A Phase I Study to Assess the Safety, Reactogenicity and Immunogenicity of Two Quadrivalent Seasonal Influenza Vaccines (Fluzone(R) or Flublok(R)) With or Without One of Two Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults 18-45 Years of Age
Phase: PHASE1
Conditions: Influenza, Influenza Immunisation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
A Phase I Study to Assess the Safety, Reactogenicity and Immunogenicity of Two 
Quadrivalent Seasonal Influenza Vaccines (Fluzone® or Flublok®) With or Without 
One of Two Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults 18-45 Years of 
Age 
 
DMID Protocol Number: 18-0011 
 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
 
Pharmaceutical Support: 
Sanofi Pasteur 
Vaxine Pty Ltd 
 
IND Sponsor: Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National Institutes of Health 
 
Lead Principal Investigator: Patricia Winokur, MD 
DMID Clinical Project Manager: Kathy Ormanoski, M.S., CCRA 
DMID Medical Monitor: Mohamed Elsafy, MD 
DMID Medical Officer: Mamodikoe Makhene, MD, MPH 
DMID Scientific Lead: Chris Roberts, PhD 
 
Version: 8.0 
01 February 2021 
 
 

DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
1 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application), 21 CFR 812 (Investigational 
Device Exemptions) 
• 
 International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH): Good Clinical Practice (GCP) E6(R2) Good Clinical Practice:  
Integrated Addendum to ICH E6(R1) Guidance for Industry,” published in the Federal 
Register (83 Federal Register 8882 (2018) 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, 
as applicable 
• 
Applicable Federal, State and Local Regulations and Guidance 
 

DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
2 
SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 GCP guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and Institutional Review Board 
(IRB)/Institutional Ethics Committee (IEC) approval, except when necessary to protect the 
safety, rights or welfare of subjects. 
Site Principal Investigator: 
 
Signed: 
 
 
Date: 
 
 
Name 
Title 
 
 
 
 
 
 

DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
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TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE .................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
LIST OF ABBREVIATIONS ..........................................................................................................9 
PROTOCOL SUMMARY .............................................................................................................13 
1 
Key Roles ..............................................................................................................................29 
2 
Background Information and Scientific Rationale ...............................................................31 
 
Background Information ...........................................................................................31 
 
Scientific Rationale ...................................................................................................36 
 
Potential Risks and Benefits .....................................................................................37 
2.3.1 Potential Risks ..............................................................................................37 
2.3.2 Known Potential Benefits .............................................................................40 
3 
Study Objectives and Outcome Measures ............................................................................42 
4 
Study Design .........................................................................................................................43 
5 
Study Enrollment and Withdrawal........................................................................................45 
 
Eligibility Criteria .....................................................................................................45 
5.1.1 Subject Inclusion Criteria .............................................................................45 
5.1.2 Subject Exclusion Criteria ............................................................................47 
5.1.3 Exclusion Criteria for Second Study Vaccination ........................................49 
 
Treatment Assignment Procedures ...........................................................................50 
5.2.1 Enrollment and Randomization Procedures..................................................50 
5.2.2 Masking Procedures ......................................................................................50 
5.2.3 Reasons for Withdrawals and Discontinuation of Study Product 
Administration ..............................................................................................51 
5.2.4 Handling of Withdrawals and Discontinuation of Study Product 
Administration ..............................................................................................52 
5.2.5 Subject Replacement .....................................................................................52 
5.2.6 Termination of Study ....................................................................................52 
6 
Study Intervention/Investigational Product ..........................................................................54 
 
Study Product Description ........................................................................................54 
6.1.1 Formulation, Storage, Packaging, and Labeling ...........................................56 
6.1.2 Study Product Storage and Stability Procedures ..........................................58 

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Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ......................................................................................................................59 
 
Accountability Procedures for the Study Intervention/Investigational Product .......61 
 
Assessment of Subject Compliance with Study Intervention/Investigational Product
...................................................................................................................................63 
 
Concomitant Medications/Treatments ......................................................................63 
7 
Study Procedures/Evaluations ..............................................................................................64 
 
Clinical Evaluations ..................................................................................................64 
 
Laboratory Evaluations .............................................................................................65 
7.2.1 Clinical Laboratory Evaluations ...................................................................65 
7.2.2 Special Assays or Procedures .......................................................................66 
7.2.3 Specimen Preparation, Handling and Shipping ............................................68 
7.2.3.1 Instructions for Specimen Preparation, Handling and Storage .........68 
7.2.3.2 Specimen Shipment ..........................................................................68 
8 
Study Schedule......................................................................................................................69 
 
Screening and Enrollment Visits ..............................................................................69 
8.1.1 Visit 00, Screening (Day -28 to -1), Clinic Visit ..........................................69 
8.1.2 Visit 01, Day 1, Enrollment (Vaccination), Clinic Visit ...............................70 
 
