A Phase II Study in Healthy Adults 18-64 Years Old to Assess the Safety, Reactogenicity and Immunogenicity of a Seqirus A/H7N9 Inactivated Influenza Vaccine Administered Intramuscularly With or Without MF59(R) Adjuvant
Phase: PHASE2
Conditions: Avian Influenza, Influenza Immunisation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
A Phase II Study in Healthy Adults 18-64 Years Old to Assess the 
Safety, Reactogenicity and Immunogenicity of a Seqirus A/H7N9 
Inactivated Influenza Vaccine Administered Intramuscularly With or 
Without MF59® Adjuvant  
DMID Protocol Number:  
17-0076 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
 
Pharmaceutical Support: 
Seqirus Inc. 
 
IND Sponsor: DMID, NIAID 
 
Lead Principal Investigator: Sharon E. Frey, MD 
DMID Clinical Project Manager: Robin M. Mason, MS 
Version: 3.0 
24 June 2019 
 
 

DMID Protocol 17-0076 
Version 3.0 
A/ 2017 H7N9 with/without MF59® in Healthy Adults 
24 June 2019 
 
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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subjects research. Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated 
under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of 
another institution after establishing a written agreement with that other institution. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DMID Protocol 17-0076 
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STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• United States 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 312 (Investigational New Drug 
Application), 21 CFR 812 (Investigational Device Exemptions) 
• 
The International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use” (ICH) E6(R2) Good Clinical Practice:  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  

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SIGNATURE PAGE 
The signature below provides the necessary assurances 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 Good Clinical Practice (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 IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 
Site Investigator Signature: 
 
Signed: 
 
 
Date: 
 
 
Name 
Title 
 
 
 

DMID Protocol 17-0076 
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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
LIST OF ABBREVIATIONS ........................................................................................................11 
PROTOCOL SUMMARY .............................................................................................................14 
1 
Key Roles ..............................................................................................................................20 
2 
Background Information and Scientific Rationale ...............................................................21 
 
Background ...............................................................................................................21 
 Public Readiness and Emergency Preparedness Act ....................................24 
 
Scientific Rationale ...................................................................................................25 
2.2.1 Purpose of Study ...........................................................................................25 
2.2.2 Study Population ...........................................................................................26 
 
Potential Risks and Benefits .....................................................................................26 
 Potential Risks ..............................................................................................26 
 Potential Benefits ..........................................................................................31 
3 
Study Design, Objectives and Endpoints or Outcome Measures .........................................32 
 
Study Design Description .........................................................................................32 
 
Study Objectives .......................................................................................................33 
 Primary ..........................................................................................................33 
 Secondary ......................................................................................................33 
3.2.3 Exploratory ...................................................................................................34 
 
Study Endpoints or Outcome Measures ....................................................................34 
 Primary ..........................................................................................................34 
 Secondary ......................................................................................................35 
 Exploratory ...................................................................................................36 
4 
Study intervention/investigational product ...........................................................................37 
 
Study Product Description ........................................................................................37 
4.1.1 Formulation, Storage, Packaging, and Labeling ...........................................37 
4.1.2 Product Storage and Stability........................................................................39 
4.2 
Acquisition/Distribution ...........................................................................................39 
4.3 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/ Investigational Product ........................................................................40 
4.4 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Subject .....................................................................................................42 

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4.5 
Accountability Procedures for the Study Intervention/ Investigational Product(s) ..42 
5 
Selection of subjects and study Enrollment and Withdrawal ...............................................44 
 
Eligibility Criteria .....................................................................................................44 
 Subject Inclusion Criteria .............................................................................44 
 Subject Exclusion Criteria ............................................................................45 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study 
Termination ...............................................................................................................48 
 Withdrawal from the Study or Discontinuation of the Study Product ..........48 
5.2.2 Subject Replacement .....................................................................................49 
5.2.3 Study Termination ........................................................................................50 
6 
Study Procedures ..................................................................................................................51 
 
Screening (Optional) Visit 00, Day -28 to -1, Clinic Visit .......................................51 
 
Enrollment, Visit 01 Day 01 for subjects previously screened at Day -28 to -1 and 
First Vaccination (Dose 1), Clinic Visit ...................................................................52 
 
Visit 01, Day 1, Enrollment/Baseline (for subjects not previously screened at Day -
28 to -1) and First Study Vaccination (Dose 1), Clinic Visit....................................54 
 
Planned Study Visits .................................................................................................56 
 Follow-up ......................................................................................................56 
 Final Study Visit, Visit 11, Day 387, Safety Follow-up, Phone Call ...........62 
 Early Termination Visit (if needed) ..............................................................62 
6.5 
Unscheduled Visit (if needed) ..................................................................................64 
6.6 
Protocol Deviations ...................................................................................................65 
7 
Description of Clinical and Laboratory Evaluations ............................................................66 
7.1 
Clinical Evaluations ..................................................................................................66 
 Assessment of Concomitant Medications/Treatments other than Study 
Product ..........................................................................................................67 
7.2 
Laboratory Evaluations .............................................................................................68 
7.2.1 Clinical Laboratory Evaluations ...................................................................68 
7.2.2 Research Assays............................................................................................68 
7.2.2.1 Laboratory Specimen Preparation, Handling, and Shipping ............69 
7.2.2.2 Laboratory Specimen Shipment ........................................................70 
8 
Assessment of safety .............................................................................................................71 
8.1 
Assessing and Recording Safety Parameters ............................................................71 
8.1.1 Adverse Events .............................................................................................71 
8.1.1.1 Adverse Events Grading ...................................................................72 
8.1.2 Reactogenicity...............................................................................................73 
8.1.3 Serious Adverse Events ................................................................................75 
8.2 
Specifications of Safety Parameters ..........................................................................77 
8.2.1 Solicited Events ............................................................................................77 
8.2.2 Unsolicited Events ........................................................................................77 

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8.2.3 Unsolicited events are any other AEs that occur following administration of 
study product. ................................................................................................77 
8.2.4 New Onset Chronic Medical Conditions (NOCMCs) ..................................77 
8.2.5 Medically Attended Adverse Events (MAAEs) ...........................................77 
8.2.6 Potentially Immune Mediated Medical Conditions (PIMMCs)....................77 
8.3 
Reporting Procedures ................................................................................................77 
8.3.1 Reporting Serious Adverse Events ...............................................................78 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID Sponsored IND
.......................................................................................................................79 
8.3.3 Reporting of Pregnancy ................................................................................79 
8.3.4 Disclosure of Study Related Information .....................................................79 
8.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................79 
8.5 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings ......................................................................................80 
8.6 
Halting Rules ............................................................................................................81 
8.6.1 Study Halting Criteria ...................................................................................81 
8.6.2 Individual Halting Criteria ............................................................................82 
8.7 
Safety Oversight........................................................................................................84 
8.7.1 Independent Safety Monitor (ISM) ...............................................................84 
8.7.2 Data and Safety Monitoring Board (DSMB) ................................................84 
9 
Human subject protection .....................................................................................................86 
9.1 
Institutional Review Board/Independent Ethics Committee.....................................86 
9.2 
Informed Consent Process ........................................................................................86 
9.3 
Consent for Future Use of Stored Specimens and Data ............................................88 
9.4 
Exclusion of Women, Minorities, and Children (Special Populations) ....................89 
9.5 
Subject Confidentiality .............................................................................................90 
9.6 
Certificate of Confidentiality ....................................................................................90 
9.7 
Costs, Subject Compensation, and Research Related Injuries ..................................91 
10 
Statistical Considerations ......................................................................................................92 
10.1 
Study Hypotheses......................................................................................................92 
10.2 
Sample Size Considerations ......................................................................................92 
10.3 
Treatment Assignment Procedures ...........................................................................94 
10.3.1 Randomization Procedures ...........................................................................94 
10.3.2 Masking Procedures ......................................................................................94 
10.4 
Planned Interim Analyses .........................................................................................95 
10.4.1 Interim Safety Review ..................................................................................95 
10.4.2 Interim Immunogenicity or Efficacy Review ...............................................96 
10.5 
Final Analysis Plan ...................................................................................................96 
10.5.1 Analysis Populations .....................................................................................97 
10.5.2 Safety Data ....................................................................................................97 

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10.5.3 Immunogenicity Data....................................................................................98 
10.5.4 Missing Values and Outliers .........................................................................99 
11 
Source Documents Access to Source Data/Documents ......................................................100 
12 
Quality Control and Quality Assurance ..............................................................................101 
13 
Data Handling and Record Keeping ...................................................................................102 
13.1 
Data Management Responsibilities.........................................................................102 
13.2 
Data Coordinating Center/Biostatistician Responsibilities .....................................102 
13.3 
Data Capture Methods ............................................................................................102 
13.4 
Types of Data ..........................................................................................................102 
13.5 
Study Records Retention.........................................................................................103 
14 
Clinical Monitoring .............................................................................................................104 
15 
Publication Policy ...............................................................................................................105 
16 
Literature References ..........................................................................................................106 
17 
Appendices ..........................................................................................................................111 
APPENDIX A: SCHEDULE OF PROCEDURES AND EVALUATIONS ...............................112 
APPENDIX B. LIST OF POTENTIALLY IMMUNE MEDIATED MEDICAL CONDITIONS
.............................................................................................................................................116 
 
 
 

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LIST OF TABLES 
Table 1: Study Design ....................................................................................................................18 
Table 2: Venipuncture Volumes (mL): ..........................................................................................69 
Table 3: Injection Site Reactogenicity Grading .............................................................................73 
Table 4: Injection Site Reactogenicity Measurements ...................................................................74 
Table 5: Subjective Systemic Reactogenicity Grading ..................................................................74 
Table 6: Quantitative Systemic Reactogenicity Grading ...............................................................75 
Table 7: Pulse and Blood Pressure Grading for Subjects 18-64 years of age................................75 
Table 8: Power (%) to Detect Safety Events: ................................................................................92 
Table 9: Precision of Binomial Confidence Intervals: ...................................................................93 
Table 10: Minimum Detectable Difference in Proportion Responders with 80% Power ..............93 
Table 11: Lower Confidence bound2 for difference in proportion of responders between 
adjuvanted (N = 100) and unadjuvanted (N = 50) arms, 18-64 years stratum ...........93 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF FIGURES 
Figure 1: Schematic of Study Design ............................................................................................19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
A/H1N1 
Influenza A Virus of the H1N1 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/H5N2 
Influenza A Virus of the H5N2 Subtype 
A/H5N6 
Influenza A Virus of the H5N6 Subtype 
A/H5N3 
Influenza A Virus of the H5N3 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 
AS03 
Adjuvant System 03 
AdvantageEDCSM 
Electronic Data Capture System 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
AESIs 
Adverse Events of Special Interest 
ANCA 
Anti-Neutrophil Cytoplasmic Antibody 
BARDA 
Biomedical Advanced Research and Development Authority 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CICP 
Countermeasure Injury Compensation Program 
CMS 
Clinical Materials Services 
CoA 
Certificate of Analysis 
CROMS 
Clinical Research Operations and Management Support 
Cr 
Creatinine 
CSL 
Commonwealth Serum Laboratories 
CSR 
Clinical Study Report 
CTAB 
Cetyltrimethylammonium bromide 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
D 
Day(s) 

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DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FWA 
Federal Wide 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 
HIV 
Human Immunodeficiency Virus 
HPAI 
Highly Pathogenic Avian Influenza 
HRSA 
Health Resources and Services Administration 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICD 
International Classification of Diseases 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IgG 
Immunoglobulin G 
IIV 
Inactivated Influenza Virus Vaccine 
IIV3 
Trivalent Inactivated Influenza Vaccine 
IIV4 
Quadrivalent Inactivated Influenza Vaccine 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IU/L 
International Unit(s) per Liter 
mcg  
Microgram(s) 
µL 
Microliter(s) 
MAAEs 
Medically-Attended Adverse Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF59® 
MF59C.1 Adjuvant 
mg/dL 
Milligram(s) per Deciliter 
mITT 
Modified Intent-to-Treat 

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mL 
Milliliter(s) 
mmHg 
Millimeters of Mercury 
MOP 
Manual of Procedures 
N 
Number of Subjects 
NA 
Neuraminidase 
Neut 
Neutralizing or Neutralization 
NI 
Neuraminidase Inhibiting  
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
NOCMCs 
New-Onset Chronic Medical Conditions 
NVD 
Novartis Vaccines and Diagnostics 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
OTC 
Over the Counter 
PBS 
Phosphate Buffered Saline 
PHI 
Personal Health Information 
PIMMCs 
Potentially Immune-Mediated Medical Conditions 
PLT 
Platelets 
PP 
Per Protocol 
PREP Act 
Public Readiness and Emergency Preparedness Act 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
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 in Healthy Adults 18-64 Years Old to Assess the 
Safety, Reactogenicity and Immunogenicity of a Seqirus A/H7N9 
Inactivated Influenza Vaccine Administered Intramuscularly With 
or Without MF59® Adjuvant  
Design of the Study: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a randomized, double-blinded, Phase II study in healthy 
males and non-pregnant females, 18-64 years of age. This clinical 
trial is designed to assess the safety, reactogenicity, and 
immunogenicity of a pre-pandemic 2017 monovalent inactivated 
influenza A/H7N9 virus vaccine (2017 H7N9 IIV) manufactured 
by Seqirus Inc (Seqirus) administered at different dosages (3.75 
microgram [mcg], 7.5 mcg and 15 mcg of hemagglutinin (HA) per 
dose) given with MF59® adjuvant manufactured by Seqirus Inc. 
(Seqirus), or without adjuvant (15 mcg of HA per dose). 
Phosphate buffered saline (PBS) diluent manufactured by Patheon 
Manufacturing Services LLC will be used to achieve certain 
targeted doses. The 2017 H7N9 inactivated influenza vaccine 
(IIV) was manufactured using a reverse genetics-derived 
reassortant candidate vaccine virus IDCDC RG56B (H7N9), 
containing the HA and neuraminidase (NA) from low pathogenic 
influenza A/Hong Kong/125/2017 (H7N9) and the PB2, PB1, PA, 
NP, M and NS from A/Puerto Rico/8/1934 (H1N1).  
Subjects who are in good health and meet all eligibility criteria 
(including a negative serum or urine pregnancy test for women of 
childbearing potential, history and physical exam) within 28 days 
prior to the first vaccination or on the day of, but prior to, first 
vaccination, will be randomized into one of 4 study groups as 
shown in Table 1. Baseline blood samples for clinical safety 
laboratories will be drawn prior to the first vaccine dose and will 
not be used to screen subjects for eligibility. 
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), 

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Study Phase: 
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 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 hemagglutinin 
inhibition (HAI) and neutralizing (Neut) antibody assays against 
the 2017 H7N9 vaccine virus on serum samples obtained 
immediately prior to each study vaccination (Days 1 and 
approximately Day 22), approximately 7 days after each study 
vaccination (Days 8 and 29), and approximately 21 and 180 days 
after the second study vaccination (Days 43 and 202). 
Novel methods for identifying and assessing alternative correlates 
of protection against influenza infection are needed.  We will 
assess the NA-specific antibody response to vaccination. In 
addition, we plan to determine the NA content of IIV using assays 
that are currently under development. If successful, we will 
determine whether the NA content correlates with the N9 NA-
specific antibody response in a dosage-specific manner. If NA 
content of the vaccine is not determined, then we will determine 
whether the NA-specific antibody response increases with 
increasing dosage of vaccine based on the HA content. 
Subjects who have not received the current season’s licensed   
seasonal trivalent or quadrivalent influenza vaccine prior to 
enrollment may receive it anytime following completion of the 
Day 43 study visit or upon early termination. 
 
