/8/1934 (H1N1). The manufacturing processes used for the 
investigational vaccine are similar to the Fluzone® family of licensed processes, except for a 
minor modification in the PBS diluent in the formulation step that was made according to 
previous experiences of manufacturing of monovalent pandemic vaccines. 
 
 
 
 
 
 
 
2017 A/H7N9 IIV 
Sanofi Pasteur has developed a monovalent split 2017 A/H7N9 IIV manufactured using a reverse 
genetics-derived reassortant candidate vaccine virus, IDCDC RG56B (H7N9), containing the HA 
and NA from low pathogenic avian influenza A/Hong Kong/125/2017 (H7N9) and the PB2, 
PB1, PA, NP, M and NS from A/Puerto Rico/8/1934 (H1N1). The manufacturing processes used 
for the investigational vaccine are similar to the Fluzone® family of licensed processes. 
 
 
 
 
 


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PBS Diluent 
The PBS diluent was manufactured by Patheon Manufacturing Services LLC in accordance with 
Good Manufacturing Practice Regulations. 
AS03 Adjuvant [Adjuvant System (03)] 
 
6.1.1 
Acquisition 
2013 and 2017 A/H7N9 IIVs will be provided by Sanofi Pasteur under contract to 
BARDA/DHHS. 
AS03 adjuvant will be provided by GSK under contract to BARDA/DHHS. 
Upon request by DMID, 2013 and 2017 A/H7N9 IIVs and AS03 adjuvant will be transferred to 
the following address: 
DMID Clinical Materials Services Contract 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com 
PBS diluent and sterile empty vials (2-mL, 3-mL or 5-mL) for admixing will be obtained by the 
DMID Clinical Materials Services (CMS) Contract, Fisher BioServices. 
2013 and 2017 A/H7N9 IIVs, PBS diluent, AS03 adjuvant, and sterile empty vials for study 
vaccine preparation will be provided through the DMID CMS to the participating VTEU sites 
prior to the start of this trial upon request and with prior approval from DMID. Should the site PI 
require additional 2103 and 2017 A/H7N9 IIVs, PBS diluent, AS03 adjuvant, or sterile empty 
vials during this trial, further instructions are provided in the protocol-specific MOP. 
6.1.2 
Formulation, Storage, Packaging, and Labeling 
2013 A/H7N9 IIV 


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Investigational influenza virus A/Shanghai vaccine (H7N9), a monovalent type A inactivated 
vaccine for intramuscular (IM) use, is a sterile suspension prepared from pandemic influenza 
virus candidate vaccine propagated in embryonated chicken eggs. Antibiotics are not used in the 
manufacture of this vaccine. This vaccine contains no preservative (thimerosal). There is no 
gelatin added to this vaccine in the manufacturing process. No components of this vaccine 
contain latex. It is essentially clear and slightly opalescent in color and supplied in single-dose 
glass vials. The vials must be stored at 2°C to 8°C (36°F to 46°F). Do not freeze. Vials will be 
provided with latex-free stoppers. 
 
 
 
 
 
 
Detailed mixing instructions to achieve the targeted dosage is included in the protocol-specific 
MOP. 
2017 A/H7N9 IIV 
Investigational influenza virus A/Hong Kong vaccine (H7N9), a monovalent type A inactivated 
vaccine for IM use, is a sterile suspension prepared from pandemic influenza virus candidate 
vaccine propagated in embryonated chicken eggs. Antibiotics are not used in the manufacture of 
this vaccine. This vaccine contains no preservative (thimerosal). There is no gelatin added to this 
vaccine in the manufacturing process. No components of this vaccine contain latex. It is 
essentially clear and slightly opalescent in color and supplied in single-dose glass vials. The vials 
must be stored at 2°C to 8°C (36°F to 46°F). Do not freeze. Vials will be provided with latex-
free stoppers. 
 
 
 
 
 
 


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Detailed mixing instructions to achieve the targeted dosages are included in the protocol-specific 
MOP. 
PBS Diluent 
 It is essentially clear and slightly opalescent in color 
and must be stored at 2°C to 8°C (36°F to 46°F). Vials will be provided with latex free stoppers. 
AS03 Adjuvant [Adjuvant System (03)] 
The AS03 adjuvant is supplied as a preservative-free, oil-in-water, whitish to yellowish 
homogenous milky liquid emulsion presented in 3 mL Type I, single-use glass vials. The vials 
must be stored at 2°C to 8°C (36°F to 46°F). Do not freeze. Vials will be provided with latex-
free stoppers. 
Each of these study products will be labeled according to manufacturer specifications and 
include the statement “Caution: New Drug Limited by Federal Law to Investigational Use.” 
Further details are included in the respective, applicable manufacturers’ Investigator’s Brochures 
for the A/H7N9 IIV and AS03 adjuvant as well as in the protocol-specific MOP. 
Sterile empty vials (2-mL, 3-mL or 5-mL) will be provided with latex-free stoppers. 
6.1.3 
Study Product Storage and Stability Procedures 
The temperature of the storage unit must be manually recorded daily (excluding non-business 
days and holidays, as applicable) and continuously monitored and recorded during the course of 
this trial per the participating VTEU site standard operating procedures (SOPs), and 
documentation will be maintained. If the temperature fluctuates outside of the required range, the 
affected study product(s) must be quarantined at the correct storage temperature and labeled as 
‘Do Not Use’ (until further notice). The participating VTEU site’s research pharmacist must alert 
the site PI and study coordinator, if the temperature fluctuates outside of the required range. In 
the event the temperature fluctuates outside of the required range, including accidental deep-
freezing or disruption of the cold chain, the affected study product(s) must not be administered. 
The site PI or responsible person should immediately contact the DMID Product Support Team 
at DMIDProductSupportTeam@niaid.nih.gov for further instructions before any additional study 
vaccinations are administered. Based on the information collected, DMID and/or the 
manufacturer will determine whether the affected study product(s) can be used. If it cannot be 
used, the site will receive specific instructions on how to return the affected study product(s) to 


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the DMID CMS or destroy it on site. Additional instructions for quarantine and DMID contact 
information are provided in the protocol-specific MOP. 
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Dosage calculations are based on the actual HA content per 0.5 mL. Each 0.5 mL dose of AS03-
adjuvanted study vaccine contains one dose (0.25 mL) of AS03 adjuvant. 
See the protocol-specific MOP Appendices for detailed information on the preparation, labeling, 
storage, and administration of study vaccine for each treatment arm. Study vaccine preparation 
will be performed by the participating VTEU site’s research pharmacist on the same day of study 
vaccine administration to the subject. 
Visually inspect the 2013 and 2017 A/H7N9 IIVs, PBS diluent and AS03 adjuvant upon receipt 
and prior to use. If the study product(s) appear(s) to have been damaged, contaminated or 
discolored, contain(s) visible particulate matter, or if there are any concerns regarding the 
integrity, do NOT use the affected study product(s). The affected study product(s) must be 
quarantined at 2°C to 8°C (36°F to 46°F) and labeled as ‘Do Not Use’ (until further notice). The 
site PI or responsible person should immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager for further 
instructions before any additional study vaccinations are administered. Based on the information 
collected, DMID and/or the manufacturer will determine whether the affected study product(s) 
can be used. If the affected study product(s) cannot be used, the site will receive specific 
instructions on how to return the affected study product(s) to the DMID CMS or destroy the 
affected study product(s) on site. If the 2013 or 2017 A/H7N9 IIVs, PBS diluent or AS03 
adjuvant is unusable, study personnel will use another vial from the study supply. Replacement 
vials may be requested by contacting DMID. Additional instructions for quarantine and DMID 
contact information are provided in the protocol-specific MOP. 
For those doses that must be admixed with PBS diluent, visually inspect the A/H7N9 IIV plus 
PBS diluent admixture (intermediate or final mixed vial depending on treatment arm) prior to 
use. The A/H7N9 IIV plus PBS diluent admixture will be essentially clear and slightly 
opalescent in color. For those doses that must be admixed with PBS diluent and AS03 adjuvant, 
visually inspect the A/H7N9 IIV/PBS diluent plus AS03 adjuvant admixture (final mixed vial) 
prior to use. The A/H7N9 IIV/PBS diluent plus AS03 adjuvant admixture will be milky (whitish 
to yellowish) in color. If the admixture(s) appear(s) to have been damaged, contaminated or 
discolored, contain(s) visible particulate matter, or if there are any concerns regarding the 
integrity, do NOT use the affected admixture(s). The affected admixture(s) must be quarantined 
at 2°C to 8°C (36°F to 46°F) for the A/H7N9 IIV plus PBS diluent admixture or room 


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temperature for the A/H7N9 IIV/PBS diluent plus AS03 adjuvant and labeled as ‘Do Not Use’ 
(until further notice). The site PI or responsible person should immediately contact the DMID 
Product Support Team at DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project 
Manager for further instructions before any additional study vaccinations are administered. 
Based on the information collected, DMID and/or the manufacturer will determine whether the 
affected admixture(s) can be used. If the affected admixture(s) cannot be used, the site will 
receive specific instructions on how to send the affected admixture(s) to the DMID CMS or 
destroy the affected admixture(s) on site. If the affected admixture is unusable, the participating 
VTEU site’s research pharmacist will prepare another admixture. Additional instructions for 
quarantine and DMID contact information are provided in the protocol-specific MOP. 
For those doses that must be admixed with PBS diluent, the A/H7N9 IIV plus PBS diluent 
admixture (intermediate or final mixed vial depending on treatment arm), once mixed, must be 
stored at 2°C to 8°C (36°F to 46°F) in an upright position and must be used within 8 hours. For 
those doses that must be admixed with PBS diluent and AS03 adjuvant, the A/H7N9 IIV/PBS 
diluent plus AS03 adjuvant admixture (final mixed vial), once mixed, must be stored at room 
temperature in an upright position and must be used within 8 hours. 
Only one- 0.5 mL dose of study vaccine should be withdrawn from the intermediate and final 
mixed vial(s). Gently invert the intermediate and final mixed vial(s) 5 to 7 times immediately 
before the single 0.5 mL dose of study vaccine is withdrawn. Do not shake the intermediate 
and final mixed vial(s). 
Study vaccine administration to the subject will be performed by an unblinded study personnel 
member who is credentialed to administer vaccines and may also participate in dose preparation, 
but will not be involved in study-related assessments or have subject contact for data collection 
following study vaccine administration to the subject. One- 0.5 mL dose of study vaccine will be 
administered to the subject via a single IM injection into the deltoid muscle of the subject’s 
preferred arm on the day of study vaccine administration to the subject. See the protocol-specific 
MOP for information on how to administer IM injections. The site of injection (right or left arm) 
and time of study vaccine administration to the subject will be recorded on the appropriate DCF. 
Study vaccinations subsequent to the first study vaccination may be given in the same preferred 
arm as long as there is no interference with the reactogenicity assessment. 
Aseptic technique will be used for the withdrawal and administration of each dose of study 
vaccine using a disposable, sterile needle appropriate in length for each subject and a 1-mL 
disposable, sterile syringe. Each dose of study vaccine must be administered within 30 minutes 
of drawing into the syringe (not to exceed 8 hours total since admixing time), and the prepared 
syringe must be stored at room temperature until administered. 


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6.3 
Modification of Study Intervention/Investigational Product for a 
Subject 
There will be no dose modifications. If a subject’s second study vaccination is deferred, it should 
be rescheduled to occur within the acceptable protocol-specified window for the Dose 2 visit. No 
exceptions to the protocol-specified window will be made. 
6.4 
Accountability Procedures for the Study Intervention/Investigational 
Product 
After receipt of the 2013 and 2017 A/H7N9 IIVs, PBS diluent, AS03 adjuvant, and sterile empty 
vials, the site PI is responsible for study product distribution and disposition, and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating 
VTEU site’s research pharmacist responsibility for study product accountability. The 
participating VTEU site’s research pharmacist will be responsible for maintaining complete 
records and documentation of study product receipt, accountability, dispensation, storage 
conditions, and final disposition of the study product(s). Study product accountability records 
and dispensing logs will also capture vial numbers, including intermediate and final mixed vial 
numbers, date of study vaccine preparation/administration, time of study vaccine preparation, 
expiration of study vaccine preparation, time study vaccine is drawn into the syringe, and amount 
of study vaccine withdrawn for administration. Time of study vaccine administration to the 
subject will be recorded on the appropriate DCF. All study product(s), including the amount of 
2013 and 2017 A/H7N9 IIVs, PBS diluent, AS03 adjuvant, and admixtures, whether 
administered or not, must be documented on the appropriate study product accountability record 
or dispensing log. The sponsor’s monitoring staff will verify the participating VTEU site’s study 
product accountability records and dispensing logs per the site monitoring plan. 
Used and unused vials of 2013 and 2017 A/H7N9 IIVs, PBS diluent, AS03 adjuvant, and 
admixtures will be retained until monitored and released for disposition, as applicable. This can 
occur on an ongoing basis for used vials of 2013 and 2017 A/H7N9 IIVs, PBS diluent, AS03 
adjuvant, and admixtures. Used vials of 2013 and 2017 A/H7N9 IIVs, PBS diluent, AS03 
adjuvant, and admixtures may be destroyed in accordance with site-specific SOPs following each 
monitoring visit where study product accountability is monitored, and resolution of any 
discrepancies. Final disposition of the unused 2013 and 2017 A/H7N9 IIVs, PBS diluent, AS03 
adjuvant, and sterile empty vials will be determined by DMID and communicated to the 
participating VTEU sites by the DMID Clinical Project Manager. 


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6.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product 
Study vaccine will be administered to the subject by an unblinded study vaccine administrator 
via IM injection at all dosing times per the subject’s randomized treatment assignment and as 
described in Section 6.2. Thus, subject compliance is not anticipated to be an issue. Deviations 
from the dose schedule may only occur as described in Section 6.3. Study vaccine administration 
to the subject will be recorded on the appropriate DCF. 
6.6 
Concomitant Medications/Treatments 
Administration of any medications, therapies or vaccines will be recorded on the appropriate 
DCF. Concomitant medications will include all current medications and medications taken in the 
60 days prior to signing the ICF through approximately 21 days after the last study vaccination 
or early termination (if prior to 21 days after the last study vaccination), whichever occurs first. 
Medications reported in the electronic case report form (eCRF) are limited to those taken within 
30 days prior to the first study vaccination through approximately 21 days after the last study 
vaccination. Prescription and over-the-counter drugs will be included as well as herbals, vitamins 
and supplements. In addition, receipt of any non-study influenza vaccines will be solicited 
through approximately 180 days after the last study vaccination, and reported in the eCRF. Use 
of a new medication should prompt evaluation for the occurrence of any MAAE, including a new 
diagnosis of chronic medical disease or condition. 
Medications that might interfere with the evaluation of the investigational product(s) should not 
be used during the trial-reporting period (approximately 12 months after the last study 
vaccination) unless clinically indicated as part of the subject’s health care. Medications in this 
category include the prohibited medications per the Subject Exclusion Criteria (see Section 
5.1.2). In addition, the site PI or appropriate sub-investigator may identify other medications that 
should not be used due to a risk to subject safety or assessment of reactogenicity and 
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7 
STUDY PROCEDURES/EVALUATIONS 
7.1 
Clinical Evaluations 
Complete medical history will be obtained by interview of subjects at the screening visit 
(optional) or on Day 1 prior to the first study vaccination. Subjects will be queried regarding a 
history of significant medical disorders of the head, eyes, ears, nose, throat, mouth, 
cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, kidney, urologic system, 
nervous system, blood, lymph nodes, endocrine system, musculoskeletal system, skin, and 
genital/reproductive tract. A history of any allergies, cancer, immunodeficiency, psychiatric 
illness, substance abuse, and autoimmune disease will be solicited. Subjects will also be queried 
regarding a personal history and family history of narcolepsy. At follow-up clinic visits after the 
first study vaccination, an interim medical history will be obtained by interview of subjects and 
any changes since the previous clinic visit or phone call will be noted. The interim medical 
history should include an assessment for new medical conditions and symptoms suggestive of 
PIMMCs. 
Concomitant medications will be collected as described in Section 6.6. 
At the screening visit (optional) or on Day 1 prior to the first study vaccination, a physical 
examination will be performed on all subjects, by a study clinician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator, to include the 
following organs and organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, 
lymph nodes, and nervous system, and as an assessment for signs suggestive of PIMMCs. At 
follow-up clinic visits after the first study vaccination, a targeted physical examination may be 
performed, if indicated based on the subject’s interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
investigator. Targeted physical examinations should also include an assessment for signs 
suggestive of PIMMCs. 
Vital signs (oral temperature, pulse and blood pressure [BP]) will be collected at the screening 
visit (optional) and prior to each study vaccination. Vital signs assessed on Day 1 prior to the 
first study vaccination will be considered as baseline. Subjects must not eat or drink anything hot 
or cold, or smoke within 10 minutes prior to taking oral temperature. 
Height and weight will be collected at the screening visit (optional) or on Day 1 prior to the first 
study vaccination for the calculation of BMI. 
Reactogenicity assessments will include an assessment of solicited AEs occurring from the time 
of each study vaccination through 7 days after each study vaccination, which includes an 


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assessment of injection site reactions including pruritus (itching), ecchymosis (bruising), 
erythema (redness), induration (hardness), edema (swelling), pain, and tenderness as well as 
systemic reactions including fever, feverishness (chills/shivering/sweating), fatigue (tiredness), 
malaise (general unwell feeling), myalgia (body aches/muscular pain exclusive of the injection 
site), arthralgia (joint pain exclusive of the injection site), headache, and nausea. Pre-
administration reactogenicity assessments will be performed immediately prior to each study 
vaccination to establish baseline, then the study vaccination will be given. 
Subjects will be observed in the clinic for at least 20 minutes after each study vaccination. The 
study vaccination site will be examined, post-administration reactogenicity assessments will be 
performed, and any AE/SAEs will be recorded on the appropriate DCF prior to discharge from 
the clinic. The study vaccination site will also be examined approximately 1, 3 and 7 days after 
each study vaccination. 
All subjects will complete a Memory Aid from the time of each study vaccination through 7 days 
after each study vaccination. Memory Aids will be reviewed with the subjects for any AEs 
(solicited injection site and systemic reactions as well as unsolicited AEs), SAEs and 
concomitant medications (including solicitation for receipt of any non-study influenza vaccines) 
approximately 1, 3 and 7 days after each study vaccination via phone call or clinic visit. 
7.2 
Laboratory Evaluations 
Clinical laboratory evaluations and special assays are described below. Refer also to Sections 4 
and 8 as well as Appendix A: Schedule of Study Procedures and Evaluations and Appendix B: 
Schedule of Special Assays. 
7.2.1 
Clinical Laboratory Evaluations 
Urine or serum pregnancy tests will be performed locally by the site at the screening visit 
(optional) and within 24 hours prior to each study vaccination for all women of childbearing 
potential. Results must be negative and known prior to randomization on Day 1 and 
administration of each study vaccination to be eligible for participation in this trial and receipt of 
each study vaccination. 
The ESR evaluation will be performed locally by the site at the screening visit (optional) or on 
Day 1 prior to the first study vaccination. Results must be known prior to randomization on Day 
1 and administration of the first study vaccination, and confirmed as less than 30 mm per hour to 
be eligible for participation in this trial and receipt of the first study vaccination. 


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Clinical safety laboratory parameters (WBC, Hgb, PLT, ALT, T. Bili, Cr) will be collected prior 
to each study vaccination and approximately 7 days after each study vaccination. These 
evaluations will be performed by the central (clinical) laboratory. The results from the clinical 
safety laboratory parameters collected on Day 1 prior to the first study vaccination will not be 
available or reviewed prior to the first study vaccination, and will serve as a baseline safety 
assessment only. The results from the clinical safety laboratory parameters collected prior to the 
second study vaccination will not be available or reviewed prior to the second study vaccination. 
The volume of venous blood to be collected for ESR and clinical safety laboratory evaluations is 
presented in Table 4 and 5. 
7.2.2 
Special Assays or Procedures 
Serological Assays 
Once the last subject completes the visits that occur through approximately 21 days after the last 
study vaccination, serum specimens collected for these visits will be shipped from the DMID 
CMS to specified research laboratories for serological analysis. Once the last subject completes 
the visit that occurs approximately 180 days after the last study vaccination, serum specimens 
collected for this visit will be shipped from the DMID CMS to specified research laboratories to 
conduct the final serological analyses. 
HAI and Neut Antibody Assays 
Assays to determine serum levels of HAI and Neut antibodies will be performed by Southern 
Research on specimens collected at multiple time points prior to and following each study 
vaccination. Subjects who withdraw early will have these assays run on available sera. 
HA Stem-Specific Assays 
Assays to determine and quantitate HA stem-specific antibodies are in development, and the 
specified research laboratories for this assessment are to be determined. It is anticipated that 
serum levels of anti-HA stem-specific antibodies will be determined from specimens collected at 
multiple time points prior to and following each study vaccination. Subjects who withdraw early 
will have these assays run on available sera. 
NA-Specific Assays 
Assays to determine the NA content and NAI antibodies are in development, and the specified 
research laboratories for this assessment is to be determined. The correlation of the NA content 
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may be determined from specimens collected at multiple time points prior to and following each 
study vaccination. 
Any research laboratory involved with the determination of NA content or N9 NA-specific 
serum antibody responses will remain blinded to the results from the HAI and Neut antibody 
assays performed by Southern Research. 
Cellular Immunology Assays 
This clinical trial will also investigate novel methods for identifying and assessing alternative 
cellular correlates of protection against influenza infection at multiple time points following each 
study vaccination. These will include longitudinal assessments of: 1) the kinetics, magnitude, 
specificity, and/or quality of influenza-specific B and T cells, cTFH cells and innate immune cells 
(monocytes, DCs and NK cells); 2) the frequency of influenza-specific IgA, IgG and IgM 
plasmablasts (ASCs); and 3) B cell receptor somatic hypermutation and repertoire assessments. 
Given the requirement for freshly isolated PBMCs, the plasmablast assay will be performed only 
on specimens collected from subjects enrolled at the specified site(s), which will perform the 
plasmablast assay. All other frozen PBMCs will be shipped from the DMID CMS to specified 
research laboratories for cellular immunology analyses. Residual plasma specimens collected 
during the processing of PBMCs may be frozen and shipped to the DMID CMS. 
Venous blood will also be collected at multiple time points following each study vaccination for 
the future research use of serum, plasma and PBMCs. 
The volume of venous blood to be collected for serological and cellular immunology assays as 
well as future research is presented in Table 4 and 5. Note: There are two different dosing 
intervals between the priming (first) and boosting (second) doses (21 days vs. 4 months). 
Treatment Arms 1 and 4 receive study vaccinations on Days 1 and 22; and Treatment Arms 2, 3, 
5, and 6 receive study vaccinations on Days 1 and 121. 
 
 






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7.2.3 
Specimen Preparation, Handling and Shipping 
7.2.3.1 
Instructions for Specimen Preparation, Handling and Storage 
Instructions for specimen preparation, handling and storage are included in the central (clinical) 
laboratory manual and protocol-specific MOP as appropriate. 
7.2.3.2 
Specimen Shipment 
Specimen shipment will occur at intervals during the course of this trial following all applicable 
International Air Transport Association (IATA) requirements and according to the specifics for 
storage temperature and documentation as detailed in the central (clinical) laboratory manual and 
protocol-specific MOP as appropriate. 
Specimens for clinical safety laboratory evaluations will be shipped from the participating VTEU 
sites to the central (clinical) laboratory. 
Specimens for HAI and Neut antibody assays will be shipped from the participating VTEU sites 
to the DMID CMS, and then provided by the DMID CMS to Southern Research in a blinded 
manner. 
Specimens for additional serological assays will be shipped from the participating VTEU sites to 
the DMID CMS, and then provided by the DMID CMS to the specified research laboratories in a 
blinded manner. 
Specimens for cellular immunology assays using frozen PBMCs will be shipped from the 
participating VTEU sites to the DMID CMS, and then provided by the DMID CMS to the 
specified research laboratories in a blinded manner. 
Specimens for the plasmablast assay using freshly isolated PBMCs will remain on site at the 
specified site(s). 
Residual plasma specimens collected during the processing of PBMCs may be frozen and 
shipped to the DMID CMS. 
Specimens for future research will be shipped from the participating VTEU sites to the DMID 
CMS. 
Further instructions for specimen shipment are included in the central (clinical) laboratory 
manual and protocol-specific MOP, as appropriate. 


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8 
STUDY SCHEDULE 
Complete study schedule details listed by type of visit are described below. Refer also to 
Sections 4 and 7 as well as Appendix A: Schedule of Study Procedures and Evaluations and 
Appendix B: Schedule of Special Assays. 
Note: There are two different dosing intervals between the priming (first) and boosting (second) 
doses (21 days vs. 4 months). Treatment Arms 1 and 4 receive study vaccinations on Days 1 and 
22; and Treatment Arms 2, 3, 5, and 6 receive study vaccinations on Days 1 and 121. 
8.1 
Screening (Optional) and Enrollment Visits 
8.1.1 
Visit 00, Screening (Day -28 to -1), Clinic Visit, All Treatment Arms, Optional 
• Subjects will be provided with a description of this trial (purpose and study procedures) 
and asked to read and sign the ICF. The ICF will be signed prior to performing any study 
procedures, including administration of the first study vaccination. 
• Demographic information will be obtained by interview of subjects. 
• Eligibility criteria will be reviewed with subjects to ensure eligibility. 
• Complete medical history will be obtained by interview of subjects to ensure eligibility. 
• All concomitant medications taken within 60 days prior to signing the ICF will be 
reviewed with subjects to determine stability of chronic diseases and eligibility. 
Medications reported in the eCRF are limited to those taken within 30 days prior to the 
first study vaccination. 
• Subject receipt of licensed, seasonal influenza vaccine over the current (2018-2019) and 
previous two influenza seasons (2016-2017 and 2017-2018), what type (inactivated or 
live attenuated) and approximate date of vaccination will be recorded on the appropriate 
DCF, if known. Prior receipt of licensed, seasonal influenza vaccine is not exclusionary, 
as long as it has been administered within the allowable window (see Section 5.1.2). 
• Subject receipt of non-seasonal influenza vaccine, including those that are experimental, 
what type (inactivated or live attenuated), what subtype (e.g., A/H3, A/H5, A/H9) and 
approximate date of vaccination will be recorded on the appropriate DCF, if known. Prior 
receipt of non-seasonal influenza vaccine is not exclusionary, except influenza A/H7 
vaccine (see Section 5.1.2). 


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• Vital signs, including oral temperature, pulse and BP, will be obtained to ensure 
eligibility. Subjects must not eat or drink anything hot or cold, or smoke within 10 
minutes prior to taking oral temperature. 
• Height and weight will be collected for the calculation of BMI. 
• A physical examination will be performed on all subjects to include the following organs 
and organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph 
nodes, and nervous system, and as an assessment for signs suggestive of PIMMCs, by a 
study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• A urine or serum pregnancy test may be performed locally by the site for all women of 
childbearing potential. Results must be negative to ensure eligibility. 
• Approximately 4 mL of venous blood will be collected for ESR, and performed locally 
by the site. The ESR value must be confirmed as less than 30 mm per hour to ensure 
eligibility. 
8.1.2 
Visit 01, Day 1, Enrollment (for subjects previously screened at Day -28 to -1) 
and First Study Vaccination (Dose 1), Clinic Visit, All Treatment Arms 
• Subject’s willingness to participate will be reconfirmed and documented in the subject’s 
study records prior to performing any further study procedures, including administration 
of the first study vaccination. 
• Eligibility criteria, including results of the ESR evaluation, will be reviewed with subjects 
prior to the first study vaccination to ensure continued eligibility. The ESR value must be 
confirmed as less than 30 mm per hour prior to randomization and first study vaccination. 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects prior to the first study vaccination. Any changes in medical history since the 
screening visit will be reviewed with subjects prior to the first study vaccination to ensure 
continued eligibility. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be reviewed with subjects prior to the first study vaccination for accuracy 
and completeness. Any new concomitant medications taken since the screening visit will 
be reviewed with subjects prior to the first study vaccination to ensure continued 


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eligibility. Medications reported in the eCRF are limited to those taken within 30 days 
prior to the first study vaccination. 
• Vital signs, including oral temperature, pulse and BP, will be obtained prior to the first 
study vaccination to ensure continued eligibility. Vital signs assessed on Day 1 prior to 
the first study vaccination will be considered as baseline. Subjects must not eat or drink 
anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed prior to the first study vaccination, if indicated based on 
review of complete medical history and any updates obtained by interview of subjects 
since the screening visit, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• A urine or serum pregnancy test will be performed locally by the site within 24 hours 
prior to the first study vaccination for all women of childbearing potential. Results must 
be negative and known prior to randomization and the first study vaccination. 
• Subjects will be enrolled in AdvantageEDCSM and randomly assigned to a treatment arm 
prior to the first study vaccination. 
• Approximately 10 mL of venous blood will be collected immediately prior to the first 
study vaccination for baseline clinical safety labs (WBC, Hgb, PLT, ALT, T. Bili, Cr) to 
be performed by the central (clinical) laboratory. The results from these evaluations will 
not be available or reviewed prior to the first study vaccination, and will serve as a 
baseline safety assessment only. 
• Approximately 15 mL of venous blood will be collected immediately prior to the first 
study vaccination for baseline serological assays. 
• Approximately 64 mL of venous blood will be collected immediately prior to the first 
study vaccination for baseline cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected immediately prior to the first 
study vaccination for future research. 
• Pre-administration reactogenicity assessments will be performed immediately prior to the 
first study vaccination to establish baseline. 
• Subjects will then receive one- 0.5 mL dose of study vaccine via a single IM injection 
into the deltoid muscle of the subjects’ preferred arm. The site of injection (right or left 


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arm) and time of study vaccine administration to the subject will be recorded on the 
appropriate DCF. Subjects will be observed in the clinic for at least 20 minutes after the 
first study vaccination. The first study vaccination site will be examined, post-
administration reactogenicity assessments will be performed, and any AE/SAEs will be 
recorded on the appropriate DCF prior to discharge from the clinic. 
• Subjects will be provided with a Memory Aid and other study-related materials to record 
daily oral temperature, solicited injection site and systemic reactions, unsolicited AEs, 
and concomitant medications. Subjects will be encouraged to take their oral temperature 
around the same time each day. Subjects must not eat or drink anything hot or cold, or 
smoke within 10 minutes prior to taking oral temperature. Subjects will be instructed on 
how to use their Memory Aid and how to measure and record AEs prior to discharge 
from the clinic. Subjects will be instructed to notify the study center if they develop any 
severe reactions after the first study vaccination. If the site PI or appropriate sub-
investigator deems the reaction severe enough, further instructions will be given to the 
subject on the proper course of action, including a return to the clinic for immediate 
evaluation if appropriate. 
8.1.3 
Visit 01, Day 1, Enrollment/Baseline (for subjects not previously screened at Day 
-28 to -1) and First Study Vaccination (Dose 1), Clinic Visit, All Treatment Arms 
• Subjects will be provided with a description of this trial (purpose and study procedures) 
and asked to read and sign the ICF. The ICF will be signed prior to performing any study 
procedures, including administration of the first study vaccination. 
• Demographic information will be obtained by interview of subjects prior to the first study 
vaccination. 
• Eligibility criteria will be reviewed with subjects prior to the first study vaccination to 
ensure eligibility. 
• Complete medical history will be obtained by interview of subjects prior to the first study 
vaccination to ensure eligibility. 
• All concomitant medications taken within 60 days prior to signing the ICF will be 
reviewed with subjects prior to the first study vaccination to determine stability of 
chronic diseases and eligibility. Medications reported in the eCRF are limited to those 
taken within 30 days prior to the first study vaccination. 
• Subject receipt of licensed, seasonal influenza vaccine over the current (2018-2019) and 


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previous two influenza seasons (2016-2017 and 2017-2018), what type (inactivated or 
live attenuated) and approximate date of vaccination will be recorded on the appropriate 
DCF, if known. Prior receipt of licensed, seasonal influenza vaccine is not exclusionary, 
as long as it has been administered within the allowable window (see Section 5.1.2). 
• Subject receipt of non-seasonal influenza vaccine, including those that are experimental, 
what type (inactivated or live attenuated), what subtype (e.g., A/H3, A/H5, A/H9) and 
approximate date of vaccination will be recorded on the appropriate DCF, if known. Prior 
receipt of non-seasonal influenza vaccine is not exclusionary, except influenza A/H7 
vaccine (see Section 5.1.2). 
• Vital signs, including oral temperature, pulse and BP, will be obtained prior to the first 
study vaccination to ensure eligibility. Vital signs assessed on Day 1 prior to the first 
study vaccination will be considered as baseline. Subjects must not eat or drink anything 
hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
• Height and weight will be collected prior to the first study vaccination for the calculation 
of BMI. 
• A physical examination will be performed on all subjects prior to the first study 
vaccination to include the following organs and organ systems: skin, head and neck, 
lungs, heart, liver, spleen, extremities, lymph nodes, and nervous system, and as an 
assessment for signs suggestive of PIMMCs, by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. 
• A urine or serum pregnancy test will be performed locally by the site within 24 hours 
prior to the first study vaccination for all women of childbearing potential. Results must 
be negative and known prior to randomization and the first study vaccination. 
• Approximately 4 mL of venous blood will be collected for ESR, and performed locally 
by the site prior to the first study vaccination. The ESR value must be confirmed as less 
than 30 mm per hour prior to randomization and first study vaccination. 
• Subjects will be enrolled in AdvantageEDCSM and randomly assigned to a treatment arm 
prior to the first study vaccination. 
• Approximately 10 mL of venous blood will be collected immediately prior to the first 
study vaccination for baseline clinical safety labs (WBC, Hgb, PLT, ALT, T. Bili, Cr) to 
be performed by the central (clinical) laboratory. The results from these evaluations will 
not be available or reviewed prior to the first study vaccination, and will serve as a 
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• Approximately 15 mL of venous blood will be collected immediately prior to the first 
study vaccination for baseline serological assays. 
• Approximately 64 mL of venous blood will be collected immediately prior to the first 
study vaccination for baseline cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected immediately prior to the first 
study vaccination for future research. 
• Pre-administration reactogenicity assessments will be performed immediately prior to the 
first study vaccination to establish baseline. 
• Subjects will then receive one- 0.5 mL dose of study vaccine via a single IM injection 
into the deltoid muscle of the subjects’ preferred arm. The site of injection (right or left 
arm) and time of study vaccine administration to the subject will be recorded on the 
appropriate DCF. Subjects will be observed in the clinic for at least 20 minutes after the 
first study vaccination. The first study vaccination site will be examined, post-
administration reactogenicity assessments will be performed, and any AE/SAEs will be 
recorded on the appropriate DCF prior to discharge from the clinic. 
• Subjects will be provided with a Memory Aid and other study-related materials to record 
daily oral temperature, solicited injection site and systemic reactions, unsolicited AEs, 
and concomitant medications. Subjects will be encouraged to take their oral temperature 
around the same time each day. Subjects must not eat or drink anything hot or cold, or 
smoke within 10 minutes prior to taking oral temperature. Subjects will be instructed on 
how to use their Memory Aid and how to measure and record AEs prior to discharge 
from the clinic. Subjects will be instructed to notify the study center if they develop any 
severe reactions after the first study vaccination. If the site PI or appropriate sub-
investigator deems the reaction severe enough, further instructions will be given to the 
subject on the proper course of action, including a return to the clinic for immediate 
evaluation if appropriate. 
8.2 
Follow-up Visits 
Follow-up visits are scheduled in reference to study vaccination dates as indicated for each visit 
window. 
 
 


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8.2.1 
Visit 02, Day 2, Clinic Visit, All Treatment Arms 
(Window: Day 2+1 day post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• The first study vaccination site will be examined. 
• Approximately 4 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.2.2 
Visit 03, Day 4, Clinic Visit, All Treatment Arms 
(Window: Day 4+1 day post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 


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a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• The first study vaccination site will be examined. 
• Approximately 8 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.2.3 
Visit 04, Day 8, Clinic Visit, All Treatment Arms 
(Window: Day 8-1/+2 days post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• The first study vaccination site will be examined. 
• Approximately 10 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, Cr) to be performed by the central (clinical) laboratory. 
• Approximately 44 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 21 mL of venous blood will be collected for future research. 
Note: Subjects that complete this visit on Day 7 will be reminded to complete their Memory Aid 
through the end of Day 8, and study personnel will contact these subjects by phone to review 
their Memory Aid information and solicit any AE/SAEs and concomitant medications (including 
solicitation for receipt of any non-study influenza vaccines). Based on the information collected, 
subjects may be asked to return to the clinic for evaluation. 


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8.2.4 
Visit 05, Day 15, Clinic Visit, All Treatment Arms 
(Window: Day 15±1 day post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• Approximately 8 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.2.5 
Clinic Visit, Treatment Arms 2, 3, 5, and 6 
Visit 06, Day 22 (Window: Day 22+7 days post first study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• Approximately 15 mL of venous blood will be collected for serological assays. 


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• Approximately 16 mL of venous blood will be collected for future research. 
8.2.6 
Safety Follow-up, Phone Call, Treatment Arms 2, 3, 5, and 6 
Visit 07, Day 61 (Window: Day 61±7 days post first study vaccination), 
Treatment Arms 2, 3, 5, and 6 
Subjects will be contacted by phone to query for safety events and concomitant medications 
(including solicitation for receipt of any non-study influenza vaccines). AEs limited to SAEs and 
MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or 
phone call will be solicited. Based on the information collected, subjects may be asked to return 
to the clinic for evaluation. 
8.2.7 
Second Study Vaccination (Dose 2), Clinic Visit, All Treatment Arms 
Visit 06, Day 22 (Window: Day 22+7 days post first study vaccination), 
Treatment Arms 1 and 4 
Visit 08, Day 121 (Window: Day 121-7/+14 days post first study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Eligibility criteria will be reviewed with subjects prior to the second study vaccination to 
ensure continued eligibility. 
• For a subject to receive the second study vaccination, refer to Section 5.2.3 for additional 
second study vaccination eligibility criteria. 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects prior to the second study vaccination. Any changes in medical history since the 
first study vaccination will be reviewed with subjects prior to the second study 
vaccination to ensure continued eligibility. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF prior to the second study vaccination. 
Any new concomitant medications taken since the first study vaccination will be 
reviewed with subjects prior to the second study vaccination to ensure continued 
eligibility. 
• All AE/SAEs will be recorded on the appropriate DCF prior to the second study 
vaccination. Note: AEs will be limited to SAEs and MAAEs, including NOCMCs and 


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PIMMCs, for subjects who are discontinued from receipt of the second study vaccination 
and being followed for safety. 
• Vital signs, including oral temperature, pulse and BP, will be obtained prior to the second 
study vaccination to ensure continued eligibility. Subjects must not eat or drink anything 
hot or cold, or smoke within 10 minutes prior to taking oral temperature. Note: Vital 
signs are not required for subjects who are discontinued from receipt of the second study 
vaccination and being followed for safety. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed prior to the second study vaccination, if indicated based on 
review of interim medical history, by a study clinician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. 
• A urine or serum pregnancy test will be performed locally by the site within 24 hours 
prior to the second study vaccination for all women of childbearing potential. Results 
must be negative and known prior to the second study vaccination. 
• Approximately 10 mL of venous blood will be collected immediately prior to the second 
study vaccination for clinical safety labs (WBC, Hgb, PLT, ALT, T. Bili, Cr) to be 
performed by the central (clinical) laboratory. The results from these evaluations will not 
be available or reviewed prior to the second study vaccination. 
• Approximately 15 mL of venous blood will be collected immediately prior to the second 
study vaccination for serological assays. 
• Approximately 32 mL of venous blood will be collected immediately prior to the second 
study vaccination for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected immediately prior to the second 
study vaccination for future research. 
• Pre-administration reactogenicity assessments will be performed immediately prior to the 
second study vaccination to establish baseline. 
• Subjects will then receive one- 0.5 mL dose of study vaccine via a single IM injection 
into the deltoid muscle of the subjects’ preferred arm. The second study vaccination may 
be given in the same preferred arm as long as there is no interference with the 
reactogenicity assessment. The site of injection (right or left arm) and time of study 
vaccine administration to the subject will be recorded on the appropriate DCF. Subjects 
will be observed in the clinic for at least 20 minutes after the second study vaccination. 