Follow-up Visits........................................................................................................72 
8.2.1 Visit 02, Day 2, Clinic Visit..........................................................................72 
8.2.2 Visit 03, Day 8, Clinic Visit..........................................................................73 
8.2.3 Visit 04, Day 29, Clinic Visit........................................................................74 
8.2.4 Visit 05, Day 57, Clinic Visit........................................................................75 
8.2.5 Visit 06, Day 90, Clinic Visit........................................................................75 
8.2.6 Visit 07, Day 118, Clinic Visit......................................................................76 
8.2.7 Visit 08, Day 180, Clinic Visit......................................................................77 
 
Final Visit..................................................................................................................77 
8.3.1 Visit 09, Day 365, Clinic Visit......................................................................77 
 
Early Termination Visit (if needed) ..........................................................................78 
 
Unscheduled Visit (if needed) ..................................................................................79 
9 
Assessment of Safety ............................................................................................................81 
 
Specification of Safety Parameters ...........................................................................81 
 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters .81 
9.2.1 Adverse Events .............................................................................................81 
9.2.2 Reactogenicity...............................................................................................84 
9.2.3 Additional Adverse Event Severity Grading ................................................86 
9.2.4 Serious Adverse Events ................................................................................88 
9.2.5 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .........................................................89 

DMID Protocol 18-0011                                                                                           Version 8.0 
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Reporting Procedures ................................................................................................89 
9.3.1 Serious Adverse Events ................................................................................89 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
.......................................................................................................................90 
9.3.3 Reporting of Pregnancy ................................................................................91 
 
Type and Duration of Follow-up of Subjects after Adverse Events .........................91 
 
Halting Rules ............................................................................................................92 
9.5.1 Halting Rules for the Sentinel Subjects ........................................................92 
9.5.2 Halting for Study...........................................................................................93 
 
Safety Oversight........................................................................................................94 
9.6.1 Independent Safety Monitor (ISM) ...............................................................94 
9.6.2 Data and Safety Monitoring Board (DSMB) ................................................94 
10 
Clinical Monitoring ...............................................................................................................97 
 
Site Monitoring Plan .................................................................................................97 
11 
Statistical Considerations ......................................................................................................98 
 
Introduction ...............................................................................................................98 
 
Study Hypotheses......................................................................................................98 
 
Study Outcome Measures .........................................................................................98 
 
Sample Size Considerations ......................................................................................98 
11.4.1 Study Population ...........................................................................................98 
11.4.2 Subject Enrollment and Follow-up ...............................................................99 
11.4.3 Sample Size ...................................................................................................99 
 
Planned Interim Analyses .......................................................................................101 
11.5.1 Interim Safety Review ................................................................................102 
 
Final Analysis Plan .................................................................................................102 
11.6.1 Analysis Populations ...................................................................................103 
11.6.2 Safety Data ..................................................................................................104 
11.6.3 Humoral Immunogenicity Data ..................................................................104 
11.6.4 Exploratory Cellular Immunogenicity Data................................................105 
11.6.5 Exploratory Transcriptomics Data ..............................................................105 
11.6.6 Missing Values and Outliers .......................................................................106 
12 
Data Collection Forms and Access to Source Data/Documents .........................................107 
13 
Quality Control and Quality Assurance ..............................................................................108 
14 
Ethics/Protection of Human Subjects .................................................................................109 
 
Ethical Standard ......................................................................................................109 
 
Institutional Review Board (IRB) ...........................................................................109 
 
Informed Consent Process ......................................................................................110 
 
Exclusion of Women, Minorities and Children (Special Populations) ...................111 
 
Subject Confidentiality ...........................................................................................112 

DMID Protocol 18-0011                                                                                           Version 8.0 
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Study Discontinuation .............................................................................................113 
 
Costs, Subject Compensation and Research Related Injuries .................................113 
 
Future Use of Stored Specimens .............................................................................114 
15 
Data Handling and Record Keeping ...................................................................................116 
 
Data Management Responsibilities.........................................................................116 
 
Data Capture Methods ............................................................................................116 
 
Types of Data ..........................................................................................................117 
 
Timing/Reports .......................................................................................................117 
 
Study Records Retention.........................................................................................118 
 
Protocol Deviations .................................................................................................118 
16 
Publication Policy ...............................................................................................................120 
17 
Literature References ..........................................................................................................121 
18 
Appendices ..........................................................................................................................126 
 
SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS .........127 
 
Adverse Events of special interest ..............................................................130 
 
 
 