II 
Study Population: 
Approximately 371 individuals 18-64 years old, who have no 
history of influenza A/H7N9 infection or prior receipt of an 
influenza virus H7 subtype vaccine. 
Number of Sites: 
Up to 7 Vaccine and Treatment Evaluation Unit (VTEU) sites 

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Description of Study 
Product or Intervention: 
Two doses delivered intramuscularly (IM) approximately 21 days 
apart of a monovalent inactivated pre-pandemic influenza A/H7N9 
vaccine (2017 H7N9 Inactivated Influenza Vaccine [IIV]) 
manufactured by Seqirus, at different dosages [3.75, 7.5 or 15 
micrograms/0.5 milliliter (mL) of hemagglutinin (HA) from 
A/Hong Kong/125/2017 H7N9 vaccine per dose] administered 
with MF59® adjuvant (Seqirus) or without adjuvant [15 
microgram (mcg) HA per dose]. 
Phosphate buffered saline (PBS) diluent manufactured by Patheon 
Manufacturing Services LLC is added to monovalent vaccine to 
achieve targeted HA content. 
Study Objectives: 
 
Primary: 
Safety: 
• To assess the safety and reactogenicity following receipt of 
two doses of 2017 H7N9 IIV administered IM at different 
dosages approximately 21 days apart given with or without 
MF59® adjuvant  
Immunogenicity: 
• To assess the serum HAI and Neut antibody responses 
approximately 21 days following receipt of two doses of 
2017 H7N9 IIV administered IM at different dosages 
approximately 21 days apart with or without MF59® 
adjuvant. 
Secondary: 
Safety: 
• To assess all unsolicited non-serious AEs following receipt 
of two doses of a 2017 H7N9 IIV administered IM at 
different dosages approximately 21 days apart with or 
without MF59® adjuvant  
• To assess MAAEs including NOCMCs, PIMMCs, and all  
SAEs following receipt of two doses of a 2017 H7N9 IIV 
administered IM at different dosages approximately 21 
days apart with or without MF59® adjuvant 
Immunogenicity: 

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• To assess the serum HAI and Neut antibody responses 
approximately 7 and 21 days following receipt of a single 
dose, and approximately 7 days following receipt of two 
doses of 2017 H7N9 IIV administered IM at different 
dosages approximately 21 days apart with or without 
MF59® adjuvant. 
Exploratory: 
Immunogenicity: 
• To assess the effects of age, sex, body mass index, and 
prior receipt of seasonal influenza vaccine(s) on serum 
HAI and Neut antibody responses following receipt of two 
doses of a 2017 H7N9 IIV administered IM at different 
dosages approximately 21 days apart with or without 
MF59® adjuvant. 
• 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 
following receipt of two doses of a 2017 H7N9 IIV 
administered IM at different dosages approximately 21 
days apart with or without MF59® adjuvant.  
• To assess the durability of serum HAI and Neut antibody 
responses at approximately 180 days following receipt of 
two doses of 2017 H7N9 IIV administered IM at different 
dosages approximately 21 days apart with or without 
MF59® adjuvant.  
• To assess the NA content of the 2017 H7N9 IIV and 
determine the serum antibody responses to NA following 
receipt of 2017 H7N9 IIV. 
 
 
 
 
 
Duration of Individual 
Subject Participation: 
Approximately thirteen (13) months 

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Estimated Time to Last 
Subject/Last Study Day: 
Approximately seventeen (17) months 
Table 1: Study Design 
Treatment Arms1 
Day 1 
Day 22 
Group 1, n=106 
Seqirus H7N9 vaccine 3.75 mcg 
plus MF59® adjuvant 
Seqirus H7N9 vaccine 3.75 mcg 
plus MF59® adjuvant 
Group 2, n=106 
Seqirus H7N9 vaccine 7.5 mcg 
plus MF59® adjuvant 
Seqirus H7N9 vaccine 7.5 mcg 
plus MF59® adjuvant 
Group 3, n=106 
Seqirus H7N9 vaccine 15 mcg 
plus MF59® adjuvant 
Seqirus H7N9 vaccine 15 mcg 
plus MF59® adjuvant 
Group 4, n=53 
Seqirus H7N9 vaccine 15 mcg 
unadjuvanted 
Seqirus H7N9 vaccine 15 mcg 
unadjuvanted 
 
1 Randomization will be stratified by site and prior receipt of at least one of the 2017-2018 
and/or 2018-2019 seasonal influenza vaccine. No target number of participants is identified for 
each prior vaccination stratum. 

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1 
KEY ROLES 
 
Lead Principal Investigator: 
 
 
 
 
Sharon Frey, MD 
Saint Louis University School of Medicine 
 
 
DMID Clinical Project Manager: 
Robin M. Mason, MS 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
Data Coordinating Center: 
The Emmes Company, LLC 
 
 
 
 
 
 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background  
The continued emergence of novel influenza A viruses in humans including subtypes H5N1, 
H3N2v, H7N7, H9N2, 2009 H1N1, and most recently H5N6 and H7N9, underscores the need 
for focused efforts to prepare for the next influenza pandemic  [1-6]. 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 [7]. Excess mortality, high morbidity, and social 
disruption were all noted during the 1957 influenza A/H2N2 and the 1968 influenza A/H3N2 
pandemics [8]. 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 IIV development programs that provided important insights into variables influencing the 
immune responses to immunization [9, 10]. 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 NA, the major surface glycoproteins on 
influenza viruses, play a key role in protective immunity to influenza virus infection [11]. Since 
protection against infection with seasonal influenza virus strains has been shown to correlate 
with both serum HAI and Neut antibody levels, their measurements are used routinely to assess 
the immunogenicity of both seasonal and pandemic IIVs. Recent data also support an important 
role for neuraminidase inhibiting (NI) antibodies in protection against disease [12]. In a recent 
human influenza challenge study, serum NI antibody levels were also identified as an 
independent correlate of protection against influenza illness [13].  In the current study, we plan 

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to assess the NA content of 2017 H7N9 IIV and determine the correlation of NA content at 
different vaccine dosages with the elicited humoral antibody responses to the NA. 
Several approaches have been used to increase the immunogenicity of IIVs. Standard-dose 
seasonal IIVs contain 7.5 mcg or 15 mcg of HA antigen per vaccine strain (for children aged <36 
months) or 15 mcg of HA antigen per vaccine strain (for persons aged ≥36 months). 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 [14-22]. Higher HA 
dosage vaccines can lead to enhanced antibody responses in the elderly [23]. In 2009, a high-
dose IIV containing 4 times the standard HA antigen per seasonal 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) 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 [24, 25]). Due to the poor immunogenicity of H5 and H7 vaccines, the inclusion of 
adjuvants was evaluated to assess their ability to boost anti-viral serum immunoglobulin G (IgG) 
levels. In the United States, 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 [26-28]. In contrast, the use of oil-in-water emulsion adjuvants, most notably 
proprietary adjuvants AS03 and MF59® produced by GlaxoSmithKline Biologicals (GSK) and 
Seqirus, respectively, has resulted in increased antibody responses to IIVs containing novel HAs 
in numerous clinical trials [29-32].  
Since 1997, MF59®, an oil-in-water adjuvant used in the seasonal influenza vaccine (FLUAD®) 
has been licensed for use in elderly individuals 65 years of age and older in 32 countries. Since 
then, FLUAD® has been licensed for children in several countries including South Africa (12 
years of age and older), Mexico (6 to 36 months of age) and Canada (6 to less than 24 months).  
FLUAD® has been licensed in the US (65 years of age and older) since November 2015 (see 
Section 2.3.1). Clinical trials performed to assess the safety, immunogenicity and efficacy of 
novel HA-containing IIV formulations with and without MF59® reported that antibody GMTs 
and seroconversion rates were significantly higher among recipients of the adjuvanted vaccine 
compared to recipients of non-adjuvanted formulations [33-34].   
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, 

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as well as MF59® adjuvants. The National Institute of Allergy and Infectious Diseases (NIAID) 
has conducted several clinical trials to evaluate avian influenza (A/H9N2, 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 [35-41]. In response to emerging H5N8 viruses that 
have caused extensive outbreaks in domestic poultry and wild birds in South East Asia [42, 43], 
NIAID has recently completed enrollment for two clinical trials with an H5N8 vaccine produced 
by bioCSL Seqirus administered with either AS03 (GSK) or MF59® (Seqirus) in healthy 
individuals 19-64 years of age,  (NCT02624219 and NCT03014310). 
Since March of 2013 [43], 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 March 2018 a total of 
1,567 laboratory-confirmed human infections with avian influenza A/H7N9 virus have been 
reported by the World Health Organization [44, 45]. Whereas most cases have been centered in 
and around mainland China, there have been several travel-associated cases, including two in 
travelers reported by Canada who were returning from China in early 2015 [46]. 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 
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 [45]. 
Laboratory studies have shown that A/H7N9 influenza 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 [47, 48]. 
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 [45]. In 
addition, an antigenically distinct lineage of these fifth wave H7N9 viruses known as the 
Yangtze River Delta lineage, has recently emerged and has been associated with an increasing 
number of human cases. This lineage has also resulted in a broader geographic spread of infected 
birds and human cases within China than previously seen. Further, several 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 [44, 49].  
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, HHS has supported the production of fifth wave inactivated influenza 

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H7N9 vaccines for the U.S. stockpile and for an assessment of its safety and immunogenicity in 
clinical trials. 
 
Public Readiness and Emergency Preparedness Act 
For this protocol, the study products monovalent inactivated influenza 2017 H7N9 virus vaccine 
manufactured by Seqirus and adjuvant (MF59®) manufactured by Seqirus 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 2017 H7N9 IIV with or without 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. 
An individual who suffers a serious physical injury or death from administration and use of the 
2017 H7N9 IIV with or without adjuvant may request benefits from the CICP. A serious physical 
injury means an injury that is life threatening, 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, the Department of 
Veterans Affairs, or Workers’ Compensation programs don’t 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, 

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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 United States Federal or a State court. 
 
Scientific Rationale 
2.2.1 
Purpose of Study 
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 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 trials have demonstrated that adjuvant use results in a significant dose-sparing 
effect. NIAID has recently completed enrollment of two “mix and match” clinical trials using an 
H5N8 vaccine antigen produced by Seqirus and mixed with either AS03 or MF59® adjuvants 
(NCT03014310, NCT02624219). 
The large number of human infections starting with the “fifth wave” of H7N9 outbreaks in late 
2016 has raised the pandemic risk assessment of influenza A/H7N9 viruses circulating in China. 
The Yangtze River Delta lineage, a distinct H7N9 viral lineage, has now emerged and has been 
associated with many of the cases in the fifth epidemic wave. This has also resulted in a broader 
geographic spread of infected birds and human cases within China than previously reported. 
Further, several H7N9 viruses in the Yangtze River Delta lineage have recently acquired genetic 
changes characteristic of HPAI viruses and have now shown an increased ability to infect and 
kill poultry [45, 49]. To date, no cases of H7N9 from the new lineage have been identified in 
birds or people infected outside of 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 H7N9 viruses and serology studies indicate that the stockpiled H7N9 vaccine 
manufactured several years ago does not induce protective HAI or Neut antibodies against the 
Yangtze River Delta lineage. Hence, there is broad consensus across HHS and interagency 
leadership that a new vaccine should be developed that would be effective against the currently 
predominating H7N9 viruses.  
Several candidate vaccine viruses are under evaluation by the Center for Disease Control (CDC) 
and the World Health Organization (WHO) H5 Reference Laboratories Network.  Under contract 
to BARDA/DHHS, Seqirus has produced a monovalent inactivated influenza pre-pandemic 2017 
A/H7N9 virus vaccine (2017 H7N9 IIV). The availability of the US Government-stockpiled 
MF59® (Seqirus) oil-in-water adjuvant provides an opportunity to determine if dose-sparing 

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effects occur when mixing the Seqirus 2017 H7N9 vaccine with the MF59® adjuvant (See 
Section 4.1 for additional details on the H7N9 vaccine). 
The goal of this clinical trial is to assess the safety, reactogenicity and immunogenicity of two 
doses of the 2017 H7N9 IIV administered with or without MF59® in healthy adults.  The 2017 
H7N9 IIV manufactured by Seqirus will be administered IM at different dosages mixed at the 
site with MF59® [3.75, 7.5 and 15 mcg HA per dose) or given without MF59® (15 mcg HA per 
dose) to evaluate the dose-sparing potential of the adjuvant. Data from phase I clinical trials of 
avian IIVs suggest that they are poorly immunogenic and require multiple high-doses or the 
inclusion of an adjuvant to induce serum HAI titer of 40 or greater against the study vaccine 
virus. In previous NIAID- sponsored clinical trials of 2013 H7N9 IIV, 2 doses of non-adjuvanted 
15 or 45 mcg of HA per dose did not confer significant seroprotection [37, 39].  In addition to 
assessing antigen-sparing strategies, another goal of this study is to assess, in at least a subset of 
samples, whether serum IgG elicited by the 2017 H7N9 IIV recognizes antigenically drifted 
variants of influenza A/H7 viruses. Since antibodies targeting the NA may represent an 
independent correlate of protection against influenza infection [11-13], we plan to assess the NA 
content of the 2017 H7N9 vaccine and determine if there is a dose-response relationship of NA 
content with elicited humoral antibody responses to the N9 NA [50]. 
Based on previously conducted studies with a 2013 H7N9 IIV manufactured by Sanofi 
administered with or without MF59®, we anticipate that two doses of the 2017 H7N9 IIV 
administered IM at different dosages with MF59® adjuvant approximately 21 days apart will be 
well-tolerated and more immunogenic compared to the non-adjuvanted vaccine in healthy adult 
individuals [37, 51]. 
2.2.2 
Study Population 
The study population will be representative of the general public from each of the VTEU 
participating sites.  Children will not be included as this study is designed for healthy adult 
subjects between the ages of 18-64 years. 
 