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The second study vaccination site will be examined, post-administration reactogenicity 
assessments will be performed, and any AE/SAEs will be recorded on the appropriate 
DCF prior to discharge from the clinic. 
• Subjects will be provided with a Memory Aid and other study-related materials to record 
daily oral temperature, solicited injection site and systemic reactions, unsolicited AEs, 
and concomitant medications. Subjects will be encouraged to take their oral temperature 
around the same time each day. Subjects must not eat or drink anything hot or cold, or 
smoke within 10 minutes prior to taking oral temperature. Subjects will be instructed on 
how to use their Memory Aid and how to measure and record AEs prior to discharge 
from the clinic. Subjects will be instructed to notify the study center if they develop any 
severe reactions after the second study vaccination. If the site PI or appropriate sub-
investigator deems the reaction severe enough, further instructions will be given to the 
subject on the proper course of action, including a return to the clinic for immediate 
evaluation if appropriate. 
8.2.8 
Clinic Visit, All Treatment Arms 
Visit 07, Day 23 (Window: Day 2+1 day post second study vaccination), 
Treatment Arms 1 and 4 
Visit 09, Day 122 (Window: Day 2+1 day post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. Note: AEs will be limited to 
SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued 
from receipt of the second study vaccination and being followed for safety. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 


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• The second study vaccination site will be examined. 
• Approximately 4 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.2.9 
Clinic Visit, All Treatment Arms 
Visit 08, Day 25 (Window: Day 4+1 day post second study vaccination), 
Treatment Arms 1 and 4 
Visit 10, Day 124 (Window: Day 4+1 day post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. Note: AEs will be limited to 
SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued 
from receipt of the second study vaccination and being followed for safety. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• The second study vaccination site will be examined. 
• Approximately 8 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
 
 


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8.2.10 
Clinic Visit, All Treatment Arms 
Visit 09, Day 29 (Window: Day 8-1/+2 days post second study vaccination), 
Treatment Arms 1 and 4 
Visit 11, Day 128 (Window: Day 8-1/+2 days post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. Note: AEs will be limited to 
SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued 
from receipt of the second study vaccination and being followed for safety. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• The second study vaccination site will be examined. 
• Approximately 10 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, Cr) to be performed by the central (clinical) laboratory. 
• Approximately 44 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 21 mL of venous blood will be collected for future research. 
Note: Subjects that complete this visit on Day 7 will be reminded to complete their Memory Aid 
through the end of Day 8, and study personnel will contact these subjects by phone to review 
their Memory Aid information and solicit any AE/SAEs and concomitant medications (including 
solicitation for receipt of any non-study influenza vaccines). Based on the information collected, 
subjects may be asked to return to the clinic for evaluation. 
 
 


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8.2.11 
Clinic Visit, All Treatment Arms 
Visit 10, Day 36 (Window: 15±1 day post second study vaccination), Treatment 
Arms 1 and 4 
Visit 12, Day 135 (Window: Day 15±1 day post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. Note: AEs will be limited to 
SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued 
from receipt of the second study vaccination and being followed for safety. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI  or sub-investigator. 
• Approximately 8 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.2.12 
Clinic Visit, All Treatment Arms 
Visit 11, Day 43 (Window: Day 22+7 days post second study vaccination), 
Treatment Arms 1 and 4 
Visit 13, Day 142 (Window: Day 22+7 days post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 


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• All AE/SAEs will be recorded on the appropriate DCF. Note: AEs will be limited to 
SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued 
from receipt of the second study vaccination and being followed for safety. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• Approximately 15 mL of venous blood will be collected for serological assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.2.13 
Safety Follow-up, Phone Call, All Treatment Arms 
Visit 12, Day 82 (Window: Day 61±7 days post second study vaccination), 
Treatment Arms 1 and 4 
Visit 14, Day 181 (Window: Day 61±7 days post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
Subjects will be contacted by phone to query for safety events and receipt of any non-study 
influenza vaccines. AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that 
have occurred since the previous clinic visit or phone call will be solicited. Based on the 
information collected, subjects may be asked to return to the clinic for evaluation. 
8.2.14 
Clinic Visit, All Treatment Arms 
Visit 13, Day 112 (Window: Day 91±14 days post second study vaccination), 
Treatment Arms 1 and 4 
Visit 15, Day 211 (Window: Day 91±14 days post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
• AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred 
since the previous clinic visit or phone call will be solicited. 


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• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• Approximately 40 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.2.15 
Safety Follow-up, Phone Call, All Treatment Arms 
Visit 14, Day 142 (Window: Day 121±14 days post second study vaccination), 
Treatment Arms 1 and 4 
Visit 16, Day 241 (Window: Day 121±14 days post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
Subjects will be contacted by phone to query for safety events and receipt of any non-study 
influenza vaccines. AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that 
have occurred since the previous clinic visit or phone call will be solicited. Based on the 
information collected, subjects may be asked to return to the clinic for evaluation. 
8.2.16 
Clinic Visit, All Treatment Arms 
Visit 15, Day 202 (Window: Day 181±14 days post second study vaccination), 
Treatment Arms 1 and 4 
Visit 17, Day 301 (Window: Day 181±14 days post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
• AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred 
since the previous clinic visit or phone call will be solicited. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 


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• Approximately 15 mL of venous blood will be collected for serological assays. 
• Approximately 32 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 16 mL of venous blood will be collected for future research. 
8.3 
Final Visit 
8.3.1 
Safety Follow-up, Phone Call, All Treatment Arms 
Visit 16, Day 387 (Window: Day 366±14 days post second study vaccination), 
Treatment Arms 1 and 4 
Visit 18, Day 486 (Window: Day 366±14 days post second study vaccination), 
Treatment Arms 2, 3, 5, and 6 
Subjects will be contacted by phone to query for safety events. AEs limited to SAEs and 
MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or 
phone call will be solicited. Based on the information collected, subjects may be asked to return 
to the clinic for evaluation. 
8.4 
Early Termination Visit (if needed) 
The following activities will be performed at the Early Termination Visit on subjects who 
withdraw, or are withdrawn or terminated from this trial: 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. 
• All concomitant medications will be recorded on the appropriate DCF (if prior to 21 days 
after the last study vaccination). Receipt of any non-study influenza vaccines will also be 
recorded on the appropriate DCF (if within 180 days after the last study vaccination). 
• All AE/SAEs will be recorded on the appropriate DCF. AEs limited to SAEs and 
MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic 
visit or phone call will be solicited (if after 21 days after the last study vaccination). 
• Memory Aid information will be reviewed with subjects (if within 7 days after the last 
study vaccination). 


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• Vital signs, including oral temperature, pulse and BP, may be obtained if indicated. 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking oral temperature. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• The study vaccination site will be examined (if within 7 days after the last study 
vaccination). 
• Post-administration reactogenicity assessments will be performed (if within 7 days after 
the last study vaccination). 
• Approximately 10 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, Cr) to be performed by the central (clinical) laboratory (if within 
7 days after the last study vaccination). 
• Approximately 15 mL of venous blood will be collected for serological assays (if within 
21 days after the last study vaccination). 
• Approximately 24 mL of venous blood will be collected for cellular immunology assays 
(if within 21 days after the last study vaccination). 
• Approximately 16 mL of venous blood will be collected for future research (if within 21 
days after the last study vaccination). 
8.5 
Unscheduled Visit (if needed) 
An Unscheduled Visit may occur at any time during this trial. Any of the following activities 
may be performed: 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted (if 
indicated). 
• All concomitant medications will be recorded on the appropriate DCF (if prior to 21 days 
after the last study vaccination). Receipt of any non-study influenza vaccines will also be 
recorded on the appropriate DCF (if within 180 days after the last study vaccination). 


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• All AE/SAEs will be recorded on the appropriate DCF. AEs limited to SAEs and 
MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic 
visit or phone call will be solicited (if after 21 days after the last study vaccination). 
• Memory Aid information will be reviewed with subjects (if within 7 days after the last 
study vaccination). 
• Vital signs, including oral temperature, pulse and BP, may be obtained if indicated. 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking oral temperature. 
• A targeted physical examination, including an assessment for signs suggestive of 
PIMMCs, may be performed, if indicated based on review of interim medical history, by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• The study vaccination site will be examined (if within 7 days after the last study 
vaccination). 
• Post-administration reactogenicity assessments will be performed (if within 7 days after 
the last study vaccination). 
• Approximately 10 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, Cr) to be performed by the central (clinical) laboratory (if 
indicated). 
• Approximately 15 mL of venous blood will be collected for serological assays (if within 
21 days after the last study vaccination). 
• Approximately 24 mL of venous blood will be collected for cellular immunology assays 
(if within 21 days after the last study vaccination). 
• Approximately 16 mL of venous blood will be collected for future research (if within 21 
days after the last study vaccination). 
 


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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
1. SAEs occurring from the time of the first study vaccination through approximately 12 
months after the last study vaccination. 
2. Solicited AEs – reactogenicity events occurring from the time of each study vaccination 
through 7 days after each study vaccination: 
a) Injection site reactions including pruritus, ecchymosis, erythema, induration 
(hardness)/edema (swelling), pain, and tenderness. 
b) Systemic reactions including fever, feverishness, fatigue, malaise, myalgia, arthralgia, 
headache, and nausea. 
3. Clinical safety laboratory AEs occurring from the time of each study vaccination through 
approximately 7 days after each study vaccination. Parameters to be evaluated include 
WBC, Hgb, PLT, ALT, T. Bili, Cr. 
4. Unsolicited AEs –non-serious AEs occurring from the time of each study vaccination 
through approximately 21 days after each study vaccination. 
5. MAAEs, including NOCMCs and PIMMCs, occurring from the time of the first study 
vaccination through approximately 12 months after the last study vaccination. 
9.2 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
9.2.1 
Adverse Events 
Adverse Event (AE): ICH E6 GCP defines an AE as any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product regardless of its 
causal relationship to the study treatment. The FDA defines an AE as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal (investigational) 


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product. The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor. 
AEs, including solicited injection site and systemic (subjective and quantitative) reactions, not 
meeting the protocol-defined criteria for SAEs, will be recorded on the appropriate DCF and 
entered into the eCRF. Information to be collected for unsolicited non-serious AEs includes 
event description, date of onset, licensed study physician’s assessment of severity and 
relationship to study product or alternate etiology (if not related to study product) (assessed only 
by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as 
the site PI or sub-investigator), date of resolution, seriousness, and outcome. AEs occurring 
during the trial-collection and reporting period will be documented appropriately regardless of 
relationship to study product. AEs will be followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it will be recorded as an AE. 
AEs must be assessed for severity and relationship to study product (see definitions below). AEs 
characterized as intermittent require documentation of onset and duration of each episode. The 
start and stop date of each reported AE will be recorded on the appropriate DCF and entered into 
the eCRF. 
Medically-Attended Adverse Events (MAAEs): For each unsolicited AE experienced, the 
subject will be asked if he/she had received medical attention, defined as hospitalization, an 
emergency room visit or an otherwise unscheduled visit to or from medical personnel for any 
reason. AEs characterized by such unscheduled medical care will be designated as MAAEs. 
New-Onset Chronic Medical Conditions (NOCMCs): NOCMCs are defined as any new ICD-
10 diagnosis (10th revision of the International Statistical Classification of Diseases and Related 
Health Problems) that is applied to the subject during the course of the study, after receipt of the 
study agent, that is expected to continue for at least 3 months and requires continued health care 
intervention. 
Potentially Immune-Mediated Medical Conditions (PIMMCs): PIMMCs constitute a group 
of AEs that includes diseases which are clearly autoimmune in etiology and other inflammatory 
and/or neurologic disorders which may or may not have autoimmune etiologies. PIMMCs 
currently in effect are presented in Appendix C: List of Potentially Immune-Mediated Medical 
Conditions. 


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Severity of Event: AEs will be assessed by a licensed study physician listed on the Form FDA 
1572 as the site PI or sub-investigator using a protocol-defined grading system (see Sections 
9.2.2 and 9.2.3). For events not included in the protocol-defined grading system, the following 
guidelines will be used to quantify severity: 
• 
Mild (Grade 1): Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures. Moderate events may cause some interference with functioning and 
daily activities. 
• 
Severe (Grade 3): Events interrupt the subject’s daily activities and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Relationship to Study Product: The licensed study physician’s assessment of an AE’s 
relationship to study product is part of the documentation process, but it is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. The relationship to study product must be 
assessed for AEs using the terms: related or not related. In a clinical trial, the study product must 
always be suspect. To help assess, the following guidelines are used: 
• Related – There is a reasonable possibility that the study product caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2 
Reactogenicity 
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine. The following Toxicity Grading Scales will be used to grade solicited 
injection site and systemic (subjective and quantitative) reactions: 
 
 
 


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Table 6: Injection Site Reactogenicity Grading 
Injection Site Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous discomfort) 
Subject is aware of pain, 
but it does not interfere 
with daily activity, and if 
pain medication is used, it 
is Over the Counter 
(OTC) and used for less 
than 24 hours 
Subject is aware of pain; 
there is interference with 
daily activity or OTC 
pain medication is used 
for more than 24 hours 
Subject is aware of pain, 
and it prevents daily 
activity or pain requires 
prescription medication 
Tenderness – hurts only 
when injection site is 
touched or the arm is 
moved 
The area immediately 
surrounding the injection 
site hurts only when 
touched or with arm 
motion, and it does not 
interfere with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
interferes with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
prevents daily activity 
Pruritus (Itching) 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis (Bruising)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema (Redness)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration 
(Hardness)/Edema 
(Swelling)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
* Will also be measured in mm but size will not be used as halting criteria. 
Ecchymosis, erythema and induration (hardness)/edema (swelling) as analyzed by measurement 
will be graded as follows: 
Table 7: Injection Site Reactogenicity Measurements 
Injection Site Reaction 
Small 
Medium 
Large 
Ecchymosis (Bruising)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema (Redness)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration (Hardness)/Edema 
(Swelling)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
* Will not be used as halting criteria. 
 
 


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Table 8: Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness 
(Chills/Shivering/Sweating) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Fatigue (Tiredness) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise (General Unwell 
Feeling) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia (Body 
Aches/Muscular Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia (Joint Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Headache 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Nausea 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
* Not at injection site. 
Oral temperature# will be graded as follows: 
Table 9: Quantitative Systemic (Oral Temperature) Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* – oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
* A fever can be considered not related to the study product if an alternative etiology can be documented. 
† Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
9.2.3 
Additional Adverse Event Severity Grading 
Pulse and BP# will be graded as follows: 
 
 


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Table 10: Pulse and BP Adverse Event Grading 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia – beats per minute 
45 – 46 
40 – 44 
<40 
Tachycardia – beats per minute 
101 – 130 
131 – 155 
>155 
Hypotension (systolic) mmHg 
80 – 84 
75 – 79 
<75 
Hypotension (diastolic) mmHg 
50 – 54 
45 – 49 
<45 
Hypertension (systolic) mmHg 
151 – 155 
156 – 160 
>160 
Hypertension (diastolic) mmHg 
96 – 100 
101 – 105 
>105 
# Pulse and BP assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
Clinical safety laboratory values# will be graded as follows: 
Table 11: Clinical Safety Laboratory Adverse Event Grading 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/µL (Decrease) 
2.5 – 3.9 
1.5 – 2.4 
<1.5 
WBC 103/µL (Increase) 
10.6 – 15.0 
15.1 – 20.0 
>20.0 
Hgb g/dL (Decrease) (Female) 
10.1 – 11.4 
8.5 – 10 
<8.5 
Hgb g/dL (Decrease) (Male) 
11.0 – 12.4 
9.5 – 10.9 
<9.5 
Platelets 103/µL (Decrease) 
125 – 139 
100 – 124 
<100 
Platelets 103/µL (Increase) 
416 – 550 
551– 750 
>750 
Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
ALT IU/L (Increase) (Female) 
44 – 100 
101 – 200 
>200 
ALT IU/L (Increase) (Male) 
61 – 138 
139 – 275 
>275 
Total Bilirubin mg/dL (Increase) – 
when accompanied by any increase in 
ALT 
1.30 – 1.59 
1.60 – 1.80 
>1.80 
Total Bilirubin mg/dL (Increase) – 
when ALT is normal 
1.30 – 1.89 
1.90 – 2.40 
>2.40 
Creatinine mg/dL (Increase) 
(Female) 
1.1 – 1.7 
1.8 – 2.0 
>2.0 
Creatinine mg/dL (Increase) (Male) 
1.4 – 1.7 
1.8 – 2.0 
>2.0 


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# Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered 
as baseline. 
9.2.4 
Serious Adverse Events 
Serious Adverse Event (SAE): An AE or suspected adverse reaction is considered “serious” if, 
in the view of either the site PI (or appropriate sub-investigator) or sponsor, it results in any of 
the following outcomes: 
• Death, 
• A life-threatening AE*, 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
* Life-threatening AE. An AE is considered “life-threatening” if, in the view of either the site PI 
(or appropriate sub-investigator) or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death. 
SAEs will be: 
• 
Assessed for severity and relationship to study product or alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
PI or sub-investigator. 
• 
Recorded on the appropriate SAE form and entered into the eCRF. 


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• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site PI or sub-investigator. 
• 
Reviewed and evaluated by the Independent Safety Monitor (ISM) (as deemed 
necessary), DSMB (periodic review unless related), DMID, and IRB. 
9.2.5 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
The site PI or appropriate sub-investigator is responsible for recording all AE/SAEs that are 
observed or reported during this trial, regardless of relationship to study product. AE/SAEs, 
abnormal laboratory test values or abnormal clinical findings will be collected, assessed, 
documented, reported, and followed appropriately, using a local laboratory as necessary. In 
determining eligibility, refer to Section 5.1 and the protocol-specific MOP. 
9.3 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be documented and reported from 
the time of each study vaccination through 7 days after each study vaccination. 
Clinical safety laboratory AEs will be documented and reported from the time of each study 
vaccination through approximately 7 days after each study vaccination. 
Unsolicited non-serious AEs will be documented and reported from the time of each study 
vaccination through approximately 21 days after each study vaccination. 
SAEs and MAAEs, including NOCMCs and PIMMCs, will be documented and reported from 
the time of the first study vaccination through approximately 12 months after the last study 
vaccination. 
9.3.1 
Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group, at the 
following address: 
 
 
 


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DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, selected SAE data fields must also be entered into 
AdvantageEDCSM. Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. 
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary) when they are 
provided to the DMID Pharmacovigilance Group. The DMID Medical Monitor and DMID 
Clinical Project Manager will be notified of the SAE by the DMID Pharmacovigilance Group. 
The DMID Medical Monitor will review and assess the SAE for regulatory reporting and 
potential impact on subject safety and protocol conduct. 
At any time after completion of this trial, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that is suspected to be related to study product, the site PI or appropriate sub-
investigator will report the event to the DMID Pharmacovigilance Group. 
9.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site PI or appropriate sub-investigator, DMID, the 
Investigational New Drug (IND) sponsor, will report any suspected adverse reaction that is both 
serious and unexpected. DMID will report an AE as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the AE. DMID will notify the 
FDA and all investigators (i.e., all participating VTEU site PIs to whom the sponsor is providing 
drug under its IND(s) or under any PI’s IND(s)) in an IND safety report of potential serious risks 
from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar 
days after the sponsor determines that the information qualifies for reporting as specified in 21 
CFR Part 312.32. DMID will also notify the FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the 
sponsor’s initial receipt of the information. Relevant follow up information to an IND safety 
report will be submitted as soon as the information is available. Upon request from the FDA, 
DMID will submit to the FDA any additional data or information that the agency deems 


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necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
request. 
All serious events designated as “not related” to study product(s) will be reported to the FDA at 
least annually in a summary format. 
9.3.3 
Reporting of Pregnancy 
Pregnancies occurring in subjects will be recorded on the Pregnancy Report DCF. No further 
study vaccinations will be administered to pregnant subjects, but with the subject’s permission, a 
venous blood sample for serological assays approximately 21 and 180 days after the last study 
vaccination will be obtained, and the subject will continue to be followed for safety for the 
duration of the prescribed safety follow-up period. Efforts will be made to follow all pregnancies 
reported during the course of this trial to pregnancy outcome pending the subject’s permission. 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be collected, assessed and followed through resolution from the time of each study 
vaccination through approximately 21 days after each study vaccination. 
SAEs and MAAEs, including NOCMCs and PIMMCs, will be collected, assessed and followed 
from the time of the first study vaccination through resolution even if this extends beyond the 
trial-reporting period (approximately 12 months after the last study vaccination). 
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Follow-up procedures, evaluations and outcomes will be recorded on the appropriate DCF and 
entered into the eCRF. 
9.5 
Halting Rules 
Additional enrollment and study interventions/administration of study products in this trial will 
be halted for DSMB review/recommendation if any of the following are reported: 
• Any subject experiences ulceration, abscess or necrosis at the injection site that is 
considered related to study product administration. 
• Any 2 or more subjects experience laryngospasm, bronchospasm or anaphylaxis within 1 
day after administration of study product that is considered related to study product. 


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• Three or more subjects experience generalized urticaria (defined as occurring at more 
than two body parts) within 3 days after administration of study product that is 
considered related to study product. 
• Any subject experiences an SAE after administration of study product that is considered 
related to study product. 
• Any subject experiences acute weakness of limbs and/or cranial nerve innervated muscles 
(description of potential signal of GBS) after administration of study product. 
• Any subject develops a PIMMC after administration of study product. 
This trial will also be halted for DSMB review/recommendation if, within 7 days after 
administration of either study vaccination, any of the following occurs: 
• 7% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date, cumulative to all study vaccine administrations, across all 
treatment arms, experience the same severe (Grade 3) study vaccine-related injection site 
reaction. Ecchymosis, erythema and induration (hardness)/edema (swelling) will also be 
measured in mm but size will not be used as halting criteria. 
• 7% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date, cumulative to all study vaccine administrations, across all 
treatment arms, experience the same severe (Grade 3) study vaccine-related subjective 
systemic reaction, for which the severity (grade) is corroborated by study personnel. 
• 7% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date, cumulative to all study vaccine administrations, across all 
treatment arms, experience the same severe (Grade 3) study vaccine-related quantitative 
systemic reaction. 
• 7% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date, cumulative to all study vaccine administrations, across all 
treatment arms, experience the same severe (Grade 3) study vaccine-related clinical 
safety laboratory AE. 
Grading scales for solicited injection site and systemic (subjective and quantitative) reactions are 
included in Section 9.2.2. 
Grading scales for clinical safety laboratory AEs are included in Section 9.2.3. 


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If any of the halting rules are met following any subject receipt of any study vaccination, then 
this trial will not continue with the remaining enrollments or study vaccinations without a review 
by and recommendation from the DSMB to proceed. 
DMID retains the authority to suspend additional enrollment and study 
interventions/administration of study products during this trial, as applicable. 
The DMID Medical Monitor is empowered to stop enrollment and study vaccinations if AEs that 
meet the halting criteria are reported. 
9.6 
Safety Oversight 
9.6.1 
Independent Safety Monitor (ISM) 
An ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion. This is a voluntary position that 
does not receive payment. The ISM must meet the requirements of the NIAID Conflict of 
Interest (COI) policy. 
For this clinical trial an ISM is not required. However, at each participating VTEU site, upon 
DMID Medical Monitor request, the site PI will identify a physician with relevant expertise, to 
act as a Secondary Medical Assessor (SMA). The SMA will examine a subject and/or medical 
records and provide to DMID a medical assessment (or second medical opinion) of the safety 
event in question. The site PI or appropriate sub-investigator will send to the DMID Medical 
Monitor, a summary of the event and include the site PI or appropriate sub-investigator and SMA 
assessments. 
Note: In the case that DMID has requested this type of evaluation multiple times, DMID may 
request the participating VTEU site(s) identify an ISM to assist DMID with safety oversight, and 
then the below requirements will apply. 
The ISM: 
• 
Is in close proximity to the study site and has the authority and ability to readily access 
subject records in real time. 
• 
May be a member of the participating VTEU site’s staff, but preferably be from a 
different organizational group within the institution. 
• 
Should not be in a direct supervisory relationship with the site PI. 


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• 
Should have no direct involvement in the conduct of the study. 
The ISM will: 
• 
Sign a COI certification at the time he/she is asked to participate and provide updates to 
this information as needed. 
• 
Receive reports of SAEs from the site PI or appropriate sub-investigator and will be 
notified by email when DMID is notified of the SAE. 
• 
Evaluate the SAE and report his/her clinical assessment to DMID in a timely manner. 
• 
Communicate with the site PI or appropriate sub-investigator at the participating VTEU 
site as needed. 
• 
Review additional safety related events at the request of DMID. 
• 
Provide additional information to DMID and/or the DSMB by teleconference as 
requested. 
9.6.2 
Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 
or other COI related to this trial. The DSMB will consist of members with appropriate expertise 
to contribute to the interpretation of the data from this trial. 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. Procedures for DSMB reviews/meetings will be defined in the 
charter. The DSMB will review applicable data to include, but not limited to, study progress and 
subject, clinical, safety, reactogenicity, and immunogenicity data. Reports may include 
enrollment and demographic information, medical history, concomitant medications, physical 
assessments, clinical laboratory values, dosing compliance, solicited and unsolicited AE/SAEs, 
and HAI and Neut antibody assay results. The DSMB will review SAEs on a regular basis and ad 
hoc during this trial. The DMID Medical Monitor and the ISM (as deemed necessary) will be 
responsible for reviewing SAEs in real time. 
The DSMB will conduct the following reviews: 
• Data review for safety at trial-specific time frames; at least annually. 


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• Electronic review when 8-day reactogenicity and clinical safety laboratory data following 
the first study vaccination is available for 25% of study subjects. 
• Data review when 8-day reactogenicity and clinical safety laboratory data following the 
first study vaccination is available for 75% of study subjects. 
• Ad hoc when a halting rule is met, or DMID/DSMB chair may convene an ad hoc 
meeting if there are immediate concerns regarding observations during the course of this 
trial. The DMID Medical Monitor is empowered to stop enrollment and study 
vaccinations if AEs that meet the halting criteria are reported. 
• Final review meeting may be held 6 to 8 months after clinical database lock to review the 
cumulative unblinded safety and immunogenicity data for this trial. If a final review 
meeting is held, the data will be provided in a standard summary format. The DSMB may 
be asked to provide recommendations in response to questions posed by DMID. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion, and may request the treatment assignment be 
unblinded for an individual subject if required for safety assessment. The DSMB will review 
grouped and unblinded data in the closed session only. As an outcome of each review/meeting, 
the DSMB will make a recommendation as to the advisability of proceeding with study 
vaccinations, as applicable, and to continue, modify or terminate this trial. 
 


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10 
CLINICAL MONITORING 
10.1 
Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study interventions/administration of study products, and data collection processes 
are of high quality and meet sponsor and ICH E6 GCP guidelines and applicable federal 
regulations, and that this trial is conducted in accordance with the protocol, protocol-specific 
MOP and applicable sponsor SOPs. DMID, the sponsoring agency, or its designee will conduct 
site-monitoring visits as detailed in the clinical monitoring plan. DMID-designated clinical 
monitors will verify that this trial is conducted and data are generated, documented (recorded) 
and reported in compliance with the protocol, ICH E6 GCP guidelines and applicable regulatory 
requirements. Clinical monitoring reports will be submitted to DMID. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID. Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, ICFs, medical and laboratory reports, and 
protocol and GCP compliance. Site monitors will have access to each participating VTEU site, 
study personnel and all study documentation according to the DMID-approved site monitoring 
plan. Study monitors will meet with site PIs to discuss any problems and actions to be taken and 
document visit findings and discussions. 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 
Introduction 
The goal of this clinical trial is to assess in healthy adults, 19 to 50 years of age, the safety, 
reactogenicity and immunogenicity of one or two doses 2013 and 2017 A/H7N9 IIVs, 
administered intramuscularly at different dosages (3.75 or 15 mcg of hemagglutinin (HA) per 
dose), given with or without AS03 adjuvant, using different heterologous and homologous 
prime-boost vaccination schedules. These treatment arms are included to allow evaluation of the 
study vaccine dosage, study vaccination schedule and potential of the adjuvant to enhance the 
immune response to the 2013 and 2017 A/H7N9 IIVs. Additional goals are to investigate novel 
methods for identifying and assessing alternative cellular correlates of protection against 
influenza infection. 
11.2 
Study Hypotheses 
This Phase II study is not designed to test a formal null hypothesis. Rather, it is intended to 
obtain sufficient data to obtain meaningful estimates of the immune response induced by this 
vaccine and to uncover any safety issues that occur at a sufficiently high rate that they might be 
observed in a study of this size. The sample size facilitates formal testing of selected hypotheses 
as discussed in Section 11.4.3, along with the probability of observing safety outcomes and the 
precision of immunogenicity outcomes. 
11.3 
Study Outcome Measures 
Please refer to Study Outcome Measures outlined in Section 3.2. 
11.4 
Sample Size Considerations 
Please refer to Study Design outlined in Section 4. 
11.4.1 
Study Population 
The study population for this clinical trial includes males and non-pregnant females, 19 to 50 
years of age, who are in good health and meet all eligibility criteria. The subjects will be 
recruited from the general population at each of the participating VTEU sites that have 
substantial experience conducting large influenza vaccine studies. 


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11.4.2 
Subject Enrollment and Follow-up 
Based on the accrual rates observed in similar studies, it seems reasonable to expect that the 
participating VTEUs will be able to enroll this trial in a timely fashion. In previous DMID trials, 
7 VTEUs recruited 388 healthy subjects, 19 to 64 years of age, in 14 weeks. Prior experience 
suggests up to 15% of subjects (approximately 10% of subjects assigned to the 4-month interval 
and 5% of subjects assigned to the 21-day interval), 19 to 64 years of age, may be excluded from 
the per protocol (PP) analysis for the primary immunogenicity outcome either because they did 
not receive the second study vaccination, were lost-to-follow-up, or because they had a protocol 
deviation requiring their exclusion from the PP analysis. 
Follow-up will consist of 2 segments. The first encompasses the core data for this trial and will 
consist of results for all study visits through approximately 21 days after the last study 
vaccination. The second segment consists of a 6-month immunogenicity assessment and follow-
up safety assessments through approximately 12 months after the last study vaccination. 
11.4.3 
Sample Size 
This study is planned to enroll up to 180 subjects. The sample size for this study was selected to 
obtain preliminary estimates in a time critical manner. While this study is not designed to test 
any specific null hypothesis, the following illustrates the precision and power that are available 
for select estimates and comparisons of interest. 
Table 12 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 a single treatment arm (N=30), or in the trial as a whole (N=180). 
 
 
 


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Table 12: Power (%) to Detect Safety Events 
Event 
Frequency 
N=30 
N=180 
≥10% 
Very Common 
95 
>99 
≥1% 
Common 
26 
83 
≥0.1% 
Uncommon 
2 
16 
≥0.01% 
Rare 
<1 
1 
Binomial confidence intervals (CI) are widest (have the least precision) when the response rate is 
50%. Table 13 is presented to indicate the worst-case scenario for precision of observed exact 
(Clopper-Pearson) binomial confidence intervals. 
Table 13: Precision of Binomial Confidence Intervals 
N 
95% CI 
30 
31-69 
180 
42-58 
Table 14 illustrates the minimum detectable differences in the proportion of subjects responding 
(e.g. attaining seroconversion or a titer ≥1:40) between any two treatment arms (N=30) using a 
two-sided Likelihood Ratio Test and alpha = 0.05. It is assumed that up to 10% of subjects (N=3) 
will be excluded from the per protocol analysis. Seroconversion rates of 10% to 50% are 
considered. 
 
 


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Table 14: Minimum Detectable Difference in Proportion Responders 
N per Group 
Proportion 
Responders in 
Comparator 
Group A 
80% Power 
Minimal 
Detectable 
Difference 
Proportion 
Responders in 
Comparator 
Group B 
N=27 
0.10 
0.32 
0.42 
0.20 
0.35 
0.55 
0.30 
0.38 
0.68 
0.40 
0.37 
0.77 
0.50 
0.34 
0.84 
11.5 
Planned Interim Analyses 
A DSMB will be convened by DMID to review study progress and subject, clinical, safety, 
reactogenicity, and immunogenicity data as described in Section 9.6.2. 
A set of “topline” immunogenicity and safety tables produced on an expedited timeline will be 
prepared as described in Section 11.6; though this report will be released while subjects remain 
in this trial for long-term safety follow-up, it will be considered the final analysis of these data. 
Emergent public health needs may dictate additional interim safety, reactogenicity and/or 
immunogenicity analyses be performed on available information at any time during this trial. If 
this occurs, immunogenicity data will be analyzed as results are available from Southern 
Research. 
Interim analyses will be used only to terminate this trial in the event that unanticipated safety 
events deemed to be of sufficient concern require such action by the sponsor. These assessments 


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will not be made on the basis of testing a formal statistical hypothesis; therefore, p-value 
adjustment will not be made to any analyses. 
11.5.1 
Interim Safety Review 
An interim safety review may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 
and solicited and unsolicited AE/SAEs. Additional data may be requested by the DSMB, and 
interim statistical reports may be generated as deemed necessary and appropriate by DMID. The 
DSMB may receive data in aggregate and presented by treatment arm. The DSMB may also be 
provided with expected and observed rates of the expected AEs in an unblinded fashion, and may 
request the treatment assignment be unblinded for an individual subject if required for safety 
assessment. The DSMB will review grouped and unblinded data in the closed session only. The 
DSMB will meet and review this data at trial-specific time frames or ad hoc as needed during 
this trial as defined in the DSMB charter. As an outcome of each review/meeting, the DSMB will 
make a recommendation as to the advisability of proceeding with study vaccinations, as 
applicable, and to continue, modify or terminate this trial. 
The interim safety reports generated for the DSMB are not intended to be published; they will be 
used only for informing emergency preparedness. 
Additionally, this trial will be monitored to determine if any of the halting rules described in 
Section 9.5 are met. 
11.5.2 
Interim Immunogenicity Review 
Should emergent public health needs dictate interim immunogenicity review, immune responses 
will be summarized in terms of strain-specific 2013 and 2017 A/H7N9 HAI and Neut antibody 
titers and the relationship to study vaccine dosage, adjuvant use and study vaccination schedule. 
It is anticipated that all analyses will be carried out in parallel for both assays, but reports may be 
prepared separately for HAIs and Neuts if results are available on different timelines. Interim 
analyses will focus on rates of titers ≥1:40, seroconversion (defined as either a pre-vaccination 
titer <1:10 and a post-vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and a minimum 
four-fold rise in post-vaccination titer) and GMTs, along with corresponding 95% CIs. No 
formal hypothesis testing will be included in the interim analysis, and interim results will not 
have impact on conduct of this trial. 
Any immunogenicity reports would be provided by the SDCC to the DMID Scientific Lead, 
DMID Clinical Project Manager and DSMB. Reports will include data summarized by unblinded 


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treatment arm, but the presentation will be in a format that prevents inadvertent unblinding of 
any individual subject. 
There is no plan to halt this trial prior to full enrollment and completion of all follow-up visits 
based on any interim immunogenicity results. 
11.6 
Final Analysis Plan 
Clinical, safety and reactogenicity data through approximately 180 days after the last study 
vaccination will represent the primary clinical database for this trial. Once the last subject 
completes the visit that occurs approximately 180 days after the second study vaccination and all 
HAI and Neut results are received, a “topline” subset of the immunogenicity and safety tables 
will be provided to DMID on an expedited timeline. These analyses may be made available to 
the sponsor for planning subsequent trials and to the lead PI for publication. These analyses will 
not be used to make any decisions concerning the conduct of this trial. As it is anticipated that 
subjects will remain in long-term safety and immunogenicity follow-up at the time of these 
analyses, blinded site investigators and DMID Medical Monitors not involved in the analysis, 
publication or clinical study report (CSR) preparation will be responsible for assessing SAEs and 
MAAEs, including NOCMCs and PIMMCs, until all subjects have completed the final follow-up 
visit. All analyses of data included in the topline tables for early release will be considered the 
final analysis of these data, and also included in the final CSR. 
Analysis of exploratory immunogenicity endpoints, including cellular immunology and 
additional serological assays, may be performed and released as the data are available from the 
research laboratories. Any such analyses would be considered the final analysis for the endpoint, 
and included in the CSR. 
The final CSR will be completed after the last subject’s last visit is completed, and the final 
clinical database, including all long-term safety follow-up data, is cleaned, monitored and 
locked. Additional exploratory immunogenicity endpoint data not available at the time of CSR 
preparation may be included in an addendum to the CSR. 
A formal statistical analysis plan (SAP) will be developed and finalized prior to unblinding for 
any analysis, which defines the analyses to be included in the topline tables and final CSR. 
11.6.1 
Analysis Populations 
The Safety Analysis population includes all subjects who received at least one dose of study 
vaccine. 