DMID Protocol 18-0011                                                                                           Version 8.0 
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LIST OF TABLES 
Table 1: Study Objectives and Outcome Measures .......................................................................14 
Table 2: Study Design ....................................................................................................................27 
Table 3: Venipuncture Volumes ....................................................................................................67 
Table 4: Injection Site Reactogenicity Grading .............................................................................84 
Table 5: Injection Site Reactogenicity Measurements ...................................................................85 
Table 6: Subjective Systemic Reactogenicity Grading ..................................................................85 
Table 7: Quantitative Systemic (Oral Temperature) Reactogenicity Grading ...............................86 
Table 8: Pulse and BP Adverse Event Grading .............................................................................86 
Table 9: Clinical Safety Laboratory Adverse Event Grading ........................................................86 
Table 10: Probability (%) to Detect Safety Events ......................................................................100 
Table 11: Precision of Binomial Confidence Intervals ................................................................100 
Table 12: Minimum Detectable Difference in Proportion Responders with 80% Power ............101 
Table 13: Schedule of Study Procedures and Evaluations...........................................................127 

DMID Protocol 18-0011                                                                                           Version 8.0 
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LIST OF FIGURES 
Figure 1: Schematic of Study Design ............................................................................................28 
 
 
 

DMID Protocol 18-0011                                                                                           Version 8.0 
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LIST OF ABBREVIATIONS 
A/H1N1 
Influenza A Virus of the H1N1 Subtype 
A/H1N2v 
Influenza A Virus of the H1N2 Variant Subtype 
A/H2N2 
Influenza A Virus of the H2N2 Subtype 
A/H3N2 
Influenza A Virus of the H3N2 Subtype 
A/H3N2v 
Influenza A Virus of the H3N2 Variant Subtype 
A/H5N1 
Influenza A Virus of the H5N1 Subtype 
A/H5N6 
Influenza A Virus of the H5N6 Subtype 
A/H5N8 
Influenza A Virus of the H5N8 Subtype 
A/H7N1 
Influenza A Virus of the H7N1 Subtype 
A/H7N7 
Influenza A Virus of the H7N7 Subtype 
A/H7N9 
Influenza A Virus of the H7N9 Subtype 
A/H9N2 
Influenza A Virus of the H9N2 Subtype 
Advax  
Trade name for delta inulin adjuvant formulation 
AE 
Adverse Event/Adverse Experience 
AESIs 
Adverse Events of Special Interest 
AF03 
Adjuvant formulation (03) 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase 
ANCA 
Anti-Neutrophil Cytoplasmic Antibody 
AS03 
Adjuvant System (03) 
AST 
Aspartate Aminotransferase 
BARDA 
Biomedical Advanced Research and Development Authority 
BLA 
Biologics License Applications 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CMS 
Clinical Materials Services 
COI 
Conflict of Interest 
CpG55.2 
Class B CpG oligonucleotide adjuvant  
Cr 
Creatinine 
CROMS 
Clinical Research Operations and Management Support 
CSL 
Commonwealth Serum Laboratories 
CSR 
Clinical Study Report 

DMID Protocol 18-0011                                                                                           Version 8.0 
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°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
D 
Day(s) 
DCF 
Data Collection Form 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDCSM 
Electronic Data Capture System 
ELISpot 
Enzyme-Linked Immunosorbent Spot 
ESR 
Erythrocyte Sedimentation Rate 
FACS 
Fluorescence-Activated Cell Sorting 
FDA 
Food and Drug Administration 
FWA 
Federal-wide Assurance 
g/dL 
Grams per Deciliter 
GBS 
Guillain-Barré Syndrome 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline Biologicals 
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLGT 
High Level Group Term 
HPAI 
Highly Pathogenic Avian Influenza 
HRSA 
Health Resources and Services Administration 
IATA 
International Air Transport Association 
ICD-10 
10th revision of the International Statistical Classification of Diseases and 
Related Health Problems 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Institutional Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IIV 
Inactivated Influenza Virus Vaccine 

DMID Protocol 18-0011                                                                                           Version 8.0 
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IIV3 
Trivalent IIV 
IM 
Intramuscular(ly) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IU/L 
International Unit(s) per Liter 
MAAE 
Medically-Attended Adverse Event 
mcg 
Microgram(s) 
µL 
Microliter(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF59 
MF59C.1 Adjuvant 
mg/dL 
Milligram(s) per Deciliter 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
mmHg 
Millimeters of Mercury 
MOP 
Manual of Procedures 
N 
Number of Subjects 
NA 
Neuraminidase 
NAI 
Neuraminidase Inhibiting or Inhibition 
Neut 
Neutralizing or Neutralization 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
NK 
Natural Killer 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
NOCMCs 
New-Onset Chronic Medical Conditions 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral Blood Mononuclear Cell 
PBS 
Phosphate Buffered Saline 
pH1N1 
2009 H1N1 Influenza 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PIMMCs 
Potentially Immune-Mediated Medical Conditions 
PLT 
Platelets 
PP 
Per Protocol 
 