Potential Risks and Benefits 
 
Potential Risks 
The potential risks of participating in this trial are those associated with having blood drawn, the 
IM injection and possible reactions to the 2017 H7N9 IIV, with or without PBS diluent and/or 
MF59® adjuvant, and breach of confidentiality. 

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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 risk to subjects who report that they are in good health but who have an 
unknown health problem at the time of vaccination.  This trial will screen by physical exam, 
history, and vital signs. To minimize the risk, subjects will not receive the second study 
vaccination if the subject meets any of the exclusion criteria listed in Section 8.6.2. 
There is potential for AEs to occur more frequently in the adjuvanted vaccine groups [32] than in 
the non-adjuvanted group and there is potentially a higher risk for AEs to occur more frequently 
in the higher dose influenza antigen groups than in the lower dose viral antigen groups. The 2017 
H7N9 IIV to be used in this study has not been tested for safety in animals and has not 
previously been evaluated in humans. The DMID, NIAID has sponsored five Phase II clinical 
trials to assess the safety, reactogenicity, and immunogenicity of one or two IM doses of a 
monovalent A/H7N9 vaccine produced by Sanofi Pasteur, Swiftwater, PA, administered with or 
without AS03 or MF59® 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 AEs of special interest (AESIs) were 
reported in this clinical trial: Hashimoto’s disease (assessed as not related to study product) and 
Hashimoto’s thyroiditis (assessed as related to study product). 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 vaccination, but 
both disorders received the diagnosis after vaccination). 
 
The manufacturing process used to produce the monovalent 2017 H7N9 IIV is the same as for 
the US licensed product Agriflu® seasonal influenza vaccine with the exception of the final steps 
being performed at the Parkville manufacturing site, which is an FDA-approved manufacturing 
site for Afluria®, but not Agriflu®. The current H7N9 monovalent subunit IIV to be used in this 
trial was derived from the influenza virus A/Hong Kong/125/2017 (H7N9). The potential risks to 
subjects are anticipated to be similar to those observed for Seqirus’ unadjuvanted, licensed 
seasonal IIV, Agriflu® (see Agriflu® Package Insert). 

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Occasionally, adult recipients of unadjuvanted licensed, IIVs may develop influenza-like 
reactions, such as fever, feverishness, fatigue, malaise, myalgia, arthralgia, headache, and/or 
nausea. Some subjects may develop reactions at the injection site, including pruritus, and/or 
ecchymosis due to the vaccination procedure, erythema, induration/swelling, pain, and/or 
tenderness [53].  
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 licensed vaccine. These reactions 
can manifest as hives, angioedema, bronchospasm, tachycardia, or 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 (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 
(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 [54]. Interestingly, although 
vaccination rates have increased in the last 10 years, the numbers of reported cases of vaccine-
associated GBS have declined [55]. A recent study in Canada showed that the 2009 H1N1 
vaccine was associated with a small but significant risk of GBS in persons 50 years and older 
[56]. An active, population-based surveillance study conducted in the United States during the 

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2009-2010 influenza season found less than 1 excess GBS case per million doses of 2009 H1N1 
vaccine administered – a rate similar to that associated with some previously administered 
annual influenza vaccines [57-59]. Another study using the Medicare system showed an elevated 
risk of GBS with 2009 H1N1 vaccination (incidence rate ratio = 2.41, 95% confidence interval: 
1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% confidence interval: 0.21, 
5.48) [60]. An international collaboration study also supported a conclusion of an association 
between 2009 H1N1 vaccination and GBS [61]. It is unknown if the administration of the 2017 
H7N9 IIV 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. 
Numerous studies have shown that the MF59® adjuvant significantly improved the 
immunogenicity of inactivated subunit influenza virus vaccines, with a clinically acceptable 
increase in the incidence of injection site reactions [33-35, 37, 39-41, 51, 62-64].There was, as 
expected, a general tendency for an increased risk of slightly more mild and transient solicited 
injection site (especially tenderness/pain) and systemic reactions in subjects exposed to MF59®, 
while there was a consistent indication for a similar or decreased overall risk of all unsolicited 
AEs, autoimmune diseases, new onset of chronic diseases, cardiovascular diseases, SAEs, 
hospitalizations, and deaths, when compared to non MF59®-adjuvanted influenza vaccines. 
Additional information can be found in the FDA-licensed FLUAD® package insert. 
Subjects should be informed that they might experience the following injection site and systemic 
AEs after vaccination with MF59®-adjuvanted vaccines: 
Injection site reactions: redness, swelling, pain, ecchymosis, induration.   
Systemic reactions: fever, malaise, chills, fatigue, headache, sweating, myalgia, arthralgia, 
shivering.   
Most reactions are mild or moderate and resolve spontaneously within one to two days.  
The following adverse events have been spontaneously reported during post-approval use of 
FLUAD® in the United States since March 2017 (package insert). Because these events are 
reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to the vaccine. 
 
Blood and lymphatic system disorders: Thrombocytopenia (some cases were severe with platelet 
counts less than 5,000 per mm3), lymphadenopathy  
General disorders and administration site conditions: Extensive swelling of injected limb lasting 
more than one week, injection site cellulitis-like reactions (some cases of swelling, pain, and 
redness extending more than 10 cm and lasting more than 1 week)  
 

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Immune system disorders:  Allergic reactions including anaphylactic shock, anaphylaxis and 
angioedema  
 
Musculoskeletal and connective tissue disorders: Muscular weakness  
 
Nervous system disorders: Encephalomyelitis, Guillain-Barré Syndrome, convulsions, neuritis, 
neuralgia, paraesthesia, syncope, presyncope  
 
Skin and subcutaneous tissue disorders:  Generalized skin reactions including erythema 
multiforme, urticaria, pruritis or non-specific rash  
 
Vascular disorders: Vasculitis with transient renal involvement 
There is substantial clinical experience with MF59® adjuvant. In a very extensive set of clinical 
studies, MF59® has proven to be an effective vaccine adjuvant with an acceptable safety and 
tolerability profile, resulting in the licensure of an MF59®-adjuvanted interpandemic seasonal 
subunit IIV3 (FLUAD®) in 32 countries worldwide including the US (US licensed since 
November 2015). FLUAD® was initially licensed for commercial sale in 1997 in Italy, and is 
currently approved with either a Mutual Recognition Procedure or a National Procedure in 11 
EU countries. It is also currently registered for use in 19 other countries worldwide. This 
adjuvanted vaccine is currently licensed for immunization of elderly people 65 years of age and 
above (with the exceptions in South Africa, where FLUAD® is licensed in subjects 12 years of 
age and above, and in Canada where FLUAD® is licensed for use in both adults 65 years of age 
and older and children ≥6 to <24 months of age).   
It is unknown if the Seqirus 2017 H7N9 IIV (A/Hong Kong/125/2017) with or without MF59® 
adjuvant poses any risks to an unborn child. Tsai et al. evaluating the clinical trial database of all 
Novartis vaccine studies from 1991-2009 found that the distribution of pregnancy outcomes 
(normal, abnormal, or ending in induced abortion) were similar in subjects exposed to MF59®-
adjuvanted and non-adjuvanted influenza vaccines at any time in pregnancy [65]. In a 
comparative cohort study, Heikkinen et al. found no differences in gestational diabetes, 
preeclampsia, stillbirth, low birth weight, neonatal deaths, or congenital malformations among 
MF59-adjuvanted A/H1N1 vaccinated and unvaccinated cohorts [66]. 
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 

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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 local Institutional Review Board (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. 
 
Potential Benefits 
Vaccination using the 2017 H7N9 IIV with or without MF59® adjuvant may or may not provide 
protection against a serious disease with the 2017 H7N9 IIV, should the participant be exposed. 
The duration of any such protection is currently unknown. The 2017 H7N9 IIV with or without 
MF59® adjuvant is 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 2017 H7N9 vaccination occurs. 

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3 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This is a randomized, double-blinded, Phase II study in 371 healthy males and non-pregnant 
females, 18-64 years of age. This clinical trial is designed to assess the safety, reactogenicity, 
and immunogenicity of a pre-pandemic 2017 H7N9 IIV manufactured by Seqirus administered at 
different dosages (3.75 mcg, 7.5 mcg and 15 mcg of HA per dose, n=106 per arm) given with 
MF59® adjuvant manufactured by Seqirus, or without adjuvant (15 mcg of HA per dose, n=53). 
The 2017 H7N9 IIV was manufactured using a reverse genetics-derived reassortant candidate 
vaccine virus IDCDC RG56B (H7N9), containing the HA and NA from low pathogenic 
influenza A/Hong Kong/125/2017 (H7N9) and the PB2, PB1, PA, NP, M and NS genes from 
A/Puerto Rico/8/1934 (H1N1). Phosphate buffered saline (PBS) diluent manufactured by 
Patheon Manufacturing Services LLC will be used to achieve certain targeted dosages. 
Subjects who are in good health and meet all eligibility criteria (including a negative serum or 
urine pregnancy test for women of childbearing potential, history and physical exam) within 28 
days prior to the first vaccination or on the day of, but prior to, first vaccination, will be 
randomized into one of 4 study groups as shown in Table 1. Baseline bloods samples for clinical 
safety laboratories will be drawn prior to the first vaccine dose and will not be used to screen 
subjects for eligibility. 
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, 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 2017 
H7N9 vaccine virus on serum samples obtained immediately prior to each study vaccination 
(Days 1 and approximately Day 22), approximately 7 days after each study vaccination (Days 8 
and 29), and approximately 21 and 180 days after the second study vaccination (Days 43 and 
202). 
Novel methods for identifying and assessing alternative correlates of protection against influenza 
infection are needed.  We will assess the dose related response of NA-specific antibody to 

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vaccination.  In addition, if an assay becomes available, we plan to determine the NA content of 
inactivated influenza vaccine. If possible, we will determine whether the NA content in a dosage-
specific manner correlates with the N9 NA-specific antibody response. If NA content of the 
vaccine is not determined, then we will determine whether the NA-specific antibody response 
increases with increasing dosage of vaccine based on the HA content. 
Subjects who have not received the current season’s licensed seasonal IIV3 or IIV4 prior to 
being enrolled in the study may receive it anytime following completion of the Day 43 study 
visit or upon early termination.  
For additional details on study procedures and evaluations and study schedule by study 
visits/days, see Sections 6 and 7 and APPENDIX A: SCHEDULE OF PROCEDURES AND 
EVALUATIONS. 
 
Study Objectives 
 
Primary 
Safety: 
• To assess the safety and reactogenicity following receipt of two doses of 2017 H7N9 IIV 
administered IM at different dosages approximately 21 days apart given with or without 
MF59® adjuvant  
Immunogenicity: 
• To assess the serum HAI and Neut antibody responses approximately 21 days following 
receipt of two doses of 2017 H7N9 IIV administered IM at different dosages approximately 
21 days apart with or without MF59® adjuvant. 
 
Secondary  
Safety: 
• To assess all unsolicited non-serious AEs following receipt of two doses of a 2017 H7N9 IIV 
administered IM at different dosages approximately 21 days apart with or without MF59® 
adjuvant  
• To assess MAAEs including NOCMCs, PIMMCs, and all SAEs following receipt of two 
doses of a 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart 
with or without MF59® adjuvant  

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Immunogenicity: 
• To assess the serum HAI and Neut antibody responses approximately 7 and 21 days 
following receipt of a single dose, and approximately 7 days following receipt of two doses 
of 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or 
without MF59® adjuvant. 
3.2.3 
Exploratory 
Immunogenicity: 
• To assess the effects of age, sex, body mass index, and prior receipt of seasonal influenza 
vaccine(s) on serum HAI and Neut antibody responses following receipt of two doses of a 
2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or 
without MF59® adjuvant. 
• 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 following 
receipt of two doses of a 2017 H7N9 IIV administered IM at different dosages approximately 
21 days apart with or without MF59® adjuvant.  
• To assess the durability of serum HAI and Neut antibody responses at approximately 180 
days following receipt of two doses of 2017 H7N9 IIV administered IM at different dosages 
approximately 21 days apart with or without MF59® adjuvant.  
• To assess the NA content of the 2017 H7N9 IIV and determine the serum antibody responses 
to NA following receipt of 2017 H7N9 IIV. 
 
Study Endpoints or Outcome Measures 
 
Primary 
Safety: 
• Occurrence of study vaccine-related 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 adverse events 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 2017 H7N9 study vaccine strain (defined as either a pre-vaccination titer <10 and a 
post-vaccination titer ≥40 or a pre-vaccination titer ≥10 and a minimum four-fold rise in 
post-vaccination titer) at approximately 21 days after the second study vaccination (Study 
Day 43). 
• For HAI and Neut antibodies, percentage of subjects achieving titer ≥40 against the influenza 
2017 H7N9 study vaccine strain at approximately 21 days after the second study vaccination 
(Study Day 43). 
• GMTs of serum HAI and Neut antibodies against the influenza 2017 H7N9 vaccine strain at 
approximately 21 days after the second study vaccination (Study Day 43).  
 
Secondary 
Safety: 
• Occurrence of study vaccine-related unsolicited non-serious AEs from the time of each study 
vaccination through approximately 21 days after each study vaccination. 
• Occurrence of all unsolicited adverse events, regardless of the assessment of seriousness or 
relatedness, from the time of each study vaccination through approximately 21 days after 
each study vaccination.  
• Occurrence of MAAEs, including NOCMCs, and PIMMCs from the time of the first study 
vaccination through approximately 12 months after the last study vaccination. 
• Occurrence of all SAEs, regardless of the assessment of relatedness, 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 2017 H7N9 vaccine strain at approximately 7, 21, and 28 days after the first study 
vaccination (Study Day 8, 22, 29). 

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• For HAI and Neut antibodies, percentage of subjects achieving titers of 40 or greater against 
the influenza 2017 H7N9 vaccine strain at baseline and approximately 7, 21, and 28 days 
after the first study vaccination (Study Day 8, 22, 29). 
• GMTs of serum HAI and Neut antibodies against the influenza 2017 H7N9 vaccine virus at 
baseline and approximately 7, 21, and 28 days after the first study vaccination (Study Day 8, 
22, 29).  
 
Exploratory 
Immunogenicity: 
• For HAI and Neut antibodies, percentage of subjects achieving seroconversion and the GMTs 
of serum HAI antibody against the 2017 H7N9 study vaccine strain approximately 21 and 
180 days after the second study vaccination (Study Day 43 and 202), stratified by sex, body 
mass index, and prior receipt of seasonal influenza vaccine(s). 
• For HAI and Neut antibodies, for at least a subset of subjects, percentage achieving 
seroconversion, percentage with titer ≥40, and GMTs against antigenically drifted variants of 
influenza A/H7 viruses at baseline and approximately 21 and 180 days after the second study 
vaccination (Study Day 43 and 202). 
• For HAI and Neut antibodies, percentage of subjects achieving seroconversion, percentage 
with titer ≥40, and GMTs against the 2017 H7N9 study vaccine strain at approximately 180 
days after the second study vaccination (Study Day 202). 
Percentage of subjects with detectable levels of serum N9 NA-specific antibody elicited by 2017 
H7N9 vaccination.  Serum N9 NA-specific antibody responses elicited by H7N9 vaccination will 
be correlated with NA content (if NA content results are available) at baseline and approximately 
7 and 21 days after the first study vaccination (Study Day 1, 8 and 22) and 7, 21 and 180 days 
after the second study vaccination (Study Day 29, 43 and 202). If the NA content of the vaccine 
is not determined, then we will determine whether the NA-specific antibody response increases 
with increasing dosage of vaccine based on the HA content. 
 