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The modified intent-to-treat (mITT) population includes all subjects who received at least one 
dose of study vaccine and contributed both pre- and at least one post-study vaccination venous 
blood samples for HAI and Neut antibody assays for which valid results were reported. For 
analyses using the mITT population, subjects will be grouped based on their randomized 
treatment arm. 
The PP population includes all subjects in the mITT subset with the following exclusions: 
• Data from all available visits for subjects found to be ineligible at baseline. 
• Data from all visits subsequent to major protocol deviations, such as: 
• Second study vaccination not received, 
• Second study vaccination received out of window, 
• Receipt of non-study licensed, live vaccine within 30 days before or after each 
study vaccination, 
• Receipt of non-study licensed, inactivated vaccine within 14 days before or after 
each study vaccination, 
• Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days 
before or after each study vaccination. 
• Data from any visit that occurs substantially out of window. 
For analyses using the PP population, subjects will be grouped based on study vaccinations 
received. 
11.6.2 
Safety Data 
Summaries and analysis of safety data will be presented for the Safety Analysis Population. All 
summaries and analyses will be presented for all subjects. 
Solicited AEs will be summarized by severity for each day after each study vaccination (Days 1-
8 post each study vaccination) and as the maximum severity over all 8 days. Additionally, 
solicited AEs will be analyzed by taking the most severe response over the follow-up period, 
dichotomizing into a binary variable (none versus mild, moderate or severe) and using standard 
techniques, such as exact CIs, to summarize the proportion of subjects reporting each symptom, 
any injection site symptom and any systemic symptom. Summaries of solicited AEs will be 
presented separately for each study vaccination as well as overall study vaccinations by 


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treatment arm. The proportion of subjects reporting symptoms may be compared between 
treatment arms using Chi-square or Fisher’s exact test. The proportion of subjects reporting 
solicited symptoms between the different study vaccinations (i.e., first and second) will be 
compared using McNemar’s test. 
Unsolicited AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) for 
preferred term and system organ class (SOC). The numbers of SAEs and MAAEs, including 
NOCMCs and PIMMCs, are likely to be small in this trial and will be reported by detailed 
listings showing the event description, MedDRA preferred term and SOC, relevant dates (study 
vaccinations and AEs), severity, relatedness, and outcome for each event. Non-serious 
unsolicited AEs will be summarized as number and percentage of subjects reporting at least one 
event in each MedDRA preferred term and SOC, cross-tabulated by severity and relationship to 
study product. Additionally, the proportion of subjects and exact 95% CIs of AEs in aggregate 
and by MedDRA categories will be computed. 
Clinical laboratory data will be summarized by severity for each visit and as the maximum over 
all post-study vaccination visits. Graphical presentations may include box plots. 
11.6.3 
Immunogenicity Data 
Summaries and analysis of immunogenicity data will be presented for the mITT and PP 
populations. 
Immune responses in terms of strain-specific 2013 and 2017 A/H7N9 HAI and Neut antibody 
titers will be summarized by treatment arm at each time point. Analyses will include number and 
percentage of subjects with a titer ≥1:40, number and percentage of subjects achieving 
seroconversion (defined as either a pre-vaccination titer <1:10 and a post-vaccination titer ≥1:40 
or a pre-vaccination titer ≥1:10 and a minimum four-fold rise in post-vaccination antibody titer), 
and GMTs along with corresponding 95% CIs. Descriptive summary statistics will be provided 
for all assays and time points. The correlation between HAI and Neut antibody titers will be 
evaluated. Plots such as reverse cumulative distributions or longitudinal presentations of GMTs 
will be presented. 
Additionally, the immune response, as described above, will be summarized by available 
covariates, such as age, sex, BMI, and prior receipt of seasonal or non-study pandemic influenza 
vaccine(s), and these covariates may be considered statistical modeling. As an exploratory 
analysis, models may be developed to evaluate the relationship between study vaccine dosage 
and adjuvant use as well as study vaccination schedule on the elicited immune response. For 
example, logistic regression may be used to examine the relationship of proportion of responders 


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with study vaccine dosage and adjuvant use as well as study vaccination schedule, and available 
covariates may be considered for inclusion in the model. 
At least a subset of samples will also be tested for cross-reactive serum HAI and Neut antibody 
responses to antigenically drifted variants of influenza A/H7 viruses. Strain-specific results will 
be summarized using descriptive statistics as described above, correlations with 2013 and 2017 
A/H7N9 responses and association with study vaccine dosage and adjuvant use as well as study 
vaccination schedule. 
In addition, N9 NA-specific antibody assays are in development. N9 NA-specific serum antibody 
responses may be assessed at baseline as well as immediately prior to and approximately 21 days 
after the second study vaccination. For each time point, summaries may include number and 
percentage of subjects with detectable N9 NA response (to be defined in SAP following assay 
development and selection) and GMTs along with corresponding 95% CIs. Descriptive summary 
statistics will be provided for all assays and time points. The correlation of N9 NA-specific 
serum antibody responses with HAI and Neut antibody titers will be evaluated, and plots such as 
reverse cumulative distributions or longitudinal presentations of GMTs will be presented. 
Furthermore, a determination of the N9 NA content in the 2013 and 2017 A/H7N9 IIVs is 
planned, and may be used to correlate the NA content of the 2013 and 2017 A/H7N9 IIVs with 
the elicited N9 NA-specific serum antibody responses. Detectable N9 NA-specific serum 
antibody responses and GMTs will be summarized stratified by NA content, and statistical 
modeling may be used to examine the relationship of NA response with NA content, HA antigen 
dosage, adjuvant, and study vaccination schedule. 
At least a subset of samples will also be tested for exploratory immunogenicity endpoints, 
including cellular immunology and additional serological assays. Exploratory immunology 
analyses will be primarily descriptive and defined in the SAP. Results of any exploratory 
immunogenicity analysis will not be published prior to publication of the primary 
immunogenicity results for this trial. 
Further immunogenicity testing and/or analyses may be carried out in the future based upon 
subjects’ prior receipt of non-seasonal influenza vaccine, including type (inactivated or live 
attenuated), what subtype (e.g. A/H3, A/H5, A/H9) and approximate date of vaccination. 
11.6.4 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol. As missing data are expected to be 
minimal, no imputation will be performed for missing values. Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier. If 
data points are identified as outliers, sensitivity analyses will be performed to examine the 


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impact of including or excluding the outliers. Any substantive differences in these analyses will 
be reported. 
 


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12 
DATA COLLECTION FORMS AND ACCESS TO 
SOURCE DATA/DOCUMENTS 
Each participating VTEU site will maintain appropriate medical and research records for this 
clinical trial, in compliance with ICH E6 GCP Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects. Each participating VTEU site will 
permit the study monitor or other authorized representatives of DMID as well as governmental 
regulatory agencies, such as the FDA, to examine (and when required by applicable law, to copy) 
clinical trial records for the purposes of quality assurance reviews, audits, monitoring and 
evaluation of the study safety and progress. These representatives will be permitted access to all 
source data, which include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files, and records kept at the pharmacy, at the laboratories and medico-technical 
departments involved in this clinical trial. Source data are all information, original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Interview of subjects is sufficient for obtaining medical history. Solicitation of medical records 
from the subject’s primary care provider is not required. 
 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating VTEU site 
(and its subcontractors) is responsible for conducting routine quality assurance (QA) and quality 
control (QC) activities to internally monitor study progress and protocol compliance. Each site PI 
will provide direct access to all study-related sites, source data/DCFs and reports for the purpose 
of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
Each site PI will ensure all study personnel are appropriately trained and applicable 
documentation is current and maintained on site. 
The SDCC will implement QC procedures beginning with the data entry system and generate 
data QC checks that will be run on the database. Any missing data or data anomalies will be 
communicated to the participating VTEU site(s) for clarification and resolution. 
 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Ethical Standard 
The site PIs will ensure that this trial is conducted in full conformity with principles of the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research [April 18, 1979]) and codified in 45 CFR 46, 21 CFR 50 and 21 CFR 56, as 
applicable. The site PIs will also ensure conformity with ICH E6 GCP and applicable federal 
regulations, guidance and guidelines for GCP and Clinical Trials with humans. 
14.2 
Institutional Review Board (IRB) 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office for Human Research Protections (OHRP) for federally funded research. The 
IRB must be registered with OHRP [OHRP-only or OHRP/FDA] as applicable to the research. 
The IRB FWA number will be provided to DMID. 
Each site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s), 
and send supporting documentation to DMID before initiating recruitment of subjects. The site 
PI will submit applicable information to the IRB on which it relies for the review, to conduct the 
review in accordance with 45 CFR 46, ICH E6 GCP guidelines, and as applicable, 21 CFR 56 
(Institutional Review Boards), 21 CFR 50 (Protection of Human Subjects), and other federal, 
state and local regulations and guidance. DMID must receive the documentation that verifies 
IRB approval for this protocol, associated informed consent documents, and upon request, any 
recruitment material and handouts or surveys intended for the subjects, prior to the recruitment 
and enrollment of subjects. 
Any amendments to the protocol or consent materials will be approved by the IRB before they 
are implemented. IRB review and approval will occur at least annually throughout the enrollment 
and follow-up of subjects, and may cease if annual review is no longer required by applicable 
regulations. The site PI will notify the IRB of protocol deviations and reportable SAEs in 
accordance with IRB requirements. 
14.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Before any study procedures 


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are performed, informed consent will be obtained and documented. Subjects will receive a 
concise and focused presentation of key information about the trial, verbally and with a written 
ICF. The explanation will be organized, and presented in lay terminology and language that 
facilitates understanding why one might or might not want to participate. The ICF must not 
include any exculpatory statements. 
The site PIs or their designees will describe the protocol to potential subjects face-to-face. The 
key information about the purpose of the trial, the procedures and experimental aspects of the 
trial, risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject. 
Subjects will also receive an explanation that the trial involves research and a detailed summary 
of the proposed study procedures and study interventions/study products. This will include 
aspects of the trial that are experimental, the probability for random assignment to treatment 
arms, any expected benefits, all possible risks (including a statement that the particular treatment 
or procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), the expected duration of the subject’s 
participation in the trial, alternative treatment/procedures that may be available, and the 
important potential benefits and risks of these available alternative treatment/procedures. 
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the site PI) for 
answers to any questions relating to the research project. 
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitors, auditors, IRB, NIAID, and regulatory authorities will be granted direct access 
to the subject’s original medical records for verification of trial procedures and/or data without 
violating the confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations, and that, by signing a written ICF, the subject is authorizing such access. 


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Subjects will be informed that records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws and/or regulations, will not be made publicly available 
and, if the results of the trial are published, the subject’s identity will remain confidential. 
Subjects will be informed whether private information collected from this research and/or 
samples/specimens will be used for additional research, even if identifiers are removed. 
Subjects will be allowed sufficient time to consider participation in the trial, and have the 
opportunity to discuss the trial with their family, friends or legally authorized representative, or 
think about it prior to agreeing to participate. 
ICFs will be IRB-approved and subjects will be asked to read and review the ICF. Subjects must 
sign the ICF prior to starting any study procedures being done specifically for the trial. 
Once signed, a copy of the ICF will be given to the subjects for their records. The subject(s) may 
withdraw consent at any time throughout the course of the trial. The rights and welfare of the 
subjects will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in or withdraw from the trial. 
New information that significantly impacts the subject’s risk of receiving the study 
interventions/study products will be communicated by the site PIs or their designees to the 
subjects who consent to participate in the trial in accordance with IRB requirements. The ICF 
will be updated and subjects will be re-consented in accordance with IRB requirements, if 
necessary. Subjects will be given a copy of all ICFs that they sign. 
Study personnel may employ IRB-approved recruitment efforts prior to obtaining study consent 
if a patient-specific screening consent is on record or if the IRB has agreed that chart review is 
allowed without a fully executed screening consent. In cases where there is not a patient-specific 
screening consent on record, Clinical Staff may pre-screen via chart review and refer potential 
subjects to the Research staff. Research staff would obtain written consent per the standard 
informed consent process before conducting protocol-specific screening activities. 
After all subjects had enrolled, it was determined that B cell repertoire sequencing is a form of 
genetic testing that will be performed as part of this trial under this primary research protocol. 
Subjects will be informed and asked for their consent to use their samples/specimens and 
information for genetic testing, such as B cell repertoire sequencing. B cell repertoire sequencing 
results (data) may be shared broadly with other researchers but will not be shared with subjects. 
Individual results will be stored indefinitely in an NIH restricted-access database, and a summary 
of results may be placed in an unrestricted (open) database. 
The samples/specimens will be encoded (labeled) only with a barcode and a unique tracking 
number to protect subject confidentiality. The genetic data in the NIH database will be coded in 


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such a way that information will be considered de-identified. Subjects will be informed of the 
risks, including potential for re-identification and possible harm from the mis-use of data, 
however, NIH will require researchers to not re-identify the subjects. 
Subjects will have the right to withdraw consent for the use of their samples/specimens and/or 
data without penalty at any time. Samples/specimens and data that have already been used for 
primary research may not be able to be withdrawn. 
"Written", or "signed", refers to the use of or writing on a paper or an electronic ICF. Re-consent 
(revised or separate consent form) for primary research using samples/specimens and 
information for genetic testing, such as B cell repertoire sequencing, may use paper or electronic 
ICFs to obtain the subject’s written consent. The subject will have a discussion with study staff, 
who is able to answer the subject’s questions, including if re-consent is obtained off-site. A paper 
copy of the signed ICF will be given to the subject in person or mailed. 
14.4 
Exclusion of Women, Minorities and Children (Special Populations) 
This trial will be inclusive of all subjects, 19 to 50 years of age, who meet the Subject Inclusion 
Criteria (see Section 5.1.1) and do not meet the Subject Exclusion Criteria (see Section 5.1.2), 
regardless of religion, sex or ethnic background. Adults aged 18 are excluded because the CDC-
recommended adult immunization schedule considers adults as age 19 and above, and therefore 
this is the subject population chosen for this study [74]. Should the outcome of this trial be 
deemed acceptable, additional trials may be initiated including those in other populations. 
It is unknown if the 2013 and 2017 A/H7N9 IIVs with or without AS03 adjuvant pose any risks 
to an unborn child. As of November 22, 2015 (per the GSK AS03 Adjuvant Investigator’s 
Brochure dated February 2016), the available data for women who become pregnant during 
clinical trials of AS03-adjuvanted (pre) pandemic influenza vaccines do not suggest any causal 
relationship between adverse pregnancy outcomes and receipt of an AS03-adjuvanted vaccine. 
Women of childbearing potential who are not sterilized via tubal ligation, bilateral 
oophorectomy, salpingectomy, hysterectomy, or successful Essure® placement (permanent, non-
surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 
days after the procedure, and still menstruating or <1 year has passed since the last menses if 
menopausal must agree to practice highly effective contraception that may include non-male 
sexual relationships, abstinence from sexual intercourse with a male partner, monogamous 
relationship with a vasectomized partner who has been vasectomized for 180 days or more prior 
to the subject receiving the first study vaccination, barrier methods such as condoms or 
diaphragms/cervical cap with spermicide, effective intrauterine devices, NuvaRing®, and 
licensed hormonal methods such as implants, injectables or oral contraceptives (“the pill”), with 
use of a highly effective method of contraception for a minimum of 30 days prior to study 


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vaccine exposure and agree to practice highly effective contraception for the duration of study 
vaccine exposure, including 60 days after their last study vaccination. A highly effective method 
of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) 
when used consistently and correctly. In addition to contraceptive use, all women of childbearing 
potential will be required to have a negative urine or serum pregnancy test within 24 hours prior 
to each study vaccination. If a female subject becomes pregnant while participating in this trial, 
we will ask her permission to follow-up with her about her health and the health of her baby 
through pregnancy outcome. 
Children will not be included in this trial as presently there are no safety or efficacy data in 
adults. 
14.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the site PIs, other study personnel, the sponsor, 
and their agents. This confidentiality includes documentation, investigation data, subject’s 
clinical information, and all other information generated during participation in this trial. No 
information concerning this trial or the data generated from this trial will be released to any 
unauthorized third party without prior written approval of the subject and DMID. 
Subject confidentiality will be maintained when trial results are published or discussed in 
conferences, and is extended to cover testing of samples/specimens. The study monitor or other 
authorized representatives of DMID as well as governmental regulatory agencies, such as the 
FDA, may inspect all documents and records required to be maintained by the site PIs. This 
includes, but is not limited to, medical records (office, clinic or hospital) and pharmacy records 
for the subjects in this trial. The participating VTEU sites will permit access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password-protected systems. All non-clinical 
samples/specimens, evaluation forms, reports, and other records that leave the site will be 
identified only by a coded number and will not be identified by the subject’s name. 
To protect privacy, we have received a Certificate of Confidentiality. With this Certificate, the 
researchers cannot be forced to release information that may identify the subject, even by a court 
subpoena, in any federal, state or local civil, criminal, administrative, legislative, or other 
proceedings. The researchers will use the Certificate to resist any demands for information that 
would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the US 
Government that is used for auditing or evaluation of federally funded projects, like this trial, or 


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for information that must be released in order to meet the requirements of the FDA. 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information. 
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse or wanting to harm themselves or others. 
14.6 
Study Discontinuation 
If this trial is prematurely terminated by the sponsor, any regulatory authority, the site PI, or 
appropriate sub-investigator for any reason, the site PI or appropriate sub-investigator will 
promptly inform the subjects and assure appropriate therapy or follow-up for the subjects, as 
necessary. The site PI or appropriate sub-investigator will provide a detailed written explanation 
of the termination to the IRB. If any subject’s private information will continue to be collected 
for this trial, the IRB must approve an ICF with the study procedures, any risks and discomforts 
as well as applicable elements, and the site PI or designee will re-consent the subjects as 
approved by the IRB. 
If this trial is discontinued, subjects, who have signed the ICF, and are randomized and 
vaccinated, will continue to be followed for safety for the duration of the prescribed safety 
follow-up period. No further study vaccinations will be administered. 
14.7 
Costs, Subject Compensation and Research Related Injuries 
There is no cost to subjects for the research tests, study procedures/evaluations or study vaccine 
while taking part in this trial. 
Subjects may be compensated for their participation in this trial. Compensation will be in 
accordance with local IRB requirements, and subject to local IRB approval. 
If it is determined by the participating VTEU site and the site PI that an injury occurred to a 
subject as a direct result of the tests or treatments that are done for this trial, then referrals to 
appropriate health care facilities will be provided to the subject. Study personnel will try to 
reduce, control and treat any complications from this trial. Immediate medical treatment may be 
provided by the participating VTEU site, such as giving emergency medications to stop 


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immediate allergic reactions to the study vaccine. No financial compensation will be provided to 
the subject by NIAID, NIH or the participating VTEU site for any injury suffered due to 
participation in this trial. 
For this protocol, the study products (2013 and 2017 A/H7N9 IIVs manufactured by Sanofi 
Pasteur and AS03 adjuvant manufactured by GSK) are covered under the PREP Act, as 
described in Section 2.1.1. 
14.8 
Future Use of Stored Specimens 
Subjects who agree to participate in this trial will have venous blood collected for ESR and 
clinical safety laboratory evaluations, serological and cellular immunology assays as well as 
future research. 
Residual samples/specimens are those that are left over after protocol-specified testing for 
serological and cellular immunology assays and this trial have been completed. Any remaining 
(residual) specimens (serum, plasma and PBMCs) derived from venous blood samples collected 
for serological and cellular immunology assays will be kept for possible use in future research 
studies, such as examining additional immunological assessments or testing for antibodies 
against other viruses or bacteria. Residual specimens for future research use will be stored 
indefinitely at a central clinical storage facility and may be shared for purposes other than PP 
analysis with investigators at the participating VTEU site and with other investigators at other 
institutions once the CSR has been finalized. An IRB will review future research prior to the use 
of identifiable specimens or data. 
Additional venous blood samples for serum, plasma and PBMC specimens will be collected 
during this trial specifically for the purpose of future research, including, but not limited to, 
detailed systems biology analyses, antibody epitope mapping, B and T cell repertoire 
determination, non-traditional immune assay development, assessing innate immune factors, and 
the ability of A/H7 study vaccine-induced antibodies to cross-react with other influenza viruses. 
These samples/specimens might be used in new or different immunological laboratory tests, to 
provide information for the development of new vaccines, or for the studies of influenza or other 
infections. Samples/specimens collected during this trial specifically for the purpose of future 
research will be stored indefinitely at a central clinical storage facility and may be shared with 
investigators at the participating VTEU site and with other investigators at other institutions. An 
IRB will review future research prior to the use of identifiable specimens or data. 
Residual specimens will be available upon the completion of this trial; however, 
samples/specimens collected during this trial specifically for the purpose of future research may 
be requested from DMID and shipped from the DMID CMS at any time. 


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There are no benefits to subjects in the collection, storage and future research use of their 
samples/specimens. Future research tests may benefit others by leading to new approaches in the 
development of vaccines or treatments for influenza. Future research use samples/specimens 
(residual specimens and samples/specimens collected during this trial specifically for the purpose 
of future research) will not be sold or used directly for production of any commercial product. 
Each sample/specimen will be encoded (labeled) only with a barcode and a unique tracking 
number to protect subject confidentiality. Reports from future research studies performed using 
subjects’ samples/specimens will NOT be kept in their health records and results will not be 
shared with subjects. 
Subjects will not be given the option to decide if they want their residual specimens to be used 
for future research or have these specimens destroyed at the end of this trial. Subjects will be 
asked to consent to the future research use of residual specimens as a condition of their study 
participation. 
Subjects will not be given the option to decide if they want their samples/specimens collected 
during this trial specifically for the purpose of future research to be used for future research or 
have these samples/specimens destroyed at the end of this trial. These samples/specimens are 
protocol-required; thus, subjects will be asked to consent to the future research use of these 
samples/specimens as a condition of their study participation. 
By signing a written ICF for this trial, subjects agree to the collection, storage and future 
research use of their samples/specimens (residual specimens and samples/specimens collected 
during this trial specifically for the purpose of future research). 
After all subjects had enrolled, it was determined that genetic testing may be performed on 
residual specimens and samples/specimens collected during this trial specifically for the purpose 
of future use, under a secondary research protocol. Secondary research is research that is not part 
of this trial and will be performed in the future. Subjects will be informed and asked for their 
consent to use their residual specimens and samples/specimens collected during this trial 
specifically for the purpose of future research and information for genetic testing for “secondary 
research”. Genetic testing could include transcriptomics, whole genome or exome sequencing, or 
other types of genetic testing. This could contribute to identifying genetic factors involved in 
vaccine responses. Genetic testing results (data) may be shared broadly with other researchers 
but will not be shared with subjects. Individual results will be stored indefinitely in an NIH 
restricted-access database, and a summary of results may be placed in an unrestricted (open) 
database. 
The samples/specimens will be labeled as above for storage. The genetic data in the NIH 
database will be coded in such a way that information will be considered de-identified. Subjects 


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will be informed of the risks, including potential for re-identification and possible harm from the 
mis-use of data, however, NIH will require researchers to not re-identify the subjects. 
Subjects will have the right to withdraw consent for the use of their samples/specimens and/or 
data without penalty at any time. Samples/specimens and data that have already been used for 
secondary research may not be able to be withdrawn. 
"Written", or "signed", refers to the use of or writing on a paper or an electronic ICF. Re-consent 
(revised or separate consent form) for secondary research using samples/specimens and 
information, such as for genetic testing, may use paper or electronic ICFs to obtain the subject’s 
written consent. The subject will have a discussion with study staff, who is able to answer the 
subject’s questions, including if re-consent is obtained off-site. A paper copy of the signed ICF 
will be given to the subject in person or mailed. 
 


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15 
DATA HANDLING AND RECORD KEEPING 
The site PIs are responsible to ensure the accuracy, completeness, legibility, and timeliness of the 
data reported. 
DCFs will be derived from the eCRF and provided by the SDCC to record and maintain data for 
each subject enrolled in this trial. All DCFs should be completed in a neat, legible manner to 
ensure accurate interpretation of data. Black or blue ink is required to ensure clarity of 
reproduced copies. When making a change or correction, cross out the original entry with a 
single line and initial and date the change. Do not erase, overwrite or use correction fluid or tape 
on the original. 
Data reported in the eCRF derived from the DCFs should be consistent with the DCFs or the 
discrepancies should be explained. 
The sponsor and/or its designee will provide guidance to the site PIs and other study personnel 
on making corrections to the DCFs and eCRF. 
15.1 
Data Management Responsibilities 
All DCFs and laboratory reports must be reviewed by the clinical team and data entry personnel, 
who will ensure that they are accurate and complete. AEs must be recorded on the appropriate 
DCF, assessed for severity and relationship, and reviewed by the site PI or appropriate sub-
investigator. 
Data collection is the responsibility of the study personnel at each participating VTEU site under 
the supervision of the respective site PI. During this trial, the site PIs must maintain complete 
and accurate documentation for this trial. 
The SDCC for this trial will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
15.2 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values), reactogenicity and immunogenicity data 
will be entered into a 21 CFR 11-compliant Internet Data Entry System provided by the SDCC. 
The data system includes password protection and internal quality checks, such as automatic 


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range checks, to identify data that appear inconsistent, incomplete or inaccurate. Clinical and 
reactogenicity data will be entered directly from the DCFs completed by the study personnel. 
15.3 
Types of Data 
Data for this trial will include clinical, safety and outcome measures (e.g., clinical laboratory 
values, and reactogenicity and immunogenicity data). 
15.4 
Timing/Reports 
Clinical, safety and reactogenicity data through approximately 180 days after the last study 
vaccination will represent the primary clinical database for this trial. Once the last subject 
completes the visit that occurs approximately 180 days after the second study vaccination and all 
HAI and Neut results are received, a “topline” subset of the immunogenicity and safety tables 
will be provided to DMID on an expedited timeline. These analyses may be made available to 
the sponsor for planning subsequent trials and to the lead PI for publication. These analyses will 
not be used to make any decisions concerning the conduct of this trial. As it is anticipated that 
subjects will remain in long-term safety and immunogenicity follow-up at the time of these 
analyses, blinded site investigators and DMID Medical Monitors not involved in the analysis, 
publication or clinical study report (CSR) preparation will be responsible for assessing SAEs and 
MAAEs, including NOCMCs and PIMMCs, until all subjects have completed the final follow-up 
visit. All analyses of data included in the topline tables for early release will be considered the 
final analysis of these data, and also included in the final CSR. 
Analysis of exploratory immunogenicity endpoints, including cellular immunology and 
additional serological assays, may be performed and released as the data are available from the 
research laboratories. Any such analyses would be considered the final analysis for the endpoint, 
and included in the CSR. 
The final CSR will be completed after the last subject’s last visit is completed, and the final 
clinical database, including all long-term safety follow-up data, is cleaned, monitored and 
locked. Additional exploratory immunogenicity endpoint data not available at the time of CSR 
preparation may be included in an addendum to the CSR. 
Additional statistical reports may be generated as deemed necessary and appropriate by DMID. 
Safety and immunogenicity summary reports may be generated for the DSMB. 
After the final CSR is complete, and upon request and DMID approval, the SDCC will provide 
the participating VTEU sites with a summary of results by treatment arm and/or subject 


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treatment assignment. In this regard, the participating VTEU sites requesting such information to 
share with subjects must do so in accordance with IRB requirements. 
15.5 
Study Records Retention 
Study records and reports, including, but not limited to, eCRFs, source documents, ICFs, and 
study drug disposition records shall be maintained for 2 years after a marketing application is 
approved for the drug for the indication for which it is being investigated; or, if no application is 
to be filed or if the application is not approved for the drug, until 2 years after the investigation is 
discontinued and the FDA has been notified. These documents will be retained for a longer 
period, however, if required by local regulations. ICFs for future research use will be maintained 
as long as the sample/specimen exists. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site PI when these documents no longer need to be retained. The 
participating VTEU sites must contact DMID for authorization prior to the destruction of any 
study records. 
15.6 
Protocol Deviations 
A protocol deviation is any noncompliance with the study protocol, GCP or protocol-specific 
MOP requirements. The noncompliance may be either on the part of the subject, the site PI or 
other study personnel. As a result of protocol deviations, corrective actions are to be developed 
by the site and implemented promptly. 
These practices are consistent with ICH E6 GCP guidelines: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2 and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1 and 5.20.2 
It is the responsibility of the site PI and other study personnel to use continuous vigilance to 
identify and report protocol deviations within five working days of identification of the protocol 
deviation, or within five working days of the scheduled protocol-required activity. Protocol 
deviations must be promptly reported to DMID, via the SDCC’s AdvantageEDCSM. 
Protocol deviations, as defined above, must be addressed on the appropriate DCF. A completed 
copy of the Protocol Deviation DCF must be maintained in the regulatory file as well as in the 


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subject’s chart. Protocol deviations must be sent to the IRB in accordance with IRB 
requirements. The site PI and other study personnel are responsible for knowing and adhering to 
IRB requirements. 
 


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16 
PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic 
version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made 
publicly available no later than 12 months after the official date of publication. The NIH Public 
Access Policy ensures the public has access to the published results of NIH funded research. It 
requires all investigators to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 12 
months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this clinical trial, the responsible party is DMID which will register this trial and post results. 
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 
 


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17 
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Leroux-Roels, I., et al., Antigen sparing and cross-reactive immunity with an adjuvanted 
rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet, 
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113 
35. 
McElhaney, J.E., et al., AS03-adjuvanted versus non-adjuvanted inactivated trivalent 
influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised 
trial. Lancet Infect Dis, 2013. 13(6): p. 485-96. 
36. 
Vogel, F.R., et al., Emulsion-based adjuvants for influenza vaccines. Expert Rev 
Vaccines, 2009. 8(4): p. 483-92. 
37. 
Choe, Y.J., G.R. Bae, and D.H. Lee, No association between influenza A(H1N1)pdm09 
vaccination and narcolepsy in South Korea: an ecological study. Vaccine, 2012. 30(52): 
p. 7439-42. 
38. 
Dauvilliers, Y., et al., Increased risk of narcolepsy in children and adults after pandemic 
H1N1 vaccination in France. Brain, 2013. 136(Pt 8): p. 2486-96. 
39. 
Eurosurveillance editorial, t., Swedish Medical Products Agency publishes report from a 
case inventory study on Pandemrix vaccination and development of narcolepsy with 
cataplexy. Euro Surveill, 2011. 16(26). 
40. 
Force, N.N.T., Increased risk of narcolepsy observed also among adults vaccinated with 
Pandemrix in Finland. N.I.f.H.a.W.T. Finland, Editor. 2013. 
41. 
Miller, E., et al., Risk of narcolepsy in children and young people receiving AS03 
adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ, 
2013. 346: p. f794. 
42. 
Montplaisir, J., et al., Risk of narcolepsy associated with inactivated adjuvanted (AS03) 
A/H1N1 (2009) pandemic influenza vaccine in Quebec. PLoS One, 2014. 9(9): p. 
e108489. 
43. 
Nohynek, H., et al., AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase 
in the incidence of childhood narcolepsy in Finland. PLoS One, 2012. 7(3): p. e33536. 
44. 
O'Flanagan, D., et al., Investigation of an association between onset of narcolepsy and 
vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. Euro 
Surveill, 2014. 19(17): p. 15-25. 
45. 
Wijnans, L., et al., The incidence of narcolepsy in Europe: before, during, and after the 
influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine, 2013. 31(8): p. 
1246-54. 
46. 
Chen, W.H., et al., Safety, Reactogenicity, and Immunogenicity of Inactivated 
Monovalent Influenza A(H5N1) Virus Vaccine Administered With or Without AS03 
Adjuvant. Open Forum Infect Dis, 2014. 1(3): p. ofu091. 
47. 
El Sahly, H.M. and D.N. NIH, A Phase II Randomized, Partially-Blinded, Controlled, 
Trial in Healthy Adults Aged 65 Years and Older to Assess the Safety, Reactogenicity, 
and Immunogenicity of an MF59-Adjuvanted, Monovalent Inactivated Influenza A/H7N9 
Virus Vaccine Administered Intramuscularly at Different Intervals and Dosages. 
48. 
Jackson, L.A., et al., Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine 
With and Without AS03 and MF59 Adjuvants on Immune Response: A Randomized 
Clinical Trial. JAMA, 2015. 314(3): p. 237-46. 
49. 
Jackson, L.A., et al., Immunogenicity and safety of varying dosages of a monovalent 2009 
H1N1 influenza vaccine given with and without AS03 adjuvant system in healthy adults 
and older persons. J Infect Dis, 2012. 206(6): p. 811-20. 
50. 
Mulligan, M.J., et al., Point-of-Use Mixing of Influenza H5N1 Vaccine and MF59 
Adjuvant for Pandemic Vaccination Preparedness: Antibody Responses and Safety. A 
Phase 1 Clinical Trial. Open Forum Infect Dis, 2014. 1(3): p. ofu102. 


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51. 
Mulligan, M.J., et al., Serological responses to an avian influenza A/H7N9 vaccine mixed 
at the point-of-use with MF59 adjuvant: a randomized clinical trial. JAMA, 2014. 
312(14): p. 1409-19. 
52. 
Lee, Y.J., et al., Novel reassortant influenza A(H5N8) viruses, South Korea, 2014. Emerg 
Infect Dis, 2014. 20(6): p. 1087-9. 
53. 
Wu, H., et al., Novel reassortant influenza A(H5N8) viruses in domestic ducks, eastern 
China. Emerg Infect Dis, 2014. 20(8): p. 1315-8. 
54. 
Gao, R., et al., Human infection with a novel avian-origin influenza A (H7N9) virus. N 
Engl J Med, 2013. 368(20): p. 1888-97. 
55. 
Influenza at the human-animal interface. Summary and Assessment, 26 January to 2 
March 2018. WHO Monthly Influenza Risk Assessment Summary, 2 March, 2018. 
56. 
Analysis of recent scientific information on avian influenza A(H7N9) virus. WHO  
Influenza Update, 2017. 
57. 
Zhou, J., et al., Biological features of novel avian influenza A (H7N9) virus. Nature, 
2013. 499(7459): p. 500-3. 
58. 
Zhu, H., et al., Infectivity, transmission, and pathology of human-isolated H7N9 influenza 
virus in ferrets and pigs. Science, 2013. 341(6142): p. 183-6. 
59. 
Li, Y., et al., Evolving HA and PB2 genes of influenza A (H7N9) viruses in the fifth wave 
- Increasing threat to both birds and humans? J Infect, 2017. 
60. 
Belshe, R.B., et al., Safety and immunogenicity of influenza A H5 subunit vaccines: effect 
of vaccine schedule and antigenic variant. J Infect Dis, 2011. 203(5): p. 666-73. 
61. 
Goji, N.A., et al., Immune responses of healthy subjects to a single dose of intramuscular 
inactivated influenza A/Vietnam/1203/2004 (H5N1) vaccine after priming with an 
antigenic variant. J Infect Dis, 2008. 198(5): p. 635-41. 
62. 
Gillard, P., et al., Long-term booster schedules with AS03A-adjuvanted heterologous 
H5N1 vaccines induces rapid and broad immune responses in Asian adults. BMC Infect 
Dis, 2014. 14: p. 142. 
63. 
Langley, J.M., et al., Immunogenicity of heterologous H5N1 influenza booster 
vaccination 6 or 18 months after primary vaccination in adults: a randomized controlled 
clinical trial. Vaccine, 2015. 33(4): p. 559-67. 
64. 
Madan, A., et al., Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic 
Influenza Vaccine in a Randomized Trial in Healthy Adults. J Infect Dis, 2016. 214(11): 
p. 1717-1727. 
65. 
Lasky, T., et al., The Guillain-Barre syndrome and the 1992-1993 and 1993-1994 
influenza vaccines. N Engl J Med, 1998. 339(25): p. 1797-802. 
66. 
Haber, P., et al., Guillain-Barre syndrome following influenza vaccination. JAMA, 2004. 
292(20): p. 2478-81. 
67. 
De Wals, P., et al., Risk of Guillain-Barre syndrome following H1N1 influenza 
vaccination in Quebec. JAMA, 2012. 308(2): p. 175-81. 
68. 
Juurlink, D.N., et al., Guillain-Barre syndrome after influenza vaccination in adults: a 
population-based study. Arch Intern Med, 2006. 166(20): p. 2217-21. 
69. 
Salmon, D.A., et al., Association between Guillain-Barre syndrome and influenza A 
(H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. Lancet, 
2013. 381(9876): p. 1461-8. 


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70. 
Wise, M.E., et al., Guillain-Barre syndrome during the 2009-2010 H1N1 influenza 
vaccination campaign: population-based surveillance among 45 million Americans. Am 
J Epidemiol, 2012. 175(11): p. 1110-9. 
71. 
Polakowski, L.L., et al., Chart-confirmed guillain-barre syndrome after 2009 H1N1 
influenza vaccination among the Medicare population, 2009-2010. Am J Epidemiol, 
2013. 178(6): p. 962-73. 
72. 
Dodd, C.N., et al., International collaboration to assess the risk of Guillain Barre 
Syndrome following Influenza A (H1N1) 2009 monovalent vaccines. Vaccine, 2013. 
31(40): p. 4448-58. 
73. 
Sullivan, S.S., Narcolepsy in adolescents. Adolesc Med State Art Rev, 2010. 21(3): p. 
542-55, x-xi. 
74. 
CDC, Recommended Immunizations for Adults: By Age. 2017. 
 
 
 


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Appendices 
Appendix A: Schedule of Study Procedures and Evaluations 
Appendix B: Schedule of Special Assays 
Appendix C: List of Potentially Immune-Mediated Medical Conditions 
 
 






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{}Targeted physical examination if indicated based on review of interim medical history. 
^ Performed locally by the site at the screening visit (optional) or within 24 hours prior to each study vaccination for all women of childbearing potential. Results 
must be negative and known prior to randomization on Day 1 and administration of each study vaccination. 
≠ Performed locally by the site at the screening visit (optional) or on Day 1 prior to the first study vaccination. The ESR value must be confirmed as less than 30 
mm per hour prior to randomization on Day 1 and administration of the first study vaccination. 
~ Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
# Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
Ψ Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone 
call rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a 
venous blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
& Inclusive of reactogenicity assessments performed on the day of each study vaccination through 7 days after each study vaccination. 
4 AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued from receipt of the second study vaccination and 
being followed for safety. 
 
 
 


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Table 16: Follow-Up Period for Treatment Arms 1 and 4 (Including Early Termination and Unscheduled Visits) 
Study Visit Number 
V12** 
V13 
V14** 
V15 
V16** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D82 
D112 
D142 
D202 
D387 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Medical History@ 
 
X 
 
X 
 
X 
X (if indicated) 
Concomitant Medicationsς 
X 
X 
X 
X 
 
X (if prior to 21 days 
after last study 
vaccination and receipt 
of any non-study 
influenza vaccines if 
within 180 days after 
last study vaccination) 
X (if prior to 21 days 
after last study 
vaccination and receipt 
of any non-study 
influenza vaccines if 
within 180 days after last 
study vaccination) 
Vital Signs (Oral Temperature%, Pulse and BP) 
 
 
 
 
 
X (may be obtained if 
indicated) 
X (may be obtained if 
indicated) 
Physical Examination 
 
{X} 
 
{X} 
 
{X} 
{X} 
Venous Blood Collection for Clinical Safety Laboratory Evaluations~ 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if indicated) 
Venous Blood Collection for Serological Assays 
 
 
 
XΨ 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days after 
last study vaccination) 
Venous Blood Collection for Cellular Immunology Assays 
 
X 
 
X 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days after 
last study vaccination) 
Venous Blood Collection for Future Research 
 
X 
 
X 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days after 
last study vaccination) 
Examine Study Vaccination Site 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days after 
last study vaccination) 


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Study Visit Number 
V12** 
V13 
V14** 
V15 
V16** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D82 
D112 
D142 
D202 
D387 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Post-Administration Reactogenicity Assessments 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days after 
last study vaccination) 
Review Memory Aid 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days after 
last study vaccination) 
AE/SAE Assessment! 
X 
X 
X 
X 
X 
X (if after 21 days after 
last study vaccination) 
X (if after 21 days after 
last study vaccination) 
**Phone call assessment. 
@ Complete medical history will be obtained by interview of subjects at the screening visit (optional) or on Day 1 prior to the first study vaccination, and interim 
medical history will be obtained by interview of subjects at follow-up visits after the first study vaccination. 
ς Receipt of any non-study influenza vaccines will be solicited through approximately 180 days after the last study vaccination, and reported in the eCRF. 
% Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
{}Targeted physical examination if indicated based on review of interim medical history. 
~ Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
Ψ Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone 
call rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a 
venous blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
! AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or phone call. 
 
 
 






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3 At the screening visit (optional) or on Day 1 prior to the first study vaccination, a physical examination will be performed on all subjects to include the 
following organs and organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, and nervous system, and as an assessment for 
signs suggestive of PIMMCs. 
{}Targeted physical examination if indicated based on review of interim medical history. 
^ Performed locally by the site at the screening visit (optional) or within 24 hours prior to each study vaccination for all women of childbearing potential. Results 
must be negative and known prior to randomization on Day 1 and administration of each study vaccination. 
≠ Performed locally by the site at the screening visit (optional) or on Day 1 prior to the first study vaccination. The ESR value must be confirmed as less than 30 
mm per hour prior to randomization on Day 1 and administration of the first study vaccination. 
~ Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
# Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
Ψ Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone 
call rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a 
venous blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
& Inclusive of reactogenicity assessments performed on the day of each study vaccination through 7 days after each study vaccination. 
! AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or phone call. 
4 AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued from receipt of the second study vaccination and 
being followed for safety. 
 