 
PRN 
As Needed 
QIV 
Quadrivalent Influenza Vaccine 

DMID Protocol 18-0011                                                                                           Version 8.0 
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QA 
Quality Assurance 
QC 
Quality Control 
RIV 
Recombinant Influenza Vaccine 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SDCC 
Statistical and Data Coordinating Center 
SMA 
Secondary Medical Assessor 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SP 
Sanofi Pasteur 
SRID 
Single Radial Immunodiffusion 
SWI 
Sterile Water for Injection 
TBD 
To Be Determined 
TIV 
Trivalent Influenza Vaccine 
TLR 
Toll-like Receptor 
T. Bili 
Total Bilirubin 
US 
United States 
V 
Visit(s) 
VTEU 
Vaccine and Treatment Evaluation Unit 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 

DMID Protocol 18-0011                                                                                           Version 8.0 
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PROTOCOL SUMMARY 
Title: 
A Phase I Study to Assess the Safety, Reactogenicity and Immunogenicity of Two 
Quadrivalent Seasonal Influenza Vaccines (Fluzone® or Flublok®) With or Without 
One of Two Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults 18-45 Years of 
Age 
Phase: 
I 
Population: 
Up to 240 males and non-pregnant females, 18 to 45 years of age, inclusive, who are in 
good health and meet all eligibility criteria 
Number of Sites: 8 Vaccine and Treatment Evaluation Unit (VTEU) sites  
Study Duration: 
Approximately 18 months 
Subject 
Participation 
Duration: 
Approximately 12 months 
Estimated Time 
to Complete 
Enrollment: 
Approximately 9 weeks 
Description of 
Agents: 
• 
Flublok Quadrivalent Influenza Vaccine (QIV) 2018/2019 Formula 
manufactured by Sanofi Pasteur (SP). 
• 
Fluzone Quadrivalent Influenza Vaccine (QIV) 2018/2019 Formula 
manufactured by SP. 
• 
Flublok Quadrivalent Influenza Vaccine (QIV) 2019/2020 Formula 
manufactured by SP. 
• 
Fluzone Quadrivalent Influenza Vaccine (QIV) 2019/2020 Formula 
manufactured by SP. 
• 
AF03 adjuvant manufactured by SP. 
• 
Advax-CpG55.2 adjuvant is a combination adjuvant comprised of Advax and 
CpG55.2 adjuvants: 
o Advax (delta inulin) adjuvant manufactured for Vaxine by Sypharma 
Pty Ltd.  
o CpG55.2 oligonucleotide adjuvant manufactured for Vaxine by Nikko 
Denka Avecia and Sypharma Pty Ltd.   

DMID Protocol 18-0011                                                                                           Version 8.0 
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Table 1: Study Objectives and Outcome Measures 
Primary Safety Objectives 
Primary Safety Outcome Measures 
• To assess the safety and 
reactogenicity of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.  
 
• Occurrence of solicited injection site and 
systemic reactogenicity events through 
approximately Day 8 after the first study 
vaccination. 
• Occurrence of unsolicited adverse events 
from the time of the first study 
vaccination through approximately Day 
29. 
• Occurrence of all SAEs through 
approximately 12 months following 
receipt of the first study vaccination. 
• Occurrence of abnormal clinical safety 
laboratory AEs from the time of study 
vaccination through approximately Day 8 
after the first study vaccination. 
Primary Immunogenicity Objectives 
Primary Immunogenicity Outcome Measures 
• To assess the serum 
hemagglutination inhibition (HAI) 
antibody responses against 
2018/2019 QIV strains from 
baseline (Day 1) to approximately 
Day 29 after receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• The percentage of subjects achieving 
HAI titer seroconversion against the 
2018/2019 QIV strains (defined as either 
a pre-vaccination titer <1:10 and a post-
vaccination titer ≥1:40 or a pre-
vaccination titer ≥1:10 and a minimum 
four-fold rise in post-vaccination 
antibody titer) on approximately Day 29 
for each study group. 
• The percentage of subjects with an HAI 
titer ≥1:40 against the 2018/2019 QIV 
strains at baseline and approximately 
Day 29 for each study group. 
• Geometric mean titers (GMTs) of serum 
HAI against the 2018/2019 QIV strains at 
baseline and approximately Day 29 for 
each study group. 

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• Ratio of GMTs of serum HAI against the 
2018/2019 QIV strains between 
adjuvanted and unadjuvanted study 
groups at baseline and approximately 
Day 29. 
• Geometric mean fold rise (GMFR) in 
HAI titers from baseline (Day 1) against 
the 2018/2019 QIV strains at 
approximately Day 29 for each study 
group 
• To assess the serum neuraminidase 
inhibition antibody (NAI) 
responses by enzyme-linked lectin 
assay (ELLA) against NA antigens 
in the 2018/2019 QIV from 
baseline (Day 1) to approximately 
Day 29 after receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.   
• The percentage of subjects achieving 
NAI seroconversion (defined as ≥4-fold 
rise in post vaccination antibody titers 
against the NA antigens in the 2018/2019 
QIV) on approximately Day 29 for each 
study group. 
• The serum NAI GMT at baseline (Day 1) 
and approximately Day 29 for each study 
group. 
• Ratio of serum NAI GMT between 
adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and 
approximately Day 29. 
• Geometric mean fold rise (GMFR) in 
NAI titers from baseline (Day 1) against 
NA antigens in the 2018/2019 QIV 
strains at approximately Day 29 for each 
study group 
• To assess the influenza neutralizing 
(Neut) antibody titer responses 
against 2018/2019 QIV strains from 
baseline (Day 1) to approximately 
Day 29 after receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax- CpG55.2 
adjuvant.  
• The percentage of subjects achieving 
Neut titer seroconversion against the 
2018/2019 QIV strains (defined as either 
a pre-vaccination titer <1:10 and a post-
vaccination titer ≥1:40 or a pre-
vaccination titer ≥1:10 and a minimum 
four-fold rise in post-vaccination 
antibody titer) on approximately Day 29 
for each study group. 