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4 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
 
Study Product Description 
2017 H7N9 IIV 
Seqirus has developed an H7N9 monovalent inactivated, “subunit” influenza virus vaccine, 2017 
H7N9 IIV manufactured from a reverse genetics-derived reassortant virus (A/Hong 
Kong/125/2017[H7N9]-PR8-IDCDC-RG56B) containing the HA and NA from influenza 
A/Hong Kong/125/2017 (H7N9) and the PB2, PB1, PA, NP, M and NS genes from A/Puerto 
Rico/8/1934 (H1N1). The manufacturing process for this monovalent 2017 H7N9 IIV is similar 
to the US-approved Agriflu seasonal influenza vaccine with the exception of the final steps being 
performed at the Parkville manufacturing site, which is an FDA-approved manufacturing site for 
Afluria®, but not Agriflu®. 
 
 
 
 
 
 
 
 
 
MF59® Adjuvant  
 
  
PBS Diluent 
The PBS diluent was manufactured by Patheon Manufacturing Services LLC in accordance with 
Good Manufacturing Practice Regulations. 
4.1.1 
Formulation, Storage, Packaging, and Labeling 
2017 H7N9 IIV 
The 2017 H7N9 IIV is provided as a clear, sterile, buffered aqueous solution containing 
primarily the outer membrane proteins, HA and NA and preservative in a 5 mL clear, Type 1 

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borosilicate glass, multi-dose vial. For the purposes of this protocol, each vial will be used as a 
single entry, single dose vial.   
Each multi-dose vial contains thimerosal, a mercury derivative, added as a preservative.  Each 
0.5 mL dose of non-adjuvanted vaccine contains approximately 50 mcg of thimerosal. The vials 
containing study product must be stored at 2°C to 8°C (36°F to 46°F). Do not freeze.  No 
component of this vaccine contains latex.  
 
 
 
 
 
 
 
Specific mixing instructions are included in the MOP to achieve specific dosages. 
The 2017 H7N9 IIV doses administered with adjuvant will be admixed with MF59® resulting in 
administration of an adjuvanted 2017 H7N9 IIV. 
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.  
MF59® Adjuvant [Microfluoridized Adjuvant 59]  
 
 
 
 
 The product is available in single-use vial.  The vials containing study product 
must be stored at 2°C to 8°C (36°F to 46°F), protected from light. Do not freeze.  

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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 Investigator’s Brochures for the 
Monovalent 2017 H7N9 A/Hong Kong/125/2017 Vaccine (IIV) and package insert for MF59® 
adjuvant, as well as in the protocol-specific MOP. 
Sterile empty vials will be provided with latex-free stoppers. 
4.1.2 
Product Storage and Stability  
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 duration 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 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 
the DMID CMS or destroy it on site.  
4.2 
Acquisition/Distribution 
2017 H7N9 IIV  
2017 H7N9 IIV will be provided by Seqirus under contract to BARDA/DHHS. 
MF59® Adjuvant  
MF59® will be provided by Seqirus under contract to BARDA/DHHS. 
Upon request by DMID, 2017 H7N9 IIV, MF59® adjuvant will be transferred to the following 
address: 
 
 

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DMID Clinical Materials Services Contract 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
 
 
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. 
2017 H7N9 IIV, MF59® adjuvant, PBS diluent, 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 2017 H7N9 IIV, MF59® adjuvant, PBS diluent or sterile empty vials during this trial, 
further instructions are provided in the protocol-specific MOP. 
4.3 
Dosage/Regimen, Preparation, Dispensing 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 
MF59®-adjuvanted study vaccine contains one dose (0.25 mL) of MF59® 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 research pharmacist on the same day of study 
vaccine administration. 
Visually inspect the 2017 H7N9 IIV, PBS diluent and MF59® adjuvant upon receipt and prior to 
use. If the study product(s) appear(s) to have been damaged, contaminated or discolored, contain 
visible particulate matter, or if there are any concerns regarding its 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 it cannot be used, the site will receive specific instructions on how to return the 
affected study product(s) to the DMID CMS or destroy it on site. If the 2017 H7N9 IIV vaccine 
PBS diluent or the MF59® adjuvant is unusable, study personnel will use another vial from the 

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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 2017 H7N9 IIV 
plus PBS diluent admixture (intermediate or final mixed vial depending on treatment arm) prior 
to use. The 2017 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 MF59 adjuvant, 
visually inspect the 2017 H7N9 IIV/PBS diluent plus MF59 adjuvant admixture (final mixed 
vial) prior to use. The 2017 H7N9 IIV/plus PBS admixture will be milky (whitish to yellowish) 
in appearance. If the admixture appears to have been damaged, contaminated or discolored, 
contain visible particulate matter, or if there are any concerns regarding its integrity, do NOT use 
the affected admixture. The affected admixture must be quarantined at 2°C to 8°C (36°F to 46°F) 
for the 2017 H7N9 IIV plus PBS diluent admixture or room temperature for the 2017 H7N9 
IIV/PBS diluent plus MF59 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 CPM 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 can be used. If it cannot 
be used, the site will receive specific instructions on how to send the affected admixture to the 
DMID CMS or destroy it on site. If the affected admixture is unusable, the participating VTEU 
sites’ 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 2017 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 MF59 adjuvant, the 2017 A/H7N9 
IIV/PBS diluent plus MF59 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 shake the intermediate and final mixed vial(s) immediately before the 
single 0.5 mL dose of study vaccine is withdrawn. 
Study vaccine administration 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. Each dose of study vaccine will be administered via a single IM injection 
given in the deltoid muscle of the subjects’ preferred arm. The site of injection (right or left arm) 
will be recorded on the appropriate data collection form. Aseptic technique will be used for the 
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appropriate in length for each subject and a disposable sterile syringe. See the protocol-specific 
MOP for information on how to administer IM injections. 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.  
4.4 
Pre-determined Modification of Study Intervention/Investigational 
Product for an Individual 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 that visit (Day 22+7 
days post first study vaccination). No exceptions to the protocol-specified window will be made. 
4.5 
Accountability Procedures for the Study Intervention/ 
Investigational Product(s) 
After receipt of the 2017 H7N9 IIV, PBS diluent, MF59® 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 will delegate to the participating 
VTEU sites’ research pharmacist responsibility for study product accountability. The 
participating VTEU sites’ 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). The study product accountability 
records and dispensing logs will also capture vial numbers, including final mixed vial number, 
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 captured on the appropriate data collection form. All study product(s), including the amount 
of 2017 H7N9 IIV, PBS diluent, MF59® adjuvant, and admixture, 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 sites’ study product 
accountability records and dispensing logs per the site monitoring plan. 
Used and unused vials of 2017 H7N9 IIV, PBS diluent, MF59® adjuvant, and admixture will be 
retained until monitored and released for disposition as applicable. This can occur on an ongoing 
basis for used vials of 2017 H7N9 IIV, PBS diluent, MF59® adjuvant, and admixture. Used vials 
of A/H7N9 vaccine, PBS diluent, MF59® adjuvant and admixture 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 
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DMID and communicated to the participating VTEU sites by the DMID Clinical Project 
Manager. 

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5 
SELECTION OF SUBJECTS AND STUDY 
ENROLLMENT AND WITHDRAWAL 
Approximately 371, 18-64 year old males and non-pregnant females who are in good health by 
history and meet all eligibility criteria, will be enrolled at up to 7 VTEU sites 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 the participating VTEU sites. Other forms and/or 
mechanisms of recruitment may also be used. The local Institutional Review Board (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. 
 
Eligibility Criteria 
 
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. Are males or non-pregnant females, 18-64 years of age, inclusive. 
4. Are in good health1. 
1As determined by physical examination and medical history 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, ER, or urgent care for condition and no adverse 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 

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criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the site 
principal investigator 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 principal investigator 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 (with the exception of inhaled corticosteroids as outlined in the 
Subject Exclusion Criteria (see Section 5.1.2), herbals, vitamins, and supplements are permitted. 
5. Oral temperature is less than 100.0°F. 
6. Pulse is 47 to 100 bpm, inclusive. 
7. Systolic blood pressure is 85 to 150 mmHg, inclusive. 
8. Diastolic blood pressure is 55 to 95 mmHg, inclusive. 
9. Women of childbearing potential2 must agree to practice 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 of 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 male or female condoms with spermicide or with the use of applied spermicide, 
intrauterine devices, NuvaRing®, and licensed hormonal methods such as implants, injectables, or oral contraceptives (“the 
pill”). 
10. Women of childbearing potential must have a negative serum or urine pregnancy test within 
24 hours prior to study vaccination. 
 
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. 
4An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the 
site principal investigator 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. 

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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, neomycin, 
kanamycin, formaldehyde, polysorbate 80, cetyltrimethylammonium bromide (CTAB), 
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 history of GBS. 
10. Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination. 
11. Have a history of PIMMCs6 
6Refer to Appendix B. List of Potentially Immune Mediated Medical Conditions  
12. Have a history of alcohol or drug abuse within 5 years prior to study vaccination. 
13. Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric 
diagnosis that may interfere with subject compliance or safety evaluations. 
14. 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. 
15. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose within 30 
days prior to study vaccination. 
16. Have taken high-dose inhaled corticosteroids7 within 30 days prior to each study vaccination. 
7High-dose defined as per age as using inhaled high dose per reference chart  
https://www.nhlbi.nih.gov/files/docs/guidelines/asthma qrg.pdf  

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17. 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. 
18. Received or plan to receive a licensed, inactivated, vaccine (excluding all flu vaccines) 
within 14 days before or after each study vaccination.  
19. Received or plan to receive seasonal IIV within 21 days before or after each study 
vaccination.  
20. Received immunoglobulin or other blood products (with exception of Rho D 
immunoglobulin) within 90 days prior to each study vaccination. 
21. Received an experimental agent8 within 30 days prior to the first study vaccination, or expect 
to receive an experimental agent9 during the 13-month trial-reporting period. 
8Including vaccine, drug, biologic, device, blood product, or medication. 
9Other than from participation in this trial. 
22. Are participating or plan to participate in another clinical trial with an interventional agent10 
that will be received during the 13-month trial-reporting period. 
10Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication. 
23. Received or plan to receive an influenza A/H7 vaccine11 or have a history of influenza A/H7 
subtype infection.  
11And assigned to a group receiving influenza A/H7 vaccine, does not apply to documented placebo recipients. 
24. Have traveled to mainland China and had substantial12 direct contact with live or freshly 
slaughtered poultry or pigeons within the past five years. 
12substantial contact is defined as visited a poultry farm and/or a live poultry market.  
25. Occupational exposure to or substantial direct physical contact13 with birds in the past year 
and through the 21 days after the second study vaccination. 
13Exposure 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. 
26. Female subjects who are breastfeeding at any given time from the first study vaccination 
until 30 days after the last study vaccination. 

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27. Plan to travel outside the US (continental US, Hawaii, and Alaska) from enrollment through 
21 days after the second study vaccination. 
28. Receipt of Multimeric-001 (M-001) vaccine. 
 
Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination 
 
Withdrawal from the Study or Discontinuation of the Study Product 
Subjects may voluntarily withdraw their consent for trial participation at any time without 
penalty or loss of benefits to which they are otherwise entitled.   
An investigator may also withdraw a subject from receiving the study product for any reason.  
Follow-up safety evaluations will be conducted, if the subject agrees. If the subject withdraws or 
is withdrawn prior to completion of the study, the reason for this decision must be recorded in 
the case report forms (CRFs). 
The reasons, might include, but are not limited to the following: 
• Subject no longer meets eligibility criteria (see Section 5.1 and 8.6.2). 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. 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 meets individual halting criteria (see Section 8.6.2). 
• Subject becomes noncompliant. 
• Subject withdrawal of consent. 
• Subject lost to follow-up. 
• Termination of this trial. 
• Subject becomes pregnant, if applicable. 
• New information becomes available that makes further participation unsafe. 

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• Determined by a physician’s discretion to require additional therapy not indicated in the 
protocol to ensure subject’s health and well-being (or treatment failure, if applicable). 
• As deemed necessary by the investigator for other reasons. 
The primary reason for withdrawal from this trial will be recorded on the Study Status data 
collection form. Subjects will be encouraged to complete the Early Termination Visit. The Early 
Termination Visit procedures are listed in Section 6.4.3. 
Although subjects are free to withdraw at any time or may be withdrawn by the investigator at 
any time, 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 immunogenicity assays at 
approximately 7 days and 21 days after their last study vaccination, if applicable. 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, 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, efforts (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 investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study. 
5.2.2 
Subject Replacement 
Subjects who sign the informed consent form (ICF), and are randomized and vaccinated, and 
subsequently withdraw, or are withdrawn or terminated from this study, or are lost to follow-up 
will not be replaced. If subjects withdraw, or are withdrawn or terminated from the study, or are 
lost to follow-up after signing the ICF and randomization but before receipt of study vaccine, 
additional subjects may be enrolled and randomized for replacement. 

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5.2.3 
Study Termination  
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. 

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6 
STUDY PROCEDURES 
Complete study schedule details listed by type of visit are described below. Refer also to 
APPENDIX A: SCHEDULE OF PROCEDURES AND EVALUATIONS. 
 
Screening (Optional) Visit 00, Day -28 to -1, Clinic Visit 
• 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. 
• 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 seasons (2016-2017 and 2017-2018), what type (inactivated or live attenuated), 
and approximate date of vaccination will be recorded on the appropriate data collection form, 
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 vaccines, 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 vaccines are not exclusionary, except influenza A/H7 
vaccines (see Section 5.1.2). 
• Vital signs, including oral temperature, pulse, and blood pressure, will be obtained to ensure 
eligibility prior to first study vaccination. 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. 

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• 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, 
abdomen, general appearance, musculoskeletal, and nervous system and as assessment for 
signs suggestive of a PIMMC, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• A serum or urine pregnancy test may be performed on all women of childbearing potential. 
Results must be negative to ensure eligibility. 
 