 
 


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Table 18: Follow-Up Period for Treatment Arms 2, 3, 5, and 6 (Including Early Termination and Unscheduled Visits) 
Study Visit Number 
V14** 
V15 
V16** 
V17 
V18** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D181 
D211 
D241 
D301 
D486 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Medical History@ 
 
X 
 
X 
 
X 
X (if indicated) 
Concomitant Medicationsς 
X 
X 
X 
X 
 
X (if prior to 21 days 
after last study 
vaccination and receipt 
of any non-study 
influenza vaccines if 
within 180 days after 
last study vaccination) 
X (if prior to 21 days 
after last study 
vaccination and receipt 
of any non-study 
influenza vaccines if 
within 180 days after last 
study vaccination) 
Vital Signs (Oral Temperature%, Pulse and BP) 
 
 
 
 
 
X (may be obtained if 
indicated) 
X (may be obtained if 
indicated) 
Physical Examination 
 
{X} 
 
{X} 
 
{X} 
{X} 
Venous Blood Collection for Clinical Safety Laboratory Evaluations~ 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if indicated) 
Venous Blood Collection for Serological Assays 
 
 
 
XΨ 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days after 
last study vaccination) 
Venous Blood Collection for Cellular Immunology Assays 
 
X 
 
X 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days after 
last study vaccination) 
Venous Blood Collection for Future Research 
 
X 
 
X 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days after 
last study vaccination) 
Examine Study Vaccination Site 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days after 
last study vaccination) 


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Study Visit Number 
V14** 
V15 
V16** 
V17 
V18** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D181 
D211 
D241 
D301 
D486 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Post-Administration Reactogenicity Assessments 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days after 
last study vaccination) 
Review Memory Aid 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days after 
last study vaccination) 
AE/SAE Assessment! 
X 
X 
X 
X 
X 
X (if after 21 days after 
last study vaccination) 
X (if after 21 days after 
last study vaccination) 
**Phone call assessment. 
@ Complete medical history will be obtained by interview of subjects at the screening visit (optional) or on Day 1 prior to the first study vaccination, and interim 
medical history will be obtained by interview of subjects at follow-up visits after the first study vaccination. 
ς Receipt of any non-study influenza vaccines will be solicited through approximately 180 days after the last study vaccination, and reported in the eCRF. 
% Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
{}Targeted physical examination if indicated based on review of interim medical history. 
~ Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
Ψ Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone 
call rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a 
venous blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
! AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or phone call. 
 






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^ Drawn up to 28 days prior to the first study vaccination. The ESR value must be confirmed as less than 30 mm per hour prior to randomization and first study 
vaccination. 
* Not required if done at the optional screening visit. 
~ Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
# Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
† Blood must be drawn immediately prior to study vaccination. 
@ All sites will collect venous blood for this assay. Specified sites will utilize freshly isolated PBMCs. All other sites will process for frozen PBMCs. 
1 Specified sites only. 
2 Sites processing only for Plasma/PBMCs. 
3 All sites. 
 
 
 
Breakdown of Future Research Samples 
‘Omics (Plasma/PBMCs) – 
specified sites only 
 
12 
12 
12 
12 
 
12 
12 
12 
12 
 
 
 
 
96 
Serum – all sites 
 
 
 
 
5 
 
 
 
 
5 
 
 
 
 
10 
Plasma/PBMCs 
 
41 or 
162 
41 or 
162 
41 or 
162 
41 or 
162 
163 
41 or 
162 
41 or 
162 
41 or 
162 
41 or 
162 
163 
163 
163 
163 
1121 
or 
2082 
Per Visit Blood Volume (BV) Totals 
Per Visit CIA/FR Blood 
Volume Total (mL) 
 
80 
20 
24 
65 
24 
48 
20 
24 
65 
24 
16 
56 
48 
514 
Per Visit Blood Volume 
Total (mL) 
4 
105 
20 
24 
75 
24 
73 
20 
24 
75 
24 
31 
56 
63 
618 
Running Blood Volume Totals 
Running Blood Volume 
Total (mL) 
4 
109 
129 
153 
228 
247 
320 
340 
364 
444 
458 
489 
545 
618 
 




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^ Drawn up to 28 days prior to the first study vaccination. The ESR value must be confirmed as less than 30 mm per hour prior to randomization and first study 
vaccination. 
* Not required if done at the optional screening visit. 
~ Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
# Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
† Blood must be drawn immediately prior to study vaccination. 
@ All sites will collect venous blood for this assay. Specified sites will utilize freshly isolated PBMCs. All other sites will process for frozen PBMCs. 
1 Specified sites only. 
2 Sites processing only for Plasma/PBMCs. 
3 All sites. 
 
 
B Cell Receptor 
Somatic 
Hypermutation and 
Repertoire 
Assessments 
 
16† 
 
 
 
 
 
 
 
 
 
 
 
 
16 
32 
Future Research (FR) 
Future Research 
 
16† 
16 
16 
21 
16 
16 
16† 
16 
16 
21 
16 
16 
16 
16 
234 
Breakdown of Future Research Samples 
‘Omics 
(Plasma/PBMCs) – 
specified sites only 
 
12 
12 
12 
12 
 
 
12 
12 
12 
12 
 
 
 
 
96 
Serum – all sites 
 
 
 
 
5 
 
 
 
 
 
5 
 
 
 
 
10 
Plasma/PBMCs 
 
41 
or 
162 
41 
or 
162 
41 
or 
162 
41 or 
162 
163 
163 
41 or 
162 
41 or 
162 
41 or 
162 
41 or 
162 
163 
163 
163 
163 
1281 
or 
2242 
Per Visit Blood Volume (BV) Totals 
Per Visit CIA/FR 
Blood Volume Total 
(mL) 
 
80 
20 
24 
65 
24 
16 
48 
20 
24 
65 
24 
16 
56 
48 
530 
Per Visit Blood 
Volume Total (mL) 
4 
105 
20 
24 
75 
24 
31 
73 
20 
24 
75 
24 
31 
56 
63 
649 
Running Blood Volume Totals 
Running Blood 
Volume Total (mL) 
4 
109 
129 
153 
228 
247 
278 
351 
371 
395 
475 
489 
520 
576 
649 
 


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APPENDIX C. LIST OF POTENTIALLY IMMUNE-MEDIATED 
MEDICAL CONDITIONS 
(also known as Adverse Events of Special Interest [AESIs]) 
 
Gastrointestinal disorders 
• 
Celiac disease 
• 
Crohn’s disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
Liver disorders 
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
Metabolic diseases 
• 
Addison’s disease 
• 
Autoimmune thyroiditis (including Hashimoto thyroiditis) 
• 
Diabetes mellitus type I 
• 
Grave’s or Basedow’s disease 
Musculoskeletal disorders 
• 
Antisynthetase syndrome 
• 
Dermatomyositis 
• 
Juvenile chronic arthritis (including Still’s disease) 
• 
Mixed connective tissue disorder 
• 
Polymyalgia rheumatic 
• 
Polymyositis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Rheumatoid arthritis 
• 
Scleroderma, including diffuse systemic form and CREST syndrome 
• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s Syndrome) 
and undifferentiated spondyloarthritis 
• 
Systemic lupus erythematosus 
• 
Systemic sclerosis 


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Neuroinflammatory disorders 
• 
Acute disseminated encephalomyelitis, including site-specific variants (e.g., non-
infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis) 
• 
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 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse myelitis 
• 
Myasthenia gravis, including Eaton-Lambert syndrome 
Skin disorders 
• 
Alopecia areata 
• 
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis 
herpetiformis 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Morphoea 
• 
Lichen planus 
• 
Psoriasis 
• 
Sweet’s syndrome 
• 
Vitiligo 
Vasculitides 
• 
Large vessels vasculitis including: giant cell arteritis such as Takayasu’s arteritis and 
temporal arteritis 
• 
Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, Kawasaki’s 
disease, microscopic polyangiitis, Wegener’s granulomatosis, Churg-Strauss syndrome 
(allergic granulomatous angiitis), Buerger’s disease thromboangiitis obliterans, 
necrotizing vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch- Schonlein purpura, Behcet’s syndrome, 
leukocytoclastic vasculitis 
 
 


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December 18, 2019 
 
134 
Others 
• 
Antiphospholipid syndrome 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, 
and mesangioproliferative glomerulonephritis) 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Autoimmune thrombocytopenia 
• 
Good pasture syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Pernicious anemia 
• 
Raynaud’s phenomenon 
• 
Sarcoidosis 
• 
Sjögren’s syndrome 
• 
Stevens-Johnson syndrome 
• 
Uveitis 
 

SAP_001.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 17-0078 
A Phase II Study to Assess the Safety, Reactogenicity and Immunogenicity of Different 
Prime-Boost Vaccination Schedules of 2013 and 2017 A/H7N9 Inactivated Influenza 
Vaccines Administered Intramuscularly with or without AS03 Adjuvant in Healthy 
Adults  
19-50 Years of Age 
 
17-0078: NCT03589807 
 
Version 1.0 
 
DATE: 18 March 2021 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


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STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 17-0078 
Development Phase: 
Phase II 
Products: 
Sanofi 2013 and 2017 A/H7N9 Inactivated Influenza Vaccines 
GSK AS03 Adjuvant 
Patheon Manufacturing Services (PBS) diluent 
Form/Route: 
IM 
Indication Studied: 
Influenza A/H7N9 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
August 21, 2018 
Clinical Trial Completion Date: 
March 12, 2020 
Date of the Analysis Plan: 
March 18, 2021 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is 
confidential. This information may not be disclosed to third parties without written authorization from Division of 
Microbiology and Infectious Diseases. This report may not be reproduced, stored in a retrieval system or transmitted 
in any form or by any means - electronic, mechanical, recording or otherwise - without the prior authorization from 
Division of Microbiology and Infectious Diseases. This document must be returned to Division of Microbiology and 
Infectious Diseases upon request. 
 


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TABLE OF CONTENTS 
STUDY TITLE ................................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
PREFACE .....................................................................................................................8 
2. 
INTRODUCTION ........................................................................................................9 
2.1. 
Purpose of the Analyses ................................................................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
3.1. 
Study Objectives .........................................................................................................10 
3.1.1. 
Primary .......................................................................................................................10 
3.1.2. 
Secondary ...................................................................................................................10 
3.1.3. 
Exploratory .................................................................................................................10 
3.2. 
Endpoints ....................................................................................................................11 
3.2.1. 
Primary .......................................................................................................................11 
3.2.2. 
Secondary ...................................................................................................................11 
3.2.3. 
Exploratory .................................................................................................................12 
3.3. 
Study Definitions and Derived Variables ...................................................................13 
4. 
INVESTIGATIONAL PLAN .....................................................................................14 
4.1. 
Overall Study Design and Plan ...................................................................................14 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ......................14 
4.3. 
Selection of Study Population ....................................................................................15 
4.4. 
Treatments ..................................................................................................................15 
4.4.1. 
Treatments Administered ............................................................................................15 
4.4.2. 
Identity of Investigational Product(s) .........................................................................15 
4.4.3. 
Method of Assigning Subjects to Study Groups (Randomization) ............................15 
4.4.4. 
Selection of Doses in the Study ..................................................................................15 
4.4.5. 
Selection and Timing of Dose for Each Subject .........................................................15 
4.4.6. 
Blinding ......................................................................................................................16 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................16 
4.4.8. 
Treatment Compliance ................................................................................................16 
4.5. 
Immunogenicity and Safety Variables ........................................................................16 
4.5.1. 
Safety Variables ..........................................................................................................16 
4.5.2. 
Immunogenicity Variables ..........................................................................................17 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................19 


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6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................20 
6.1. 
General Principles .......................................................................................................20 
6.2. 
Timing of Analyses .....................................................................................................20 
6.2.1. 
CSR .............................................................................................................................20 
6.3. 
Analysis Populations ..................................................................................................21 
6.3.1. 
Safety Population ........................................................................................................21 
6.3.2. 
Modified Intent-to-Treat (mITT) Population ..............................................................21 
6.3.3. 
Per Protocol Population ..............................................................................................21 
6.4. 
Covariates and Subgroups ..........................................................................................23 
6.5. 
Missing Data ...............................................................................................................23 
6.6. 
Interim Analyses and Data Monitoring ......................................................................23 
6.6.1. 
Interim Safety Review ................................................................................................23 
6.6.2. 
Interim Immunogenicity Review ................................................................................24 
6.7. 
Multicenter Studies .....................................................................................................24 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................24 
7. 
STUDY SUBJECTS ...................................................................................................25 
7.1. 
Disposition of Subjects ...............................................................................................25 
7.2. 
Protocol Deviations ....................................................................................................25 
8. 
IMMUNOGENICITY EVALUATION .....................................................................26 
8.1. 
Primary Immunogenicity Analysis .............................................................................26 
8.2. 
Secondary Immunogenicity Analyses ........................................................................26 
8.3. 
Exploratory Immunogenicity Analyses ......................................................................26 
8.3.1. 
HAI and Neut Covariate Analysis ..............................................................................27 
8.3.2. 
HAI and Neut Regression Modeling ..........................................................................27 
8.3.3. 
Antibody Secreting Cells (Plasmablasts) ....................................................................28 
8.3.4. 
Other Assays ...............................................................................................................28 
9. 
SAFETY EVALUATION ..........................................................................................29 
9.1. 
Demographic and Other Baseline Characteristics ......................................................29 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................29 
9.1.2. 
Prior and Concomitant Medications ...........................................................................29 
9.2. 
Measurements of Treatment Compliance ...................................................................29 
9.3. 
Adverse Events ...........................................................................................................30 


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9.3.1. 
Solicited Events and Symptoms .................................................................................30 
9.3.2. 
Unsolicited Adverse Events ........................................................................................31 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................31 
9.5. 
Pregnancies .................................................................................................................32 
9.6. 
Clinical Laboratory Evaluations .................................................................................32 
9.7. 
Vital Signs and Physical Evaluations .........................................................................32 
9.8. 
Concomitant Medications ...........................................................................................33 
10. 
REPORTING CONVENTIONS ................................................................................34 
11. 
TECHNICAL DETAILS ............................................................................................35 
12. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................36 
13. 
REFERENCES ...........................................................................................................37 
14. 
APPENDICES ............................................................................................................38 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................39 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................160 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................178 


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LIST OF ABBREVIATIONS 
2013 A/H7N9 
Influenza A Virus A/Shanghai/2/2013 
2017 A/H7N9 
Influenza A Virus A/Hong Kong/125/2017 
A/H7N9 
Influenza A Virus of the H7N9 Subtype 
AE 
Adverse Event/ Adverse Experience 
AESIs 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase 
ASC 
Antibody-Secreting Cells 
AS03 
Adjuvant System (03) 
BMI 
Body Mass Index 
BP 
Blood Pressure  
C 
Celsius 
CI 
Confidence Interval 
Cr 
Creatinine 
CRF 
Case Report Form 
°C 
Degrees Celsius 
CSR 
Clinical Study Report 
DC 
Dendritic Cells 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-Linked Immunosorbent Assay 
ELLA 
Enzyme-Linked Lectin Assay 
ESR 
Erythrocyte Sedimentation Rate 
°F 
Degrees Fahrenheit 
FDA 
U.S. Food and Drug Administration 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline Biologicals 
HAI 
Hemagglutination Inhibition Antibody 
Hgb 
Hemoglobin 
DHHS 
Department of Health and Human Services 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IgA 
Immunoglobulin A 


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IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IIV 
Inactivated Influenza Vaccine 
IM 
Intramuscularly 
IRB 
Institutional Review Board 
L 
Liter 
MAAE 
Medically Attended Adverse Event 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
mITT 
Modified Intent-to-Treat 
N, n 
Number of Subjects 
NA 
Neuraminidase 
NAI 
Neuraminidase Inhibition 
Neut 
Neutralizing Antibody 
NIH 
National Institutes of Health 
NK 
Natural Killer 
NOCMC 
New Onset Chronic Medical Condition 
PBS 
Phosphate Buffered Saline 
PIMMC 
Potentially Immune Mediated Medical Condition 
PP 
Per Protocol 
PLT 
Platelets 
PT 
Preferred Term 
RCD 
Reverse Cumulative Distribution  
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
SP 
Sanofi Pasteur 
T. Bili 
Total Bilirubin 
VTEU 
Vaccine and Treatment Evaluation Unit 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) DMID Protocol 17-0078, “A Phase II Study to Assess the Safety, 
Reactogenicity and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 
A/H7N9 Inactivated Influenza Vaccines Administered Intramuscularly with or without AS03 Adjuvant in 
Healthy Adults 19-50 Years of Age” describes and expands upon the statistical information presented in the 
protocol. 
This document describes all planned analyses and provides reasons and justifications for these analyses. It 
also includes sample tables, listings, and figures (TFLs) planned for (1) final analyses included in the topline 
set, and (2) analyses included in the Clinical Study Report (CSR). Regarding the final analyses and Clinical 
Study Report (CSR), this SAP follows the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, as indicated in Topic E3 
(Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 (General 
Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). The structure and 
content of the SAP provides sufficient detail to meet the requirements identified by the FDA and ICH, while 
all work planned and reported for this SAP will follow internationally accepted guidelines published by the 
American Statistical Association and the Royal Statistical Society for statistical practice. 
This document contains four sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for immunogenicity and safety outcomes, and (4) a list of 
proposed TFLs. Following any protocol amendment, this SAP will be reviewed and revised (if needed) to 
address any changes in the protocol impacting analysis. Any deviation from the final SAP will be described 
and justified in the CSR. The reader of this SAP is encouraged to also review the study protocol for details on 
conduct of the study and the operational aspects of clinical assessments. 
 


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2. 
INTRODUCTION 
Since March of 2013 [1], avian influenza A/H7N9 viruses have continued to circulate in China causing 
discrete outbreaks (or waves) in humans with high mortality over the past 5 years. By late 2016, a fifth wave 
of outbreaks was identified in China and as of May 18, 2017, a total of 1,463 laboratory-confirmed human 
infections with avian influenza A/H7N9 virus have been reported by the World Health Organization [2, 3]. 
Since the onset of the fifth wave of H7N9 outbreaks in October 2016, more human cases of H7N9 infection 
have been reported in China than any prior H7N9 epidemic wave [3]. The U.S. Department of Health and 
Human Services (DHHS) recently assessed H7N9 influenza virus as having a significant potential to cause a 
pandemic, and the greatest risk of causing severe disease. As a result, DHHS has supported the production of 
fifth wave A/H7N9 inactivated influenza vaccines (IIVs) for the U.S. stockpile and for an assessment of their 
safety and immunogenicity in clinical trials. 
The goal of this trial is to assess in healthy adults the safety, reactogenicity, and immunogenicity  of one or 
two vaccinations of  2013 and 2017 A/H7N9 (influenza A viruses A/Shanghai/2/2013 and A/Hong 
Kong/125/2017, respectively) IIVs administered intramuscularly at different dosages (3.75 or 15 mcg of 
hemagglutinin (HA) per dose), given with or without AS03 adjuvant, using different heterologous and 
homologous prime-boost vaccination schedules to evaluate  the study vaccine dosage, dose-sparing potential 
of the adjuvant, optimal prime-boost interval for immunogenicity (two doses administered 21 days vs.  
4 months apart), and priming effects of different A/H7N9 IIVs. In addition to assessing antigen-sparing 
strategies, another goal of this study is to assess in at least a subset of samples, if serum immunoglobulin 
elicited by the 2013 and 2017 A/H7N9 IIVs recognize antigenically drifted variants of influenza A/H7 
viruses. 
2.1. 
Purpose of the Analyses 
These analyses will assess the immunogenicity and safety of two vaccinations of 2013 and 2017 A/H7N9 IIVs 
administered IM either approximately 21 days or approximately 4 months apart with or without AS03 
adjuvant and will be included in the topline set of tables and/or clinical study report.  


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary 
Safety: 
• To assess the safety and reactogenicity of 2013 and 2017 A/H7N9 IIVs given with or without 
AS03 adjuvant following receipt of each study vaccine. 
Immunogenicity: 
• To assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody responses 
following receipt of the second study vaccine. 
3.1.2. 
Secondary 
Safety: 
• To assess unsolicited non-serious adverse events (AEs) following receipt of each study vaccine. 
• To assess medically attended adverse events (MAAEs), including new-onset chronic medical 
conditions (NOCMCs) and potentially immune-mediated medical conditions (PIMMCs), 
following receipt of each study vaccine. 
Immunogenicity: 
• To assess the kinetics and durability of serum HAI and Neut antibody responses following receipt 
of each study vaccine. 
3.1.3. 
Exploratory 
Immunogenicity: 
• To assess the effects of age, sex, body mass index (BMI), and prior receipt of seasonal or non-
study pandemic influenza vaccine(s) on serum HAI and Neut antibody responses following receipt 
of the second study vaccine. 
• To assess the neuraminidase (NA) content of the 2013 and 2017 A/H7N9 IIVs and determine, in at 
least a subset of samples, the serum antibody responses to N9 NA. 
• To assess, in at least a subset of samples, HA stem-specific antibody responses. 
• To assess, in at least a subset of samples, the cross-reactivity of serum HAI and Neut antibody 
responses to antigenically drifted variants of influenza A/H7 viruses. 
• To assess, in at least a subset of samples, the frequency of influenza-specific (A/H7N9 antigens) 
IgA, IgG and IgM memory B cells (MBCs). 
• To assess, in at least a subset of samples, the frequency of influenza-specific (A/H7N9 antigens) 
IgA, IgG and IgM plasmablasts (antibody-secreting cells [ASCs]). 
• To assess, in at least a subset of samples, the multifunctional cytokine/chemokine profile of 
influenza A/H7N9-specific CD4 and CD8 T cells. 


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• To assess, in at least a subset of samples, the characterization of circulating T follicular helper 
(cTFH) cells. 
• To assess, in at least a subset of samples, the study vaccine-induced changes in populations and/or 
activation status of innate immune cells (monocytes, dendritic cells [DCs] and natural killer [NK] 
cells). 
• To assess, in at least a subset of samples, the study vaccine-induced activation status of B cells. 
• To assess, in at least a subset of samples, the B cell receptor repertoire and degree of somatic 
hypermutation generated in response to study vaccination. 
3.2. 
Endpoints 
3.2.1. 
Primary 
Safety: 
• Occurrence of all serious adverse events (SAEs) from the time of the first study vaccination 
through approximately 12 months after the last study vaccination. 
• Occurrence of solicited injection site and systemic reactogenicity events from the time of each 
study vaccination through 7 days after each study vaccination. 
• Occurrence of clinical safety laboratory AEs from the time of each study vaccination through 
approximately 7 days after each study vaccination. 
Immunogenicity: 
• For HAI and Neut antibodies, percentage of subjects achieving seroconversion against the 
influenza A/H7N9 study vaccine viruses (defined as either a pre-vaccination titer <1:10 and a post-
vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and a minimum four-fold rise in post-
vaccination antibody titer) approximately 21 days after the second study vaccination. 
• For HAI and Neut antibodies, percentage of subjects achieving titer ≥1:40 against the influenza 
A/H7N9 study vaccine viruses approximately 21 days after the second study vaccination. 
• Geometric mean titers (GMTs) of serum HAI and Neut antibodies against the influenza A/H7N9 
study vaccine viruses approximately 21 days after the second study vaccination. 
3.2.2. 
Secondary 
Safety: 
• Occurrence of all unsolicited non-serious AEs from the time of each study vaccination through 
approximately 21 days after each study vaccination. 
• Occurrence of all MAAEs, including NOCMCs and PIMMCs, from the time of the first study 
vaccination through approximately 12 months after the last study vaccination. 
Immunogenicity: 
• For HAI and Neut antibodies, percentage of subjects achieving seroconversion against the 
influenza A/H7N9 study vaccine viruses approximately 21 days after the first study vaccination as 
well as immediately prior to and approximately 180 days after the second study vaccination. 


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• For HAI and Neut antibodies, percentage of subjects achieving titer ≥1:40 against the influenza 
A/H7N9 study vaccine viruses immediately prior to each study vaccination, approximately 21 days 
after the first study vaccination and approximately 180 days after the second study vaccination. 
• GMTs of serum HAI and Neut antibodies against the influenza A/H7N9 study vaccine viruses 
immediately prior to each study vaccination, approximately 21 days after the first study 
vaccination and approximately 180 days after the second study vaccination. 
3.2.3. 
Exploratory 
Immunogenicity: 
• For HAI and Neut antibodies, GMTs and percentage of subjects achieving seroconversion against 
the influenza A/H7N9 study vaccine viruses approximately 21 days after the second study 
vaccination, by age, sex, BMI, and prior receipt of seasonal or non-study pandemic influenza 
vaccine(s). 
• GMTs and percentage of subjects achieving seroconversion (defined as four-fold change from 
baseline) of serum anti-NA (by enzyme-linked immunosorbent assay [ELISA]) or anti-
neuraminidase inhibition (NAI) (by enzyme-linked lectin assay [ELLA]) antibodies immediately 
prior to and approximately 21 days after each study vaccination as well as approximately 180 days 
after the second study vaccination. 
• Correlate the HA and/or NA content of 2013 and 2017 A/H7N9 IIVs with the elicited HA or N9 
NA-specific antibody titer approximately 21 days after each study vaccination as well as 
immediately prior to and approximately 180 days after the second study vaccination. 
• GMTs of HA stem-specific antibody immediately prior to and approximately 21 days after each 
study vaccination as well as approximately 180 days after the second study vaccination. 
• For HAI and Neut antibodies, GMTs and percentage of subjects achieving seroconversion against 
antigenically drifted variants of influenza A/H7 viruses approximately 21 days after the second 
study vaccination. 
• Percentage of influenza-specific (A/H7N9 antigens) IgA, IgG and IgM MBCs at baseline and 
approximately 90 and 180 days after the second study vaccination. 
• Frequency of influenza-specific (A/H7N9 antigens) IgA, IgG and IgM plasmablasts (ASCs) 
present in circulation approximately 7 days after each study vaccination. 
• Percentage of influenza A/H7N9-specific CD4 and CD8 T cells producing cytokines/chemokines 
immediately prior to and approximately 7 days after each study vaccination as well as 
approximately 90 days after the second study vaccination. 
• Percentage of cTFH cells producing cytokines/chemokines immediately prior to and approximately 
3, 7 and 14 days after each study vaccination. 
• Percentage and activation status of innate immune cells (monocytes, DCs and NK cells) 
immediately prior to and approximately 1, 3, 7 and 14 days after each study vaccination. 
• Percentage of activated B cells immediately prior to and approximately 1, 3, 7 and 14 days after 
each study vaccination. 


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• Evaluation of B cell receptor repertoire and degree of somatic hypermutation of anti-HA (H7) and 
anti-NA (N9) antibodies at baseline and approximately 180 days after the second study 
vaccination. 
• Correlation of the above exploratory immunologic parameters with HAI and Neut antibodies. 
3.3. 
Study Definitions and Derived Variables  
For individual subjects, fold rise will be calculated as the ratio of: 
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
𝑝𝑝𝑝𝑝𝑝𝑝−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡, where pre-vaccination 
value is always the result obtained at Day 1, prior to the priming vaccination. 
HAI Seroconversion is defined as either a pre-vaccination HAI titer <10 and a post-vaccination HAI titer ≥40 
or a pre-vaccination HAI titer ≥10 and a minimum four-fold rise in post-vaccination HAI titer [5]. 
Neut Seroconversion is defined as either a pre-vaccination Neut titer <1:10 and a post-vaccination Neut titer 
≥1:40 or a pre-vaccination Neut titer ≥1:10 and a minimum four-fold rise in post-vaccination Neut antibody 
titer. 
 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
DMID Protocol 17-0078 follows a Phase II randomized, partially-blinded study design enrolling males and 
non-pregnant females aged 19 to 50 years of age, inclusive, who are in good health as determined by medical 
history and physical examination, and meet all eligibility criteria, including erythrocyte sedimentation rate 
(ESR), hematology, and biochemistry parameter within acceptable range, and negative urine or serum 
pregnancy test (for females). This clinical trial is designed to assess the safety, reactogenicity and 
immunogenicity of one or two vaccinations of monovalent inactivated split influenza 2013 and 2017 A/H7N9 
virus vaccines (2013 and 2017 A/H7N9 IIVs) manufactured by Sanofi Pasteur (SP), administered 
intramuscularly at different dosages (3.75 or 15 mcg of HA per dose), given with or without AS03 adjuvant 
manufactured by GlaxoSmithKline Biologicals (GSK), using different heterologous and homologous prime-
boost vaccination schedules.   
Subjects will be randomly assigned to 1 of 6 study groups with equal allocation 1:1:1:1:1:1 (see Table 1). 
Subjects assigned to Groups 1, 2, and 3 will receive an adjuvanted 2013 A/H7N9 IIV on Day 1 while those in 
Groups 4, 5, and 6 receive an adjuvanted 2017 A/H7N9 IIV on Day 1. Subjects assigned to Groups 1 and 4 
will return approximately 21 days after their first vaccination to receive an adjuvanted 2017 A/H7N9 IIV. 
Subjects assigned to Groups 2,3,5, and 6 will return approximately after 120 days to receive their second 
vaccination of 2017 A/H7N9 IIV with or without AS03.  
Reactogenicity will be measured by the occurrence of solicited injection site and systemic reactions from the 
time of each study vaccination through 7 days after each study vaccination. Unsolicited non-serious AEs will 
be collected from the time of each study vaccination through approximately 21 days after each study 
vaccination. SAEs and MAAEs, including NOCMCs and PIMMCs, will be collected from the time of the first 
study vaccination through approximately 12 months after the last study vaccination. Clinical laboratory 
evaluations for safety will be performed on venous blood collected prior to each study vaccination and 
approximately 7 days after each study vaccination. 
Immunogenicity testing will include performing HAI and Neut antibody assays against the influenza A/H7N9 
study vaccine viruses on serum samples collected immediately on Day 1, Day 22 post vaccination 1, Day 121 
post vaccination 1 for study groups 2,3,5,6, and on approximately Day 181 post vaccination 2. 
Novel methods for identifying and assessing alternative correlates of protection against influenza infection are 
needed. To assess the NA specific antibody response to vaccination, it is first necessary to determine the NA 
content of inactivated influenza vaccine; this assay is under development. If successful, the NA content in a 
dosage specific manner can be correlated to the N9 NA-specific antibody responses elicited by the 2013 and 
2017 H7N9 IIVs.  The analyses for this exploratory endpoint will be described in an addendum to this SAP, if 
the assay becomes available. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
This study uses a dose comparison concurrent control design. Study subjects received either 2013 A/H7N9 
IIV or 2017 A/H7N9 IIV with differing dosages with or without adjuvants and on differing administration 
schedules. 


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4.3. 
Selection of Study Population 
The study population for this clinical trial is 180 males and non-pregnant females, 19 to 50 years of age, 
inclusive, who are in good health and meet all eligibility criteria.  The subjects will be recruited from the 
general population at the participating Vaccine Trial and Evaluation Unit (VTEU) sites that have substantial 
experience conducting large influenza vaccine studies. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
2013 and 2017 A/H7N9 Inactivated Influenza Vaccines and AS03 Adjuvant will be administered. 
4.4.2. 
Identity of Investigational Product(s) 
See the study protocol for details of study product formulation. 
4.4.3. 
Method of Assigning Subjects to Study Groups (Randomization) 
Enrollment/randomization will be performed through the enrollment module in the electronic data capture 
system, maintained by the SDCC. 
Eligible subjects will be stratified by clinical site and prior receipt of seasonal influenza vaccine and randomly 
assigned with equal allocation (1:1:1:1:1:1) to 1 of 6 study groups indicated in Table 1. The treatment 
sequence was generated using permuted block randomization to provide an approximately balanced allocation 
to the study groups during the study.  
4.4.4. 
Selection of Doses in the Study 
Subjects in Groups 1, 2, and 3 are to receive a first vaccination of AS03 adjuvanted 2013 A/H7N9 IIV at HA 
dose of 3.75mcg, and a second vaccination of either AS03 adjuvanted 2017 A/H7N9 IIV at HA dose of 
3.75mcg (Groups 1 and 2) or unadjuvanted 2017 A/H7N9 IIV at HA dose of 15mcg (Group 3).  Subjects in 
Groups 4, 5 are to receive two AS03 adjuvanted 2017 A/H7N9 vaccinations at HA doses of 3.75. Subjects in 
Group 6 are to receive a first vaccination of AS03 adjuvanted 2017 A/H7N9 IIV at HA dose of 3.75mcg, and 
a second vaccination of unadjuvanted 2017 A/H7N9 IIV at HA dose of 15mcg. 
The 3.75 mcg with AS03 dose was selected to evaluate safety and immunogenicity of antigen sparing dose 
strategies compared to that of using a higher dose of 15 mcg without adjuvant. Using the 2013 and 2017 
A/H7N9 IIVs allows the evaluation of priming effects of different A/H7N9 IIVs. 
4.4.5. 
Selection and Timing of Dose for Each Subject 
Each subject is to be randomly assigned to a study group which will define the number and timing of 2013 
and/or 2017 A/H7N9 vaccinations. The first vaccination for all subjects takes place on the day of 
randomization and will include vaccination with AS03 adjuvanted 2013 A/H7N9 IIV (Groups 1,2,3) or AS03 
adjuvanted 2017 A/H7N9 IIV (Groups 4,5,6). The second vaccination of 2017 A/H7N9 IIV takes place 
approximately 21 days after the first vaccination for Groups 1 and 4 (protocol defined window of 21-28 days 
post first vaccination), and approximately 120 days after the first vaccination for Groups 2, 3, 5, and 6 
(protocol defined window of 113-134 days post first vaccination). 


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4.4.6. 
Blinding 
This is a partially blinded clinical trial. Subjects, site investigators, and study personnel performing any study-
related assessments following study vaccine administration to the subject are partially blinded (blinded to 
vaccine antigen and dosage and unblinded to vaccine administration interval). Laboratory personnel 
performing HAI and Neut antibody assays will receive serum specimens blinded to subject ID number and 
specimen visit number. 
The randomization scheme will be generated by the SDCC and provided to unblinded study personnel (i.e., 
research pharmacists performing study vaccination preparations and unblinded study vaccine administrators) 
at the participating VTEU sites. 
The unblinded study vaccine administrator is a study personnel member credentialed to administer vaccines 
and may also participate in dose preparation but will not be involved in study-related assessments or have 
subject contact for data collection following study vaccine administration to the subject. 
The Data and Safety Monitoring Board (DSMB) may receive data in aggregate and presented by study 
groups. The DSMB may also be provided with expected and observed rates of the expected AEs in an 
unblinded fashion and may request the treatment assignment be unblinded for an individual subject if required 
for safety assessment. The DSMB will review grouped and unblinded data in the closed session only.  
4.4.7. 
Prior and Concomitant Therapy  
Administration of any medications, therapies, or vaccines (including prescription and over-the-counter drugs 
as well as herbals, vitamins, and supplements) from 60 days prior to study vaccination through 21 days post 
final vaccination will be solicited from the participant during screening, enrollment, and follow-up. Any 
reported prior therapies from up to 30 days prior to vaccination through 21 days post final vaccination will be 
recorded in the appropriate data collection form.  
Use of concomitant medications is allowed prior to and during the trial with the exception of medications and 
therapies that might interfere with the evaluation of the investigational product. Medications in this category 
include the prohibited medication per the Subject Exclusion Criteria (protocol Section 5.1.2). In addition, the 
site principal investigator or appropriate sub-investigator may identify other medications that should not be 
used due to a risk to subject safety or assessment of reactogenicity and immunogenicity. 
4.4.8. 
Treatment Compliance 
All subjects are to receive two vaccinations of study product administered in the clinic based on study group 
assignment.  
4.5. 
Immunogenicity and Safety Variables 
See Table 2, Table 3, Table 4, and Table 5 for schedules of study procedures by study groups. 
4.5.1. 
Safety Variables  
Safety will be assessed by the frequency and severity of: 
1. SAEs occurring from the time of the first study vaccination through approximately 12 months after the 
last study vaccination. 
2. Solicited AEs – reactogenicity events occurring from the time of each study vaccination through 7 
days after each study vaccination: 


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• Injection site reactions including pruritus, ecchymosis, erythema, induration (hardness)/edema 
(swelling), pain, and tenderness. 
• Systemic reactions including fever, feverishness, fatigue, malaise, myalgia, arthralgia, headache, 
and nausea. 
3. Clinical safety laboratory AEs occurring from the time of each study vaccination through 
approximately 7 days after each study vaccination. Parameters to be evaluated include white blood 
cells (WBC), hemoglobin (Hgb), platelets (PLT), alanine aminotransferase (ALT), total bilirubin (T. 
Bili), and creatinine (Cr). 
4. Unsolicited AEs – non-serious AEs occurring from the time of each study vaccination through 
approximately 21 days after each study vaccination. 
5. MAAEs, including NOCMCs, and PIMMCs occurring from the time of the first study vaccination 
through approximately 12 months after the last study vaccination. 
Grading scales for injection site and systemic solicited reactions, vital signs, and clinical laboratory 
parameters are provided in Table 10, Table 11, Table 12, and Table 13. 
For each unsolicited AE experienced, the subject will be asked if he/she had received medical attention, 
defined as hospitalization, an emergency room visit or an otherwise unscheduled visit to or from medical 
personnel for any reason. AEs characterized by such unscheduled medical care will be designated as MAAEs. 
NOCMCs are defined as any new ICD-10 diagnosis (10th revision of the International Statistical 
Classification of Diseases and Related Health Problems) that is applied to the subject during the course of the 
study, after receipt of the study agent, that is expected to continue for at least 3 months and requires continued 
health care intervention. 
PIMMCs constitute a group of AEs that includes diseases which are clearly autoimmune in etiology and other 
inflammatory and/or neurologic disorders which may or may not have autoimmune etiologies. For a list of 
PIMMCs currently if effect, refer to protocol Appendix B.  
4.5.2. 
Immunogenicity Variables 
Individual HAI and Neut results will be reported by the central immunology laboratory for the homologous 
2013 A/H7N9 vaccine strain and 2017 A/H7N9 vaccine strain. Assay results are reported as a reciprocal titer 
with values of 10*2k, where k=0, 1, 2, etc. The lower limit of detection (LLOD) for the HAI and Neut assays 
is 1:10; values below the limit of detection are imputed for analysis as one-half the limit of detection (10/2 = 
5). For analysis, the geometric mean (calculated on natural log scale) of repeated results for each sample will 
be computed and used as the response for all subsequent calculations. The variation arising from multiple 
measurements for an individual at a single time point is not used in subsequent calculations. See Section 3.3 
for definitions of derived variables for the analysis of HAI and Neut data. HAI and Neut data will be uploaded 
into the SDCC’s electronic data capture system.  
Frequency of strain-specific (2013 and 2017 A/H7N9) plasmablasts (IgA, IgG and IgM ASCs) will be 
characterized by the local laboratory using freshly collected PBMCs. A single frequency value will be 
reported, with a LLOD of 6 and an ULOD of 8000. Values below the LOD will be reported as one-half the 
LLOD (6/2 = 3). Values above the ULOD will be assessed for accuracy. 
A plan for receipt of exploratory data will be determined with the assaying laboratories and documented in the 
SAP addendum.  


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The assay to determine the influenza virus N9 Neuraminidase (NA) antibody response to vaccination is under 
development. An addendum to the SAP will be generated to outline the planned analyses when assay 
development is complete and after receiving confirmation of this plan from DMID.  