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• The percentage of subjects with a Neut 
titer ≥1:40 against the 2018/2019 QIV 
strains at baseline (Day 1) and 
approximately Day 29 for each study 
group. 
• Serum Neut GMT at baseline (Day 1) 
and approximately Day 29 for each study 
group 
• Ratio of serum Neut GMT between 
adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and 
approximately Day 29. 
• Geometric mean fold rise (GMFR) in 
Neut titers from baseline (Day 1) against 
the 2018/2019 QIV strains at 
approximately Day 29 for each study 
group 
Secondary Safety Objectives 
Secondary Safety Outcome Measures 
• To assess protocol specified AESIs, 
medically-attended adverse events 
(MAAEs), including new-onset 
chronic medical conditions 
(NOCMCs) and potentially 
immune-mediated medical 
conditions (PIMMCs) that occur 
after receipt of study product. 
• Occurrence of all protocol specified 
AESIs, MAAEs, including NOCMCs and 
PIMMCs, from the time of the first study 
vaccination through approximately 12 
months following the first vaccination. 
 
Secondary Immunogenicity Objectives  
Secondary Immunogenicity Outcome 
Measures 
• To assess the HAI, Neut and NAI 
ELLA responses to the 2019/2020 
QIV strains prior to (Day 1) and 
approximately 28 days after 
vaccination with the 2019/2020 
QIV in all study groups 
• The percentage of subjects achieving an 
HAI titer ≥1:40 against 2019/2020 QIV 
strains approximately on Days D90 
(baseline) and D118 (28 days post-
2019/2020 vaccine) for each study group. 
• The percentages of subjects achieving 
HAI, Neut and NAI titer seroconversion, 
against 2019/2020 QIV strains on 

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approximately Day 118 for each study 
group (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMTs 
against 2019/2020 QIV strains 
approximately on Days D90 (baseline) 
and D118 (28 days post-2019/2020 QIV) 
for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3).  
• Ratio of serum Neut, HAI and NAI 
GMTs against 2019/2020 QIV strains 
between adjuvanted and unadjuvanted 
study groups approximately on Days D90 
(baseline) and D118 (28 days post-
2019/2020 QIV). NAI titers will only be 
assessed on study groups 1,2 and 3. 
• Serum Neut, HAI and NAI GMFRs 
against 2019/2020 QIV strains from 
baseline (D90) on approximately D118 
for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3). 
• To assess the HAI antibody 
responses against heterologous 
influenza A/H1 and H3 strains from 
baseline (Day 1) to approximately 
Days 8, 29, 57, 90, and 118 after 
receipt of 2018/2019 Fluzone or 
Flublok with and without AF03 or 
Advax-CpG55.2 adjuvant.  
 
• The percentages of subjects achieving 
HAI titer seroconversion, against 
heterologous H1 and H3 influenza strains 
on approximately Days 8, 29, 57, 90, and 
118 for each study group.  
• The percentage of subjects achieving an 
HAI titer ≥1:40 against heterologous H1 
and H3 influenza strains at baseline (Day 
1) and approximately Days 8, 29, 57, 90, 
and 118 for each study group. 
• Serum HAI GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 8, 29, 
57, 90, and 118 for each study group.  
• Ratio of serum HAI GMT against 
heterologous H1 and H3 influenza strains 

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between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 8, 29, 57, 90, and 
118.  
• Geometric mean fold rise (GMFR) in 
HAI from baseline (Day 1) against 
heterologous H1 and H3 influenza strains 
at approximately Days 8, 29, 57, 90, and 
118 for each study group 
• To assess NAI ELLA responses 
against heterologous N1 and N2 
NA antigens from baseline (Day 1) 
to approximately Days 8, 29, 57, 
90, and 118 after administration of 
2018/2019 Fluzone with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• The percentage of subjects achieving 
seroconversion against heterologous N1 
and N2 NA antigens on approximately 
Days 8, 29, 57, 90, and 118 for study 
groups 1, 2 and 3. 
• Serum NAI GMTs against heterologous 
N1 and N2 NA antigens at baseline and 
approximately Days 8, 29, 57, 90, and 
118 for study groups 1, 2 and 3. 
• Ratio of serum NAI GMTs against 
heterologous N1 and N2 NA antigens 
between adjuvanted and unadjuvanted 
study groups at baseline and 
approximately Days 8, 29, 57, 90, and 
118 (NAI titers will only be assessed on 
study groups 1,2 and 3). 
• Geometric mean fold rise (GMFR) in 
serum NAI from baseline against 
heterologous N1 and N2 NA antigens at 
baseline and approximately Days 8, 29, 
57, 90, and 118 for study groups 1, 2 and 
3. 
 