Enrollment, Visit 01 Day 01 for subjects previously screened at Day -
28 to -1 and First Vaccination (Dose 1), Clinic Visit 
• 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 will be reviewed prior to administration of the first study vaccination to 
ensure continued eligibility.  
• 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 study vaccination and any changes since the previous clinic visit or 
contact will be noted. 
• All concomitant medications 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 and assessed for continued eligibility prior 
to the first study vaccination.  
• Vital signs, including oral temperature, pulse, and blood pressure, will be obtained to ensure 
eligibility prior to first 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. 
• 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. 

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• A serum or urine pregnancy test will be performed within 24 hours prior to the first study 
vaccination on all women of childbearing potential. Results must be negative and known 
prior to randomization and first study vaccination. 
• Subjects will be enrolled in AdvantageEDCSM and assigned randomly to a treatment arm 
prior to the first study vaccination. 
• Pre-administration reactogenicity assessments will be performed prior to the first study 
vaccination to establish baseline.  
• Approximately 10 mL of venous blood will be collected immediately prior to the first study 
vaccination for baseline serum antibody assays. 
• 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, and Cr), and 
performed by the central (clinical) laboratory. The results from this blood draw will not be 
available or reviewed prior to study vaccination, and will serve as a safety baseline 
assessment only. 
• Approximately 10 mL of venous blood will be collected prior to study vaccination for future 
research from subjects who consent to collection of serum for future use either by signing an 
ICF that includes collection of future use samples as a condition of study participation or by 
indicating that they can opt in to sample collection for future use if the ICF allows the option 
to choose that option. 
• Subjects will then receive a single dose of study vaccine via IM injection into the deltoid 
muscle of the preferred arm. The site of injection (right or left arm) and time of 
administration will be recorded on the appropriate data collection form. 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 data collection form 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, any 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 

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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. 
• Subjects may be re-screened if they have an acute illness, present with scheduling conflicts, 
have abnormal vital sign(s), or have any other issue that the investigator thinks is acceptable 
to postpone receipt of study product to another date. 
 
Visit 01, Day 1, Enrollment/Baseline (for subjects not previously 
screened at Day -28 to -1) and First Study Vaccination (Dose 1), 
Clinic Visit 
• 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. 
• 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. 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 seasons (2016-2017 and 2017-2018), what type (inactivated or live attenuated), 
and approximate date of vaccination will be recorded on the appropriate data collection form, 
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 vaccines, 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 vaccines are not exclusionary, except influenza A/H7 
vaccines (see Section 5.1.2). 
• Vital signs, including oral temperature, pulse, and blood pressure, will be obtained to ensure 
eligibility prior to first 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. 

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• 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 to include the following organs and 
organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, 
abdomen, general appearance, musculoskeletal and nervous system and as assessment for 
signs suggestive of a PIMMC, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• Eligibility criteria will be reviewed with subjects prior to the first study vaccination to ensure 
continued eligibility. 
• A serum or urine pregnancy test will be performed within 24 hours prior to the first study 
vaccination on all women of childbearing potential. Results must be negative and known 
prior to randomization and first study vaccination. 
• Subjects will be enrolled in AdvantageEDCSM and assigned randomly to a treatment arm 
prior to the first study vaccination. 
• Pre-administration reactogenicity assessments will be performed prior to the first study 
vaccination to establish baseline.  
• Approximately 10 mL of venous blood will be collected immediately prior to the first study 
vaccination for baseline serum antibody assays. 
• 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, and Cr), and 
performed by the central (clinical) laboratory. The results from this blood draw will not be 
available or reviewed prior to study vaccination, and will serve as a safety baseline 
assessment only. 
• Approximately 10 mL of venous blood will be collected prior to study vaccination for future 
research from subjects who consent to collection of serum for future use, either by signing an 
ICF that includes collection of future use samples as a condition of study participation or by 
indicating that they opt in to sample collection for future use if the ICF allows the option to 
choose that option. 
• Subjects will then receive a single dose of study vaccine via IM injection into the deltoid 
muscle of the preferred arm. The site of injection (right or left arm) and time of 
administration will be recorded on the appropriate data collection form. Subjects will be 
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vaccination site will be examined, post-administration reactogenicity assessments will be 
performed, and any AE/SAEs will be recorded on the appropriate data collection form 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, any 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 principal investigator 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. 
 
Planned Study Visits 
 
Follow-up  
Follow-up visits are scheduled in reference to study vaccination dates as indicated for each visit 
window. 
Visit 02, Day 4, Memory Aid Review, Phone Call 
(Window: Day 4±1 days post first study vaccination) 
Study personnel will contact subjects by phone to solicit any 
AEs/SAEs/MAAEs/NOCMCs/PIMMCs, medical history, and concomitant medication 
information and review information on their Memory Aid. Based on the information, subjects 
may be asked to return to the clinic for evaluation. 
Visit 03, Day 8, Clinic Visit 
(Window: Day 8+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 contact will be noted. 
• Memory Aid information will be reviewed with subjects. 

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• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines), 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 and not previously collected). 
• All AE/SAEs/MAAEs/NOCMCs/PIMMCs will be recorded on the appropriate data 
collection form.  
• 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), and performed by the central (clinical) laboratory.  
• Approximately 10 mL of venous blood will be collected for serum antibody assays. 
• Approximately 10 mL of venous blood will be collected for future research from subjects 
who consent to collection of serum for future use either by signing an ICF that includes 
collection of future use samples as a condition of study participation or by indicating that 
they can opt in to sample collection for future use if the ICF allows the option to choose that 
option. 
Visit 04, Day 22, Second Study Vaccination (Dose 2), Clinic Visit 
(Window: Day 22+7 days post first study vaccination) 
• 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 8.6.2 for second 
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 and any changes since the previous clinic visit 
or contact will be noted. 

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• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines), 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 and not previously collected. Prior receipt of non-seasonal 
influenza vaccines are not exclusionary, except influenza A/H7 vaccines (see Section 5.1.2) 
will be recorded on the appropriate data collection form prior to the second study 
vaccination. 
• All AEs/SAEs/MAAEs/NOCMCs/PIMMCs will be recorded on the appropriate data 
collection form.  
• Vital signs, including oral temperature, pulse, and blood pressure, will be obtained prior to 
the second study vaccination. 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 are 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 serum or urine pregnancy test will be performed within 24 hours prior to the second study 
vaccination on all women of childbearing potential. Results must be negative and known 
prior to the second study vaccination. 
• Pre-administration reactogenicity assessments will be performed prior to the second study 
vaccination to establish baseline.  
• 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, and Cr), and 
performed by the central (clinical) laboratory. The results from this blood draw will not be 
available or reviewed prior to study vaccination. 
• Approximately 10 mL of venous blood will be collected immediately prior to the second 
study vaccination for serum antibody assays. 
• Approximately 10 mL of venous blood will be collected immediately prior to the second 
study vaccination for future research from subjects who consent to collection of serum for 
future use either by signing an ICF that includes collection of future use samples as a 

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condition of study participation or by indicating that they can opt in to sample collection for 
future use if the ICF allows the option to choose that option. 
• Subjects will then receive a single dose of study vaccine via IM injection into the deltoid 
muscle of the 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 administration will be recorded on the appropriate 
data collection form. Subjects will be observed in the clinic for at least 20 minutes after the 
second study vaccination. 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 data collection form 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, any 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. 
Visit 05, Day 25, Memory Aid Review, Phone Call 
(Window: Day 4 ±1 days post second study vaccination) 
Study personnel will contact subjects by phone to solicit any AE/SAE, medical history, and 
concomitant medication information (including solicitation for receipt of any non-study 
influenza vaccines), 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 and not previously collected) and review information 
on their Memory Aid. Based on the information, subjects may be asked to return to the clinic for 
evaluation. Note: For subjects who are discontinued from the receipt of the second study 
vaccination, AEs will be limited to SAEs, MAAEs, including NOCMCs, and PIMMCs. 
Visit 06, Day 29, Clinic Visit 
(Window: Day 8+2 days post second 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 contact will be noted. 

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• Memory Aid information will be reviewed with subjects. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines), 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 and not previously collected). 
• All AE/SAEs will be recorded on the appropriate data collection form. Note: for subjects 
who discontinued from the receipt of the second study vaccination, AEs will be limited to 
SAEs, MAAEs, including NOCMCs, and PIMMCs. 
• 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, and Cr), and performed by the central (clinical) laboratory.  
• Approximately 10 mL of venous blood will be collected for serum antibody assays. 
• Approximately 10 mL of venous blood will be collected for future research from subjects 
who consent to collection of serum for future use either by signing an ICF that includes 
collection of future use samples as a condition of study participation or by indicating that 
they can opt in to sample collection for future use if the ICF allows the option to choose that 
option. 
Visit 07, Day 43, Clinic Visit 
(Window: Day 22+7 days post second 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 contact will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines), 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 and not previously collected). 

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• All AE/SAEs will be recorded on the appropriate data collection form. Note: for subjects 
who discontinued from the receipt of the second study vaccination, AEs will be limited to 
SAEs, MAAEs, including NOCMCs, and PIMMCs. 
• 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 10 mL of venous blood will be collected for serum antibody assays.  
• Approximately 10 mL of venous blood will be collected for future research from subjects 
who consent to collection of serum for future use either by signing an ICF that includes 
collection of future use samples as a condition of study participation or by indicating that 
they can opt in to sample collection for future use if the ICF allows the option to choose that 
option. 
Visit 08, Day 82, Safety Follow-up, Phone Call 
(Window: Day 61±7 days post second study vaccination) 
Subjects will be contacted by phone to query for safety events and solicitation for receipt of all 
concomitant medications (including any solicitation for receipt of any non-study influenza 
vaccines), 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 and not previously collected. Adverse events limited to MAAEs 
including NOCMCs, PIMMCs, and SAEs that have occurred since the previous clinic visit or 
contact will be solicited. Based on the information, subjects may be asked to return to the clinic 
for evaluation. 
Visit 09, Day 142, Safety Follow-up, Phone Call 
(Window: Day 121±14 days post second study vaccination) 
Subjects will be contacted by phone to query for safety events and solicitation for receipt of all 
concomitant medications (including any solicitation for receipt of any non-study influenza 
vaccines), 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 and not previously collected. Adverse events limited to MAAEs 
including NOCMCs, PIMMCs, and SAEs that have occurred since the previous clinic visit or 
contact will be solicited. Based on the information, subjects may be asked to return to the clinic 
for evaluation. 

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Visit 10, Day 202, Safety Follow-up, Clinic Visit 
(Window: Day 181±14 days post second study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic medical diseases, and symptoms suggestive of PIMMCs, will be obtained by 
interview of subjects and any changes since the previous clinic visit or contact will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines), 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 and not previously collected). 
• Adverse events limited to MAAEs including NOCMCs, PIMMCs, and SAEs that have 
occurred since the previous clinic visit or contact 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. 
• Approximately 10 mL of venous blood will be collected for serum antibody assays.  
• Approximately 10 mL of venous blood will be collected for future research from subjects 
who consent to collection of serum for future use either by signing an ICF that includes 
collection of future use samples as a condition of study participation or by indicating that 
they can opt in to sample collection for future use if the ICF allows the option to choose that 
option. 
 
Final Study Visit, Visit 11, Day 387, Safety Follow-up, Phone Call 
(Window: Day 366±14 days post second study vaccination) 
Subjects will be contacted by phone to query for safety events.  AEs limited to MAAEs 
including NOCMCs, and PIMMCS, and SAEs that have occurred since the previous clinic visit 
or contact will be solicited.  Based on the information, subjects may be asked to return to the 
clinic for evaluation. 
 
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: 

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• Interim medical history, including an assessment for new medical conditions and symptoms 
suggestive of PIMMCs, will be obtained by interview of subjects and any changes since the 
previous clinic visit or contact will be noted. 
• Memory Aid information will be reviewed with subjects (if within 7 days after the last study 
vaccination). 
• All concomitant medications will be recorded on the appropriate data collection form (if 
within 180 days after the last study vaccination, 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 and not previously 
collected). Receipt of any non-study influenza vaccine will be recorded if within 180 days 
after the last 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, MAAEs, 
including NOCMCs, and PIMMCs will be documented and reported from the time of the 
first study vaccination through approximately  12 months after last study vaccination).  
• Vital signs, including oral temperature, pulse, and blood pressure, 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 serum antibody assays (if within 
21 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, and Cr), and performed by the central (clinical) laboratory if done within 
7 days after the last study vaccination.  

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• Approximately 10 mL of venous blood will be collected for future research (if within 21 days 
after the last study vaccination) from subjects who consent to collection of serum for future 
use either by signing an ICF that includes collection of future use samples as a condition of 
study participation or by indicating that they can opt in to sample collection for future use if 
the ICF allows the option to choose that option. 
6.5 
Unscheduled Visit (if needed) 
Unscheduled visits 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 and symptoms 
suggestive of PIMMCs, will be obtained by interview of subjects and any changes since the 
previous clinic visit or contact will be noted (if indicated). 
• Memory Aid information will be reviewed with subjects (if within 7 days after the last study 
vaccination). 
• All concomitant medications will be recorded on the appropriate data collection form (if 
within 180 days after the last study vaccination). Receipt of any non-study 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 and not previously collected will be recorded if within 180 
days after the last 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, 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. 
• Vital signs, including oral temperature, pulse, and blood pressure, 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). 

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• 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 serum antibody assays (if within 
21 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, and Cr), and performed by the central (clinical) laboratory if indicated.  
• Approximately 10 mL of venous blood will be collected for future research from subjects 
who consent to collection of serum for future use (if within 21 days after the last study 
vaccination) either by signing an ICF that includes collection of future use samples as a 
condition of study participation or by indicating that they can opt in to sample collection for 
future use if the ICF allows the option to choose that option. 
6.6 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, or protocol-specific 
MOP requirements.  The noncompliance may be either on the part of the subject, the site PI, or 
the site personnel.  As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly. 
These practices are consistent with ICH E6: 
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 personnel to use continuous vigilance to identify and 
report deviations within five working days of identification of the protocol deviations, or within 
five working days of the scheduled protocol-required activity.  All deviations must be promptly 
reported to DMID per the SDCC protocol deviation reporting procedures. 
All deviations, as defined above, must be addressed in study subject data collection forms.  A 
completed copy of the DMID Protocol Deviation Form must be maintained in the regulatory file, 
as well as the subject’s chart.  Protocol deviations must be sent to the local IRB/IEC per their 
guidelines.  The site PI and personnel are responsible for knowing and adhering to their IRB 
requirements 

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7 
DESCRIPTION OF CLINICAL AND LABORATORY 
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. At follow-up visits after the 
first study vaccination, an interim medical history will be obtained by interview of subjects 
noting any changes since the previous clinic visit or contact. 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 7.1.1. 
At the screening visit (optional) or the baseline visit (Day 1) a physical examination will be 
performed on all subjects to include the following organs and organ systems: including skin, 
head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, abdomen, general 
appearance, musculoskeletal, and nervous system, by a study clinician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. At follow-up 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) will be collected at the screening visit 
(optional) and prior to each study vaccination (Days 1 and 22). 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 Day 8 after each study vaccination, which includes an 
assessment of injection site reactions including pruritus, ecchymosis, erythema, induration/ 
swelling, pain, and tenderness as well as systemic reactions including fever, feverishness, 

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fatigue, malaise, myalgia, arthralgia, headache, and nausea. Pre-administration reactogenicity 
assessments will be performed 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 data collection form prior to 
discharge from the clinic. The study vaccination site will also be examined approximately 7 days 
after each study vaccination. 
All subjects will complete a subject Memory Aid from the time of each study vaccination 
through 7 days after each study vaccination. Subject Memory Aids will be reviewed with the 
subjects for AEs (solicited injection site and systemic reactions and unsolicited AEs) 
approximately 3 and 7 days after each study vaccination via phone call (Day 4) and clinical visit 
(Day 8). 
 