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5. 
SAMPLE SIZE CONSIDERATIONS 
This study is planned to enroll up to 180 subjects.  This study is not designed to test a formal null hypothesis. 
Rather, it is intended to obtain sufficient data to obtain meaningful estimates of the immune response and to 
uncover any safety issues that occur at a sufficiently high rate that they might be observed in a study of this 
size. As such, the type I error rate, alpha = 0.05, is not adjusted for multiple comparisons. While this study is 
not designed to test any specific null hypothesis, the following tables illustrate the precision and power that is 
available for select estimates and comparisons of interest. 
Table 6 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 a single study group 
(N = 30), or in the trial as a whole (N=180). 
Binomial confidence intervals (CI) are widest (have the least precision) when the response rate is 50%.  
Table 7 is presented to indicate the worst-case scenario for precision of observed exact (Clopper-Pearson) 
binomial confidence intervals. 
Table 8 illustrates the minimum detectable differences in the proportion of subjects responding (e.g. attaining 
seroconversion or a titer ≥1:40) between any two study groups (N=30) using a two-sided Likelihood Ratio 
Test and alpha = 0.05. It is assumed that up to 10% of subjects (N=3) will be excluded from the per protocol 
analysis. Seroconversion rates of 10% to 50% are considered. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Unless otherwise specified, continuous variables will be summarized using the following descriptive 
statistics: n (non-missing sample size), mean and/or geometric mean (as appropriate), standard deviation, 
median, maximum and minimum. The frequency and percentages (based on the non-missing sample size) of 
observed levels will be reported for all categorical measures. In general, all data will be listed, sorted by study 
vaccination and subject, and when appropriate by visit number within subject. All summary tables will be 
structured with a column for each study group in the following order: 
• Group 1: 2013 3.75 + AS03 / 2017 3.75 + AS03 (D1-D22)  
• Group 2: 2013 3.75 + AS03 / 2017 3.75 + AS03 (D1-D121) 
• Group 3: 2013 3.75 + AS03 / 2017 15 (D1-D121) 
• Group 4: 2017 3.75 + AS03 / 2013 3.75 + AS03 (D1-D22) 
• Group 5: 2017 3.75 + AS03 / 2017 3.75 + AS03 (D1-D121) 
• Group 6: 2017 3.75 + AS03 / 2017 15 (D1-D121) 
All tables will be annotated with the total population size relevant to that table/treatment, including any 
missing observations. 
6.2. 
Timing of Analyses 
6.2.1. 
CSR 
Clinical, safety and reactogenicity data through approximately 180 days after the last study vaccination will 
represent the primary clinical database for this trial. Once the last subject completes the visit that occurs 
approximately 180 days after the last study vaccination and all HAI and Neut results are received and clinical 
data lock has occurred, a "topline" subset of the immunogenicity and safety tables will be provided to DMID 
on an expedited timeline. These analyses may be made available to the sponsor for planning subsequent trials 
and to the lead PI for publication. These analyses will not be used to make any decisions concerning the 
conduct of this trial. As it is anticipated that subjects may remain in long-term safety and immunogenicity 
follow-up at the time of these analyses, blinded site investigators and DMID Medical Monitors not involved 
in the analysis, publication or clinical study report (CSR) preparation will be responsible for assessing SAEs 
and MAAEs, including NOCMCs and PIMMCs, until all subjects have completed the final follow-up visit. 
All analyses of data included in the topline tables for early release will be considered the final analysis of 
these data, and also included in the final CSR. 
Tables and figures to be included in the topline set are indicated with the symbol * in the title. 
Analysis of exploratory immunogenicity endpoints, including cellular immunology and additional serological 
assays, may be performed and released as the data are available from the research laboratories. Any such 
analyses would be considered the final analysis for the endpoint and included in the CSR. 
The final CSR will be completed after the last subject’s last visit is completed, and the final clinical database, 
including all long-term safety follow-up data, is cleaned, monitored and locked. Additional exploratory 


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immunogenicity endpoint data not available at the time of CSR preparation may be included in an addendum 
to the CSR. 
6.3. 
Analysis Populations 
6.3.1. 
Safety Population 
The Safety Analysis population includes all subjects who received at least one study vaccination. 
6.3.2. 
Modified Intent-to-Treat (mITT) Population 
The modified Intent-to-treat (mITT) population includes all subjects who received at least one study 
vaccination and contributed both pre- and at least one post-study vaccination venous blood samples for 
immunogenicity testing (HAI or Neut antibody assays) for which valid results were reported. For analyses 
using the mITT population, subjects will be grouped based on randomized study group. Subject inclusion in 
mITT analyses will be considered individually for each assay.  
6.3.3. 
Per Protocol Population 
The per protocol (PP) population includes all subjects in the mITT subset with the following exclusions: 
• Data from all available visits for subjects found to be ineligible at baseline. 
• Data from all visits subsequent to major protocol deviations, such as: 
− Second study vaccination not received, 
− Second study vaccination received out of window, 
− Receipt of non-study licensed, live vaccine within 30 days before or after each study 
vaccination, 
− Receipt of non-study licensed, inactivated vaccine within 14 days before or after each study 
vaccination, 
− Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days before or after 
each study vaccination. 
• Data from any visit that occurs out of window by more than one day. However, use exact window 
for visits that occur either 1 day or 3 days post study vaccinations: 
− Visit 2 data collected before 1 day or after 2 days post first study vaccination. 
− Visit 3 data collected before 3 days or after 4 days post first study vaccination. 
− Visit 4 data collected before 5 days or after 10 days post first study vaccination. 
− Visit 5 data collected before 12 days or after 16 days post first study vaccination. 
− Visit 6 data collected before 20 days or after 29 days post first study vaccination.  
− Visit 7 data collected before 1 day or after 2 days post second study vaccination for study 
groups 1 and 4. 
 
 


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− Visit 8  
 Data collected before 3 days or after 4 days post second study vaccination for study 
groups 1 and 4. 
 Data collected before 112 days or after 135 days post first study vaccination for 
study groups 2, 3, 5, and 6. 
− Visit 9 
 Data collected before 5 days or after 10 days post second study vaccination for 
study groups 1 and 4. 
 Data collected before 1 day or after 2 days post second study vaccination for study 
groups 2, 3, 5, and 6. 
− Visit 10  
 Data collected before 12 days or after 16 days post second study vaccination for 
study groups 1 and 4. 
 Data collected before 3 days or after 4 days post second study vaccination for study 
groups 2, 3, 5, and 6. 
− Visit 11 
 Data collected before 20 days or after 29 days post second study vaccination for 
study groups 1 and 4. 
 Data collected before 5 days or after 10 days post second study vaccination for 
study groups 2, 3, 5, and 6. 
− Visit 12  
 Data collected before 53 days or after 67 days post second study vaccination for 
study groups 1 and 4. 
 Data collected before 12 days or after 16 days post second study vaccination for 
study groups 2, 3, 5, and 6. 
− Visit 13 
 Data collected before 75 days or after 105 days post second study vaccination for 
study groups 1 and 4. 
 Data collected before 20 days or after 29 days post second study vaccination for 
study groups 2, 3, 5, and 6. 
− Visit 15 
 Data collected before 165 days or after 195 days post second study vaccination for 
study groups 1 and 4. 
 Data collected before 75 days or after 105 days post second study vaccination for 
study groups 2, 3, 5, and 6. 


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− Visit 17 data collected before 165 days or after 195 days post second study vaccination for 
study groups 2, 3, 5, and 6. 
For analyses using the PP population, subjects will be grouped based on study vaccinations received. 
Analyses will be conducted using the PP population only if 10% or more of subjects are excluded from a 
primary or secondary analysis timepoint. 
6.4. 
Covariates and Subgroups 
As a protocol defined exploratory analysis, HAI antibody response following the second vaccination will be 
summarized stratified by the following covariates: age (categorical: 19-34, 35-50), sex (male, female), body 
mass index (<30, ≥30), and prior receipt of seasonal influenza vaccine(s). Prior receipt of influenza vaccines, 
including any reported prior receipt of A/H5 vaccinations, or reported seasonal vaccination receipt will also 
be included as covariates. Summaries of prior seasonal vaccination will include breakdowns of receipt of the 
two seasonal vaccinations prior to study initiation (did not receive 2016-2017 or 2018-2019; received 2016-
2017 and/or 2018-2019) as well as independently assessing subject receipt of 2018-2019 seasonal vaccine 
(did not receive/received) prior to the second dose of study vaccine. These covariates will be considered in 
statistical modeling as described in Section 8.3. As these analyses are exploratory, the study was not powered 
for any subgroup analyses.  
6.5. 
Missing Data 
All attempts will be made to collect all data per protocol. As missing data are expected to be minimal, no 
imputation will be performed for missing values. Any data point that appears to be erroneous or inexplicable 
based on clinical judgment will be investigated as a possible outlier. If data points are identified as outliers, 
sensitivity analyses will be performed to examine the impact of including or excluding the outliers. Any 
substantive differences in these analyses will be reported. 
6.6. 
Interim Analyses and Data Monitoring 
Interim analyses will only be used to terminate this trial in the event that unanticipated safety events deemed 
to be of sufficient concern require such action by the sponsor. These assessments will not be made on the 
basis of testing a formal statistical hypothesis; therefore, p-value adjustment will not be made to any analyses. 
A DSMB will be convened by DMID to review study progress and participant, clinical, safety, and 
reactogenicity and immunogenicity data. 
Emergent public health needs may dictate additional interim safety, reactogenicity, and/or immunogenicity 
analyses be performed on available information at any time during the trial. If this occurs, immunogenicity 
data will be analyzed as results are available from the central immunogenicity laboratory. 
6.6.1. 
Interim Safety Review 
An interim safety review may include enrollment and demographic information, medical history, concomitant 
medications, physical assessments, clinical laboratory values, dosing compliance, and solicited and 
unsolicited AE/SAEs. Additional data may be requested by the DSMB, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by study group. The DSMB may also be provided with expected and observed rates of the expected 
AEs in an unblinded fashion and may request the treatment assignment be unblinded for an individual subject 
if required for safety assessment. The DSMB will review grouped and unblinded data in the closed session 


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only. The DSMB will meet and review this data at trial-specific time frames or ad hoc as needed during this 
trial as defined in the DSMB charter. As an outcome of each review/meeting, the DSMB will make a 
recommendation as to the advisability of proceeding with study vaccinations, as applicable, and to continue, 
modify or terminate this trial. 
The interim safety reports generated for the DSMB are not intended to be published; they will be used only 
for informing emergency preparedness. 
Additionally, this trial will be monitored to determine if any of the halting rules described in Protocol Section 
9.5 are met. 
6.6.2. 
Interim Immunogenicity Review 
No interim immunogenicity analysis is planned. Should emergent public health needs dictate interim 
immunogenicity review, immune responses will be summarized in terms of strain-specific 2013 and 2017 
A/H7N9 HAI and Neut antibody titers and the relationship to study vaccine dosage, adjuvant use and study 
vaccination schedule. It is anticipated that all analyses will be carried out in parallel for both assays, but 
reports may be prepared separately for HAIs and Neuts if results are available on different timelines. Interim 
analyses will focus on rates of titers ≥1:40, seroconversion (see definition in Section 3.3) and GMTs, along 
with corresponding 95% CIs. No formal hypothesis testing will be included in the interim analysis, and 
interim results will not have impact on conduct of this trial. All interim analyses will use the mITT 
population. 
Any immunogenicity reports would be provided by the SDCC to the DMID Scientific Lead, DMID Clinical 
Project Manager and DSMB. Reports will include data summarized by unblinded study group, but the 
presentation will be in a format that prevents inadvertent unblinding of any individual subject. 
There is no plan to halt this trial prior to full enrollment and completion of all follow-up visits based on any 
interim immunogenicity results. 
6.7. 
Multicenter Studies 
Randomization was stratified by site, but data will be pooled across all clinical sites for all analyses. Center 
effects are not anticipated because the sites use standardized procedures for vaccination and assessment of 
solicited and unsolicited AEs, and the study relies on a central laboratory for immunogenicity assessments. 
6.8. 
Multiple Comparisons/Multiplicity 
This study was designed to obtain preliminary estimates of safety and immune response to the 2013 and 2017 
A/H7N9 vaccinations in healthy adults. The study was not designed to test any specific null hypothesis, and 
as such no adjustment for multiple comparisons will be performed. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Table 14 will present a summary of the reasons that subjects were screened but not enrolled.  
The number and percentage of enrolled subjects excluded from each analysis population by study group are 
presented in Table 15. A listing of subjects excluded from each analysis population will be presented in 
Listing 5. 
The disposition of subjects in the study will be tabulated by study group (Table 16). The table will show the 
total number of subjects screened, randomized, receiving the first vaccination, receiving the second 
vaccination, completing the blood draw for the primary immunogenicity endpoints, and completing the last 
visit. 
A flowchart showing the disposition of study subjects, adapted from the CONSORT Statement [4] will be 
included and will present the number of subjects screened, randomized, lost to follow up, and analyzed, by 
study group (Figure 1). 
A listing of subjects who were discontinued from treatment or terminated from study follow-up and the reason 
will be included in Listing 2. 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by the deviation category and deviation 
type, and study group for all enrolled subjects (Table 9). Major deviations that will be reviewed for possible 
exclusion of immunogenicity results from the PP population include deviations related to 
eligibility/enrollment, treatment administration schedule, follow-up visit schedule, and receipt of exclusionary 
vaccines or medications. All subject-specific protocol deviations and non-subject-specific protocol deviations 
will be included in Listing 3 and Listing 4. 


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8. 
IMMUNOGENICITY EVALUATION 
Immunogenicity data summaries and analysis for primary and secondary endpoints will be presented for the 
mITT population, which is the primary population for analysis. The Per Protocol population displays will be 
generated only if >10% of subjects are found to have data excluded from a primary or secondary timepoint. 
Immune responses in terms of strain-specific 2013 and 2017 A/H7N9 HAI and Neut antibody titers will be 
summarized by study group at each time point. Descriptive summary statistics will be provided for all assays 
and time points including number of subjects with non-missing results, percentage of subjects with titers 
≥1:40, percentage of subjects achieving seroconversion, and GMTs along with corresponding 95% CI. Exact 
confidence intervals will be presented for proportional endpoints. Summaries of primary and secondary 
immunogenicity endpoints are presented for the 2013 A/H7N9 strain in Table 24, Table 25, Table 26, and 
Table 27 and for the 2017 A/H7N9 strain in Table 28, Table 29, Table 30, and Table 31.  
Reverse cumulative distribution (RCD) curves will be presented for post-vaccination HAI and Neut antibody 
titers. Plots for each assay will be generated with 3 columns (Day 22 post vaccination 1, Day 22 post 
vaccination 2, and Day 181 post vaccination 2) and 2 rows (2013 A/H7N9, 2017 A/H7N9), and separate 
curves within each panel for each study group, as shown in Figure 2, Figure 3, Figure 4, and Figure 5. 
Figures depicting the HAI and Neut GMT over time will also be presented as shown in Figure 6, Figure 7, 
Figure 8, and Figure 9 for both 2013 and 2017 A/H7N9 strains. 
The spearman correlation between HAI and Neut antibody titers will be calculated at each time point over all 
groups. The correlation will be depicted in scatter plots as Figure 10 and Figure 11 for both the 2013 and 
2017A/H7N9 strain. 
Individual HAI and Neut assay results will be provided in Listing 9. 
8.1. 
Primary Immunogenicity Analysis  
The primary immunogenicity endpoints HAI and Neut seroconversion, percentage of subjects with titer 
≥1:40, and GMTs against the 2013 and 2017A/H7N9 vaccine strains 21 days after the second vaccination will 
be summarized as described above.  The primary analysis population will be mITT, with results from the PP 
population providing a comparison of the sensitivity of immunogenicity results to subject adherence to 
protocol-defined conditions. Regression modelling of seroconversion and log titers is planned as described in 
Section 8.3.2. 
8.2. 
Secondary Immunogenicity Analyses 
The secondary immunogenicity endpoints HAI and Neut seroconversion, percentage of subjects with titer 
≥40, and GMTs against the 2013 and 2017 A/H7N9 vaccine viruses prior to each study vaccination, 21 days 
after the first vaccination and 180 days after the second vaccination will be summarized as described above. 
No formal hypothesis testing is planned. 
8.3. 
Exploratory Immunogenicity Analyses 
Exploratory immunogenicity data summaries and analysis for exploratory endpoints will be presented for the 
PP population if >10% of subjects are found to have data excluded from a primary or secondary timepoint. 
Otherwise, exploratory displays will be presented for the modified intent to treat population. 


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8.3.1. 
HAI and Neut Covariate Analysis 
As an exploratory analysis, seroconversion and GMT of serum antibody for both HAI and Neut against the 
homologous 2013 A/H7N9 strain at 21 and 180 days after the second study vaccination will be summarized 
by study group stratified by age (categorized as those subjects ages 19-34, 35-50 years) (Table 32, Table 33, 
Table 34, and Table 35), by sex (Table 40, Table 41, Table 42, and Table 43), by BMI (Table 48, Table 49, 
Table 50, and Table 51), and by prior receipt of the 2016-2017 and/or 2017-2018 and /or 2018-2019 seasonal 
influenza vaccines (Table 56, Table 57, Table 58, and Table 59). These analyses will be repeated for HAI and 
Neut titer results against the 2017 A/H7N9 strain at 21 and 180 days post receipt of the second study 
vaccination by age category (Table 36, Table 37, Table 38, and Table 39) by sex (Table 44, Table 45, 
Table 46, and Table 47), by BMI (Table 52, Table 53, Table 54, and Table 55) by prior receipt of seasonal 
influenza vaccine (Table 60, Table 61, Table 62, and Table 63). 
The stratified summaries will be presented for the PP population. It is anticipated that subjects will have little 
to no pre-existing antibody at baseline, so seroconversion and titer ≥40 endpoints will be similar.  
8.3.2. 
HAI and Neut Regression Modeling 
Regression modeling will be utilized to test for the effect of treatment variables i.e. prime boost combination 
(PrimeBoost), Boost dose (BoostDose), and interval between vaccinations (Interval), on immune response. 
Logistic regression will be fit for the seroconversion outcome.  If the available titer data meet the required 
assumptions of normality after log transformation, multiple linear regression will be fit to log-transformed 
titers. Separate models will be fit for each assay (HAI, Neut), each strain (2013 A/H7N9, 2017 A/H7N9) and 
each time point (Day 22 post vaccination 1, Day 22 post vaccination 2, Day 181 post vaccination 2). All 
models will be fit with a similar structure for PrimeBoost, BoostDose, Interval, and covariates, for the PP 
population. The treatment variables will be defined as PrimeBoost (homologous, heterologous), BoostDose 
(3.75 mcg+AS03, 15 mcg), and Interval (21 days, 120 days). All models will be fit with and without 
adjustment for the following covariates (Z): age in years, sex (female, male), BMI (<30, ≥30), and prior 
receipt of seasonal influenza vaccine in the current season (did not receive 2018-2019 seasonal influenza 
vaccine, received 2018-2019 seasonal influenza vaccine)  (did not receive 2016-2017or 2017-2018 seasonal 
influenza vaccines, received 2016-2017 and/or 2017-2018 seasonal influenza vaccine). The models as shown 
below assume a linear relationship between age in years and both probability of seroconversion and GMT. 
The validity of this assumption will be assessed prior to analysis and, if the relationship between age and 
response is found to be non-linear, adjustments will be made to model parameters to satisfy regression 
assumptions. Modeling assumptions will be checked using standard diagnostic methods (e.g., using the 
INFLUENCE option in PROC LOGISTIC or PROC GLM). Parameter estimates and odds ratio estimates for 
the logistic models will be presented for the 2013 and 2017 A/H7N9 strains without covariate adjustment in 
Table 64, Table 65, Table 66, Table 67, and with covariate adjustment in Table 68, Table 69, Table 70, 
Table 71. Parameter estimates for the multiple linear regression models will be presented for the 2013 and 
2017 A/H7N9s strain without covariate adjustment in Table 72, Table 73, Table 74, Table 75, and with 
covariate adjustment in Table 76, Table 77, Table 78, Table 79. 
Model 1A: Logistic Regression (without covariate adjustment): 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙[𝑃𝑃(𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠)]
= 𝛽𝛽0 + 𝛽𝛽1 × 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃+ 𝛽𝛽2 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵+ 𝛽𝛽3 × 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼
+ 𝛽𝛽4 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵) + 𝛽𝛽5 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) +  𝜀𝜀 
 


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Model 1B: Logistic Regression (with covariate adjustment): 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙[𝑃𝑃(𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠)]
= 𝛽𝛽0 + 𝛽𝛽1 × 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃+ 𝛽𝛽2 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵+ 𝛽𝛽3 × 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼
+ 𝛽𝛽4 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵) + 𝛽𝛽5 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) + 𝛽𝛽6 × 𝑍𝑍+ 𝜀𝜀 
Model 2A: Multiple Linear Regression (without covariate adjustment): 
𝑙𝑙𝑙𝑙𝑙𝑙(𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡) = 𝛽𝛽0 + 𝛽𝛽1 × 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃+ 𝛽𝛽2 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵+ 𝛽𝛽3 × 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼
+ 𝛽𝛽4 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵) + 𝛽𝛽5 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) + 𝜀𝜀 
Model 2B: Multiple Linear Regression (with covariate adjustment): 
𝑙𝑙𝑙𝑙𝑙𝑙(𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡) = 𝛽𝛽0 + 𝛽𝛽1 × 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃+ 𝛽𝛽2 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵+ 𝛽𝛽3 × 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼+ 𝛽𝛽4 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵)
+ 𝛽𝛽5 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) + 𝛽𝛽6 × 𝑍𝑍+ 𝜀𝜀 
Where Z is the matrix of covariates age, sex, BMI, and prior receipt of seasonal influenza vaccine as defined 
in Section 6.4. Subjects missing data for one or more covariates will be excluded from Models 1B and 2B. 
8.3.3. 
Antibody Secreting Cells (Plasmablasts) 
Due to the requirement for freshly isolated PBMCs, the plasmablast (antibody secreting cell [ASC]) assay will 
be performed only on specimens collected from subjects enrolled at Emory Children’s Center and the Hope 
Clinic of Emory Vaccine Center. Values below the lower limit of detection will be handled as described in 
Section 4.5.2. The frequency of strain-specific 2013 and 2017 A/H7N9 IgA, and IgG ASCs will be 
summarized for the mITT and PP populations by study group at 8 days post each study vaccination. 
Descriptive summary statistics will be provided for both time points including the number of subjects with 
non-missing results, mean, standard deviation and corresponding 95% CI as well as median, minimum and 
maximum values. Geometric mean and 95% CI may also be assessed depending on the observed distribution 
of the data. Summaries are presented for the 2013 A/H7N9 strain in Table 80 and for the 2017 A/H7N9 strain 
in Table 81. 
Box and whisker plots will summarize the distribution of ASC results for each immunoglobulin type, strain, 
and study day (Figure 12, Figure 13, Figure 14, Figure 15, Figure 16, Figure 17). Scatterplot matrices 
depicting the relationship and correlation between immunoglobulin types for the strain-specific ASCs at the 
same day, as well as between the same immunoglobulin types post each study vaccination, will be shown in 
Figure 18, Figure 19, Figure 20, Figure 21, Figure 22, Figure 23, Figure 24 and Figure 25. Strain-specific 
ASC frequency at 8 days post vaccination will also be correlated with HAI and Neut titer at 21 days post 
vaccination as shown in Figure 22, Figure 23, Figure 24, and Figure 25. The statistician will determine if the 
Pearson or the Spearman Rank-Order correlation is appropriate at the time of analysis. 
8.3.4. 
Other Assays 
Descriptions of the NA assays and all other exploratory assays and the associated planned analyses will be 
described in an addendum to this SAP. 


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9. 
SAFETY EVALUATION 
All summaries and analysis of safety data will be presented for the Safety Analysis Population. Safety 
summaries will be presented overall and grouped by study group. 
Continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation, median, maximum and minimum. All categorical measures will be 
summarized by the frequency and percentages of observed levels will be reported for all categorical measures. 
The denominator for the percentages may be based on the number of non-missing observations for an 
assessment or based on the number of subjects in a population. This will be described for each table. 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of age, sex, ethnicity, race, BMI, and prior receipt of seasonal influenza vaccine will be presented 
by site (Table 19, Table 20) and by study group (Table 21, Table 22). Age will be summarized as a 
continuous variable. Ethnicity is categorized as Hispanic or Latino, or not Hispanic and not Latino. In 
accordance with NIH reporting policy, subjects may self-designate as belonging to more than one race or may 
refuse to identify a race, the latter reflected in the electronic case report form (eCRF) as “No” to each racial 
option. BMI will be summarized as a continuous as well as categorical variable, categorized as (<30, ≥30). 
Self-reported history of prior receipt of influenza vaccines will be broken down by the following categories: 
receipt of seasonal vaccines for prior seasons (2016-2017, 2017-2018), receipt of seasonal vaccine for the 
current season (2018-2019; considered up to receipt of study dose 2), and receipt of any A/H5 vaccines prior 
to enrollment. Demographic information for individual subjects will be provided in Listing 6. Subjects’ prior 
influenza vaccination history (seasonal and non-seasonal) will be provided in Listing 8. 
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past or pre-existing medical conditions will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 20.0 or higher. 
Summaries of subjects’ prior and concurrent medical conditions will be presented by study group (Table 23). 
Individual subject listings will be presented for all reported medical history including prior and concurrent 
medical conditions (Listing 7). 
9.1.2. 
Prior and Concomitant Medications  
Concomitant medications will be coded to the Anatomical Therapeutic Classification using the WHO Drug 
Dictionary. The use of concomitant medications during the study will be summarized by ATC1 and ATC2 
code and study group for the Safety population (Table 132). A listing of concomitant medications will be 
presented (Listing 18). 
9.2. 
Measurements of Treatment Compliance 
All subjects are to receive 2 study vaccinations administered in the clinic. The number of study vaccinations 
administered to subjects will be presented by study group in Table 17 and Table 18 and as part of the subject 
disposition tables (Table 16). Listing 1 presents subjects who received investigational product with study 
group and study product received for each vaccination. 


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9.3. 
Adverse Events 
A summary of all adverse events is provided in Table 82. A summary of those events that occurred in ≥5% of 
subjects in any study group is provided in Table 83. 
9.3.1. 
Solicited Events and Symptoms 
Systemic solicited adverse events were collected pre-vaccination, and systemic and local solicited adverse 
events were collected at-least 20 minutes post-vaccination and then daily for 7 days after each vaccination and 
graded on a scale of 0 (absent), 1 (mild), 2 (moderate) and 3 (severe). Systemic events include fever, 
feverishness, fatigue, malaise, myalgia, arthralgia, headache, and nausea. The grading scale for systemic 
events, including quantitative grading for fever, is included in Table 11. Local events include pruritus, 
ecchymosis, erythema, induration/swelling, pain, and tenderness. Ecchymosis, erythema, and induration are 
measured by both functional and measurement grading scales as defined in Table 10. 
When calculating the incidence of solicited events, each subject will be counted once at the highest severity 
following the applicable vaccination, and any repetitions will be ignored. For summaries presented separately 
for each vaccination, the denominator for percentages will be the number of subjects who received the 
respective vaccination with non-missing data for the event summarized. For summaries over all vaccinations 
the denominator will be the number of subjects who received at least one vaccination with non-missing data 
for the event summarized. 
The number and percentage of subjects reporting at least one solicited adverse event of each severity will be 
summarized for each solicited symptom, any systemic symptom, any local symptom, and any symptoms. For 
each event the denominator is the number of subjects who received the applicable vaccination with non-
missing data for the specific event. The 95% CI calculated using Clopper-Pearson methodology from a 
binomial distribution (SAS Proc Freq with a binomial option) will be presented (Table 84, Table 85, 
Table 86). Logistic regression models will be fit to estimate the effect of prime-boost combination 
(PrimeBoost), Boost dose (BoostDose), and interval between vaccinations (Interval) on the probability of 
reporting any local event or reporting any systemic event after either vaccination (Table 87, Table 88). If 
statistically significant effects are observed in the model for local events or systemic events, then additional 
models will be fit for each individual event of that type. 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙[𝑃𝑃(𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸)] = 𝛽𝛽0 + 𝛽𝛽1 × 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃+ 𝛽𝛽2 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵+ 𝛽𝛽3 × 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼+
 𝛽𝛽4 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃∗𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵) + 𝛽𝛽5 × (𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑜𝑜𝑜𝑜𝑜𝑜∗𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) + 𝜀𝜀, 
For each systemic and local event, any systemic event, any local event, and any solicited event, the maximum 
severity over 7 days after each vaccination will be summarized for the Safety population. The number and 
percentage of subjects reporting each event will be summarized by the maximum severity and study group, 
separately for each vaccination and over both vaccinations. For each event the denominator is the number of 
subjects who received the applicable vaccination with non-missing data for the specific event. The 95% CI 
calculated using Clopper-Pearson methodology from a binomial distribution (SAS Proc Freq with a binomial 
option) will be presented (Table 89, Table 90, Table 91). 
The number of subjects reporting a solicited adverse event will be summarized for each day post vaccination 
for each vaccination and for both vaccinations combined both in a summary table (Table 92, Table 93, 
Table 94) and graphically in a bar chart (Figure 26 and Figure 27). A comparison of the event rate for each 
study group between study vaccinations will be presented, including p-values from McNemar’s test 
performed (Table 95, Table 96). 


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Systemic and Local solicited events reported by subject will be presented in Listing 11 and Listing 12, sorted 
by subject ID, vaccination number, parameter, and study day. 
9.3.2. 
Unsolicited Adverse Events 
When calculating the incidence of unsolicited AEs (i.e., on a per subject basis), each subject will only be 
counted once at the highest severity and/or relationship, and any repetitions of AEs within a subject will be 
ignored; the denominator will be the total number of subjects in the safety population. All AEs reported will 
be included in the summaries and analyses. 
The number and percentage of subjects reporting at least one unsolicited AE will be summarized by MedDRA 
system organ class and preferred term. A 95% CI will be presented for the percentage of subjects reporting 
any unsolicited AE (serious or non-serious) for each MedDRA system organ class and preferred term over all 
study vaccinations (Table 97). 
The following summaries for unsolicited AEs will be presented by MedDRA system organ class, preferred 
term, and study group: 
• Incidence of AEs by severity and relationship to study product (Table 98, Table 99); 
• Incidence of non-serious, related AEs by severity (Table 100, Table 101); 
• Incidence of AEs over time (Days 1-8, Days 9-22 post each study vaccination) (Table 102); 
• Incidence of non-serious, related AEs over time (Days 1-8, Days 9-22 post each study vaccination) 
(Table 103) – note this table presents results for secondary safety endpoint, “Occurrence of study 
vaccine-related unsolicited non-serious AEs from the time of each study vaccination through 
approximately 21 days after each study vaccination”; 
• Total frequency of AEs over time (Days 1-8, Day 9 through approximately Day22 post each study 
vaccination) (Table 104, Table 105); 
• Subject listing of non-serious AEs of moderate or greater severity (Table 110);  
• Bar chart displaying total frequency of AEs by severity and MedDRA system organ class and 
study group (Figure 28, Figure 29); 
• Bar chart displaying incidence of AEs by severity and MedDRA system organ class, and study 
group (Figure 30, Figure 31); 
• Bar chart displaying total frequency and incidence of AEs by relationship to study product, 
MedDRA system organ class, and study group (Figure 32, Figure 33, Figure 34, Figure 35). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
The following listings will be presented including Subject ID, Age (years) AE Description, AE Onset 
Date/End Date, Last Vaccination Received/Days Post Vaccination, Reason Reported as an SAE, Relationship 
to Study Vaccination, Alternate Etiology if not Related, Outcome, and Duration of Event (days): 
• Deaths and Serious Adverse Events (Table 106); 
• Medically Attended Adverse Events (Table 107); 
• Potentially Immune Mediated Medical Conditions (Table 108); 


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• New Onset Chronic Medical Conditions (Table 109). 
A listing of all reported AEs by subject will be presented in Listing 13, sorted by Study Group, Subject ID, 
and AE Number. 
9.5. 
Pregnancies 
For any subjects in the Safety population who became pregnant during the study, every attempt will be made 
to follow these subjects to completion of pregnancy to document the outcome, including information 
regarding any complications with pregnancy and/or delivery.  
Listing 19, Listing 20, Listing 21, Listing 22, and Listing 23 will present any study pregnancies and their 
outcomes. 
9.6. 
Clinical Laboratory Evaluations 
Clinical safety laboratory parameters (WBC, Hgb, PLT, ALT, T. Bili, Cr) will be collected from each subject 
prior to each study vaccination and approximately 7 days after each study vaccination. These evaluations will 
be performed by the central clinical laboratory. The grading scale for clinical laboratory evaluations is 
presented in Table 13. Clinical laboratory evaluations assessed on Day 1 prior to the first study vaccination 
will be considered as baseline. Safety laboratory parameters are allowed to be repeated at the central clinical 
laboratory one time per protocol for AE follow-up, after which follow-up is required to be done at the site’s 
local laboratory, if needed. Results from safety laboratories run locally are not included in any exhibits but 
rather are used to inform subject safety and may be included in unsolicited adverse event comments, if 
applicable. 
The distribution of laboratory results by severity, study day and study group will be presented in Table 111, 
Table 112, Table 113, Table 114, Table 118, Table 119, Table 120, and Table 121.  Descriptive statistics 
including mean, standard deviation, median, minimum and maximum values and change from baseline by 
study day will be summarized for each parameter in Table 115, Table 116, Table 117, Table 122, Table 123, 
and Table 124. Box plots illustrating the change from baseline for each laboratory parameter will be presented 
in Figure 36, Figure 37, Figure 38, Figure 39, Figure 40, and Figure 41. Subject visits with abnormal 
laboratory results, Grade 1 severity or higher, will be presented in Table 125 and Table 126 for Chemistry and 
Hematology parameters, respectively. 
A complete listing of individual clinical laboratory results will be presented in Listing 14 and Listing 15 for 
chemistry and hematology, respectively, sorted by subject ID, parameter, and visit number. 
9.7. 
Vital Signs and Physical Evaluations 
Vital signs oral temperature, systolic blood pressure, diastolic blood pressure, and pulse will be assessed prior 
to study vaccination on Days 1 and 22 for study groups 1 and 4 and on Days 1 and 121 for study groups 2, 3, 
5, and 6. The grading scale for vital sign evaluations is presented in Table 12. Summaries of vital signs by 
maximum severity will be tabulated by visit, and study group (Table 127, Table 128, Table 129, Table 130, 
Table 131). A listing of vital signs will be presented (Listing 16). 
Targeted physical examinations will be performed, if indicated, based a subject’s medical history. A listing of 
physical exam findings will be presented (Listing 17). 


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9.8. 
Concomitant Medications 
Concomitant medications will be collected for the 30 days prior to the first study vaccination through 21 days 
after the second study vaccination. Concomitant medications will be coded to the Anatomical Therapeutic 
Classification (ATC) using the WHO Drug Dictionary. The use of prior and concomitant medications taken 
during the study will be recorded on the CRFs. A by-subject listing of concomitant medication use will be 
presented (Listing 18). The use of concomitant medications during the study will be summarized by ATC1, 
ATC2 code, study group for the Safety population (Table 132). 


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10. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”; p-values greater than 0.999 will be reported as “> 0.999“. The mean, standard deviation, and any 
other statistics other than quantiles, will be reported to one decimal place greater than the original data. 
Quantiles, such as median, or minimum and maximum will use the same number of decimal places as the 
original data. Proportions will be presented as two decimal places; values <0.01 will be presented as “<0.01”. 
Percentages will be reported to the nearest whole number; non-zero values < 1% will be presented as “<1%”; 
values greater than 99% but less than 100% will be presented as “>99%”. Estimated parameters, not on the 
same scale as raw observations (e.g. regression coefficients) will be reported to 3 significant figures. 


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11. 
TECHNICAL DETAILS 
SAS version 9.4 or above will be used to generate all tables, figures and listings. 
 


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12. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
This SAP does not include any changes from the analyses described in the protocol. 


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13. 
REFERENCES 
1. Gao, R., et al., Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med, 
2013. 368(20): p. 1888-97. 
2. Analysis of recent scientific information on avian influenza A(H7N9) virus. WHO Influenza Update, 
2017. 
3. Human infection with avian influenza A(H7N9) virus – China: 18 May 2017. WHO Emergencies 
preparedness, response, 2017. 
4. Drummond R. CONSORT Revised: Improving the Reporting of Randomized Clinical Trials. JAMA. 
2001; 285(15):2006-2007. 
5. FDA Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated 
Influenza Vaccines (US DHHS, FDA, CBER, May 2007). 
 
 


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14. 
APPENDICES 
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. Tables included in the topline set are 
indicated by *. 
 