• To assess the influenza neutralizing 
(Neut) antibody titer responses 
against heterologous influenza 
A/H1 and H3 strains from baseline 
(Day 1) to approximately Days 8, 
• The percentage of subjects achieving 
Neut titer seroconversion against 
heterologous H1 and H3 influenza strains 

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29, 57, 90, and 118 after 
administration of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.  
 
on approximately Days 8, 29, 57, 90, and 
118 for each study group. 
• Serum Neut GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 8, 29, 
57, 90, and 118 for each study group. 
• Ratio of serum Neut GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 8, 29, 57, 90, and 
118. 
• Geometric mean fold rise (GMFR) of 
neut antibody titers from baseline against 
heterologous H1 and H3 influenza strains 
at baseline (Day 1) and approximately 
Days 8, 29, 57, 90, and 118 for each 
study group. 
• To assess the longitudinal kinetics 
and durability of the HAI, NAI, and 
Neut responses against the 
2018/2019 QIV strains on 
approximately Days 8, 57, 90, and 
118 following receipt of the 
2018/2019 Fluzone and Flublok 
with and without AF03 or Advax-
CpG55.2 adjuvant.   
 
• The percentage of subjects achieving 
HAI, NAI and Neut titer seroconversion 
against 2018/2019 QIV antigens and 
strains on approximately Days 8, 57, 90, 
and 118 for each study group (NAI titers 
will only be assessed on study groups 1,2 
and 3). 
• The percentage of subjects achieving an 
HAI and Neut titer ≥1:40 against 
2018/2019 QIV strains on approximately 
Days 8, 57, 90, and 118 for each study 
group (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMT against 
2018/2019 QIV strains on approximately 
Days 8, 57, 90, and 118 for each study 
group (NAI titers will only be assessed 
on study groups 1,2 and 3). 

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• Ratio of serum Neut, HAI and NAI GMT 
against 2018/2019 QIV strains between 
adjuvanted and unadjuvanted study 
groups on approximately Days 8, 57, 90, 
and 118  (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• Geometric mean fold rise (GMFR) in 
HAI, Neut and NAI titers from baseline 
(Day 1) against the 2018/2019 QIV 
strains at approximately Day 8, 57, 90, 
and 118 for each study group (NAI titers 
will only be assessed on study groups 1,2 
and 3). 
Exploratory Immunogenicity Objectives 
Exploratory Immunogenicity Study 
Outcomes 
• To assess the HAI antibody 
responses against heterologous 
influenza A/H1 and H3 strains from 
baseline (Day 1) to approximately 
Days 180 and 365 after receipt of 
2018/2019 Fluzone or Flublok with 
and without AF03 or Advax-
CpG55.2 adjuvant.  
 
• The percentages of subjects achieving 
HAI titer seroconversion, against 
heterologous H1 and H3 influenza strains 
on approximately Days 180 and 365 for 
each study group.  
• The percentage of subjects achieving an 
HAI titer ≥1:40 against heterologous H1 
and H3 influenza strains at baseline (Day 
1) and approximately Days 180 and 365 
for each study group. 
• Serum HAI GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 180 and 
365 each study group.  
• Ratio of serum HAI GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 180 and 365.  
• Geometric mean fold rise (GMFR) in 
HAI from baseline (Day 1) against 
heterologous H1 and H3 influenza strains 

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at approximately Days 180 and 365 for 
each study group 
• To assess NAI ELLA responses 
against heterologous N1 and N2 
NA antigens from baseline (Day 1) 
to approximately Days 180 and 365 
administration of 2018/2019 
Fluzone with and without AF03 or 
Advax-CpG55.2 adjuvant. 
 
• The percentage of subjects achieving 
seroconversion against heterologous N1 
and N2 NA antigens on approximately 
Days 180 and 365 for study groups 1, 2 
and 3. 
• Serum NAI GMTs against heterologous 
N1 and N2 NA antigens at baseline and 
approximately Days 180 and 365 for 
study groups 1, 2 and 3. 
• Ratio of serum NAI GMTs against 
heterologous N1 and N2 NA antigens 
between adjuvanted and unadjuvanted 
study groups at baseline and 
approximately Days 180 and 365 for 
study groups 1,2 and 3. 
• Geometric mean fold rise (GMFR) in 
serum NAI from baseline against 
heterologous N1 and N2 NA antigens at 
baseline and approximately Days 180 
and 365 for study groups 1, 2 and 3. 
 