Assessment of Concomitant Medications/Treatments other than Study Product 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
data collection form. Concomitant medications will include all current medications and 
medications taken in the 60 days prior to signing the ICF through approximately 180 days after 
the last study vaccination or early termination (if prior to 180 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 180 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 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 
immunogenicity. 

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7.2 
Laboratory Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
Serum or urine pregnancy tests will be performed.    Serum or urine pregnancy tests will be 
performed locally by site laboratory.  Pregnancy testing will be done at the screening visit 
(optional) and within 24 hours prior to each study vaccination on 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.  
Clinical safety laboratory parameters (WBC, Hgb, PLT, ALT, T. Bili, and 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. Venous 
blood samples (approximately 10 mL) will be collected for these safety labs. The results from the 
clinical safety laboratory parameters collected on Day 1 will not be available or reviewed prior to 
study vaccination, and will serve as a safety baseline assessment only. 
The volume of venous blood to be collected for the clinical safety laboratory evaluations is 
presented in Table 2. 
7.2.2 
Research Assays  
Immunogenicity 
Assays to determine serum levels of HAI and Neut antibodies will be performed at Southern 
Research. Venous blood samples (approximately 10 mL) for antibody assays will be collected 
from each subject immediately prior to each study vaccination (Day 1 and approximately Day 
22) and, approximately 7 days after each study vaccination (approximately Day 8 and Day 29), 
and approximately 21 days and 180 days after the second study vaccination (approximately Days 
43 and 202). Subjects who withdraw early will have HAI and Neut antibody assays run on 
available sera. 
Venous blood samples (10 mL) will also be collected for future use at the same time points. Sites 
may elect to allow subjects to consent to study participation but to have the option to opt in for 
the collection of the future use samples, or may include collection of future use samples as a 
condition of study participation and not allow the option.  
The assays for determination of the NA content and antibodies to the NA are under development. 
If successful, the correlation of NA content in the 2017 H7N9 IIV with elicited N9 NA-specific 
serum antibody responses may be assessed; no additional venous blood will be collected from 

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7.2.2.2 
Laboratory 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 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 the NA antibody assays will be shipped from the participating VTEU sites to the 
DMID CMS, and then provided by the DMID CMS to the NA antibody assay laboratory once it 
has been identified. 
Further instructions for specimen shipment are included in the central (clinical) laboratory 
manual and protocol-specific MOP, as appropriate. 
 
 

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8 
ASSESSMENT OF SAFETY 
8.1 
Assessing and Recording 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/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, and 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. 
8.1.1 
Adverse Events 
Adverse Event (AE): (ICH) E6 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. 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) 
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. 

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All AEs, including solicited local (injection site) and systemic (subjective and quantitative) 
reactions, will be captured on the appropriate data collection form and eCRF. Information to be 
collected for AEs includes event description, date of onset, assessment of severity, relationship to 
study product and alternate etiology (assessed only by those with the training and authority to 
make a diagnosis and listed on the Form FDA 1572 as an investigator), date of resolution, 
seriousness, and outcome. AEs occurring during the trial collection and reporting period will be 
documented appropriately regardless of relationship. 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 unsolicited AE. However, if the severity or frequency of any 
pre-existing medical condition increases, it will be recorded as an unsolicited AE. 
If an event meets both the criteria of a study endpoint and an adverse event, the event will be 
reported either as a study endpoint or as an adverse event (not both). 
8.1.1.1 
Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for 
relationship to study product (see definitions). 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 data collection form and eCRF. Changes in the severity 
of an AE will be documented to allow an assessment of the duration of the event at each level of 
intensity. 
Severity of Event: 
AEs will be assessed by the investigator using a protocol-defined grading system (toxicity table). 
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. 

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Changes in the severity of an AE should be documented to allow for assessment of the duration 
of the event at each level of intensity to be performed.  AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Relationship to Study Product: The assessment of the relationship of an AE to the 
administration of study product is made only by those with the training and authority to make a 
diagnosis and listed on the Form FDA 1572 as an investigator based on all available information 
at the time of the completion of the eCRF.  Whether the AE is related or not, 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.  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. 
8.1.2 
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 
local (injection site) and systemic (subjective and quantitative) reactions: 
Table 3: 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 
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 

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Injection Site Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
interfere with daily 
activity 
Pruritus (Itching) 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration/Swelling 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis, erythema, and induration/swelling as analyzed by measurement will be graded as 
follows: 
Table 4: Injection Site Reactogenicity Measurements 
Injection Site Reaction 
Small 
Medium 
Large 
Ecchymosis* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration/Swelling* 
<20 mm 
20 mm – 50 mm 
>50 mm 
* Will not be used as halting criteria. 
Table 5: Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness  
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Fatigue  
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise  
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia* 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia * 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 

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Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
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 6: 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 
# 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. 
Table 7: Pulse and Blood Pressure Grading for Subjects 18-64 years of age 
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. 
8.1.3 
Serious Adverse Events 
Serious Adverse Event (SAE):  An AE or suspected adverse reaction is considered “serious” if, 
in the view of either the site principal investigator or sponsor, it results in any of the following 
outcomes: 

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• 
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 
principal 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 and alternate etiology. 
• 
Recorded on the appropriate SAE data collection form and eCRF. 
• 
Followed through resolution. 
• 
Reviewed and evaluated by an Independent Safety Monitor (ISM) (as deemed necessary), 
the SMC (periodic review unless related), DMID, and the IRB. 
At any time after protocol follow up period or completion of this study, if the site principal 
investigator or appropriate sub-investigator becomes aware of an SAE that is suspected to be 
related to study product, the site principal investigator or appropriate sub-investigator will report 
the event to the DMID Pharmacovigilance Group. 

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8.2 
Specifications of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
8.2.1 
Solicited Events 
Solicited events are AEs that are common and known to occur following administration of study 
product. 
8.2.2 
Unsolicited Events 
Unsolicited events are any other AEs that occur following administration of study product. 
8.2.3 
New Onset Chronic Medical Conditions (NOCMCs) 
NOCMCs are defined as any new ICD-10 that is applied to the subject during the duration 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. 
8.2.4 
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. 
8.2.5 
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 B. LIST OF 
POTENTIALLY IMMUNE MEDIATED MEDICAL CONDITIONS  
8.3 
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. 

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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, 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. 
8.3.1 
Reporting Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
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: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
 
 
 
 
In addition to the SAE form, selected SAE data fields must also be entered into the DCC system 
(for example AdvantageEDC). 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 study 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. 

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8.3.2 
Regulatory Reporting for Studies Conducted Under DMID Sponsored IND 
Following notification from the 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 FDA and all participating site 
investigators (i.e., all investigators 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 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 FDA, DMID will submit to FDA any additional 
data or information that the agency deems 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. 
8.3.3 
Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported via AdvantageEDCSM on the Pregnancy 
Report form. No further study vaccinations will be administered to pregnant subjects, but with 
the subject’s permission all protocol-required venous blood samples will be obtained and the 
subject will continue to be followed for safety for the duration of this trial. Efforts will be made 
to follow all pregnancies reported during the course of this trial to pregnancy outcome pending 
the subject’s permission. 
8.3.4 
Disclosure of Study Related Information 
Subjects can choose to receive written disclosure of their treatment assignment after the database 
has been locked.  
8.4 
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. 

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SAEs, 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 data 
collection form. 
8.5 
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 the 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. 
Clinical safety laboratory results# will be graded as follows: 
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 

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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 
# Clinical laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered as 
baseline. 
 
 
8.6 
Halting Rules 
8.6.1 
Study Halting Criteria 
Further enrollment and study vaccinations 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 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. 
• 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 a study vaccine-related SAE from the time of the first study 
vaccination through the subject’s last study visit. 
• 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 within the MF59®-
adjuvanted treatment arms or within the one unadjuvanted treatment arm.   
• 7% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date, cumulative to both vaccine administrations, across all groups, 
experience the same severe (Grade 3) study vaccine-related injection site reaction. 

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Ecchymosis, erythema, and induration/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 both vaccine administrations, across all groups, 
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 both vaccine administrations, across all groups, 
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 both vaccine administrations, across all groups, 
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 8.1.2. 
Grading scales for clinical safety laboratory AEs are included in Section 8.5. 
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 product during the entire trial, as applicable. 
The DMID Medical Monitor is empowered to stop enrollment and study vaccinations if AEs that 
meet the halting criteria are reported. 
8.6.2 
Individual Halting Criteria 
The second study vaccination will not be administered to a subject if any of the following criteria 
are met: 
•  Subject meets any criteria in Section 5.2.1, Withdrawal from the Study or Discontinuation of 
the Study Product.  
• 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 

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vaccination should be postponed/deferred until signs, symptoms, or acute illness have 
resolved, or are improving as further specified below, and if within the acceptable protocol-
specified window for that visit (Day 22+7) (note:  Grade 1 vaccine related solicited AE are 
permitted, see below). 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 that visit (Day 22+7), 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.  
• Grade 3 solicited or unsolicited AE that is ongoing, whether or not it is improved or 
resolving.  
• Any unresolved or continuing Grade 2 AE that has not decreased in severity to Grade 1 or 
less.   
• An unresolved or continuing Grade 1 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 solicited or unsolicited AE that occurs without alternative etiology in the 8 days 
following the first study vaccination. 
• Grade 3 clinical safety laboratory value (according to the toxicity table, Section 8.5) that does 
not decrease to Grade 2 or less prior to the second study vaccination.  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-specific window for that visit (Day 22+7 days post first study 
vaccination).  No exceptions to the protocol-specified window will be made. 
• Subject no longer meets eligibility criteria the Subject Exclusion Criteria (see Section 5.1.2). 
Note: exception for Medication changes described in Section 5.2.1.  
• Hospitalization that occurs before administration of the second study vaccination.  

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8.7 
Safety Oversight 
8.7.1 
Independent Safety Monitor (ISM) 
The ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion. For this trial an ISM is not required. 
However, at each participating VTEU site, upon DMID Medical Monitor request, the 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 a medical assessment (or 
second medical opinion) to the DMID of the safety event in question.  The PI will send to the 
DMID, MM, a summary of the event and include the PI and SMA assessments. 
Note: In case that DMID has requested this type of evaluation multiple times, DMID may 
request the site(s) identify an ISM to assist DMID with safety oversight. 
8.7.2 
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 conflict of interest 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. Procedures for DSMB reviews/meetings will be defined in the charter. 
Reports may include enrollment and demographic information, medical history, concomitant 
medications, physical assessments, clinical laboratory values, dosing compliance, and solicited 
and unsolicited AE/SAEs, 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: 
• Bi-monthly (every two months) safety data reviews (including monthly safety data and 
cumulative safety data) until the last subject completes the visit that occurs approximately 21 
days after the last study vaccination.  
• Data review 9 days after all subjects have received Dose 2 (complete study visit number 
V06). This review may be conducted as part of the scheduled monthly reviews. 
• 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. 

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• Final review meeting: 6 to 8 months after clinical database lock to review the cumulative 
unblinded safety and immunogenicity data for this trial. 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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9 
HUMAN SUBJECT PROTECTION 
9.1 
Institutional Review Board/Independent Ethics Committee 
Each site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s), 
and send supporting documentation to the DMID before initiating recruitment of subjects.  The 
investigator will submit applicable information to the IRB/IEC on which it relies for the review, 
to conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as applicable, 21 CFR 
56 (Institutional Review Boards) and 21 CFR 50 (Protection of Human Subjects), other federal, 
state, and local regulations.  The IRB/IEC must be registered with the Office of Human Research 
Protection (OHRP) as applicable to the research.  DMID must receive the documentation that 
verifies IRB/IEC-approval for this protocol, associated ICFs, and upon request any recruitment 
material and handouts or surveys intended for the subjects, prior to recruitment and enrollment of 
subjects. 
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before 
they are implemented.  IRB/IEC 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 investigator will notify the IRB/IEC of deviations from the protocol 
and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federal Wide Assurance (FWA) 
issued by the OHRP for federally funded research.   
9.2 
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 
are performed, informed consent will be obtained from the subject and documented.  Subjects 
will receive a concise and focused presentation of key information about the clinical 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. 
An investigator or designee will describe the protocol to potential subjects face-to-face.  The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
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/products.  This will include aspects of 

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the trial that are experimental, the probability for random assignment to treatment groups, 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 procedures that may be available and the important potential 
benefits and risks of these available alternative 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 investigator) 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 monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct 
access to the subject’s original medical records for verification of clinical 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.  
 
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 specimens will be used for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial, and have 
the opportunity to discuss this 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 consent form. 
Subjects must sign the ICF prior to starting any study procedures being done specifically for this 
trial. 
 

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Once signed, a copy of the ICF will be given to the subject(s) for their records.  The subject(s) 
may withdraw consent at any time throughout the course of the trial.  The rights and welfare of 
the subject(s) 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 this study. 
Study personnel may employ 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, site 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. 
New information will be communicated by the site principal investigator to subjects who consent 
to participate in this trial in accordance with IRB requirements.  The ICF will be updated and 
subjects will be re-consented per IRB requirements, if necessary.  Subjects will be given a copy 
of all ICFs that they sign. 
9.3 
Consent for Future Use of Stored Specimens and Data 
Residual samples/specimens are those that are left over after protocol-specified testing and this 
study has been completed.  Subjects may be asked for permission to keep any remaining 
(residual) serum derived from venous blood samples for possible use in future research studies, 
such as examining additional immunological assessments or testing for antibodies against other 
viruses or bacteria, or this permission may be a condition of study participation.  Residual 
clinical samples for future use will be stored indefinitely at a central clinical storage facility and 
may be shared with investigators at the participating site and with other investigators at other 
institutions. The recipients of specimens will be informed that these specimens have a NIH 
certificate of confidentiality.  The information provided to the recipient will not contain direct 
identifiable information.  Use of the specimens will require review by an IRB. 
Non-protocol Extra Samples 
Other blood samples are being collected during the study specifically for future use, from 
subjects who consent to collection of those specimens either by signing an informed consent 
form that includes collection of future use samples as a condition of study participation or by 
indicating that they opt in to sample collection for future use if the informed consent allows the 
option to choose that option. It is anticipated that up to 5 mL of serum from venous blood 
samples will be available specifically for the purpose of future research, including but not limited 
to non-traditional immune assay development, assessing innate immune factors and the ability of 
H7 vaccine-induced antibodies to cross-react with other influenza viruses.  These future use 
clinical samples will be stored indefinitely at a central clinical storage facility. 