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APPENDIX 1. TABLE MOCK-UPS 
 
 


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LIST OF TABLES 
Table 1: 
Study Design ...............................................................................................................48 
Table 2: 
Schedule of Study Procedures – Vaccination Period for Study Groups 1 and 4 ........49 
Table 3: 
Schedule of Study Procedures – Follow-Up Period for Study Groups 1 and 4 (Including 
early termination and unscheduled visits) ..................................................................53 
Table 4: 
Schedule of Study Procedures – Vaccination Period for Study Groups 2, 3, 5, and 656 
Table 5: 
Schedule of Study Procedures – Follow-Up Period for Study Groups 2, 3, 5, and 6 
(Including early termination and unscheduled visits) .................................................60 
Table 6: 
Power (%) to Detect Safety Events ............................................................................63 
Table 7: 
Precisions of Binomial Confidence Intervals .............................................................63 
Table 8: 
Minimum Detectable Difference in Proportion Responders ......................................64 
Table 9: 
Distribution of Protocol Deviations by Category, Type, and Study Group................65 
Table 10: Solicited Adverse Event Grading Scale – Local .........................................................68 
Table 11: Solicited Adverse Event Grading Scale - Systemic ....................................................69 
Table 12: Vital Signs Adverse Event Grading Scale ..................................................................70 
Table 13: Laboratory Adverse Event Grading Scale ..................................................................71 
Table 14: Ineligibility Summary of Screen Failures ...................................................................72 
Table 15: Analysis Populations by Study Group – All Enrolled Subjects .................................73 
Table 16: Subject Disposition by Study Group, All Enrolled Subjects ......................................77 
Table 17: Dates of First Study Vaccination by Site and Study Group .......................................78 
Table 18: Dates of Second Study Vaccination by Site and Study Group ...................................78 
Table 19: Summary of Categorical Demographic and Baseline Characteristics by Site, All Enrolled 
Subjects .......................................................................................................................79 
Table 20: Summary of Continuous Demographic and Baseline Characteristics by Site, All Enrolled 
Subjects .......................................................................................................................81 
Table 21: Summary of Categorical Demographic and Baseline Characteristics by Study Group, All 
Enrolled Subjects ........................................................................................................82 
Table 22: Summary of Continuous Baseline Characteristics by Study Group, All Enrolled Subjects
 ....................................................................................................................................85 
Table 23: Summary of Subjects with Prior or Concurrent Medical Conditions by MedDRA® 
System Organ Class and Study Group, Safety Population .........................................86 
Table 24: Summaries of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Day and Study Group, Modified Intent-to-Treat Population* ...87 
Table 25: Summaries of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Day and Study Group, Per Protocol Population* ......................89 


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Table 26: Summaries of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Day and Study Group, Modified Intent-to-Treat Population*....................................89 
Table 27: Summaries of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Day and Study Group, Per Protocol Population* .......................................................89 
Table 28: Summaries of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Day and Study Group, Modified Intent-to-Treat Population* ...89 
Table 29: Summaries of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Day and Study Group, Per Protocol Population* ......................89 
Table 30: Summaries of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by 
Study Day and Study Group, Modified Intent-to-Treat Population* .........................89 
Table 31: Summaries of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by 
Study Day and Study Group, Per Protocol Population* .............................................89 
Table 32: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and Age Group at 21 Days Post Second Vaccination, Per 
Protocol Population ....................................................................................................90 
Table 33: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and Age Group at 180 Days Post Second Vaccination, Per 
Protocol Population ....................................................................................................91 
Table 34: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and Age Group at 21 Days Post Second Vaccination, Per Protocol Population91 
Table 35: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and Age Group at 180 Days Post Second Vaccination, Per Protocol Population
 ....................................................................................................................................91 
Table 36: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and Age Group at 21 Days Post Second Vaccination, Per 
Protocol Population ....................................................................................................91 
Table 37: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and Age Group at 180 Days Post Second Vaccination, Per 
Protocol Population ....................................................................................................91 
Table 38: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and Age Group at 21 Days Post Second Vaccination, Per Protocol Population91 
Table 39: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and Age Group at 180 Days Post Second Vaccination, Per Protocol Population
 ....................................................................................................................................91 
Table 40: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and Sex at 21 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................92 


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Table 41: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and Sex at 180 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................93 
Table 42: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and Sex at 21 Days Post Second Vaccination, Per Protocol Population .........93 
Table 43: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and Sex at 180 Days Post Second Vaccination, Per Protocol Population .......93 
Table 44: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and Sex at 21 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................93 
Table 45: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and Sex at 180 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................93 
Table 46: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and Sex at 21 Days Post Second Vaccination, Per Protocol Population .........93 
Table 47: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and Sex at 180 Days Second Vaccination, Per Protocol Population ...............93 
Table 48: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and BMI at 21 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................94 
Table 49: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and BMI at 180 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................95 
Table 50: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and BMI at 21 Days Post Second Vaccination, Per Protocol Population .......95 
Table 51: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and BMI at 180 Days Post Second Vaccination, Per Protocol Population .....95 
Table 52: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and BMI at 21 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................95 
Table 53: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and BMI at 180 Days Post Second Vaccination, Per Protocol 
Population ...................................................................................................................95 
Table 54: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and BMI at 21 Days Post Second Vaccination, Per Protocol Population .......95 
Table 55: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and BMI at 180 Days Second Vaccination, Per Protocol Population .............95 


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Table 56: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and Seasonal Influenza Vaccination Status at 21 Days Post 
Second Vaccination, Per Protocol Population ............................................................96 
Table 57: Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 
(A/H7N9) by Study Group and Prior Seasonal Influenza Vaccination at 180 Days Post 
Second Vaccination, Per Protocol Population ............................................................98 
Table 58: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and Prior Seasonal Influenza Vaccination at 21 Days Post Second Vaccination, Per 
Protocol Population ....................................................................................................98 
Table 59: Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study 
Group and Prior Seasonal Influenza Vaccination at 180 Days Post Second Vaccination, 
Per Protocol Population ..............................................................................................98 
Table 60: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and Prior Seasonal Influenza Vaccination at 21 Days Post 
Second Vaccination, Per Protocol Population ............................................................98 
Table 61: Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 
(A/H7N9) by Study Group and Prior Seasonal Influenza Vaccination at 180 Days Post 
Second Vaccination, Per Protocol Population ............................................................98 
Table 62: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and Prior Seasonal Influenza Vaccination at 21 Days Post Second Vaccination, Per 
Protocol Population ....................................................................................................98 
Table 63: Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study 
Group and Prior Seasonal Influenza Vaccination at 180 Days Second Vaccination, Per 
Protocol Population ....................................................................................................98 
Table 64: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
HAI Seroconversion Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, 
Per Protocol Population ..............................................................................................99 
Table 65: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
HAI Seroconversion Against A/H7N9 Strains at 180 Days Post Second Study 
Vaccination, Per Protocol Population .........................................................................99 
Table 66: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
Neut Seroconversion Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, 
Per Protocol Population ..............................................................................................99 
Table 67: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
Neut Seroconversion Against A/H7N9 Strains at 180 Days Post Second Study 
Vaccination, Per Protocol Population .........................................................................99 
Table 68: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
HAI Seroconversion Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, 
Adjusted for Baseline Covariates, Per Protocol Population (N=X) .........................100 


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Table 69: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
HAI Seroconversion Against A/H7N9 Strains at 180 Days Post Second Study 
Vaccination, Adjusted for Baseline Covariates, Per Protocol Population ................101 
Table 70: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
Neut Seroconversion Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, 
Adjusted for Baseline Covariates, Per Protocol Population .....................................101 
Table 71: Logistic Regression Model to Evaluate the Relationship of Administration Schedule with 
Neut Seroconversion Against A/H7N9 Strains at 180 Days Post Second Study 
Vaccination, Adjusted for Baseline Covariates, Per Protocol Population ................101 
Table 72: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted HAI Titer Against A/H7N9 Strains at 21 Days Post Second 
Study Vaccination, Per Protocol Population (N=X) .................................................102 
Table 73: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted HAI Titer Against A/H7N9 Strains at 180 Days Post Second 
Study Vaccination, Per Protocol Population ............................................................102 
Table 74: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted Neut Titer Against A/H7N9 Strains at 21 Days Post Second 
Study Vaccination, Per Protocol Population ............................................................102 
Table 75: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted Neut Titer Against A/H7N9 Strains at 180 Days Post 
Second Study Vaccination, Per Protocol Population ................................................102 
Table 76: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted HAI Titer Against A/H7N9 Strains at 21 Days Post Second 
Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population .....103 
Table 77: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted HAI Titer Against A/H7N9 Strains at 180 Days Post Second 
Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population .....104 
Table 78: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted Neut Titer Against A/H7N9 Strains at 21 Days Post Second 
Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population .....104 
Table 79: Multiple Linear Regression Model to Evaluate the Relationship of Administration 
Schedule with Log-Adjusted Neut Titer Against A/H7N9 Strains at 180 Days Post 
Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population
 ..................................................................................................................................104 
Table 80: Summary of A/Shanghai/2/2013 (A/H7N9)–Specific Antibody Secreting Cells by 
Immunoglobulin Type, Study Group, and Study Day, Per Protocol Population ......105 
Table 81: Summary of A/Hong Kong/125/2017 (A/H7N9)–Specific Antibody Secreting Cells by 
Immunoglobulin Type, Study Group, and Study Day, Per Protocol Population ......106 
Table 82: Overall Summary of Adverse Events, Safety Population* .......................................107 


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Table 83: Number of Adverse Events Occurring in 5% of Subjects in Any Study Group by 
MedDRA® System Organ Class and Preferred Term, and Study Group, Safety Population
 ..................................................................................................................................109 
Table 84: Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence 
Intervals by Symptom and Study Group (Safety Population) – Post Any Study 
Vaccination ...............................................................................................................110 
Table 85: Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence 
Intervals by Symptom and Study Group (Safety Population) – Post Study Vaccination 1
 ..................................................................................................................................112 
Table 86: Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence 
Intervals by Symptom and Study Group (Safety Population) – Post Study Vaccination 2
 ..................................................................................................................................112 
Table 87: Logistic Regression Model to Evaluate the Relationship of Study Vaccination with 
Reporting Any Local Event Post Second Study Vaccination, Safety Population ....113 
Table 88: Logistic Regression Model to Evaluate the Relationship of Study Vaccination with 
Reporting Any Systemic Event Post Second Study Vaccination, Safety Population113 
Table 89: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, 
Maximum Severity and Study Group (Safety Population) – Post Any Study Vaccination
 ..................................................................................................................................114 
Table 90: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, 
Maximum Severity and Study Group (Safety Population) – Post Study Vaccination 1119 
Table 91: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, 
Maximum Severity and Study Group (Safety Population) – Post Study Vaccination 2119 
Table 92: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, 
Severity, Day Post Study Vaccination, and Study Group (Safety Population) – Post Any 
Study Vaccination .....................................................................................................120 
Table 93: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, 
Severity, Day Post Study Vaccination, and Study Group (Safety Population) – Post Study 
Vaccination 1 ............................................................................................................124 
Table 94: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, 
Severity, Day Post Study Vaccination, and Study Group (Safety Population) – Post Study 
Vaccination 2 ............................................................................................................124 
Table 95: Number and Percentage of Subjects Experiencing Solicited Systemic Events for Study 
Vaccination 1 Compared with Study Vaccination 2 by Study Group– Safety Population
 ..................................................................................................................................125 
Table 96: Number and Percentage of Subjects Experiencing Solicited Local Events for Study 
Vaccination 1 Compared with Study Vaccination 2 by Study Group, Safety Population
 ..................................................................................................................................126 


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Table 97: Number and Percentage of Subjects Experiencing Unsolicited Adverse Events with 95% 
Confidence Intervals by MedDRA® System Organ Class and Preferred Term, and Study 
Group, Safety Population* ........................................................................................127 
Table 98: Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by 
MedDRA® System Organ Class and Preferred Term, Maximum Severity, Relationship, 
and Study Group, Safety Population ........................................................................128 
Table 99: Number and Percentage of Subjects Experiencing Unsolicited Adverse Events within 21 
Days of Study Vaccination by MedDRA® System Organ Class and Preferred Term, 
Maximum Severity, Relationship, and Study Group, Safety Population .................130 
Table 100 Number and Percentage of Subjects Experiencing Non-Serious Related Unsolicited 
Adverse Events by MedDRA® System Organ Class and Preferred Term, Maximum 
Severity, and Study Group, Safety Population .........................................................131 
Table 101: Number and Percentage of Subjects Experiencing Non-Serious Related Unsolicited 
Adverse Events Within 21 Days Post Study Vaccination by MedDRA® System Organ 
Class and Preferred Term, Maximum Severity, and Study Group, Safety Population133 
Table 102: Number and Percentage of Subjects Experiencing Unsolicited Adverse Events Within 21 
Days Post Study Vaccination by MedDRA® System Organ Class and Preferred Term, 
Day Post Study Vaccination, and Study Group, Safety Population .........................134 
Table 103: Number and Percentage of Subjects Experiencing Non-Serious, Related Unsolicited 
Adverse Events Within 21 Days Post Study Vaccination by MedDRA® System Organ 
Class and Preferred Term, Vaccination and Study Group, Safety Population .........135 
Table 104: Number of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Day Post Study Vaccination, and Study Group, Safety Population ...............136 
Table 105: Number of Non-Serious, Related, Unsolicited Adverse Events by MedDRA® System 
Organ Class and Preferred Term, Day Post Study Vaccination, and Study Group, Safety 
Population .................................................................................................................136 
Table 106: Listing of Serious Adverse Events – Safety Population * ........................................137 
Table 107: Listing of Medically Attended Adverse Events – Safety Population .......................138 
Table 108: Listing of Potentially Immune Mediated Medical Conditions .................................138 
Table 109: Listing of New Onset Chronic Medical Conditions .................................................138 
Table 110: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events .............138 
Table 111: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – All Chemistry Parameters– Safety Population ......................140 
Table 112: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – Alanine aminotransferase (ALT) ...........................................142 
Table 113: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – Total Bilirubin .......................................................................142 
Table 114: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – Creatinine ..............................................................................142 


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Table 115: Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and 
Study Group (Safety Population) – Alanine Aminotransferase (ALT) ....................143 
Table 116: Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and 
Study Group (Safety Population) – Total Bilirubin ..................................................144 
Table 117: Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and 
Study Group (Safety Population) – Creatinine .........................................................144 
Table 118: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – All Hematology Parameters ..................................................145 
Table 119: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – Hemoglobin ...........................................................................146 
Table 120: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – White Blood Cells .................................................................147 
Table 121: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group 
(Safety Population) – Platelets ..................................................................................149 
Table 122: Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and 
Study Group (Safety Population) – Hemoglobin ......................................................150 
Table 123: Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and 
Study Group (Safety Population) – White Blood Cells ............................................151 
Table 124: Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and 
Study Group (Safety Population) – Platelets ............................................................151 
Table 125: Listing of Abnormal Laboratory Results - Chemistry ..............................................153 
Table 126: Listing of Abnormal Laboratory Results - Hematology ...........................................154 
Table 127: Vital Signs by Assessment, Maximum Severity, Study Day, Study Group (Safety 
Population) – Any Assessment .................................................................................155 
Table 128: Vital Signs by Assessment, Maximum Severity, Study Day, Study Group (Safety 
Population) – Oral Temperature ...............................................................................156 
Table 129: Vital Signs by Assessment, Maximum Severity, Study Day, and Study Group (Safety 
Population) – Systolic Blood Pressure .....................................................................157 
Table 130: Vital Signs by Assessment, Maximum Severity, Study Day, and Study Group (Safety 
Population) – Diastolic Blood Pressure ....................................................................158 
Table 131: Vital Signs by Assessment, Maximum Severity, Study Day, and Study Group (Safety 
Population) – Pulse ...................................................................................................158 
Table 132: Number and Percentage of Subjects with Prior and Concurrent Medications by WHO 
Drug Classification and Study Group .......................................................................159 
 
 


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9.1 
Overall Study Design and Plan Description 
Table 1: 
Study Design 
Influenza A/H7 
Vaccine/Infection Naïve 
Subjects (Total N=180) 
Study 
Group/N 
1st Study Vaccination 
Day 1 
2nd Study 
Vaccination 
~ Day 22 post 
Vaccination 1 
2nd Study Vaccination 
~ Day 121 post 
Vaccination 1 
Study 
Vaccination 
Schedule 
Heterologous 
Prime-Boost 
1/30 
2013 A/H7N9 IIV 3.75 
mcg + AS03 
2017 A/H7N9 IIV 
3.75 mcg + AS03 
 
2/30 
2013 A/H7N9 IIV 3.75 
mcg + AS03 
 
2017 A/H7N9 IIV 3.75 
mcg + AS03 
3/30 
2013 A/H7N9 IIV 3.75 
mcg + AS03 
 
2017 A/H7N9 IIV 
15 mcg 
Homologous 
Prime-Boost 
4/30 
2017 A/H7N9 IIV 3.75 
mcg + AS03 
2017 A/H7N9 IIV 
3.75 mcg + AS03 
 
5/30 
2017 A/H7N9 IIV 3.75 
mcg + AS03 
 
2017 A/H7N9 IIV 3.75 
mcg + AS03 
6/30 
2017 A/H7N9 IIV 3.75 
mcg + AS03 
 
2017 A/H7N9 IIV 
15 mcg 
 


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9.5.1 
Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 2: 
Schedule of Study Procedures – Vaccination Period for Study Groups 1 and 4 
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D23 
D25 
D29 
D36 
D43 
Study Day post second study vaccination 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
Informed Consent∞ 
X 
X†¬ 
 
 
 
 
Demographic Information 
X 
X†* 
 
 
 
 
Eligibility Criteria 
X 
X†¬1 
 
 
X†1 
 
 
Medical History@ 
X 
X†¬ 
X 
X 
X 
X 
X† 
X 
X 
X 
X 
X 
Concomitant Medicationsς 
X 
X†¬ 
X 
X 
X 
X 
X† 
X 
X 
X 
X 
X 
Vital Signs (Oral Temperature%, Pulse and BP) 
X 
X†$ 
 
 
X†2 
 
 
Height and Weight 
X 
X†* 
 
 
 
 
Physical Examination 
X3 
X†3*{} 
{X} 
{X} 
{X} 
{X} 
{X}† 
{X} {X} 
{X} 
{X} 
{X} 
Urine or Serum Pregnancy Test 
X^ 
X†^ 
 
 
X†^ 
 
 
Venous Blood Collection for ESR 
X≠ 
X≠* 
 
 
 
 
Enrollment in AdvantageEDCSM and Randomization 
 
X† 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D23 
D25 
D29 
D36 
D43 
Study Day post second study vaccination 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
Venous Blood Collection for Clinical Safety Laboratory 
Evaluations~ 
 
X†# 
 
 
X 
 
X† 
 
 
X 
 
 
Venous Blood Collection for Serological Assays 
X† 
 
 
X†Ψ 
 
 
X 
Venous Blood Collection for Cellular Immunology 
Assays 
 
X† 
X 
X 
X 
X 
X† 
X 
X 
X 
X 
 
Venous Blood Collection for Future Research 
X† 
X 
X 
X 
X 
X† 
X 
X 
X 
X 
X 
Pre-Administration Reactogenicity Assessments 
X† 
 
 
X† 
 
 
Study Vaccination 
 
X 
 
 
 
 
X 
 
 
 
 
 
20-minute Evaluation After Study Vaccination 
X 
 
 
X 
 
 
Examine Study Vaccination Site 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Post-Administration Reactogenicity Assessments 
X 
 
 
X 
 
 
Distribute Memory Aid and Study-Related Materials 
X 
 
 
X 
 
 
Review Memory Aid 
X 
X 
X 
 
X 
X 
X 
 
AE/SAE Assessment 
X& 
X& 
X& 
X& 
X 
X&4 
X&4 
X&4 
X&4 
X4 
X4 
∞ 
Prior to study procedures. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D23 
D25 
D29 
D36 
D43 
Study Day post second study vaccination 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
¬  
Review/confirm information or activity in subjects previously consented and screened. 
†  
Prior to study vaccination. 
*  
Not required if done at the optional screening visit. 
1  
Review results of ESR or clinical safety laboratory evaluations. 
@ 
Complete medical history will be obtained by interview of subjects at the screening visit (optional) or on Day 1 prior to the first study vaccination, and interim 
medical history will be obtained by interview of subjects at follow-up visits after the first study vaccination. 
ς  
Receipt of any non-study influenza vaccines will be solicited through approximately 180 days after the last study vaccination, and reported in the eCRF. 
$  
Vital signs assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
% 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
2  
Vital signs are not required for subjects who are discontinued from receipt of the second study vaccination and being followed for safety. 
3  
At the screening visit (optional) or on Day 1 prior to the first study vaccination, a physical examination will be performed on all subjects to include the following 
organs and organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, and nervous system, and as an assessment for signs suggestive 
of PIMMCs. 
{} 
Targeted physical examination if indicated based on review of interim medical history. 
^  
Performed locally by the site at the screening visit (optional) or within 24 hours prior to each study vaccination for all women of childbearing potential. Results must 
be negative and known prior to randomization on Day 1 and administration of each study vaccination. 
≠  
Performed locally by the site at the screening visit (optional) or on Day 1 prior to the first study vaccination. The ESR value must be confirmed as less than 30 mm 
per hour prior to randomization on Day 1 and administration of the first study vaccination. 
~  
Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
#  
Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered as baseline. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D23 
D25 
D29 
D36 
D43 
Study Day post second study vaccination 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
Ψ 
Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone call 
rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a venous 
blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
& 
Inclusive of reactogenicity assessments performed on the day of each study vaccination through 7 days after each study vaccination. 
4  
AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued from receipt of the second study vaccination and being 
followed for safety. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 3: 
Schedule of Study Procedures – Follow-Up Period for Study Groups 1 and 4 (Including early termination and unscheduled 
visits) 
Study Visit Number 
V12** 
V13 
V14** 
V15 
V16** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D82 
D112 
D142 
D202 
D387 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Medical History@ 
 
X 
X 
 
X 
X (if indicated) 
Concomitant Medicationsς 
X 
X 
X 
X 
 
X (if prior to 21 days 
after last study 
vaccination and 
receipt of any non-
study influenza 
vaccines if within 180 
days after last study 
vaccination) 
X (if prior to 21 days 
after last study 
vaccination and receipt 
of any non-study 
influenza vaccines if 
within 180 days after 
last study vaccination) 
Vital Signs (Oral Temperature%, Pulse and BP) 
 
 
 
X (may be obtained if 
indicated) 
X (may be obtained if 
indicated) 
Physical Examination 
 
{X} 
 
{X} 
 
{X} 
{X} 
Venous Blood Collection for Clinical Safety Laboratory Evaluations~ 
 
 
 
 
 
X (if within 7 days 
after last study 
vaccination) 
X (if indicated) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V12** 
V13 
V14** 
V15 
V16** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D82 
D112 
D142 
D202 
D387 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Venous Blood Collection for Serological Assays 
 
 
 
XΨ 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days 
after last study 
vaccination) 
Venous Blood Collection for Cellular Immunology Assays 
 
X 
 
X 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days 
after last study 
vaccination) 
Venous Blood Collection for Future Research 
 
X 
 
X 
 
X (if within 21 days 
after last study 
vaccination) 
X (if within 21 days 
after last study 
vaccination) 
Examine Study Vaccination Site 
 
 
 
 
 
X (if within 7 days 
after last study 
vaccination) 
X (if within 7 days 
after last study 
vaccination) 
Post-Administration Reactogenicity Assessments 
 
 
 
X (if within 7 days 
after last study 
vaccination) 
X (if within 7 days 
after last study 
vaccination) 
Review Memory Aid 
 
 
 
 
 
X (if within 7 days 
after last study 
vaccination) 
X (if within 7 days 
after last study 
vaccination) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V12** 
V13 
V14** 
V15 
V16** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D82 
D112 
D142 
D202 
D387 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
AE/SAE Assessment! 
X 
X 
X 
X 
X 
X (if after 21 days 
after last study 
vaccination) 
X (if after 21 days after 
last study vaccination) 
** 
Phone call assessment. 
@ 
Complete medical history will be obtained by interview of subjects at the screening visit (optional) or on Day 1 prior to the first study vaccination, and interim 
medical history will be obtained by interview of subjects at follow-up visits after the first study vaccination. 
ς  
Receipt of any non-study influenza vaccines will be solicited through approximately 180 days after the last study vaccination, and reported in the eCRF. 
% 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
{} 
Targeted physical examination if indicated based on review of interim medical history. 
~  
Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
Ψ 
Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone call 
rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a venous 
blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
!  
AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or phone call. 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 4: 
Schedule of Study Procedures – Vaccination Period for Study Groups 2, 3, 5, and 6 
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07** 
V08 
V09 
V10 
V11 
V12 
V13 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D61±7d 
D121-7/+14d 
D122 
D124 
D128 
D135 
D142 
Study Day post second study vaccination 
 
 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
Informed Consent∞ 
X 
X†¬ 
 
 
 
 
 
 
Demographic Information 
X 
X†* 
 
 
 
 
 
 
Eligibility Criteria 
X 
X†¬1 
 
 
 
 
X†1 
 
 
Medical History@ 
X 
X†¬ 
X 
X 
X 
X 
X 
Xς 
X† 
X 
X 
X 
X 
X 
Concomitant Medicationsς 
X 
X†¬ 
X 
X 
X 
X 
X 
X 
X† 
X 
X 
X 
X 
X 
$Vital Signs (Oral Temperature%, Pulse and 
BP) 
X 
X†$ 
 
 
 
 
X†2 
 
 
Height and Weight 
X 
X†* 
 
 
 
 
 
 
Physical Examination 
X3 
X†3*{} 
{X} 
{X} 
{X} 
{X} 
{X} 
 
{X}† 
{X} {X} 
{X} 
{X} 
{X} 
Urine or Serum Pregnancy Test 
X^ 
X†^ 
 
 
 
 
X†^ 
 
 
Venous Blood Collection for ESR 
X≠ 
X≠* 
 
 
 
 
 
 
Enrollment in AdvantageEDCSM and 
Randomization 
 
X† 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07** 
V08 
V09 
V10 
V11 
V12 
V13 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D61±7d 
D121-7/+14d 
D122 
D124 
D128 
D135 
D142 
Study Day post second study vaccination 
 
 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
Venous Blood Collection for Clinical Safety 
Laboratory Evaluations~ 
X†# 
 
X 
 
 
 
X† 
 
X 
 
Venous Blood Collection for Serological 
Assays 
X† 
 
 
X 
 
X†Ψ 
 
 
X 
Venous Blood Collection for Cellular 
Immunology Assays 
 
X† 
X 
X 
X 
X 
 
 
X† 
X 
X 
X 
X 
 
Venous Blood Collection for Future 
Research 
X† 
X 
X 
X 
X 
X 
 
X† 
X 
X 
X 
X 
X 
Pre-Administration Reactogenicity 
Assessments 
 
X† 
 
 
 
 
 
 
X† 
 
 
 
 
 
Study Vaccination 
X 
 
 
 
 
X 
 
 
20-minute Evaluation After Study 
Vaccination 
X 
 
 
 
 
X 
 
 
Examine Study Vaccination Site 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Post-Administration Reactogenicity 
Assessments 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07** 
V08 
V09 
V10 
V11 
V12 
V13 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D61±7d 
D121-7/+14d 
D122 
D124 
D128 
D135 
D142 
Study Day post second study vaccination 
 
 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
Distribute Memory Aid and Study-Related 
Materials 
X 
 
 
 
 
X 
 
 
Review Memory Aid 
X 
X 
X 
 
 
 
X 
X 
X 
 
AE/SAE Assessment 
X& 
X& 
X& 
X& 
X 
X 
X! 
X& 
X&4 
X&4 
X&4 
X4 
X4 
** 
Phone call assessment. 
∞ 
Prior to study procedures. 
¬  
Review/confirm information or activity in subjects previously consented and screened. 
†  
Prior to study vaccination. 
*  
Not required if done at the optional screening visit. 
1  
Review results of ESR or clinical safety laboratory evaluations. 
@ 
Complete medical history will be obtained by interview of subjects at the screening visit (optional) or on Day 1 prior to the first study vaccination, and interim 
medical history will be obtained by interview of subjects at follow-up visits after the first study vaccination. 
ς  
Receipt of any non-study influenza vaccines will be solicited through approximately 180 days after the last study vaccination and reported in the eCRF. 
$  
Vital signs assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
% 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
2  
Vital signs are not required for subjects who are discontinued from receipt of the second study vaccination and being followed for safety. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07** 
V08 
V09 
V10 
V11 
V12 
V13 
Study Day post first study vaccination 
Screening 
(Optional) 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
D61±7d 
D121-7/+14d 
D122 
D124 
D128 
D135 
D142 
Study Day post second study vaccination 
 
 
 
 
 
 
 
 
Dose 2 
D1 
D2+1d 
D4+1d 
D8-1/+2d 
D15±1d 
D22+7d 
Study Procedure/Evaluation 
3  
At the screening visit (optional) or on Day 1 prior to the first study vaccination, a physical examination will be performed on all subjects to include the following 
organs and organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, and nervous system, and as an assessment for signs suggestive 
of PIMMCs. 
{} 
Targeted physical examination if indicated based on review of interim medical history. 
^  
Performed locally by the site at the screening visit (optional) or within 24 hours prior to each study vaccination for all women of childbearing potential. Results must 
be negative and known prior to randomization on Day 1 and administration of each study vaccination. 
≠  
Performed locally by the site at the screening visit (optional) or on Day 1 prior to the first study vaccination. The ESR value must be confirmed as less than 30 mm 
per hour prior to randomization on Day 1 and administration of the first study vaccination. 
~  
Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
#  
Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
Ψ 
Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone call 
rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a venous 
blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
& 
Inclusive of reactogenicity assessments performed on the day of each study vaccination through 7 days after each study vaccination. 
!  
AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or phone call. 
4  
AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, for subjects who are discontinued from receipt of the second study vaccination and being 
followed for safety. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 5: 
Schedule of Study Procedures – Follow-Up Period for Study Groups 2, 3, 5, and 6 (Including early termination and 
unscheduled visits) 
Study Visit Number 
V14** 
V15 
V16** 
V17 
V18** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D181 
D211 
D241 
D301 
D486 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Medical History@ 
 
X 
X 
 
X 
X (if indicated) 
Concomitant Medicationsς 
X 
X 
X 
X 
 
X (if prior to 21 days 
after last study 
vaccination and receipt of 
any non-study influenza 
vaccines if within 180 
days after last study 
vaccination) 
X (if prior to 21 days 
after last study 
vaccination and 
receipt of any non-
study influenza 
vaccines if within 180 
days after last study 
vaccination) 
Vital Signs (Oral Temperature%, Pulse and BP) 
 
 
 
X (may be obtained if 
indicated) 
X (may be obtained if 
indicated) 
Physical Examination 
 
{X} 
 
{X} 
 
{X} 
{X} 
Venous Blood Collection for Clinical Safety Laboratory Evaluations~ 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if indicated) 
Venous Blood Collection for Serological Assays 
 
 
 
XΨ 
 
X (if within 21 days after 
last study vaccination) 
X (if within 21 days 
after last study 
vaccination) 


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Study Visit Number 
V14** 
V15 
V16** 
V17 
V18** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D181 
D211 
D241 
D301 
D486 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
Venous Blood Collection for Cellular Immunology Assays 
 
X 
 
X 
 
X (if within 21 days after 
last study vaccination) 
X (if within 21 days 
after last study 
vaccination) 
Venous Blood Collection for Future Research 
 
X 
 
X 
 
X (if within 21 days after 
last study vaccination) 
X (if within 21 days 
after last study 
vaccination) 
Examine Study Vaccination Site 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days 
after last study 
vaccination) 
Post-Administration Reactogenicity Assessments 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days 
after last study 
vaccination) 
Review Memory Aid 
 
 
 
 
 
X (if within 7 days after 
last study vaccination) 
X (if within 7 days 
after last study 
vaccination) 
AE/SAE Assessment! 
X 
X 
X 
X 
X 
X (if after 21 days after 
last study vaccination) 
X (if after 21 days 
after last study 
vaccination) 
** 
Phone call assessment. 


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Study Visit Number 
V14** 
V15 
V16** 
V17 
V18** 
Early Termination 
(if needed) 
Unscheduled 
(if needed) 
Study Day post first study vaccination 
D181 
D211 
D241 
D301 
D486 
Study Day post second study vaccination 
D61±7d 
D91±14d 
D121±14d 
D181±14d 
D366±14d 
Study Procedure/Evaluation 
@ 
Complete medical history will be obtained by interview of subjects at the screening visit (optional) or on Day 1 prior to the first study vaccination, and interim 
medical history will be obtained by interview of subjects at follow-up visits after the first study vaccination. 
ς  
Receipt of any non-study influenza vaccines will be solicited through approximately 180 days after the last study vaccination, and reported in the eCRF. 
% 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
{} 
Targeted physical examination if indicated based on review of interim medical history. 
~  
Includes WBC, Hgb, PLT, ALT, T. Bili, Cr. 
Ψ 
Subjects who receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up safety assessments (may be conducted by phone call 
rather than in person) continuing through approximately 12 months after their last study vaccination. These subjects will also be encouraged to provide a venous 
blood sample for serological assays approximately 21 and 180 days after their last study vaccination. 
!  
AEs limited to SAEs and MAAEs, including NOCMCs and PIMMCs, that have occurred since the previous clinic visit or phone call. 


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9.7.1 
Sample Size 
Table 6: 
Power (%) to Detect Safety Events 
Event Frequency 
N=30 
N=180 
≥10% 
Very Common 
95 
>99 
≥1% 
Common 
26 
83 
≥0.1% 
Uncommon 
2 
16 
≥0.01% 
Rare 
<1 
1 
Table 7: 
Precisions of Binomial Confidence Intervals 
N 
95% CI 
30 
31-69 
180 
42-58 
 
 
 


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Table 8: 
Minimum Detectable Difference in Proportion Responders 
N per Group 
Proportion Responders 
in Comparator Group A 
80% Power 
Minimal Detectable 
Difference 
Proportion Responders in 
Comparator Group B 
N=27 
0.10 
0.32 
0.42 
0.20 
0.35 
0.55 
0.30 
0.38 
0.68 
0.40 
0.37 
0.77 
0.50 
0.34 
0.84 
 
 


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10.2 
Protocol Deviations 
Table 9: 
Distribution of Protocol Deviations by Category, Type, and Study Group 
Category 
Deviation Type 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
Eligibility/ 
enrollment 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Did not meet inclusion 
criterion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Met exclusion criterion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF not signed prior to 
study procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
administration 
schedule 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed visit/visit not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Delayed treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Category 
Deviation Type 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
Follow-up visit 
schedule 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed visit/visit not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
procedure/ 
assessment 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incorrect version of ICF 
signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood not collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine not collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other specimen not 
collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Too few aliquots obtained 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen result not 
obtained 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done 
incorrectly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Category 
Deviation Type 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
 
Study product temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
administration 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done 
incorrectly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study product temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinding policy/ 
procedure 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment unblinded 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects enrolled. 
Implementation Note: Shell has placeholders for all types of deviations possible. The final table will be limited to deviations actually reported in 
the study. 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
12.2.2 Displays of Adverse Events 
Table 10: 
Solicited Adverse Event Grading Scale – Local 
Local (Injection Site) Reactogenicity Grading 
Local (Injection Site) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous discomfort) 
Subject is aware of pain, 
but it does not interfere 
with daily activity, and no 
pain medication is taken 
Subject is aware of pain; 
there is interference with 
daily activity, or it 
requires repeated use of a 
non-narcotic pain reliever 
for >24 hours 
Subject is aware of pain, and 
it prevents daily activity or 
requires any use of a narcotic 
pain reliever 
Tenderness – hurts only 
when injection site is 
touched, or the arm is 
moved 
The area immediately 
surrounding the injection 
site hurts only when 
touched or with arm 
motion, and it does not 
interfere with daily activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
interferes with daily 
activity 
The area immediately 
surrounding the injection site 
hurts when touched or with 
arm motion, and it prevents 
daily activity 
Pruritus (Itching) 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis (Bruising)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema (Redness)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration 
(Hardness)/Swelling* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Local (Injection Site) Reactogenicity Measurements 
Local (Injection Site) 
Reaction 
Small (Grade 1) 
Medium (Grade 2) 
Large (Grade 3) 
Ecchymosis (Bruising)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema (Redness)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration 
(Hardness)/Swelling* 
<20 mm 
20 mm – 50 mm 
>50 mm 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 11: 
Solicited Adverse Event Grading Scale - Systemic 
Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness 
(Chills/Shivering/Sweating) 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Fatigue (Tiredness) 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise (General Unwell 
Feeling) 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia (Body Aches/Muscular 
Pain)* 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia (Joint Pain)* 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Headache 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Nausea 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Quantitative Systemic Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever# - oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
*  Not at injection site. 
#  Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as baseline. A fever can be 
considered not related to the study product if an alternative etiology can be documented. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 12: 
Vital Signs Adverse Event Grading Scale 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia - beats per minute 
45 – 46 
40 – 44 
<40 
Tachycardia - beats per minute 
101 – 130 
131 – 155 
>155 
Hypotension (systolic) mmHg 
80 – 84 
75 – 79 
<75 
Hypotension (diastolic) mmHg 
50 – 54 
45 – 49 
<45 
Hypertension (systolic) mmHg 
151 – 155 
156 – 160 
>160 
Hypertension (diastolic) mmHg 
96 – 100 
101 – 105 
>105 
# Pulse and blood pressure assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 13: 
Laboratory Adverse Event Grading Scale 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/µL (Decrease) 
2.5 – 3.9 
1.5 – 2.4 
<1.5 
WBC 103/µL (Increase) 
10.6 – 15.0 
15.1 – 20.0 
>20.0 
Hgb g/dL (Decrease) (Female) 
10.1 – 11.4 
8.5 – 10 
<8.5 
Hgb g/dL (Decrease) (Male) 
11.0 – 12.4 
9.5 – 10.9 
<9.5 
Platelets 103/µL (Decrease) 
125 – 139 
100 – 124 
<100 
Platelets 103/µL (Increase) 
416 – 550 
551– 750 
>750 
Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
ALT IU/L (Increase) (Female) 
44 – 100 
101 – 200 
>200 
ALT IU/L (Increase) (Male) 
61 – 138 
139 – 275 
>275 
Total Bilirubin mg/dL (Increase) – 
when accompanied by any increase in 
ALT 
1.30 – 1.59 
1.60 – 1.80 
>1.80 
Total Bilirubin mg/dL (Increase) – 
when ALT is normal 
1.30 – 1.89 
1.90 – 2.40 
>2.40 
Creatinine mg/dL (Increase) (Female) 
1.1 – 1.7 
1.8 – 2.0 
>2.0 
Creatinine mg/dL (Increase) (Male) 
1.4 – 1.7 
1.8 – 2.0 
>2.0 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.1 
Description of Study Subjects 
14.1.1 Disposition of Subjects 
Table 14: 
Ineligibility Summary of Screen Failures 
Category 
Criterion 
na 
%b 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
x 
x 
Inclusion 
Any inclusion criterion 
x 
x 
 
[inclusion criterion 1] 
x 
x 
 
[inclusion criterion 2] 
x 
x 
 
[inclusion criterion 3] 
x 
x 
Exclusion 
Any exclusion criterion 
x 
x 
 
[exclusion criterion 1] 
x 
x 
 
[exclusion criterion 2] 
x 
x 
 
[exclusion criterion 3] 
x 
x 
Eligible but Not Enrolled 
Any reason 
x 
x 
 
[reason 1] 
x 
x 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 15: 
Analysis Populations by Study Group – All Enrolled Subjects 
[Implementation Note: Only include reasons actually reported, omit lines for any reasons that were not observed in the trial.] 
Analysis Populations 
Reason Subjects Excluded 
Group 1 
2013 
3.75+AS03/  
20173.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Safety Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 1 Not Received 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Modified Intent-to-Treat 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 1 Not Received 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
No Baseline Results Available 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
No Post-Vaccination Results 
Available 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Per Protocol, Day 22 post 
Vac 1 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 1 Not Received 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
No Baseline Results Available 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 No Day 22 post Vac 1 Result 
Reported by Lab 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Lost to Follow-up Before Day 22 
post Vac 1 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Non-Study Vaccination 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Immunosuppressive 
medication 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Analysis Populations 
Reason Subjects Excluded 
Group 1 
2013 
3.75+AS03/  
20173.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Day 22 post Vac 1 Visit Out of 
Window 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Per Protocol, Day 121 post 
Vac 1 
Any Reason 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 1 Not Received 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 2 Not Received 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 2 Out of 
Window 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
No Baseline Results Available 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
No Day 121 post Vac 1 Result 
Reported by Lab 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
Lost to Follow-up Before Day 121 
post Vac 1 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Non-Study Vaccination 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Immunosuppressive 
medication 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
 
Day 121 post Vac 1 Visit Out of 
Window 
NA 
NA 
x 
xx 
x 
xx 
NA 
NA 
x 
xx 
x 
xx 
x 
xx 
Per Protocol, Day 22 post 
Vac 2 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 1 Not Received 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 2 Not Received 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Analysis Populations 
Reason Subjects Excluded 
Group 1 
2013 
3.75+AS03/  
20173.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Study Vaccination 2 Out of 
Window 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
No Baseline Results Available 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
No Day 22 post Vac 2 Result 
Reported by Lab 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Lost to Follow-up Before Day 22 
post Vac 2 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Non-Study Vaccination 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Immunosuppressive 
medication 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 Day 22 post Vac 2 Visit Out of 
Window 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Per Protocol, Day 181 post 
Vac 2 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 1 Not Received 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 2 Not Received 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Vaccination 2 Out of 
Window 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
No Baseline Results Available 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
No Day 181 post Vac 2 Result 
Reported by Lab 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Analysis Populations 
Reason Subjects Excluded 
Group 1 
2013 
3.75+AS03/  
20173.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Lost to Follow-up Before Day 181 
post Vac 2 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Non-Study Vaccination 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Receipt of Immunosuppressive 
medication 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Day 181 post Vac 2 Visit Out of 
Window 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 16: 
Subject Disposition by Study Group, All Enrolled Subjects 
Subject 
Disposition  
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Screened 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
Enrolled/Randomized 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
Received Vaccination 1 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Received Vaccination 2 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Received All Scheduled 
Vaccinations a 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Blood Draw for 
Primary Immunogenicity 
Analysisb 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Included in Per Protocol 
Immunogenicity Analysis 
of Primary Immunogenicity 
Outcomesb c 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Primary Follow-
upa b c 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Final Study 
Visitb 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N=Number of subjects enrolled. 
a Refer to Listing 2 for reasons subjects discontinued from study vaccinations or terminated early. 
b The final blood draw for Primary Immunogenicity Analysis occurs at 21 days post final vaccination (Day 43 for Groups 1 and 4; Day 142 for Groups 2, 3, 5 and 6). 
c Refer to Listing 5 for reasons subjects are excluded from the Per Protocol Population. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 17: 
Dates of First Study Vaccination by Site and Study Group 
Dates of Dosing 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All Subjects 
(N=X) 
[Site 1] 
Total (Entire period of enrollment) 
x 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
x 
…. 
 
 
 
 
 
 
 
[Site 2] 
Total (Entire period of enrollment) 
x 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
x 
…. 
 
 
 
 
 
 
 
[Repeat for all sites] 
N= Number of subjects in the Safety Population. 
 