• To assess the influenza neutralizing 
(Neut) antibody titer responses 
against heterologous influenza 
A/H1 and H3 strains from baseline 
(Day 1) to approximately Days 180 
and 365 after administration of 
2018/2019 Fluzone and Flublok 
with and without AF03 or Advax-
CpG55.2 adjuvant.  
 
• The percentage of subjects achieving 
Neut titer seroconversion against 
heterologous H1 and H3 influenza strains 
on approximately Days 180 and 365 for 
each study group. 
• Serum Neut GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 180 and 
365 for each study group. 
• Ratio of serum Neut GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 180 and 365. 

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• Geometric mean fold rise (GMFR) of 
neut antibody titers from baseline against 
heterologous H1 and H3 influenza strains 
at baseline (Day 1) and approximately 
Days 180 and 365 for each study group. 
• To assess the longitudinal kinetics 
and durability of the HAI, NAI, and 
Neut responses against the 
2018/2019 QIV strains on 
approximately Days 180 and 365 
following receipt of the 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.   
 
• The percentage of subjects achieving 
HAI, NAI and Neut titer seroconversion 
against 2018/2019 QIV antigens and 
strains on approximately Days 180 and 
365 for each study group (NAI titers will 
only be assessed on study groups 1,2 and 
3). 
• The percentage of subjects achieving an 
HAI and Neut titer ≥1:40 against 
2018/2019 QIV strains on approximately 
Days 180 and 365 for each study group 
(NAI titers will only be assessed on study 
groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMT against 
2018/2019 QIV strains on approximately 
Days 180 and 365 for each study group 
(NAI titers will only be assessed on study 
groups 1,2 and 3). 
• Ratio of serum Neut, HAI and NAI GMT 
against 2018/2019 QIV strains between 
adjuvanted and unadjuvanted study 
groups on approximately Days 180 and 
365 (NAI titers will only be assessed on 
study groups 1,2 and 3). 
• Geometric mean fold rise (GMFR) in 
HAI, Neut and NAI titers from baseline 
(Day 1) against the 2018/2019 QIV 
strains at approximately Day 180 and 365 
for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3). 
• To assess the HAI, Neut and NAI 
ELLA responses to the 2018/2019 
at all timepoints and 2019/2020 
QIV strains prior to and 
• The percentage of subjects achieving an 
HAI titer ≥1:40 against 2018/2019 QIV 
strains at all timepoints and against 
2019/2020 QIV strains at approximately 
D90 and D118. 

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approximately 28 days after 
vaccination with the 2019/2020 
QIV in all study groups, according 
to serostatus at baseline and 
previous influenza vaccination  
• The percentages of subjects achieving 
HAI, Neut and NAI titer seroconversion, 
against 2018/2019 QIV strains at 
approximately D29 and against 
2019/2020 QIV strains at approximately 
D118.  
• Serum Neut, HAI and NAI GMTs 
against 2018/2019 QIV strains at all 
timepoints (for study groups 4, 5 and 6 
NAI titers will only be assessed at D1 
and D29) and against 2019/2020 QIV 
strains at approximately D90 and D118 
(NAI titers will only be assessed on study 
groups 1,2 and 3).  
• Serum Neut, HAI and NAI GMFRs 
against 2018/2019 QIV strains on 
approximately Days 8, 29, 57, 90, 118, 
180 and 365 (for study groups 4, 5 and 6 
NAI titers will only be assessed at D1 
and D29) and against 2019/2020 QIV 
strains at approximately D118 (NAI titers 
will only be assessed on study groups 1,2 
and 3).  
• To assess B Cell effector and 
memory responses prior to (Day 1) 
and following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• Change in the frequency of influenza 
specific-IgG, IgM and IgA B memory 
cells using multiplexed FluroSpot from 
baseline (Day 1) to approximately Days 
29 and 90 for each study group. 
• Change in frequency of influenza-
specific IgG, IgM and IgA effector B 
cells (plasmablast) using multiplexed 
Fluorospot from baseline (Day 1) to 
approximately Day 8 for each study 
group. 
• To assess plasmablast and T 
follicular helper (Tfh cell responses 
prior to (Day 1) and following 
receipt of 2018/2019 Fluzone and 
Flublok with and without AF03 or 
Advax-CpG55.2 adjuvant. 
• Change in the frequency of plasmablast 
and Tfh cells using multiparametric flow 
cytometry from baseline (Day 1) to 
approximately Day 8 for each study 
group. 
 