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Residual specimens will be available upon the completion of this trial.  Extra samples/specimens 
collected during this study may be requested from DMID CMS while this study is ongoing or 
after the study, after IRB review. 
There are no benefits to subjects in the collection, storage and subsequent future use of their 
samples/specimens.  Future use samples/specimens will not be sold or used directly for 
production of any commercial product.  No genetic tests will be performed on 
samples/specimens.  Each sample/specimen will be encoded (labeled) only with a barcode and a 
unique tracking number that connects to a code key at the study site.  Restricted access to the 
code key is maintained by the PI to protect subject confidentiality.  Reports from future research 
studies performed using subjects’ samples/specimens will NOT be kept in their health records. 
Subjects may 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, or this permission may 
be a condition of study participation.  If given the option, the subject’s decision can be changed 
at any time by notifying the study doctors or nurses in writing.  However, if the subject originally 
consents to the future use of residual specimens and subsequently changes his/her decision, any 
data from a previously collected specimen may be used for future research. 
9.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will be inclusive of all subjects age 18 years and above 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. Should the outcome of this trial be deemed 
acceptable, additional trials may be initiated, including those in other populations. 
It is unknown if the 2017 H7N9 IIV with or without MF59® adjuvant poses any risks to an 
unborn child. The available data for women who become pregnant during clinical trials of 
MF59®-adjuvanted (pre) pandemic influenza vaccines do not suggest any causal relationship 
between adverse pregnancy outcomes and receipt of an MF59®-adjuvanted vaccine. Women of 
childbearing age who have undergone sterilization via tubal sterilization, bilateral oophorectomy, 
salpingectomy, hysterectomy, or successful Essure® placement (permanent, non-surgical, non-
hormonal sterilization) with documented radiological confirmation at least 90 days after the 
procedure are considered sterilized.  All other women of childbearing age who are still 
menstruating or < 1 year out from the last menses if menopausal must agree to practice highly 
effective contraception that may include, but not limited to, 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, male or female condoms with spermicide or with the use of 
applied spermicide, intrauterine devices, NuvaRing®, and licensed hormonal methods such as 
implants, injectables, or oral contraceptives (“the pill”),  with use of a highly effective method of 

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contraception for a minimum of 30 days prior to study product exposure and agree to practice 
highly effective contraception for the duration of study product 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. 
9.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study.    
No information concerning the study or the data generated from the study will be released to any 
unauthorized third party without prior written approval of the DMID and the subject.  Subject 
confidentiality will be maintained when study results are published or discussed in conferences. 
The study monitor or other authorized representatives of the sponsor or governmental regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the subjects in this study. The clinical study site 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 specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number.   
9.6 
Certificate of Confidentiality 
To protect privacy we have a Certificate of Confidentiality.  With this Certificate, the researchers 
cannot be forced to release information that may identify the research subject, even by a court 
subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, for example, if there is a court subpoena. 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 United 

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States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the Federal 
Food and Drug Administration (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.   
9.7 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial. Procedures and treatment for clinical care may be billed to the subject, subject’s 
insurance or third party.  Subjects may be compensated for their participation in this trial. 
Compensation will be in accordance with the local IRB’s policies and procedures, and subject to 
IRB approval. 
If it is determined by 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 site.   No 
financial compensation will be provided to the subject by the NIAID, NIH to the subject, or by 
the participating site for any injury suffered due to participation in this trial. 
For this protocol, the study products (monovalent inactivated influenza 2017 H7N9 virus vaccine 
manufactured by Seqirus and adjuvant (MF59®) manufactured by Seqirus), are covered under the 
Public Readiness and Emergency Preparedness Act (PREP Act), as described in Section 2.1.1. 
 

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10 
STATISTICAL CONSIDERATIONS 
10.1 
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 10.2, along with the probability of observing safety outcomes and the 
precision of immunogenicity outcomes. 
10.2 
Sample Size Considerations 
This study is planned to enroll 106 subjects in each adjuvanted treatment arm, and 53 subjects in 
the unadjuvanted treatment arm. Randomization at each site will be stratified by prior receipt of 
seasonal influenza vaccines, however there is no enrollment target for these strata.  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 tables illustrate the 
precision and power that is available for select estimates and comparisons of interest. 
Table 8 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 = 53, 106), and for all subjects receiving adjuvanted vaccine 
(N = 318). 
Table 8: Power (%) to Detect Safety Events: 
Event 
Frequency 
N = 53 
N = 106 
N = 318 
≥10% 
Very Common 
>99 
>99 
>99 
≥1% 
Common 
41 
65 
95 
≥0.1% 
Uncommon 
45 
10 
27 
≥0.01% 
Rare 
<1 
1 
3 
Binomial confidence intervals (CI) are widest (have the least precision) when the response rate is 
50%.  
 
 
 is presented to indicate the worst case scenario for precision of observed exact (Clopper-
Pearson) binomial confidence intervals. 

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Table 9: Precision of Binomial Confidence Intervals: 
N 
95% CI 
53 
36-64 
106 
40-60 
318 
44-56 
 
Table 10 illustrates the minimum detectable differences in the proportion of subjects responding 
(e.g., attaining seroconversion or a titer ≥40) between two adjuvanted treatment arms using a 
two-sided Likelihood Ratio Test and alpha = 0.05. 
Power calculations will assume n=100 per adjuvanted group and n=50 for the unadjuvanted 
group. Based on previous DMID A/H7N9 trials it is expected 5% of enrolled subjects may be 
excluded from analysis of the primary endpoint.  
Table 10: Minimum Detectable Difference in Proportion Responders with 80% Power 
Assumed Proportion of subjects with titer ≥40 in 
comparator arm 
Minimum Detectable 
Difference 
(N = 100) 
0.40 
0.20 
0.50 
0.20 
0.60 
0.19 
0.70 
0.17 
0.80 
0.14 
0.90 
0.09 
Per FDA guidance [67], the lower confidence limit on the appropriate point estimate excluding 
equality (i.e., a difference [adjuvanted – unadjuvanted] greater than zero in HAI antibody 
response rates) may be sufficient to demonstrate the added value of the adjuvant. Table 11 shows 
the lower bound of the 95% confidence interval for the differenc42 in the proportion responders 
between the adjuvanted and unadjuvanted arms (e.g. 15 mcg + MF59® minus 15 mcg 
unadjuvanted) assuming the proportion of responders in the unadjuvanted arm is 0.10 and 
considering a range for the proportion of responders in the adjuvanted arm ranges from 0.50 to 
0.90.  
Table 11: Lower Confidence bound2 for difference in proportion of responders between 
adjuvanted (N = 100) and unadjuvanted (N = 50) arms, 18-64 years stratum 
Adjuvanted Arm 
Unadjuvanted 
Arm 
Difference 
Lower Confidence 
Bound 
0.50 
0.10 
0.40 
0.26 

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0.60 
0.10 
0.50 
0.36 
0.70 
0.10 
0.60 
0.46 
0.80 
0.10 
0.70 
0.56 
0.90 
0.10 
0.80 
0.67 
10.3 
Treatment Assignment Procedures 
10.3.1 
Randomization Procedures 
Per ICH guideline E6: Good Clinical Practice (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 
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, randomly assigned to 1 of 4 treatment groups. All subjects will 
receive 2 vaccinations; the same dose will be given to the subject at both the first and second 
vaccination. Subjects will be randomized with allocation 2:2:2:1 into 4 groups, stratified by site 
(see Table 1) and by prior receipt of at least one of the 2017-2018 and/or 2018-2019 seasonal 
influenza vaccines to receive IM 2017 H7N9 IIV at 3.75 mcg, 7.5 mcg or 15 mcg at Days 1 and 
22 with MF59® adjuvant or 15 mcg at Days 1 and 22 administered without adjuvant. 
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 
participating VTEU site temporarily loses access to the Internet or the online enrollment system 
is unavailable. 
10.3.2 
Masking Procedures 
This is a double-blind clinical trial. 
Subjects, investigators, study personnel performing any study-related assessments following 
study vaccine administration are blinded to study treatment. Laboratory personnel performing 
HAI and Neut antibody assays will receive serum samples blinded to subject ID number and 
sample visit number. 

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The randomization scheme will be generated by the DCC and provided to unblinded study 
personnel (i.e., research pharmacists performing study vaccine 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. 
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 arm be unblinded for an 
individual subject if required for safety assessment. The DSMB will review grouped and 
unblinded data in the closed session only. 
10.4 
Planned Interim Analyses 
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, reactogenicity and immunogenicity data as 
described in Section 8.7.2. 
A set of “topline” immunogenicity and safety tables produced on an expedited timeline will be 
prepared as described in section 10.6; though this report will be released while subjects remain in 
the 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 the trial. If 
this occurs, immunogenicity data will be analyzed as results are available from the central 
immunogenicity laboratory. 
10.4.1 
Interim Safety Review 
An interim safety review may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, 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 

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will review grouped and unblinded data in the closed session only. The DSMB will meet and 
review this data at scheduled time points 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. 
Additionally, this trial will be monitored to determine if any of the halting rules described in 
Section 8.6.1 are met. 
10.4.2 
Interim Immunogenicity or Efficacy Review 
Should emergent public health needs dictate interim immunogenicity review, immune responses 
will be summarized in terms of strain-specific 2017 A/H7N9 HAI and Neut antibody titers. Any 
immunogenicity reports would be provided by the SDCC to the DMID Scientific Lead and CPM, 
and the DSMB. Reports would include data summarized by treatment arm.  
10.5 
Final Analysis Plan 
Clinical, safety, and reactogenicity data through approximately 180 days after the second study 
vaccination will represent the primary clinical database for this trial. Once the last subject 
completes the visit that occurs approximately 180 days after 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 follow-up at the time of these analyses, blinded 
investigators and DMID medical monitors not involved in the analysis, publication, or clinical 
study report preparation will be responsible for assessing SAEs and MAAEs including PIMMCs 
and new onset chronic medical conditions 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 clinical study report (CSR). 
Analysis of exploratory immunogenicity endpoints may be performed and released as the data 
are available from the research laboratory. 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 will be developed and finalized prior to unblinding for any 

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analysis, which defines the analyses to be included in the topline tables and the final CSR. 
10.5.1 
Analysis Populations 
The Safety Analysis population includes all subjects who received at least one dose of study 
vaccine. 
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 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 treatment arm.  
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 substantially out of window. 
For analyses using the PP population, subjects will be grouped based on study vaccinations 
received. 
10.5.2 
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-
7 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, 

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dichotomizing into a binary variable (none versus mild, moderate, or severe) and using standard 
techniques, such as exact confidence intervals, 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 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, 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% confidence intervals of 
AEs in aggregate and by MedDRA categories will be computed. 
10.5.3 
Immunogenicity Data  
Summaries and analysis of immunogenicity data will be presented for the mITT and PP 
populations. 
Immune responses in terms of strain-specific 2017 H7N9 HAI and Neut antibody titers will be 
summarized by treatment arm at each time point. Analyses will include percentage of subjects 
with a titer ≥40, percentage of subjects achieving seroconversion (defined as either a pre-
vaccination titer <10 and a post-vaccination titer ≥40 or a pre-vaccination titer ≥10 and a 
minimum four-fold rise in post-vaccination antibody titer), and GMTs along with corresponding 
95% confidence intervals. 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, body mass index, and prior receipt of seasonal influenza vaccine(s), 
and these covariates may be considered statistical modeling. As an exploratory analysis, models 
will be developed to evaluate the relationship between dosage and adjuvant on immune response. 
For example, logistic regression may be used to examine the relationship of proportion of 
responders with dosage and adjuvant, and available covariates may be considered for inclusion in 
the model. 
Additionally, N9 NA specific antibody assays are in development.  N9 NA specific responses 

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may be assessed at baseline, and 8, 22, 29, 43 and 202 after receipt of the first study vaccination.  
For each time point summaries will include percentage of subjects with detectable N9 NA 
response (to be defined in SAP following assay development and selection) and GMTs along 
with corresponding 95% confidence intervals. Descriptive summary statistics will be provided 
for all assays and time points. The correlation of N9 NA response with HAI and Neut antibody 
titers will be evaluated, and plots such as reverse cumulative distributions or longitudinal 
presentations of GMTs will be presented. 
Further, a determination of the NA content of the 2017 H7N9 IIV is planned if an assay becomes 
available and may be used to correlate the N9 NA elicited antibody responses to the NA content 
of the 2017 H7N9 IIV. Detectable NA antibody responses and GMTs will be summarized and 
evaluated for a dose response.  If the NA content is available, NA antibody responses will be 
stratified by NA content, and statistical modeling may be used to examine the relationship of NA 
response with NA vaccine content, HA antigen dosage, and adjuvant.  
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 2017 H7N9 
responses, and association with study vaccine dose and adjuvant. 
Further immunogenicity testing and/or analyses may be carried out in the future based upon 
subjects’ prior receipt of non-seasonal influenza vaccines, including type (inactivated or live 
attenuated), what subtype (e.g. A/H3, A/H5, A/H9) and approximate date of vaccination. 
10.5.4 
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 
impact of including or excluding the outliers. Any substantive differences in these analyses will 
be reported. 

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11 
SOURCE DOCUMENTS ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records in compliance 
with ICH E6, section 4.9, and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Each site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, 
to copy) clinical trial records for the purposes of quality assurance reviews, audits, evaluation of 
the study safety and progress. These representatives will be permitted access to all source data 
and source documents, which include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ Memory Aid or 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 the clinical trial.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating site(s) and 
its subcontractors are responsible for conducting routine quality assurance (QA) and quality 
control (QC) activities to internally monitor study progress and protocol compliance. The site PI 
will provide direct access to all study-related sites, source data/data collection forms, and reports 
for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. The site PI will ensure all study personnel are appropriately trained and training 
documentation is current and maintained on site. 
The DCC 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 site(s) for clarification and resolution. 