Table with similar format: 
Table 18: 
Dates of Second Study Vaccination by Site and Study Group 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.1.2 Demographic Data by Study Group 
Table 19: 
Summary of Categorical Demographic and Baseline Characteristics by Site, All Enrolled Subjects 
Variable 
Characteristic 
[Site 1] 
(N=X) 
[Site 2] 
(N=X) 
[Site 3] 
(N=X) 
[Site 4] 
(N=X) 
[Site 5] 
(N=X) 
[Site 6] 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
< 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≥ 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Hispanic or Latino 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race  
American Indian or Alaska Native 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Asian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Native Hawaiian or Other Pacific 
Islander 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Black or African American 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
White 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multi-Racial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Seasonal Influenza 
Vaccination (Prior Seasons) 
2016-2017 Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2016-2017 Not Received   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Variable 
Characteristic 
[Site 1] 
(N=X) 
[Site 2] 
(N=X) 
[Site 3] 
(N=X) 
[Site 4] 
(N=X) 
[Site 5] 
(N=X) 
[Site 6] 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
  
2016-2017 Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2017-2018 Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2017-2018 Not Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2017-2018 Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seasonal Influenza Vaccination 
(Current Season) 
2018-2019 Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2018-2019 Not Received   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
2018-2019 Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Receipt of H5 Influenza 
Vaccine 
No Prior H5 Influenza Vaccination(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Received Prior H5 Influenza 
Vaccination(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N= Number of subjects enrolled. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 20: 
Summary of Continuous Demographic and Baseline Characteristics by Site, All Enrolled Subjects 
Variable 
Statistic 
[Site 1] 
(N=X) 
[Site 2] 
(N=X) 
[Site 3] 
(N=X) 
[Site 4] 
(N=X) 
[Site 5] 
(N=X) 
[Site 6] 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
BMI 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
N= Number of subjects enrolled. 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 21: 
Summary of Categorical Demographic and Baseline Characteristics by Study Group, All Enrolled Subjects 
Variable 
Characteristic 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
< 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≥ 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age 
19-34 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
35-50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Hispanic or Latino 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race  
American Indian or Alaska 
Native 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Asian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Native Hawaiian or Other 
Pacific Islander 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Black or African American 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
White 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Variable 
Characteristic 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Multi-Racial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
Seasonal 
Influenza 
Vaccination 
(Prior 
Seasons) 
2016-2017 Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2016-2017 Not Received   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
2016-2017 Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2017-2018 Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2017-2018 Not Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2017-2018 Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seasonal 
Influenza 
Vaccination 
(Current 
Season) 
2018-2019 Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2018-2019 Not Received   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
2018-2019 Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Variable 
Characteristic 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Prior Receipt 
of H5 Influenza 
Vaccine 
No Prior H5 Influenza 
Vaccinations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Received Prior H5 Influenza 
Vaccinations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N= Number of subjects enrolled. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 22: 
Summary of Continuous Baseline Characteristics by Study Group, All Enrolled Subjects 
Variable 
Statistic 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
Age 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
BMI 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
N= Number of subjects enrolled. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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14.1.3 Prior and Concurrent Medical Conditions 
Table 23: 
Summary of Subjects with Prior or Concurrent Medical Conditions by MedDRA® System Organ Class and Study Group, 
Safety Population 
MedDRA® System Organ Class 
Group 1 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N=Number of subjects in the Safety Population;  
n = Number of subjects reporting medical history within the specified SOC. A subject is only counted once per SOC. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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14.2 
Immunogenicity Data 
14.2.1 Antibody Response Against 2013 and 2017 A/H7N9 
Table 24: 
Summaries of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Day and Study Group, 
Modified Intent-to-Treat Population* 
Time Point 
Statistic 
Group 1 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Day 1  
(Pre-Vaccination 1) 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) c 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI) d 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 22 Post 
Vaccination 1 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)c 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)d 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)c 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Seroconversion - % (95% CI)d 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 121 post 
Vaccination 1 
n 
NA 
x 
x 
NA 
x 
x 
GMT (95% CI)c 
NA 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
NA 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)d 
NA 
xx (xx, xx) 
xx (xx, xx) 
NA 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)c 
NA 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
NA 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Time Point 
Statistic 
Group 1 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Seroconversion - % (95% CI)d 
NA 
xx (xx, xx) 
xx (xx, xx) 
NA 
xx (xx, xx) 
xx (xx, xx) 
Day 22 Post 
Vaccination 2a 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)c 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)d 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)c 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Seroconversion - % (95% CI)d 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 181 Post 
Vaccination 2b 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)c 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)d 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)c 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Seroconversion - % (95% CI)d 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N = number of subjects in the Modified Intent-to-Treat Population; n = number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean 
Fold Rise (relative to baseline). 
a Day 22 post vaccination 2 varies by group (Day 43 for Groups 1 and 4; Day 142 for Groups 2, 3,5, and 6). 
b Day 181 post vaccination 2 varies by group (Day 202 for Groups 1 and 4; Day 301 for Groups 2, 3,5, and 6). 
c Confidence Interval calculated based on the student’s T distribution. 
d Exact binomial confidence interval calculated using the Clopper-Pearson methodology. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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Tables with similar format 
Table 25: 
Summaries of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Day and Study Group, 
Per Protocol Population* 
Table 26: 
Summaries of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Day and Study Group, Modified 
Intent-to-Treat Population* 
Table 27: 
Summaries of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Day and Study Group, Per Protocol 
Population* 
Table 28: 
Summaries of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Day and Study 
Group, Modified Intent-to-Treat Population* 
Table 29: 
Summaries of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Day and Study 
Group, Per Protocol Population* 
Table 30: 
Summaries of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Day and Study Group, Modified 
Intent-to-Treat Population* 
Table 31: 
Summaries of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Day and Study Group, Per 
Protocol Population* 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 32: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Age Group 
at 21 Days Post Second Vaccination, Per Protocol Population 
Statistic 
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Age 19-34 years 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % (95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Age 35-50 years 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
 
 
 
 
 
 
Seroconversion - % (95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N = number of subjects in the Per Protocol Population; n = number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise 
(relative to baseline). 
a Confidence Interval calculated based on the student’s T distribution. 
b Exact binomial confidence interval calculated using the Clopper-Pearson methodology. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Tables with similar format: 
Table 33: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Age Group 
at 180 Days Post Second Vaccination, Per Protocol Population 
Table 34: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Age Group at 21 Days Post 
Second Vaccination, Per Protocol Population 
Table 35: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Age Group at 180 Days Post 
Second Vaccination, Per Protocol Population 
Table 36: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Age 
Group at 21 Days Post Second Vaccination, Per Protocol Population 
Table 37: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Age 
Group at 180 Days Post Second Vaccination, Per Protocol Population 
Table 38: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Age Group at 21 Days 
Post Second Vaccination, Per Protocol Population 
Table 39: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Age Group at 180 Days 
Post Second Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 40: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Sex at 21 
Days Post Second Vaccination, Per Protocol Population 
Statistic 
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Female 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % (95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Male 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % (95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N = number of subjects in the Per Protocol Population; n = number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise 
(relative to baseline). 
a Confidence Interval calculated based on the student’s T distribution. 
b Exact binomial confidence interval calculated using the Clopper-Pearson methodology. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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Tables with similar format: 
Table 41: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Sex at 180 
Days Post Second Vaccination, Per Protocol Population 
Table 42: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Sex at 21 Days Post Second 
Vaccination, Per Protocol Population 
Table 43: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Sex at 180 Days Post Second 
Vaccination, Per Protocol Population 
Table 44: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Sex at 
21 Days Post Second Vaccination, Per Protocol Population 
Table 45: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Sex at 
180 Days Post Second Vaccination, Per Protocol Population 
Table 46: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Sex at 21 Days Post 
Second Vaccination, Per Protocol Population 
Table 47: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Sex at 180 Days Second 
Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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Table 48: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and BMI at 21 
Days Post Second Vaccination, Per Protocol Population 
Statistic 
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
BMI < 30 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % (95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
BMI ≥ 30 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % (95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N = number of subjects in the Per Protocol Population; n = number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise 
(relative to baseline). 
a Confidence Interval calculated based on the student’s T distribution. 
b Exact binomial confidence interval calculated using the Clopper-Pearson methodology. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 49: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and BMI at 180 
Days Post Second Vaccination, Per Protocol Population 
Table 50: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and BMI at 21 Days Post Second 
Vaccination, Per Protocol Population 
Table 51: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and BMI at 180 Days Post 
Second Vaccination, Per Protocol Population 
Table 52: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and BMI at 
21 Days Post Second Vaccination, Per Protocol Population 
Table 53: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and BMI at 
180 Days Post Second Vaccination, Per Protocol Population 
Table 54: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and BMI at 21 Days Post 
Second Vaccination, Per Protocol Population 
Table 55: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and BMI at 180 Days Second 
Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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Table 56: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Seasonal 
Influenza Vaccination Status at 21 Days Post Second Vaccination, Per Protocol Population 
Receipt of 2018-
2019 Seasonal 
Influenza Vaccine 
Statistic 
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Did Not Receive Prior 2016-2017 or 2017-2018 Seasonal Influenza Vaccination 
Did Not Receive 
2018-2019 Seasonal 
Influenza Vaccine 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% 
CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % 
(95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Received 2018-2019 
Seasonal Influenza 
Vaccine 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% 
CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % 
(95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Received Prior 2016-2017 and/or 2017-2018 Seasonal Influenza Vaccination 
Did Not Receive 
2018-2019 Seasonal 
Influenza Vaccine 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% 
CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Receipt of 2018-
2019 Seasonal 
Influenza Vaccine 
Statistic 
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Seroconversion - % 
(95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Received 2018-2019 
Seasonal Influenza 
Vaccine 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Titer ≥ 1:40 - %(95% 
CI)b 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI)a 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
xxx.x(xxx.x,xxx.x) 
Seroconversion - % 
(95% CI)b  
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Note: Receipt of 2018-2019 vaccine is counted at any timepoint prior to receipt of the second study vaccination. 
N = number of subjects in the Per Protocol Population; n = number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise 
(relative to baseline). 
a Confidence Interval calculated based on the student’s T distribution. 
b Exact binomial confidence interval calculated using the Clopper-Pearson methodology. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 57: 
Summary of Hemagglutination Inhibition Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Prior 
Seasonal Influenza Vaccination at 180 Days Post Second Vaccination, Per Protocol Population 
Table 58: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Prior Seasonal Influenza 
Vaccination at 21 Days Post Second Vaccination, Per Protocol Population 
Table 59: 
Summary of Neutralizing Antibody Against A/Shanghai/2/2013 (A/H7N9) by Study Group and Prior Seasonal Influenza 
Vaccination at 180 Days Post Second Vaccination, Per Protocol Population 
Table 60: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Prior 
Seasonal Influenza Vaccination at 21 Days Post Second Vaccination, Per Protocol Population 
Table 61: 
Summary of Hemagglutination Inhibition Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Prior 
Seasonal Influenza Vaccination at 180 Days Post Second Vaccination, Per Protocol Population 
Table 62: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Prior Seasonal Influenza 
Vaccination at 21 Days Post Second Vaccination, Per Protocol Population 
Table 63: 
Summary of Neutralizing Antibody Against A/Hong Kong/125/2017 (A/H7N9) by Study Group and Prior Seasonal Influenza 
Vaccination at 180 Days Second Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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Table 64: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with HAI Seroconversion Against 
A/H7N9 Strains at 21 Days Post Second Study Vaccination, Per Protocol Population 
[Implementation Note: Two- and three-way interaction terms will be included in the model at first. If interactions are not significant, fit final model in this table 
without interaction, and add footnote in table “No interaction terms were significant.”]  
Model 
Parameter 
Parameter Category 
A/Shanghai/2/2013 (A/H7N9)  
A/Hong Kong/125/2017 (A/H7N9) 
Parameter 
Estimate 
SE 
p-value 
Odds 
Ratio 
95%CI 
Parameter 
Estimate 
SE 
p-value 
Odds 
Ratio 
95%CI 
Intercept 
N/A 
xxx.x 
xxx.x 
x.xxx 
- 
- 
xxx.x 
xxx.x 
x.xxx 
- 
- 
Prime-boost 
Homologous (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Heterologous 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
Boost Dose 
15 mcg (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
3.75 mcg + AS03 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
Interval 
21 days (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
120 days 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
n= XX (number of subjects with results available at 21 days post second study vaccination in the Per Protocol Population.)  
XX subjects missing covariate data were excluded from this analysis. 
SE = Standard Error. 
 
Tables with similar format 
Table 65: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with HAI Seroconversion Against 
A/H7N9 Strains at 180 Days Post Second Study Vaccination, Per Protocol Population 
Table 66: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with Neut Seroconversion Against 
A/H7N9 Strains at 21 Days Post Second Study Vaccination, Per Protocol Population 
Table 67: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with Neut Seroconversion Against 
A/H7N9 Strains at 180 Days Post Second Study Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 68: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with HAI Seroconversion Against 
A/H7N9 Strains at 21 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population 
(N=X) 
Model Parameter 
Parameter Category 
A/Shanghai/2/2013 (A/H7N9)  
A/Hong Kong/125/2017 (A/H7N9) 
Parameter 
Estimate 
SE 
p-
value 
Odds 
Ratio 
95%CI 
Parameter 
Estimate 
SE 
p-
value 
Odds 
Ratio 
95%CI 
Intercept 
N/A 
xxx.x 
xxx.x 
x.xxx 
- 
- 
xxx.x 
xxx.x 
x.xxx 
- 
- 
Prime-boost 
Homologous (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Heterologous 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
Boost Dose 
15 mcg (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
3.75 mcg + AS03 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
Interval 
21 days (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
120 days 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
Age (years) 
N/A 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
Sex 
 Female (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 Male 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
BMI 
 <30 (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 ≥30 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
Prior Receipt of Influenza Vaccine 
(Prior Seasons) 
Did Not Receive 2016-2017 or 
2017-2018 Seasonal Influenza 
Vaccination (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Received 2016-2017 and/or 
2017-2018 Seasonal Influenza 
Vaccination 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Model Parameter 
Parameter Category 
A/Shanghai/2/2013 (A/H7N9)  
A/Hong Kong/125/2017 (A/H7N9) 
Parameter 
Estimate 
SE 
p-
value 
Odds 
Ratio 
95%CI 
Parameter 
Estimate 
SE 
p-
value 
Odds 
Ratio 
95%CI 
Receipt of Influenza Vaccine 
(Concurrent Season) 
Did Not Receive 2018-2019 
Seasonal Influenza Vaccine 
(reference) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Received 2018-2019 Seasonal 
Influenza Vaccine (reference) 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
Prior Receipt of H5 Influenza 
Vaccine 
No Prior H5 Influenza 
Vaccinations 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Received Prior H5 Influenza 
Vaccinations 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-
xx.x 
Note: Receipt of 2018-2019 vaccine is counted at any timepoint prior to receipt of the second study vaccination. 
n= XX (number of subjects with results available at 21 days post second study vaccination in the Per Protocol Population).  
XX subjects missing covariate data were excluded from this analysis. 
SE = Standard Error. 
 
Tables with similar format: 
Table 69: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with HAI Seroconversion Against 
A/H7N9 Strains at 180 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population 
Table 70: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with Neut Seroconversion Against 
A/H7N9 Strains at 21 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population 
Table 71: 
Logistic Regression Model to Evaluate the Relationship of Administration Schedule with Neut Seroconversion Against 
A/H7N9 Strains at 180 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 72: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted HAI Titer 
Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, Per Protocol Population (N=X) 
 
Model Parameter 
Parameter Category 
A/Shanghai/2/2013 (A/H7N9)  
A/Hong Kong/125/2017 (A/H7N9) 
Parameter 
Estimate 
SE 
95%CI 
p-value 
Parameter 
Estimate 
SE 
95%CI 
p-value 
Intercept 
 N/A 
xxx.x 
xxx.x 
x.xxx 
x.xxx 
xxx.x 
xxx.x 
x.xxx 
x.xxx 
Prime-boost 
Homologous (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
Heterologous 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
Boost Dose 
15 mcg (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
3.75 mcg + AS03 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
Interval 
21 days (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
120 days 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
n = XX (number of subjects with results available at 21 days post second study vaccination in the Per Protocol Population).  
XX subjects missing covariate data were excluded from this analysis. 
SE = Standard Error. 
 
Tables with similar format: 
Table 73: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted HAI Titer 
Against A/H7N9 Strains at 180 Days Post Second Study Vaccination, Per Protocol Population 
Table 74: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted Neut Titer 
Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, Per Protocol Population 
Table 75: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted Neut Titer 
Against A/H7N9 Strains at 180 Days Post Second Study Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 76: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted HAI Titer 
Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol 
Population 
Model Parameter 
Parameter Category 
A/Shanghai/2/2013 (A/H7N9)  
A/Hong Kong/125/2017 (A/H7N9) 
Parameter 
Estimate 
SE 
95%CI 
p-
value 
Parameter 
Estimate 
SE 
95%CI 
p-
value 
Intercept 
 N/A 
xxx.x 
xxx.x 
- 
x.xxx 
xxx.x 
xxx.x 
- 
x.xxx 
Prime-boost 
Homologous (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
Heterologous 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
Boost Dose 
15 mcg (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
3.75 mcg + AS03 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
Interval 
21 days (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
120 days 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xxx.x 
xxx.x 
x.xxx 
xx.x 
Age (years) 
N/A 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
 Sex 
Female (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
Male 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
BMI 
<30 (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
≥30 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
Prior Receipt of Influenza Vaccine 
(Prior Seasons) 
Did Not Receive 2016-2017 or 2017-
2018 Seasonal Influenza Vaccination 
(reference) 
- 
- 
- 
- 
- 
- 
- 
- 
Received 2016-2017 and/or 2017-
2018 Seasonal Influenza Vaccination 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
Receipt of Influenza Vaccine 
(Concurrent Season) 
Did Not Receive 2018-2019 Seasonal 
Influenza Vaccine (reference) 
- 
- 
- 
- 
- 
- 
- 
- 
Received 2018-2019 Seasonal 
Influenza Vaccine (reference) 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
No Prior H5 Influenza Vaccinations 
- 
- 
- 
- 
- 
- 
- 
- 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Model Parameter 
Parameter Category 
A/Shanghai/2/2013 (A/H7N9)  
A/Hong Kong/125/2017 (A/H7N9) 
Parameter 
Estimate 
SE 
95%CI 
p-
value 
Parameter 
Estimate 
SE 
95%CI 
p-
value 
Prior Receipt of H5 Influenza 
Vaccine 
Received Prior H5 Influenza 
Vaccinations 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
xxx.x 
xxx.x 
xx.x-xx.x 
x.xxx 
Note: Receipt of 2018-2019 vaccine is counted at any timepoint prior to receipt of the second study vaccination. 
n = XX (number of subjects with results available at 21 days post second study vaccination in the Per Protocol Population).  
XX subjects missing covariate data were excluded from this analysis. 
SE = Standard Error. 
 
Tables with similar format: 
Table 77: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted HAI Titer 
Against A/H7N9 Strains at 180 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol 
Population  
Table 78: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted Neut Titer 
Against A/H7N9 Strains at 21 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol 
Population 
Table 79: 
Multiple Linear Regression Model to Evaluate the Relationship of Administration Schedule with Log-Adjusted Neut Titer 
Against A/H7N9 Strains at 180 Days Post Second Study Vaccination, Adjusted for Baseline Covariates, Per Protocol 
Population  
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.2.2 Plasmablast Response Against 2013 and 2017 A/H7N9 
Table 80: 
Summary of A/Shanghai/2/2013 (A/H7N9)–Specific Antibody Secreting Cells by Immunoglobulin Type, Study Group, and 
Study Day, Per Protocol Population  
Time Point 
Statistic 
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
IgA Antibody Secreting Cells 
Day 8 Post 
Vac 1 
n  
x 
x 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
95% CI 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Median  
[IQR] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Day 8 Post 
Vac 2a 
n  
x 
x 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
95% CI 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Median  
[IQR] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
IgG Antibody Secreting Cells 
Day 8 Post 
Vac 1 
n  
x 
x 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
95% CI 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Median  
[IQR] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
n  
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Statistic 
Group 1 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 2 
2013 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 3 
2013 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Group 4 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D22)  
(N=X) 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 3.75+AS03/  
2017 15 
 (D1-D121)  
(N=X) 
Day 8 Post 
Vac 2a 
Mean (SD) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
95% CI 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Median  
[IQR] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
IgM Antibody Secreting Cells 
Day 8 Post 
Vac 1 
n  
x 
x 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
95% CI 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Median  
[IQR] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Day 8 Post 
Vac 2a 
n  
x 
x 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
95% CI 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Median  
[IQR] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
xx [xx, xx] 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
N = Number of subjects in the Modified Intent-to-Treat Population; n = number of subjects with results reported. 
a Day 8 post vaccination 2 varies by group (Day 29 for Groups 1 and 4; Day 128 for Groups 2, 3,5, and 6). 
Table with similar format: 
Table 81: 
Summary of A/Hong Kong/125/2017 (A/H7N9)–Specific Antibody Secreting Cells by Immunoglobulin Type, Study Group, 
and Study Day, Per Protocol Population 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 82: 
Overall Summary of Adverse Events, Safety Population* 
AE Category 
AE Subcategory 
Group 1 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013  
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All 
Subjects  
(N=X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
At least one local solicited 
adverse event 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one systemic solicited 
adverse event 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one laboratory adverse 
event 
Any Grade 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate (Grade 2)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe (Grade 3)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one unsolicited 
adverse event 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related unsolicited 
adverse event 
Any Grade 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate (Grade 2)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe (Grade 3)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one severe (Grade 3) 
unsolicited adverse event 
Any Relationship 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Related  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unrelated 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
AE Category 
AE Subcategory 
Group 1 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013  
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All 
Subjects  
(N=X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
At least one serious adverse 
eventb 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related, serious 
adverse event 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse event 
leading to early terminationc  
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one medically 
attended adverse event 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one new onset chronic 
medical condition 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
At least one potentially 
immune mediated medical 
condition 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
N = Number of subjects who received at least one study vaccination; n= Number of subjects in the indicated category 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of Serious Adverse Events is included in Error! Reference source not found.. 
c As reported on the Adverse Event eCRF. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 83: 
Number of Adverse Events Occurring in 5% of Subjects in Any Study Group by MedDRA® System Organ Class and 
Preferred Term, and Study Group, Safety Population 
[Implementation Note: this table combines all adverse events – solicited events, unsolicited events, and clinical laboratory events. Sort data by SOC then PT. If 
>= X SAEs are reported, repeat this table for all reported SAEs] 
MedDRA System 
Organ Class  
Preferred 
Term 
Group 1 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects  
(N=X) 
 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SOC1 
PT1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other (Non-serious) Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
SOC1 
PT1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = number of subjects in the Safety Population (number of subjects at risk); n= number of subjects reporting event. Events = total frequency of events reported. 
MedDRA Version X.X. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 110 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.1.1  
Solicited Adverse Events  
Table 84: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom and Study 
Group (Safety Population) – Post Any Study Vaccination 
Symptom 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
Any Symptom 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Any Systemic Symptom 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Fever 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Feverishness 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Fatigue 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Malaise 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Myalgia 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Arthralgia 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Headache 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 111 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
Nausea 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Any Local Symptom 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Pain 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Tenderness 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Pruritus 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Ecchymosis 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Ecchymosis (measurement) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Erythema 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Erythema (measurement) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Induration/Swelling 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
Induration/Swelling 
(measurement) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
N = Number of subjects in the Safety Population who received any study vaccination;  
n = Number of subjects reporting event 
95% CI estimated using the Clopper-Pearson exact method 
 
Tables with similar format: 
Table 85: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom and 
Study Group (Safety Population) – Post Study Vaccination 1 
[Footnote update] N = Number of subjects in the Safety Population who received the first study vaccination. 
Table 86: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom and 
Study Group (Safety Population) – Post Study Vaccination 2 
[Footnote update] N = Number of subjects in the Safety Population who received the second study vaccination. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 113 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 87: 
Logistic Regression Model to Evaluate the Relationship of Study Vaccination with Reporting Any Local Event Post Second 
Study Vaccination, Safety Population 
[Implementation Note: If statistically significant effects (defined as p-value <0.05) are observed in the model for local events then this table should be repeated 
for additional models which will be fit for each individual local event.  Any solicited local event grade 1 or higher reported within 7 days of study vaccination 
will count as a reported event.] 
Model Parameter 
Parameter Category 
Parameter 
Estimate 
SE 
p-value 
Odds Ratio 
95%CI 
Intercept 
N/A 
xxx.x 
xxx.x 
x.xxx 
- 
- 
Prime-boost 
Homologous (reference) 
- 
- 
- 
- 
- 
 
Heterologous 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
Boost Dose 
15 mcg (reference) 
- 
- 
- 
- 
- 
 
3.75 mcg + AS03 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
Interval 
21 days (reference) 
- 
- 
- 
- 
- 
 
120 days 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
N = XX (number of subjects in the Safety Population) 
 
Table with similar format: 
Table 88: 
Logistic Regression Model to Evaluate the Relationship of Study Vaccination with Reporting Any Systemic Event Post 
Second Study Vaccination, Safety Population 
[Implementation Note: If statistically significant effects defined p-value <0.05 are observed in the model for systemic events then this table should be repeated 
for additional models which will be fit for each individual systemic event. Any solicited systemic event grade 1 or higher reported within 7 days of study 
vaccination will count as a reported event.] 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 114 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 89: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity and 
Study Group (Safety Population) – Post Any Study Vaccination 
Symptom 
Severity 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
Any Symptom 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Any Systemic 
Symptom 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Fever 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Feverishness 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 115 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
Fatigue 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Malaise 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Myalgia 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Arthralgia 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Headache 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 116 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Nausea 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Any Local 
Symptom 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Pain 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Tenderness 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Pruritus 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 117 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Ecchymosis 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Ecchymosis 
(measurement) 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Erythema 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Erythema 
(measurement) 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 118 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Group 1 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
n 
%  
(95% CI) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Induration/Swelling 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
Induration/Swelling 
(measurement) 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Moderate 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Severe 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
N = Number of subjects in the Safety Population who received any study vaccination; n = Number of subjects reporting event. 
95% CI estimated using Clopper-Pearson exact method. 
Severity is the maximum severity reported over all solicited symptoms post dosing for each subject.   
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 119 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 90: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity and Study Group 
(Safety Population) – Post Study Vaccination 1 
[Footnote Update] N = Number of subjects in the Safety Population who received the first study vaccination = Number of subjects reporting event. 
Table 91: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity and Study Group 
(Safety Population) – Post Study Vaccination 2 
[Footnote Update] N = Number of subjects in the Safety Population who received the second study vaccination; n = Number of subjects reporting 
event. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 120 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 92: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Severity, Day Post Study Vaccination, and 
Study Group (Safety Population) – Post Any Study Vaccination 
Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: 2013 3.75+AS03/ 2017 3.75+AS03 (D1-D22) (N=X) 
Any Symptom 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Any Systemic Symptom 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Fever 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Feverishness 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Fatigue 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 121 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Malaise 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Myalgia 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Arthralgia 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Headache 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Nausea 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Any Local Symptom 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 122 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pain 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Tenderness 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pruritus 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Ecchymosis 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Ecchymosis (measurement) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Erythema 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 123 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Erythema (measurement) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Induration/Swelling 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Induration/Swelling (measurement) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Mild 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Severe 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[repeat for all study groups & All Subjects] 
N = Number of subjects in the Safety Population who received any study vaccination; n = Number 
Severity is the maximum severity reported post dosing for each subject for each day. 
[Implementation Note: The value considered for Day 8+ for each subject will be the maximum value reported at Day 8 or after for subjects with symptoms 
ongoing at Day 8.] 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 124 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 93: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Severity, Day Post Study Vaccination, and 
Study Group (Safety Population) – Post Study Vaccination 1 
Table 94: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Severity, Day Post Study Vaccination, and 
Study Group (Safety Population) – Post Study Vaccination 2  
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 125 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 95: 
Number and Percentage of Subjects Experiencing Solicited Systemic Events for Study Vaccination 1 Compared with Study 
Vaccination 2 by Study Group– Safety Population 
 
 
Subjects with No 
Symptoms 
Subjects with Mild or Greater 
Symptoms 
Total Number of Subjects 
n (Percent) 
[p-value*] 
Study Vaccination 1 vs Study Vaccination 2 
Group 1: 
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22) 
(N=X) 
Subjects with No Symptoms  
x (%) 
x (%) 
x (%) 
Subjects with Mild or Greater 
Symptoms  
x (%) 
x (%) 
x (%) 
Total Number of Subjects  
x (%) 
x (%) 
x (100%) 
[0.xxx] 
Group 2: 
2013 3.75+AS03/ 
2017 3.75+AS03  
(D1-D121) 
(N=X) 
Subjects with No Symptoms  
x (%) 
x (%) 
x (%) 
Subjects with Mild or Greater 
Symptoms  
x (%) 
x (%) 
x (%) 
Total Number of Subjects  
x (%) 
x (%) 
x (100%) 
[0.xxx] 
Group 3: 
2013 3.75+AS03/  
2017 15  
(D1-D121) 
(N=X) 
Subjects with No Symptoms  
x (%) 
x (%) 
x (%) 
Subjects with Mild or Greater 
Symptoms  
x (%) 
x (%) 
x (%) 
Total Number of Subjects  
x (%) 
x (%) 
x (100%) 
[0.xxx] 
Group 4: 
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22) 
(N=X) 
Subjects with No Symptoms  
x (%) 
x (%) 
x (%) 
Subjects with Mild or Greater 
Symptoms  
x (%) 
x (%) 
x (%) 
Total Number of Subjects  
x (%) 
x (%) 
x (100%) 
[0.xxx] 
Group 5: 
Subjects with No Symptoms  
x (%) 
x (%) 
x (%) 
Subjects with Mild or Greater 
Symptoms  
x (%) 
x (%) 
x (%) 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 126 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
 
Subjects with No 
Symptoms 
Subjects with Mild or Greater 
Symptoms 
Total Number of Subjects 
n (Percent) 
[p-value*] 
2017 3.75+AS03/ 
2017 3.75+AS03  
(D1-D121) 
(N=X) 
Total Number of Subjects  
x (%) 
x (%) 
x (100%) 
[0.xxx] 
Group 6:  
2017 3.75+AS03/  
2017 15  
(D1-D121) 
(N=X) 
Subjects with No Symptoms  
x (%) 
x (%) 
x (%) 
Subjects with Mild or Greater 
Symptoms  
x (%) 
x (%) 
x (%) 
Total Number of Subjects  
x (%) 
x (%) 
x (100%) 
[0.xxx] 
All Subjects 
(N=X) 
Subjects with No Symptoms  
x (%) 
x (%) 
x (%) 
Subjects with Mild or Greater 
Symptoms  
x (%) 
x (%) 
x (%) 
Total Number of Subjects  
x (%) 
x (%) 
x (100%) 
[0.xxx] 
Note: Denominators for percentages are the number of subjects in the Safety Population who received both the first and second study vaccination. Subjects who did not 
receive both indicated vaccinations are not included in this table. [x] subjects did not receive the second study vaccination.  
* P-value is calculated from McNemar's test for each study group. 
 
Table with similar format: 
Table 96: 
Number and Percentage of Subjects Experiencing Solicited Local Events for Study Vaccination 1 Compared with Study 
Vaccination 2 by Study Group, Safety Population  
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 127 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.1.2 
Unsolicited Adverse Events 
Table 97: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events with 95% Confidence Intervals by 
MedDRA® System Organ Class and Preferred Term, and Study Group, Safety Population* 
MedDRA® System 
Organ Class 
MedDRA® Preferred 
Term 
Group 1 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All Subjects 
(N=X) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
n 
%  
(95% 
CI) 
Any SOC 
Any PT 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
[SOC 1] 
Any PT 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
 
[PT 1] 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
 
[PT 2] 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
[SOC 2] 
Any PT 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
 
[PT 1] 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
 
[PT 2] 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
x 
xx  
(xx-xx) 
N = number of subjects in the Safety Population who received any study vaccination.  
This table presents number and percentage of subjects. A subject is only counted once per PT. 
[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row should be omitted.]


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 128 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 98: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA® System Organ Class and 
Preferred Term, Maximum Severity, Relationship, and Study Group, Safety Population 
Study Group 
MedDRA® System 
Organ Class 
MedDRA® Preferred Term 
Any  
Incidence 
Severity [1] 
Relationship to Study 
Vaccination [2] 
Mild 
Moderate 
Severe 
Not Related 
Related 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: 
2013 3.75+AS03/ 
2017 3.75+AS03 
(D1-D22) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2: 
2013 3.75+AS03/ 
2017 3.75+AS03  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3: 
2013 3.75+AS03/ 
2017 15  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 129 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4: 
2017 3.75+AS03/ 
2017 3.75+AS03 
(D1-D22) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5: 
2017 3.75+AS03/ 
2017 3.75+AS03  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6:  
2017 3.75+AS03/ 
2017 15  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects  
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


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[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row will be omitted. Only the SOC/PT with >= 1 event reported will be shown for 
each group.] 
Table with similar format: 
Table 99: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events within 21 Days of Study Vaccination by 
MedDRA® System Organ Class and Preferred Term, Maximum Severity, Relationship, and Study Group, Safety 
Population 
[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row will be omitted. Only the SOC/PT with >= 1 event reported will be shown for 
each group. Events through 'Day 22' include events through the study visit planned for 21 days post the relevant vaccination. If that visit is missed, then a cutoff 
of exactly 21 days post vaccination will be used.] 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Safety Population.  
[1] For severity, a subject is counted once per preferred term and is summarized according to their highest severity. 
[2] For relationship, a subject is only counted once per preferred term and is summarized according to their closest relationship. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 100 
Number and Percentage of Subjects Experiencing Non-Serious Related Unsolicited Adverse Events by MedDRA® System 
Organ Class and Preferred Term, Maximum Severity, and Study Group, Safety Population 
Study Group 
MedDRA® System Organ 
Class 
MedDRA® Preferred 
Term 
Any Incidence 
Severity [1] 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: 
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2: 
2013 3.75+AS03/ 
2017 3.75+AS03  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3: 
2013 3.75+AS03/  
2017 15  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4: 
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5: 
2017 3.75+AS03/ 
2017 3.75+AS03  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6:  
2017 3.75+AS03/  
2017 15  
(D1-D121) 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
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[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row will be omitted. Only the SOC/PT with >= 1 event reported will be shown for 
each group.] 
Table with similar format: 
Table 101: 
Number and Percentage of Subjects Experiencing Non-Serious Related Unsolicited Adverse Events Within 21 Days Post 
Study Vaccination by MedDRA® System Organ Class and Preferred Term, Maximum Severity, and Study Group, Safety 
Population 
[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row will be omitted. Only the SOC/PT with >= 1 event reported will be shown for 
each group. Events through 'Day 22' include events through the study visit planned for 21 days post the relevant vaccination. If that visit is missed, then a cutoff 
of exactly 21 days post vaccination will be used.] 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Safety Population. [1] For severity, a subject is counted once per preferred term and is summarized according to their highest severity. 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 102: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events Within 21 Days Post Study Vaccination by 
MedDRA® System Organ Class and Preferred Term, Day Post Study Vaccination, and Study Group, Safety Population 
MedDRA® System Organ 
Class 
MedDRA® Preferred 
Term 
Post Vaccination 1 
Post Vaccination 2 
Post Any 
Vaccination 
Day 1-8 
Day 9-22 
Day 1-22 
Day 1-8 
Day 9-22 
Day 1-22 
Day 1-22  
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: 2013 3.75+AS03/ 2017 3.75+AS03 (D1-D22) (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[Repeat for all study groups & All Subjects] 
N = Number of subjects in the Safety Population. This table presents number and percentage of subjects. For each time period, a subject is only counted once per PT. 
[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row will be omitted. Only the SOC/PT with >= 1 event reported will be shown for 
each group. Events through 'Day 22' include events through the study visit planned for 21 days post the relevant vaccination. If that visit is missed, then a cutoff 
of exactly 21 days post vaccination will be used.] 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 103: 
Number and Percentage of Subjects Experiencing Non-Serious, Related Unsolicited Adverse Events Within 21 Days Post 
Study Vaccination by MedDRA® System Organ Class and Preferred Term, Vaccination and Study Group, Safety 
Population 
MedDRA® System Organ 
Class 
MedDRA® Preferred 
Term 
Post Vaccination 1 
Post Vaccination 2 
Post Any 
Vaccination 
Day 1-8 
Day 9-22 
Day 1-22 
Day 1-8 
Day 9-22 
Day 1-22 
Day 1-22 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: 2013 3.75+AS03/ 2017 3.75+AS03 (D1-D22) (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[Repeat for all study groups & All Subjects] 
N = Number of subjects in the Safety Population. This table presents number and percentage of subjects. For each time period, a subject is only counted once per PT. 
[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row will be omitted. Only the SOC/PT with >= 1 event reported will be shown for 
each group. Events through 'Day 22' include events through the study visit planned for 21 days post the relevant vaccination. If that visit is missed, then a cutoff 
of exactly 21 days post vaccination will be used.] 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 104: 
Number of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Day Post Study Vaccination, 
and Study Group, Safety Population 
MedDRA® System Organ 
Class 
MedDRA® Preferred 
Term 
Number of Events 
Post Vaccination 1 
Post Vaccination 2 
Post Any 
Vaccination 
Day 1-8 
Day 9-22 
Day 1-22 
Day 1-8 
Day 9-22 
Day 1-22 
Day 1-22 
Group 1: 2013 3.75+AS03/ 2017 3.75+AS03 (D1-D22) (N=X) 
Any SOC 
Any PT 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
x 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
x 
x 
x 
x 
x 
x 
x 
 
[PT 2] 
x 
x 
x 
x 
x 
x 
x 
[SOC 2] 
Any PT 
x 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
x 
x 
x 
x 
x 
x 
x 
 
[PT 2] 
x 
x 
x 
x 
x 
x 
x 
[Repeat for all study groups & All Subjects] 
N = Number of subjects in the Safety Population. This table presents number of events; a subject may be counted multiple times. 
[Implementation Note: If an SOC has only one PT reported, the ‘Any PT’ row will be omitted. Only the SOC/PT with >= 1 event reported will be shown for 
each group. Events through 'Day 22' include events through the study visit planned for 21 days post the relevant vaccination. If that visit is missed, then a cutoff 
of exactly 21 days post vaccination will be used.] 
Table with similar format: 
Table 105: 
Number of Non-Serious, Related, Unsolicited Adverse Events by MedDRA® System Organ Class and Preferred Term, Day 
Post Study Vaccination, and Study Group, Safety Population


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.2 Listing of Serious and Significant Adverse Events 
Table 106: 
Listing of Serious Adverse Events – Safety Population * 
Adverse 
Event 
Associated 
with Vac # 
# of Days 
Post 
Associated 
Vac 
(Duration) 
# of 
Days 
Post 
Vac the 
Event 
Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship 
to Study 
Vaccination 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA® 
Sytem 
Organ 
Class 
MedDRA® 
Preferred 
Term 
Subject ID: , Study Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID:, Study Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Table 107: 
Listing of Medically Attended Adverse Events – Safety Population 
[Implementation Note: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” column, 
merge the 2 data fields for collecting alternate etiology, separate by a colon.] 
 
Adverse 
Event 
Associated 
with Vac # 
# of Days 
Post 
Associated 
Vac 
(Duration) 
SAE? 
Severity 
Relationship 
to Study 
Vaccination 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to AE 
Outcome 
PIMMC? 
NOCMC? 
MedDRA® 
System 
Organ 
Class 
MedDRA® 
Preferred 
Term 
Subject ID: , Study Group: , AE Number:  
 
 
 
SAE: No 
Mild 
 
 
 
 
 
 
 
 
Comments: 
 
 
Subject ID: , Study Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Tables with similar format: 
Table 108: 
Listing of Potentially Immune Mediated Medical Conditions 
[Implementation Note: Update column ‘PIMMC? NOCMC?’ to ‘MAAE? NOCMC?’] 
Table 109: 
Listing of New Onset Chronic Medical Conditions 
[Implementation Note: Update column ‘PIMMC? NOCMC?’ to ‘MAAE? PIMMC?’] 
Table 110: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
[Implementation Note: Update column ‘MAAE? PIMMC? NOCMC?’ to ‘MAAE? PIMMC?’] 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.4 Displays of Laboratory Results 
14.3.4.1 Displays of Chemistry Results 
Table 111: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – All Chemistry 
Parameters– Safety Population 
Study Group 
Study Day 
N* 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 22) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3:  
2013 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4:  
2017 3.75+AS03/  
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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Study Group 
Study Day 
N* 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
2017 3.75+AS03  
(D1-D22) (N=X) 
Pre-Vac 2 
(Day 22) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6:  
2017 3.75+AS03/  
2017 15 
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects 
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 Pre-Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N=Number of subjects in the Safety Population; N* = Number of subjects who completed the indicated visit. 
 