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13 
DATA HANDLING AND RECORD KEEPING 
13.1 
Data Management Responsibilities 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported. All source data collection forms should be completed in a neat, legible manner 
to ensure accurate interpretation of data. Black or blue permanent 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. 
Copies of the electronic CRF (eCRF) will be provided for use as source data collection forms 
and maintained for recording data for each subject enrolled in the study.  Data reported in the 
eCRF derived from the source data collection forms should be consistent or the discrepancies 
should be explained. 
The sponsor and/or its designee will provide guidance to the site PI and other study personnel on 
making corrections to the data collection forms and eCRF. 
13.2 
Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study personnel at each participating clinical site under 
the supervision of the site PI. During this trial, the site PI must maintain complete and accurate 
documentation for the study. 
The Data Coordinating Center for this study will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
13.3 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments), and reactogenicity will be collected on data collection forms by study 
personnel then entered into eCRF via a 21 CFR 11-compliant Internet Data Entry System 
provided by the study data coordinating center. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. 
13.4 
Types of Data 
Data for this trial will include clinical, safety, and outcome measures (e.g., reactogenicity and 
immunogenicity data). 

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13.5 
Study Records Retention 
Study records and reports including, but not limited to, CRFs, source documents, ICFs, 
laboratory test results, and study drug disposition records will be retained for a minimum of 2 
years after a marketing application is approved for the study product for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for the study 
product, 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 use will be maintained as long as the sample/specimen exists.  
No records will be destroyed without written consent of the sponsor.  It is the responsibility of 
the sponsor to inform the investigator when these documents no longer need to be retained. The 
participating VTEU site(s) must contact DMID for authorization prior to the destruction of any 
study records. 

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CLINICAL MONITORING 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures. DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
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 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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15 
PUBLICATION POLICY 
Following completion of the study, the lead PI is expected to publish the results of this research 
in a scientific journal.  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 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 trial the responsible party is DMID which will register the trial and post results.   
The responsible party plans not 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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16 
LITERATURE REFERENCES 
1. 
Centers for disease, C. and Prevention, Emergence of avian influenza A(h7n9) virus 
causing severe human illness - China, February-April 2013. MMWR Morb Mortal Wkly Rep, 
2013. 62(18): p. 366-71. 
2. 
Fouchier, R.A., et al., Avian influenza A virus (H7N7) associated with human 
conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A, 
2004. 101(5): p. 1356-61. 
3. 
Lindstrom, S., et al., Human infections with novel reassortant influenza A(H3N2)v 
viruses, United States, 2011. Emerg Infect Dis, 2012. 18(5): p. 834-7. 
4. 
Peiris, M., et al., Human infection with influenza H9N2. Lancet, 1999. 354(9182): p.  
916-7. 
5. 
Perez-Padilla, R., et al., Pneumonia and respiratory failure from swine-origin influenza A 
(H1N1) in Mexico. N Engl J Med, 2009. 361(7): p. 680-9. 
6. 
Subbarao, K., et al., Characterization of an avian influenza A (H5N1) virus isolated from 
a child with a fatal respiratory illness. Science, 1998. 279(5349): p. 393-6. 
7. 
Oxford, J.S., Influenza A pandemics of the 20th century with special reference to 1918: 
virology, pathology and epidemiology. Rev Med Virol, 2000. 10(2): p. 119-33. 
8. 
Patriarca, P.A. and N.J. Cox, Influenza pandemic preparedness plan for the United 
States. J Infect Dis, 1997. 176 Suppl 1: p. S4-7. 
9. 
Galasso, G.J., F.J. Tyeryar, Jr., and J.R. La Montagne, Overview of clinical trials of 
influenza vaccines, 1976. J Infect Dis, 1977. 136 Suppl: p. S425-8. 
10. 
La Montagne, J.R., et al., Summary of clinical trials of inactivated influenza vaccine - 
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Couch, R.B., et al., Antibody correlates and predictors of immunity to naturally 
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Keitel, W.A., et al., High doses of purified influenza A virus hemagglutinin significantly 
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Matzkin, H. and E. Nili, Accidental tenfold overdose of influenza vaccine: a clinical and 
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18. 
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19. 
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Remarque, E.J., et al., Improvement of the immunoglobulin subclass response to 
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21. 
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22. 
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23. 
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24. 
Couch, R.B., et al., A randomized clinical trial of an inactivated avian influenza A 
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25. 
Treanor, J.J., et al., Safety and immunogenicity of an inactivated subvirion influenza A 
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30. 
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31. 
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influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. 
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32. 
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33. 
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multicenter, Phase III pediatric trial in Mexico. Hum Vaccin Immunother, 2017: p. 0. 
34. 
Nicholson, K.G., et al., Safety and antigenicity of non-adjuvanted and MF59-adjuvanted 
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against H5N1 influenza. Lancet, 2001. 357(9272): p. 1937-43. 
35. 
El Sahly, H., et al., 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. Manuscript in 
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36. 
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. 
37. 
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With and Without AS03 and MF59 Adjuvants on Immune Response: A Randomized Clinical 
Trial. JAMA, 2015. 314(3): p. 237-46. 
38. 
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. 
39. 
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. 
40. 
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. 
41. 
Atmar, R.L., et al., Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted 
influenza A/H9N2 vaccine preparations.  Clin Infect Dis, 2006. 43(9): p. 1135-42. 
42. 
Wu, H., et al., Novel reassortant influenza A(H5N8) viruses in domestic ducks, eastern 
China. Emerg Infect Dis, 2014. 20(8): p. 1315-8. 
43. 
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. 
44. 
Analysis of recent scientific information on avian influenza A(H7N9) virus. WHO  
Influenza Update, 2017. 
45. 
Influenza at the human-animal interface.  Summary and Assessment, 26 January to 2 
March 2018.  WHO Monthly Influenza Risk Assessment Summary, 2 March, 2018. 
46. 
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47. 
Zhou, J., et al., Biological features of novel avian influenza A (H7N9) virus. Nature, 
2013. 499(7459): p. 500-3. 
48. 
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. 
49. 
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. 
50. 
Kilbourne, E.D., et al., Purified influenza A virus N2 neuraminidase vaccine is 
immunogenic and non-toxic in humans.  Vaccine, 1995. 13(18): p. 1799-803. 
51. 
Bart, S.A. et al., A cell culture-derived MF59-adjuvanted A/H7N9 vacine is immunogenic 
in adults.  Sci Transl Med, 2014.  6(234): p. 1-10. 
52. 
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-
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53. 
Grohskopf L.A., et al., Prevention and control of seasonal influenza vaccines. MMWR 
Recomm Rep, 2016. 65(5): p. 1-54. 
54. 
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. 
55. 
Haber, P., et al., Guillain-Barre syndrome following influenza vaccination. JAMA, 2004. 
292(20): p. 2478-81. 
56. 
De Wals, P., et al., Risk of Guillain-Barre syndrome following H1N1 influenza 
vaccination in Quebec. JAMA, 2012. 308(2): p. 175-81. 
57. 
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. 
58. 
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. 
59. 
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. 
60. 
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. 
61. 
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. 
62. 
Tsai, T.F. FLUAD®-MF59-adjuvanted influenza vaccine in older adults.  Infect 
Chemother, 2013, 45(2): p. 159-174. 
63. 
Black, S. et al., Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccine in 
children and adolescents: an integrated analysis. Vaccine, 2010. 28(45): p. 7331-6. 

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64. 
Pelligrini, M. et al., MF-59-adjuvanted versus non-adjuvanted influenza vaccine:  an 
integrated analysis from a large safety database.  Vaccine, 2009. 27(49): p. 6959-65. 
65. 
Tsai, T., et al., Exposure to MF59-adjuvanted influenza vaccines during pregnancy--a 
retrospective analysis. Vaccine, 2010. 28(7): p. 1877-80. 
66. 
Heikkinen T., et al., Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: 
a comparative cohort study.  Am J Obstet Gynecol, 2012. 207: p. e1-8. 
67. 
FDA, Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal 
Inactivated Influenza Vaccines, 2007. 
 
 
 
 
 
 

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17 
APPENDICES 
APPENDIX A: SCHEDULE OF PROCEDURES AND EVALUATIONS 
 
APPENDIX B. LIST OF POTENTIALLY IMMUNE MEDIATED MEDICAL CONDITIONS

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APPENDIX A: SCHEDULE OF PROCEDURES AND EVALUATIONS 
Study Visit 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Early Term 
Unscheduled 
Study Day Post 1st 
Vaccination 
Screen 
Optional  
D-28 to  
-1 
Dose 1 
D1 
D4 
±1d 
D8 
+2d 
D22 
+7d 
D25 
D29 
D43 
D82 
D142 
D202 
D387 
 
 
Study Day Post 2nd 
Vaccination 
 
 
 
 
Dose 2 
D1 
D4 
±1d 
D8 
+2d 
D22 
+7d 
D61 
±7d 
D121 
±14d 
D181
±14d 
D366 
±14d 
 
 
Obtain Informed 
Consent 
X∞ 
X∞¬ 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Demographic 
Information 
X 
X†* 
 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
X†¬ 
 
 
X† 
 
 
 
 
 
 
 
 
 
Medical History@ 
X 
X†¬ 
X 
X 
X† 
X 
X 
X 
 
 
X 
 
X 
X(if indicated) 
Concomitant 
Medications5 
X 
X†¬ 
X 
X 
X† 
X 
X 
X 
X 
X 
X 
 
X (if within 180 
days after last 
study 
vaccination) 
X (if prior to 180 
days after last study 
vaccination) 
Vital Signs$ (Oral 
Temperature%, Pulse, 
and BP) 
X 
X† 
 
 
X†2 
 
 
 
 
 
 
 
X (may be 
obtained if 
indicated) 
X (may be obtained 
if indicated) 
Height and Weight 
X 
X†* 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination3 
X 
X†*6 
 
{X} 
{X}† 
 
{X} 
{X} 
 
 
{X} 
 
{X} 
{X} 
 
 
 
 
 
 

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Study Visit 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Early Term 
Unscheduled 
Study Day Post 1st 
Vaccination 
Screen 
Optional  
D-28 to  
-1 
Dose 1 
D1 
D4 
±1d 
D8 
+2d 
D22 
+7d 
D25 
D29 
D43 
D82 
D142 
D202 
D387 
 
 
Study Day Post 2nd 
Vaccination 
 
 
 
 
Dose 2 
D1 
D4 
±1d 
D8 
+2d 
D22 
+7d 
D61 
±7d 
D121 
±14d 
D181
±14d 
D366 
±14d 
 
 
Serum or Urine 
Pregnancy Test 
X^ 
X†^ 
 
 
X†^ 
 
 
 
 
 
 
 
 
 
Venous Blood 
Collection for Clinical 
Safety Laboratory 
Evaluations 
 
X1 
 
X1 
X1 
 
X1 
 
 
 
 
 
X (if within 7 
days after the 
last study 
vaccination) 
X (if indicated) 
Venous Blood 
Collection for 
Immunongenicity 
Assays 
 
X† 
 
X 
X†Ψ 
 
X 
X 
 
 
XΨ 
 
X (if within 21 
days after last 
study 
vaccination) 
X (if prior to 21 days 
after last study 
vaccination) 
Serum Sample 
Collected for Future 
Research4 
 
X† 
 
X 
X† 
 
X 
X 
 
 
 
X 
 
X(if within 21 
days after last 
study 
vaccination 
X(if prior to 21 days 
after last study 
vaccination 
Enrollment in 
AdvantageEDCSM and 
Randomization 
 
 
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 (if within 7 
days after last 
study 
vaccination) 
X (if within 7 days 
after last study 
vaccination) 
 
 

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Study Visit 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Early Term 
Unscheduled 
Study Day Post 1st 
Vaccination 
Screen 
Optional  
D-28 to  
-1 
Dose 1 
D1 
D4 
±1d 
D8 
+2d 
D22 
+7d 
D25 
D29 
D43 
D82 
D142 
D202 
D387 
 
 
Study Day Post 2nd 
Vaccination 
 
 
 
 
Dose 2 
D1 
D4 
±1d 
D8 
+2d 
D22 
+7d 
D61 
±7d 
D121 
±14d 
D181
±14d 
D366 
±14d 
 
 
Post-Administration 
Reactogenicity 
Assessments 
 
X 
 
 
X 
 
 
 
 
 
 
 
X (if within 7 
days after last 
study 
vaccination) 
X (if within 7 days 
after last study 
vaccination) 
Distribute Memory Aid 
and Study-Related 
Materials 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Review Memory Aid 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
X (if within 7 
days after last 
study 
vaccination) 
X (if within 7 days 
after last study 
vaccination) 
AE Assessment 
 
X& 
X& 
X& 
X& 
X& 
X& 
X 
 
 
 
 
 
 
X 
SAEs/MAAEs/ 
NOCMCs/PIMMCs 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Phone Call 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
 
 
∞ Prior to performing any study procedures. 
† Prior to study vaccination.  
   Review results of safety laboratory evaluations¬ Review/confirm information or activity in subjects previously consented and screened 
@ Complete medical history will be obtained by interview of subjects at the first visit (either screening [optional] or on Day 1 prior to the first study vaccination) 
and interim medical history will be obtained by interview of subjects at subsequent visits. 
*    Not required if done at the optional screening visit 
$ 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 are being followed for safety. 
3 At the screening (or baseline if not done at screening) visit, 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, abdomen, general appearance, musculoskeletal, and nervous system and as 
assessment for signs suggestive of a PIMMC. 
{}Targeted physical examination if indicated based on review of interim medical history. 

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^ Will be performed on all women of childbearing potential at screening (optional) and within 24 hours prior to each study vaccination and results must be negative 
and known prior to each study vaccination. 
Ψ  Subjects who do not receive the second study vaccination will continue with follow-up safety assessments (may be conducted by phone call) rather than in person 
continuing through approximately 12 months after their first study vaccination. These subjects will also be encouraged to provide a venous blood sample for anti-
viral antibody assays at approximately 21 days after their first study vaccination 
4 For subjects who have consented to collection of serum for future use either by signing an ICF that includes collection of future use samples as a condition of 
study participation or by indicating that they opt in to sample collection for future use if the ICF allows the option to choose that option. 
& Inclusive of reactogenicity assessments performed on the day of each study vaccination through 7 days after each study vaccination. 
 
5 All concomitant medications taken within 60 days prior to signing the ICF will be reviewed with subjects.  Medications reported in the eCRF are limited to those taken within 30 
days prior to the first study vaccination through approximately 180 days after the last study vaccination, including receipt of any non-study influenza vaccine. 
6 Targeted physical examination may be done at Visit 01 if Visit 00, screening visit was conducted, and if indicated based on review of interim medical history.   
 
 
 

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APPENDIX B. LIST OF POTENTIALLY IMMUNE MEDIATED 
MEDICAL CONDITIONS 
[also known as Adverse Events of Special Interest (AESIs).  This list is not all inclusive]. 
 
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 rheumatica 
• 
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 

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• 
Systemic sclerosis 
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 
• 
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 (granulomatosis with 
polyangiitis), 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 
Others 
• 
Antiphospholipid syndrome 

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