[Implementation Note: A subject should be counted within N* only if they completed the study visit in-person (i.e. not a phone visit).] 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 142 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 112: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – Alanine 
aminotransferase (ALT)  
Table 113: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – Total Bilirubin  
Table 114: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – Creatinine 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 115: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Group (Safety Population) – 
Alanine Aminotransferase (ALT) 
Study Group 
Study Day 
N* 
Value 
Change from Baseline 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Group 1:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
 Pre-Vac 2 (Day 22) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 2:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D121)   
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
 Pre-Vac 2 (Day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 3:  
2013 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
 Pre-Vac 2 (Day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 4:  
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 22) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 144 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Study Group 
Study Day 
N* 
Value 
Change from Baseline 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Group 6:  
2017 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
All Subjects 
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2  
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
N= Number of subjects in the Safety Population; N* = Number of subjects with lab values available. 
Tables with similar format: 
Table 116: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Group (Safety Population) – 
Total Bilirubin 
Table 117: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Group (Safety Population) – 
Creatinine 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 145 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.4.1 Displays of Hematology Results 
Table 118: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – All Hematology 
Parameters 
Study Group 
Study Day 
N* 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 22) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3:  
2013 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4:  
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22) (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 22) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 146 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Study Group 
Study Day 
N* 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6:  
2017 3.75+AS03/  
2017 15 
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects 
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N=Number of subjects in the Safety Population; N* = Number of subjects who completed the indicated visit. 
[Implementation Note: A subject should be counted within N* only if they completed the study visit in-person (i.e. not a phone visit).] 
Table with similar format: 
Table 119: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – Hemoglobin 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 147 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 120: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – White Blood 
Cells 
Study Group 
Study Day 
N* 
None 
Mild / Grade 1 
Moderate / Grade 2 
Severe / Grade 3 
Missing 
Low 
High 
Low 
High 
Low 
High 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 
22) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 
121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3:  
2013 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 
121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 148 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Study Group 
Study Day 
N* 
None 
Mild / Grade 1 
Moderate / Grade 2 
Severe / Grade 3 
Missing 
Low 
High 
Low 
High 
Low 
High 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 8 post Vac 
2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4:  
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 
22) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 
121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6:  
2017 3.75+AS03/  
2017 15 
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 (Day 
121) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
- 149 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Study Group 
Study Day 
N* 
None 
Mild / Grade 1 
Moderate / Grade 2 
Severe / Grade 3 
Missing 
Low 
High 
Low 
High 
Low 
High 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 8 post Vac 
2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects 
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
1 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pre-Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 post Vac 
2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population; N* = the number of subjects that completed the indicated visit. 
Table with similar format: 
Table 121: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Group (Safety Population) – Platelets 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
Version 1.0 
18MAR2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 122: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Group (Safety Population) – 
Hemoglobin 
Study Group 
Study Day 
N* 
Value 
Change from Baseline 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Group 1:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 22) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 2:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D121)   
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 3:  
2013 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 4:  
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 22) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
 Pre-Vac 2 (day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 


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Study Group 
Study Day 
N* 
Value 
Change from Baseline 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Group 6:  
2017 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Day 8 post Vac 1 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Pre-Vac 2 (Day 121) 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
All Subjects 
(N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
Pre-Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day of Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
Day 8 post Vac 2 
x 
xx.x 
xx.x 
xx 
xx, xx 
xx.x 
xx.x 
xx 
xx, xx 
N= Number of subjects in the Safety population; N* = Number of subjects with lab values available. 
Tables with similar format: 
Table 123: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Group (Safety Population) – 
White Blood Cells 
Table 124: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Group (Safety Population) – 
Platelets 
 


Statistical Analysis Plan - DMID Protocol: 17-0078  
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14.3.4.5 
Clinical Laboratory Reference Ranges 
(Placeholder for the CSR) 
 
 


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14.3.5 Abnormal Laboratory Value Listings (by Subject)  
Table 125: 
Listing of Abnormal Laboratory Results - Chemistry  
Subject 
ID 
Study 
Group 
Sex 
Age 
(years) 
Planned 
Time 
Point 
Actual 
Study 
Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship 
to Study 
Vaccination 
If Not 
Related, 
Alternate 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to 
Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 126: 
Listing of Abnormal Laboratory Results - Hematology 
Subject 
ID 
Study 
Group 
Sex 
Age 
(years) 
Planned 
Time 
Point 
Actual 
Study 
Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship 
to Study 
Vaccination 
If Not 
Related, 
Alternate 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to 
Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.6 Displays of Vital Signs 
Table 127: 
Vital Signs by Assessment, Maximum Severity, Study Day, Study Group (Safety Population) – Any Assessment 
Study Group 
Study Day 
N* 
None 
Mild 
Moderate 
Severe 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 22 post Vac 1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post 
Baseline  
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post Vac 1 (Vac 
2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post 
Baseline  
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3:  
2013 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post Vac 1 (Vac 
2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4:  
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 22 post Vac 1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post Vac 1 (Vac 
2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


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Study Group 
Study Day 
N* 
None 
Mild 
Moderate 
Severe 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 6:  
2017 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post Vac 1 (Vac 
2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects 
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population; N* = Number of subjects who completed the indicated visit 
Table with similar format: 
Table 128: 
Vital Signs by Assessment, Maximum Severity, Study Day, Study Group (Safety Population) – Oral Temperature 
 


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Table 129: 
Vital Signs by Assessment, Maximum Severity, Study Day, and Study Group (Safety Population) – Systolic Blood Pressure 
Study Group 
Study Day 
N* 
None 
Mild 
Moderate 
Severe 
Missing 
Low 
High 
Low 
High 
Low 
High 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1:  
2013 3.75+AS03/  
2017 3.75+AS03 
(D1-D22)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 22 post Vac 
1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2:  
2013 3.75+AS03/  
2017 3.75+AS03  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post 
Vac 1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3:  
2013 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post 
Vac 1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4:  
2017 3.75+AS03/  
2017 3.75+AS03  
(D1-D22)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 22 post Vac 
1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post 
Vac 1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 


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Study Group 
Study Day 
N* 
None 
Mild 
Moderate 
Severe 
Missing 
Low 
High 
Low 
High 
Low 
High 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 5 
2017 3.75+AS03/  
2017 3.75+AS03 
 (D1-D121)  
(N=X) 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6:  
2017 3.75+AS03/  
2017 15  
(D1-D121)  
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 121 post 
Vac 1 (Vac 2) 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects 
(N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Vac 2 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity 
Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population. 
Tables with similar format: 
Table 130: 
Vital Signs by Assessment, Maximum Severity, Study Day, and Study Group (Safety Population) – Diastolic Blood Pressure 
Table 131: 
Vital Signs by Assessment, Maximum Severity, Study Day, and Study Group (Safety Population) – Pulse 
 
 


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14.4 
Summary of Concomitant Medications 
Table 132: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Study Group 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Group 1 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 2 
2013 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D121)  
(N=X) 
Group 3 
2013 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
Group 4 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
(D1-D22)  
(N=X) 
Group 5 
2017 
3.75+AS03/ 
2017 
3.75+AS03 
 (D1-D121)  
(N=X) 
Group 6 
2017 
3.75+AS03/ 
2017 15 
(D1-D121)  
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 – 1] 
Any [ATC 1 – 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 3] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 3] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N= Number of subjects in the Safety Population. n = Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 
 
 


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APPENDIX 2. FIGURE MOCK-UPS 
 
 


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LIST OF FIGURES 
Figure 1: 
CONSORT Flow Diagram .......................................................................................164 
Figure 2: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody by Study Day 
and Study Group, Modified Intent-to-Treat Population ...........................................165 
Figure 3: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody by Study Day 
and Study Group, Per Protocol Population ...............................................................165 
Figure 4: 
Reverse Cumulative Distribution of Neutralizing Antibody by Study Day and Study 
Group, Modified Intent-to-Treat Population ............................................................165 
Figure 5: 
Reverse Cumulative Distribution of Neutralizing Antibody by Study Day and Study 
Group, Per Protocol Population ................................................................................165 
Figure 6: 
Geometric Mean Titers of Hemagglutination Inhibition Antibody by Study Day and 
Study Group, Modified Intent-to-Treat Population ..................................................166 
Figure 7: 
Geometric Mean Titers of Hemagglutination Inhibition Antibody by Study Day and 
Study Group, Per Protocol Population ......................................................................166 
Figure 8: 
Geometric Mean Titers of Neutralizing Antibody by Study Day and Study Group, 
Modified Intent-to-Treat Population .........................................................................166 
Figure 9: 
Geometric Mean Titers of Neutralizing Antibody by Study Day and Study Group, Per 
Protocol Population ..................................................................................................166 
Figure 10: Correlation of Hemagglutination Inhibition Antibody and Neutralizing Antibody by 
Study Day and Study Group, Modified Intent-to-Treat Population .........................167 
Figure 11: Correlation of Hemagglutination Inhibition Antibody and Neutralizing Antibody by 
Study Day and Study Group, Per Protocol Population .............................................167 
Figure 12: Box Plots of IgA Antibody Secreting Cells by A/H7N9 Strain, Study Day and Study 
Group, Modified Intent-to-Treat Population ............................................................168 
Figure 13: Box Plots of IgA Antibody Secreting Cells by A/H7N9 Strain, Study Day and Study 
Group, Per Protocol Population ................................................................................169 
Figure 14: Box Plots of IgG Antibody Secreting Cells by A/H7N9 Strain, Study Day and Study 
Group, Modified Intent-to-Treat Population ............................................................169 
Figure 15: Box Plots of IgG Antibody Secreting Cells by A/H7N9 Strain, Study Day and Study 
Group, Per Protocol Population ................................................................................169 
Figure 16: Box Plots of IgM Antibody Secreting Cells by A/H7N9 Strain, Study Day and Study 
Group, Modified Intent-to-Treat Population ............................................................169 
Figure 17: Box Plots of IgM Antibody Secreting Cells by A/H7N9 Strain, Study Day and Study 
Group, Per Protocol Population ................................................................................169 
Figure 18: Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 1, Per Protocol Population ........170 
Figure 19: Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 2, Per Protocol Population ........171 


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Figure 20: Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 1, Per Protocol Population ........171 
Figure 21: Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 2, Per Protocol Population ........171 
Figure 22: Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells at Day 8 
Post Vaccination 1 with Antibody Response at Day 21 Post Vaccination 1, Per Protocol 
Population .................................................................................................................171 
Figure 23: Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells at Day 8 
Post Vaccination 2 with Antibody Response at Day 21 Post Vaccination 2, Per Protocol 
Population .................................................................................................................171 
Figure 24: Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells at 
Day 8 Post Vaccination 1 with Antibody Response at Day 21 Post Vaccination 1, Per 
Protocol Population ..................................................................................................171 
Figure 25: Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells at 
Day 8 Post Vaccination 2 with Antibody Response at Day 21 Post Vaccination 2, Per 
Protocol Population ..................................................................................................171 
Figure 26: Maximum Severity of Solicited Systemic Symptoms per Subject by Day Post Study 
Vaccination ...............................................................................................................172 
Figure 27: Maximum Severity of Solicited Local Symptoms per Subject by Day Post Study 
Vaccination ...............................................................................................................172 
Figure 28: Frequency of Unsolicited Adverse Events by MedDRA® System Organ Class and 
Severity .....................................................................................................................173 
Figure 29: Frequency of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® 
System Organ Class and Severity .............................................................................173 
Figure 30: Incidence of Unsolicited Adverse Events by MedDRA® System Organ Class and 
Severity .....................................................................................................................174 
Figure 31: Incidence of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® 
System Organ Class and Severity .............................................................................174 
Figure 32: Frequency of Adverse Events by MedDRA® System Organ Class and Relationship to 
Study Vaccination .....................................................................................................175 
Figure 33: Frequency of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® 
System Organ Class and Relationship to Study Vaccination ...................................175 
Figure 34: Incidence of Adverse Events by MedDRA® System Organ Class and Relationship to 
Study Vaccination .....................................................................................................176 
Figure 35: Incidence of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® 
System Organ Class and Relationship to Study Vaccination ...................................176 
Figure 36: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Study Group – White Blood Cells ....................................................177 


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Figure 37: Laboratory Summary Statistics of Change from Baseline by Parameter, Maximum 
Severity, Study Day, and Study Group – Hemoglobin .............................................177 
Figure 38: Laboratory Summary Statistics of Change from Baseline Results by Parameter, 
Maximum Severity, Study Day, and Study Group – Platelets .................................177 
Figure 39: Laboratory Summary Statistics of Change from Baseline by Parameter, Maximum 
Severity, Study Day, and Study Group – Alanine Aminotransferase (ALT) ...........177 
Figure 40: Laboratory Summary Statistics of Change from Baseline Results by Parameter, 
Maximum Severity, Study Day, and Study Group – Total Bilirubin .......................177 
Figure 41: Laboratory Summary Statistics of Change from Baseline Results by Parameter, 
Maximum Severity, Study Day, and Study Group – Creatinine ..............................177 
 
 


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10.1 
Disposition of Subjects 
Figure 1: 
CONSORT Flow Diagram 
    
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Assessed for Eligibility (N=X) 
 
Excluded* (N=X) 
♦ [Reason 1] (N=X) 
♦ [Reason 2] (N=X) 
 
Enrolled and Randomized (N=X) 
 
Enrollmen
t 
Screening 
Group 1 
2013 3.75+AS03/ 
2017 3.75+AS03 
 (D1-D22) 
Vaccination 1: N=X 
Vaccination 2: N=X 
Vaccination 
Group 5 
2017 3.75+AS03/ 
2017 3.75+AS03 (D1-
D121) 
    Vaccination 1: N=X 
Vaccination 2: N=X 
Group 3 
2013 3.75+AS03/ 
2017 15 
(D1-D22) 
Vaccination 1: N=X 
Vaccination 2: N=X 
PP 
Analysis, 
Day 22 post 
Group 4 
2017 3.75+AS03/ 
2017 3.75+AS03 
(D1-D22) 
 Vaccination 1: 
N=X 
Vaccination 2:
Group 2 
2013 3.75+AS03/ 
2017 3.75+AS03 
(D1-D121) 
Vaccination 1: N=X 
Vaccination 2: N=X 
Group 6 
2017 3.75+AS03/ 
2017 15 
(D1-D121) 
 Vaccination 1: 
N=X 
Vaccination 2:
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
PP 
Analysis, 
Day 181 
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   
N = X 
♦  -x Reason 1    
♦  -x Reason 2   


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14.2.2 Immunogenicity Figures 
14.2.2.1  
Serum Antibody Figures  
Figure 2: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody by Study Day 
and Study Group, Modified Intent-to-Treat Population 
[Implementation Note: A generic sample figure is shown below. The RCD curves should be presented in a 
single figure with six separate panels (4 columns for timepoints (Day 1, Day 22 post Vac 1, Day 22 post Vac 
2, Day 181 Post Vac 2), and 2 rows for strains (A/Shanghai/2/2013 (A/H7N9), A/Hong Kong/125/2017 
(A/H7N9))). Visit labels should be included in the panel headers. Within each panel individual curves should 
be used for each Study Group (six curves).] 
 
Figures with similar format: 
Figure 3: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody by Study Day 
and Study Group, Per Protocol Population 
Figure 4: 
Reverse Cumulative Distribution of Neutralizing Antibody by Study Day and Study 
Group, Modified Intent-to-Treat Population 
Figure 5: 
Reverse Cumulative Distribution of Neutralizing Antibody by Study Day and Study 
Group, Per Protocol Population 
 
 


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Figure 6: 
Geometric Mean Titers of Hemagglutination Inhibition Antibody by Study Day and 
Study Group, Modified Intent-to-Treat Population 
[Implementation Note: A generic sample figure is shown below. Planned Study Day is plotted along the x-
axis, with visit labels as tick labels. This figure will have two panels for the A/Shanghai/2/2013 (A/H7N9) 
and A/Hong Kong/125/2017 (A/H7N9) strains.  Titer is plotted on the y-axis on the log-10 scale. GMT should 
be plotted at each visit with upper and lower error bars for the 95% CI for each study group with different 
marker shapes/colors for each study group. Each study group should have a separate color and marker shape]  
 
 
Figures with similar format: 
Figure 7: 
Geometric Mean Titers of Hemagglutination Inhibition Antibody by Study Day and 
Study Group, Per Protocol Population 
Figure 8: 
Geometric Mean Titers of Neutralizing Antibody by Study Day and Study Group, 
Modified Intent-to-Treat Population 
Figure 9: 
Geometric Mean Titers of Neutralizing Antibody by Study Day and Study Group, Per 
Protocol Population 
 
 


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Figure 10: 
Correlation of Hemagglutination Inhibition Antibody and Neutralizing Antibody by 
Study Day and Study Group, Modified Intent-to-Treat Population 
[Implementation Note: A generic sample figure is shown below. The scatter plots should be presented in a 
seven figure files (one for each study group, and one for overall) each with 8 separate panels (4 columns  for 
each visit (Baseline, Day 22 post vaccination 1, Day 22 post vaccination 2, and Day 181 post vaccination 2) 
and 2 rows for the strains (A/Shanghai/2/2013 (A/H7N9), A/Hong Kong/125/2017 (A/H7N9))). Visit labels 
should be included in the panel header. Within each panel distinct marker types and colors should be used to 
indicate the study groups, with study group labels included in a legend. Each study group should have a 
unique color and marker shape used within its individual figure file. The spearman correlation should be 
calculated over all subjects and annotated within each panel as “Spearman Correlation (r=0.xx, p=0.xx)”] 
 
Figure with Similar format: 
Figure 11: 
Correlation of Hemagglutination Inhibition Antibody and Neutralizing Antibody by 
Study Day and Study Group, Per Protocol Population 


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14.2.2.2  
Antibody Secreting Cell Figures  
Figure 12: 
Box Plots of IgA Antibody Secreting Cells by A/H7N9 Strain, Study Day and 
Study Group, Modified Intent-to-Treat Population 
[Implementation Note: A generic sample figure is shown below. The box plots should be 
presented in a single figure with 4 separate panels (2 columns for each visit (Day 8 post 
vaccination 1 and Day 8 post vaccination 2) and 2 rows for the strains (A/Shanghai/2/2013 
(A/H7N9), A/Hong Kong/125/2017 (A/H7N9))). Visit labels should be included in the panel 
header. Within each panel distinct marker types and colors should be used to indicate the study 
groups, with study group labels included in a legend. Each study group should have a unique 
color and marker shape.] 
 


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Figures with similar format: 
Figure 13: 
Box Plots of IgA Antibody Secreting Cells by A/H7N9 Strain, Study Day and 
Study Group, Per Protocol Population 
Figure 14: 
Box Plots of IgG Antibody Secreting Cells by A/H7N9 Strain, Study Day and 
Study Group, Modified Intent-to-Treat Population 
Figure 15: 
Box Plots of IgG Antibody Secreting Cells by A/H7N9 Strain, Study Day and 
Study Group, Per Protocol Population 
Figure 16: 
Box Plots of IgM Antibody Secreting Cells by A/H7N9 Strain, Study Day and 
Study Group, Modified Intent-to-Treat Population 
Figure 17: 
Box Plots of IgM Antibody Secreting Cells by A/H7N9 Strain, Study Day and 
Study Group, Per Protocol Population 
 


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Figure 18: 
Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 1, Per Protocol Population  
[Implementation Note: A generic sample figure is shown below. The scatter matrix should be presented in a 
single figure with as shown below. Within each panel distinct marker types and colors should be used to 
indicate the study groups, with study group labels included in a legend. Each study group should have a 
unique color and marker shape. The spearman correlation should be calculated over all subjects an included in 
the top-right diagonal as “Spearman Correlation (r=0.xx, p=0.xx)” A legend will include the axis units. The 
Scatterplot matrix will be repeated twice in the same figure file for HA and NA specific ASC expression.] 
 
 
 


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Figures with similar format: 
Figure 19: 
Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 2, Per Protocol Population 
Figure 20: 
Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 1, Per Protocol Population  
Figure 21: 
Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells by 
Immunoglobulin Type at Day 8 Post Vaccination 2, Per Protocol Population  
Figure 22: 
Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells at Day 8 
Post Vaccination 1 with Antibody Response at Day 21 Post Vaccination 1, Per Protocol 
Population 
[Implementation Note Update: The scatter matrix should be presented in a single figure with one column for 
each Immunoglobulin type (IgM, IgG, IgA) and one row for each antibody titer (HAI, Neut). Within each 
panel distinct marker types and colors should be used to indicate the study groups, with study group labels 
included in a legend. Each study group should have a unique color and marker shape. The spearman 
correlation should be calculated over all subjects an included in the top-right diagonal as “Spearman 
Correlation (r=0.xx, p=0.xx)” A legend will include the axis units. The Scatterplot matrix will be repeated 
twice in the same figure file for HA and NA specific ASC expression.] 
Figure 23: 
Correlation of A/Shanghai/2/2013 (A/H7N9)-Specific Antibody Secreting Cells at Day 8 
Post Vaccination 2 with Antibody Response at Day 21 Post Vaccination 2, Per Protocol 
Population 
Figure 24: 
Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells at 
Day 8 Post Vaccination 1 with Antibody Response at Day 21 Post Vaccination 1, Per 
Protocol Population 
Figure 25: 
Correlation of A/Hong Kong/125/2017 (A/H7N9)-Specific Antibody Secreting Cells at 
Day 8 Post Vaccination 2 with Antibody Response at Day 21 Post Vaccination 2, Per 
Protocol Population 
 


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14.3.1.1 
Solicited Adverse Events 
Figure 26: 
Maximum Severity of Solicited Systemic Symptoms per Subject by Day Post Study 
Vaccination 
[Implementation Note: A Generic figure is shown below. A horizontal bar chart should be presented in 6 
image files (one per study group) with separate panels for each study vaccination (2 columns for vaccination 
#). Axes should be labeled as follows: x-axis label: Study Day, y-axis label: Percentage of Subjects (%). 
Study vaccination should be indicated in the panel headers including “(N=X)”, where N = the number of 
subjects in the Safety Population who received the relevant study vaccination. Subjects are counted at most 
once at the maximum severity across all systemic events reported for the specified time point] 
 
Figure with similar format: 
Figure 27: 
Maximum Severity of Solicited Local Symptoms per Subject by Day Post Study 
Vaccination 
 
 


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14.3.1.2 
Unsolicited Adverse Events 
Figure 28: 
Frequency of Unsolicited Adverse Events by MedDRA® System Organ Class and 
Severity 
[Implementation Note: A Generic figure is shown below. This figure includes all unsolicited events across all 
doses. A horizontal bar chart should be presented in 3 image files (one per vaccination, and one for all 
vaccinations) with separate panels for each study groups (6 columns (study groups)). Axes should be labeled 
as follows: y-axis label: System Organ Class, y-axis label: Number of Events. The study groups should be 
indicated in the panel headers including “(N=X)”, where N = the number of subjects in the Safety Population. 
The y-axis should present all SOCs reported by at least 1 subject and an “All Events” category. Y-axis should 
be sorted with “All Events” first, then in decreasing order of total incidence] 
 
 
 
Figures with similar format: 
Figure 29: 
Frequency of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® 
System Organ Class and Severity 


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Figure 30: 
Incidence of Unsolicited Adverse Events by MedDRA® System Organ Class and Severity 
[Implementation Note: A Generic figure is shown below. This figure includes all unsolicited events across all 
doses. A horizontal bar chart should be presented in 3 image files (one per vaccination, and one for all 
vaccinations) with separate panels for each study group (6 columns). Axes should be labeled as follows: y-
axis label: System Organ Class, x-axis label: Percentage of Subjects (%). The study groups should be 
indicated in the panel headers including “(N=X)”, where N = the number of subjects in the in the Safety 
Population. Subjects are counted at most once at the maximum severity across for any events in the applicable 
SOC. The y-axis should present all SOCs reported by at least 1 subject and an “All Events” category. Y-axis 
should be sorted with “All Events” first then in decreasing order of total incidence]  
 
Figure with similar format: 
Figure 31: 
Incidence of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® System 
Organ Class and Severity 


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Figure 32: 
Frequency of Adverse Events by MedDRA® System Organ Class and Relationship to 
Study Vaccination  
[Implementation Note: A generic sample figure is shown below. This figure includes all unsolicited events 
across all doses. A horizontal bar chart should be presented in 1 image file with separate panels for each study 
group and study dose (6 columns (study groups). Axes should be labeled as follows: y-axis label: System 
Organ Class, y-axis label: Number of Events. The study groups should be indicated in the panel headers 
including “(N=X)”, where N = the number of subjects in the in the Safety Population. The y-axis should 
present all SOCs reported by at least 1 subject and an “All Events” category. Y-axis should be sorted with 
“All Events first then in decreasing order of total frequency] 
 
 
Figure with similar format: 
Figure 33: 
Frequency of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® 
System Organ Class and Relationship to Study Vaccination 
 
 


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Figure 34: 
Incidence of Adverse Events by MedDRA® System Organ Class and Relationship to 
Study Vaccination 
[Implementation Note: A Generic figure is shown below. This figure includes all unsolicited events across all 
doses. A horizontal bar chart should be presented in a 1 image file with separate panels for each study group 
(6 columns (study groups)). Axes should be labeled as follows: y-axis label: System Organ Class, x-axis 
label: Percentage of Subjects (%). The study groups should be indicated in the panel headers including 
“(N=X)”, where N = the number of subjects in the in the Safety Population. Subjects are counted at most once 
at the maximum relationship (related >not-related) across for any events in the applicable SOC. The y-axis 
should present all SOCs reported by at least 1 subject and an “All Events” category. Y-axis should be sorted 
with “All Events first, then in decreasing order of total incidence across groups]  
 
Figures with similar format: 
Figure 35: 
Incidence of Unsolicited Adverse Events Within 21 Days Post Dose by MedDRA® System 
Organ Class and Relationship to Study Vaccination 
 
 


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14.3.5 
Displays of Laboratory Results 
Figure 36: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Study Group – White Blood Cells 
[Implementation note: A generic figure is shown below. Plot should be generated with all study groups in a 
single image file with panels for each study group (6 columns (study groups)) with a box plot shown for each 
post-baseline study day that labs are drawn (Day 8 post first vaccination, Day 121 Post  first vaccination (only 
for study groups 2,3,5, and 6), and Day 22 post first vaccination, Day 8 post second study vaccination). Y-
axis should be labeled “[Parameter] Change from baseline ([units]). Repeat for all clinical laboratory 
parameters: WBC, Hgb, PLT, ALT, T. Bili, Cr] 
 
Figures with similar format: 
Figure 37: 
Laboratory Summary Statistics of Change from Baseline by Parameter, Maximum 
Severity, Study Day, and Study Group – Hemoglobin 
Figure 38: 
Laboratory Summary Statistics of Change from Baseline Results by Parameter, 
Maximum Severity, Study Day, and Study Group – Platelets 
Figure 39: 
Laboratory Summary Statistics of Change from Baseline by Parameter, Maximum 
Severity, Study Day, and Study Group – Alanine Aminotransferase (ALT) 
Figure 40: 
Laboratory Summary Statistics of Change from Baseline Results by Parameter, 
Maximum Severity, Study Day, and Study Group – Total Bilirubin 
Figure 41: 
Laboratory Summary Statistics of Change from Baseline Results by Parameter, 
Maximum Severity, Study Day, and Study Group – Creatinine 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
 
 


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LISTINGS 
Listing 1: 16.1.6 - Listing of Subjects Receiving Investigational Product ...............................180 
Listing 2: 16.2.1 - Early Terminations or Discontinued Subjects .............................................181 
Listing 3: 16.2.2.1 - Subject-Specific Protocol Deviations .......................................................182 
Listing 4: 16.2.2.2 - Non-Subject-Specific Protocol Deviations ..............................................183 
Listing 5: 16.2.3: Subjects Excluded from Analysis Populations .............................................184 
Listing 6: 16.2.4.1 - Demographics Data ..................................................................................185 
Listing 7: 16.2.4.2 – Pre-Existing and Concurrent Medical Conditions ...................................186 
Listing 8: 16.2.4.3 – Influenza Vaccination History .................................................................187 
Listing 9: 16.2.6.1 - Individual Immunogenicity Response Data (HAI and Neut) ...................189 
Listing 10: 16.2.6.2 - Individual Immunogenicity Response Data (Antibody Secreting Cells) .189 
Listing 11: 16.2.7.1 - Solicited Events – Systemic Symptoms ...................................................190 
Listing 12: 16.2.7.2 - Solicited Events – Local Symptoms .........................................................191 
Listing 13: 16.2.7.3 - Unsolicited Adverse Events .....................................................................192 
Listing 14: 16.2.8.1 - Clinical Laboratory Results – Chemistry .................................................193 
Listing 15: 16.2.8.2 - Clinical Laboratory Results – Hematology ..............................................194 
Listing 16: 16.2.9.1 - Vital Signs ................................................................................................195 
Listing 17: 16.2.9.2 - Physical Exam Findings ...........................................................................196 
Listing 18: 16.2.10 - Concomitant Medications ..........................................................................197 
Listing 19: 16.2.11.1 - Pregnancy Reports – Maternal Information ...........................................198 
Listing 20: 16.2.11.2 - Pregnancy Reports – Gravida and Para ..................................................198 
Listing 21: 16.2.11.3 - Pregnancy Reports – Live Birth Outcomes ............................................199 
Listing 22: 16.2.11.4 - Pregnancy Reports – Still Birth Outcomes.............................................199 
Listing 23: 16.2.11.5 - Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................199 
 


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16.1.6 Listing of Subjects Receiving Investigational Product 
Listing 1: 
16.1.6 - Listing of Subjects Receiving Investigational Product 
Subject ID 
Randomized  
Study Group 
Product Received Study 
Vaccination 1 
Product Received Study 
Vaccination 2 
XXXXXXXXXX 
Group 1 
2013 A/H7N9 IIV + AS03 
2017 A/H7N9 IIV + AS03 
XXXXXXXXXX 
Group 2 
2013 A/H7N9 IIV + AS03 
2017 A/H7N9 IIV + AS03 
XXXXXXXXXX 
Group 3 
2013 A/H7N9 IIV + AS03 
2017 A/H7N9 IIV   
XXXXXXXXXX 
Group 4 
2017 A/H7N9 IIV + AS03 
2017 A/H7N9 IIV + AS03 
XXXXXXXXXX 
Group 5 
2017 A/H7N9 IIV + AS03 
2017 A/H7N9 IIV + AS03 
XXXXXXXXXX 
Group 6 
2017 A/H7N9 IIV + AS03 
2017 A/H7N9 IIV   
 
 


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16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 2: 
16.2.1 - Early Terminations or Discontinued Subjects 
[Implementation Note: Category will be either “Early Termination” or “Treatment Discontinuation.” In the “Reason” column, concatenate any 
“specify” fields, including AE number and DV number.] 
Subject ID 
Study Group 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 3: 
16.2.2.1 - Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” 
is “Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.”] 
Subject 
ID 
Study 
Group 
DV 
Number 
Deviation 
Deviation 
Category 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 4: 
16.2.2.2 - Non-Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” 
is “Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.”] 
Site 
Deviation 
Start 
Date 
End 
Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Subjects Excluded from the Analysis 
Listing 5: 
16.2.3: Subjects Excluded from Analysis Populations 
[Implementation Note: This data in this listing should be congruent with the “Analysis Populations by Study Group” table. The reasons included  
here should match the SAP text that describes who will be excluded from analyses.]
Study Group 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
 
[e.g., Safety, ITT, PP] 
[e.g., Safety, ITT, PP, Day x] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the 
analysis. 
 
 
 


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16.2.4 Demographic Data 
Listing 6: 
16.2.4.1 - Demographics Data 
[Implementation Note: If a subject is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).”] 
Subject ID 
Study Group 
Sex 
Age at Enrollment (years) 
Ethnicity 
Race 
BMI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 7: 
16.2.4.2 – Pre-Existing and Concurrent Medical Conditions 
[Implementation Note: “Condition Start Day” and “Condition End Day” are relative to enrollment (which is Day 1, day before enrollment is  
Day -1). If ongoing, display “Ongoing” in the “Condition End Day” column] 
Subject ID 
Study 
Group 
MH 
Number 
Medical History 
Term 
Condition Start 
Day  
Condition End 
Day 
MedDRA® System Organ 
Class 
MedDRA® Preferred Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 8: 
16.2.4.3 – Influenza Vaccination History 
Subject ID 
Study group 
Vaccine Type 
Month/Year Received 
Vaccination Type / Subtype 
 
 
[Inactivated/ LAIV/ Unknown] 
September 2018 
Seasonal Influenza Vaccination (2017-2018) 
 
 
[Inactivated/ LAIV/ Unknown] 
June 2017 
Non-Seasonal Influenza A Vaccine Subtype H5N8 
 
 
[Inactivated/ LAIV/ Unknown] 
June 2017 
Non-Seasonal Influenza Vaccinae Subtype M-001 
 
 
 


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16.2.5 Compliance and/or Drug Concentration Data (if available) 
Not applicable for this study. 
 


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16.2.6 Individual Immunogenicity Response Data 
Listing 9: 
16.2.6.1 - Individual Immunogenicity Response Data (HAI and Neut) 
Subject ID 
Study Group 
Planned Time Point 
Actual Study 
Day 
Assay 
Strain 
Titer Replicate 1 
Titer Replicate 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 10: 
16.2.6.2 - Individual Immunogenicity Response Data (Antibody Secreting Cells) 
Subject ID 
Study Group 
Planned Time Point 
Actual Study 
Day 
Strain 
IgA 
Frequency 
IgG 
Frequency 
IgM 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.7 Adverse Events 
Listing 11: 
16.2.7.1 - Solicited Events – Systemic Symptoms 
Subject ID 
Study Group 
Vaccination 
Number 
Post Dose Day 
Assessment1 
Symptom 
Severity 
Attributed to 
Alternate 
Etiology?2 
Alternate 
Etiology 
 
 
 
 
MA 
 
 
 
 
 
 
 
 
Clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 MA = Data reported by subject on the Memory Aid and reviewed by clinic staff and reported in Solicited Events eCRF. 
Clinic = Data collected by clinic staff during physical exam or symptom assessment (treatment administration record, in-clinic assessment, etc.). 
2 Grade 3 events only. 
 


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Listing 12: 
16.2.7.2 - Solicited Events – Local Symptoms  
Subject ID 
Study Group 
Vaccination 
Number 
Product 
Received1 
Post Vaccination 
Day 
Assessment1 
Symptom 
Severity 
 
 
 
 
 
MA 
 
 
 
 
 
 
 
Clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 MA = Data reported by subject on the Memory Aid and reviewed by clinic staff and reported in Solicited Events eCRF. 
Clinic = Data collected by clinic staff during physical exam or symptom assessment (treatment administration record, in-clinic assessment, etc.). 
 
 


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Listing 13: 
16.2.7.3 - Unsolicited Adverse Events 
Adverse 
Event 
Associated 
with Vac # 
# of Days 
Post 
Associated 
Vac 
(Duration) 
Severity 
SAE? 
MAAE? 
PIMMC? 
Relationship 
to Study 
Vaccination 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA® 
System 
Organ 
Class 
MedDRA® 
Preferred 
Term 
Subject ID: , Study Group: , AE Number:  
 
 
 
 
SAE: No 
MAAE: Yes 
PIMMC: No 
 
 
 
 
 
 
 
Comments: 
Subject ID: , Study Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Section 14.3.3 . 
 
 
 


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16.2.8 Individual Laboratory Measurements 
Listing 14: 
16.2.8.1 - Clinical Laboratory Results – Chemistry 
[Implementation Note: These listings (for hematology and chemistry) include all laboratory results, scheduled and unscheduled. These listings are 
not color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). The “extra” fields that are 
completed for abnormal results are not included in this listing; they are included in the listing of abnormal laboratory results that is included in the 
table shells.] 
Subject ID 
Study Group 
Sex 
Age 
(years) 
Planned 
Time 
Point 
Actual 
Study 
Day 
Alanine aminotransferase  
(IU/L) 
Total Bilirubin 
(mg/dL) 
Creatinine 
(mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 15: 
16.2.8.2 - Clinical Laboratory Results – Hematology 
Subject ID 
Study Group 
Sex 
Age 
(years) 
Planned 
Time 
Point 
Actual 
Study 
Day 
White Blood Cell 
(103/µL) 
Hemoglobin 
(g/dL) 
Platelets 
(103/µL)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 16: 
16.2.9.1 - Vital Signs 
[Implementation Note: This listing includes all vital sign assessments, scheduled and unscheduled. These listings are not color-coded, but the 
severity should be included in parentheses after the result for abnormal assessments, e.g., 100.7 (Mild).] 
Subject ID 
Study Group  
Planned Time 
Point 
Actual Study 
Day 
Temperature 
(°C) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
Pulse 
(beats/min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 17: 
16.2.9.2 - Physical Exam Findings 
[Implementation Note: This listing includes all physical exam findings, scheduled and unscheduled. If a subject does not have any findings upon 
examination, they will not be included in this listing. If reported as an AE, display “Yes” with the AE Number in parentheses, e.g., “Yes (7)”.] 
Subject ID 
Study Group 
Planned 
Time Point 
Actual 
Study Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.10 
Concomitant Medications 
Listing 18: 
16.2.10 - Concomitant Medications 
[Implementation Note: “Medication Start Day” and “Medication End Day” are relative to enrollment (which is Day 1, day before enrollment is Day 
-1). For medication start dates that are > 30 days prior to enrollment, rather than use exact study days, categorize as follows: 
• > 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
If ongoing, display “Ongoing” in the “Medication End Day” column. If taken for an AE or MH, display “Yes” with the AE or MH Number in 
parentheses, e.g., “Yes (7)”.] 
Subject 
ID 
Study 
Group 
CM 
Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an 
AE? 
(AE Number) 
Taken for a condition 
on Medical History? 
(MH Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.11 Pregnancy Reports 
[Implementation Note: Only include the “Pregnancy Number” column if a subject has more than 1 pregnancy. Date of Conception will be 
calculated based on estimated delivery date. BMI will be calculated based on pre-pregnancy height and weight. Mother’s weight gain will be 
calculated based on pre-pregnancy weight and end of pregnancy weight. If a major congenital anomaly with previous pregnancy, display “Yes” and 
the text from the “specify” field, separated by a colon. If any substance use is reported, include a listing of substance use. If autopsy revealed an 
alternate etiology, display “Yes” and the text from the “specify” field, separated by a colon. If abnormality in product of conception, display “Yes” 
and the text from the “specify” field, separated by a colon.] 
Listing 19: 
16.2.11.1 - Pregnancy Reports – Maternal Information 
Subject 
ID 
Study 
Group 
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 
Listing 20: 
16.2.11.2 - Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PB1 
Very 
Early 
PB1 
Early 
PB1 
Late 
PB1 
Early 
TB2 
Full 
TB2 
Late 
TB2 
Post 
TB2 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Preterm Birth. 
2 Term Birth. 
Note: Gravida includes the current pregnancy, para events do not. 
 
 


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Listing 21: 
16.2.11.3 - Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 
1 
minute 
Apgar 
Score, 5 
minutes 
Cord 
pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month 
of Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing.  
Listing 22: 
16.2.11.4 - Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, 
Etiology for Still 
Birth Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 23: 
16.2.11.5 - Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy 
Outcome (for this 
Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of 
Conception? 
Reason for Therapeutic 
Abortion