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• To assess the functional non-
neutralizing Fc-effector antibody 
responses prior to (Day 1) and 
following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.   
• GMT of functional non-neutralizing Fc-
effector antibodies against vaccine strain 
antigens at baseline (Day 1) and 
approximately Day 29 after vaccination 
for each study group. 
• Geometric mean fold rise (GMFR) in 
functional non-neutralizing Fc-effector 
antibody titers from baseline (Day 1) 
against the 2018/2019 QIV strains at 
approximately Day 29 for each study 
group 
• To assess responses from baseline 
(Day 1) in transcriptomic profiling 
on approximately Days 2 and 8 
following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
• Differential expression of transcription 
profiles comparing samples taken just 
prior to (Day 1) and on approximately 
Days 2 and 8 following receipt of the 
2018/2019 QIV vaccination in at least a 
subset of subjects for each study group . 
 
• To evaluate the relationship of non-
neutralizing Fc-effector antibodies 
titers with HAI and NA responses 
following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• The association of non-neutralizing Fc-
effector antibodies GMT with HAI and 
Neut antibody GMT, seroprotection and 
seroconversion rates to variant influenza 
strains and the 2018/2019 QIV vaccine 
strains. 
• To describe the non-neutralizing 
Ab responses to different influenza 
HA antigens by a multiplex ELISA 
assay at all time points in each 
study group 
• Quantification of HA binding antibodies 
against different influenza HA antigens 
at baseline (Day 1) and Days 8, 29, 57, 
90, 118, 180 and 365 in each study 
group. 
• To describe the NA binding 
antibody response to NA antigens 
corresponding to the vaccine strain 
antigens by an ELISA assay after 
administration of Fluzone with and 
• Quantification of NA binding antibodies 
against  influenza NA antigens 
corresponding to the vaccine strain 
antigens at baseline (Day 1), Day 29, 57, 
90 and D118 in Groups 1, 2, 3.  
Additional studies on Days180 and 365 

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without AF03 or Advax-CpG55.2 
adjuvant. 
in Groups 1,2,3 will be contingent on 
seeing increased seroconversion rates to 
homologous vaccine strain antigens 
 
Description of 
Study Design: 
 
This is a Phase I, randomized, double blinded, clinical trial in up to 240 males and non-
pregnant females, 18-45 years of age, inclusive, who are in good health and meet all 
eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and 
immunogenicity of either the 2018/2019 Fluzone or Flublok Quadrivalent Influenza 
Vaccines (QIV), manufactured by Sanofi Pasteur (SP) given without adjuvant or with 
one of two adjuvant formulations, AF03 (SP) or Advax-CpG55.2 (Vaxine Pty Ltd).  
Fluzone is a quadrivalent split virion inactivated vaccine whereas Flublok is a 
quadrivalent influenza vaccine that contains recombinant hemagglutinin proteins. AF03 
is a squalene-based emulsion adjuvant, whereas Advax-CpG55.2 is a combination 
adjuvant comprised of delta inulin and the oligonucleotide, CpG55.2. Enrollment will 
occur in the second and third quarters of calendar year 2019 to allow antibody titers to 
previous doses of 2018/2019 IIV to wane. 
Subjects will be stratified by prior receipt of licensed, seasonal influenza vaccine 
(defined as receipt of at least one of the 2017/2018 and/or 2018/2019 influenza 
vaccines) and will be randomly assigned to 1 of 6 treatment arms to receive a single 
dose of one of the two seasonal 2018/2019 QIV vaccine formulations with or without 
one of the two adjuvants (Day 1).  On approximately Day 90, each subject will receive a 
single dose of the seasonal 2019/2020 influenza vaccine.  Groups 1, 2 and 3 will receive 
2019/2020 Fluzone QIV and Groups 4, 5 and 6 will receive 2019/2020 Flublok QIV. 
To determine early safety signals for this Phase I study, enrollment will proceed in a 
staged fashion for the first 6 sentinel subjects. The first six subjects will be randomized 
and vaccinated with one each from Groups 1-6. These six subjects will be followed 
through Day 8. If any of the pre-specified halting rules for the sentinel subjects occur, 
the study will be halted and reviewed by the DSMB.  If no pre-specified safety signals 
are encountered enrollment will proceed. 
It is anticipated that both adjuvant formulations (AF03 and Advax-CpG55.2) will be 
available at the start of study enrollment. However, if the Advax–CpG55.2 is not 
available, the study will proceed only with groups 1, 2, 4 and 5 open for enrollment for 
the remaining subjects (up to 240, 60 per group). For the sentinel subjects, one subject 
from groups 1, 2, 4 and 5 will be enrolled and followed through Day 8.  If any of the 
pre-specified halting rules for sentinel subjects occur, the study will be halted 
and reviewed by the DSMB. If no pre-specified events occur, randomization will 
proceed in groups 1, 2, 4 and 5 for the remaining subjects. 
The DSMB will review the data when the 8-day reactogenicity and clinical safety 
laboratory data following the first study vaccination are available for 50% of study 

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subjects. Enrollment will not be paused for this review.  An additional scheduled DSMB 
review will occur when all HAI, NAI and Neut data for Day 1, and Day 29 and safety 
data through Day 57 following the first study vaccination, are available.  
Reactogenicity will be measured by the occurrence of solicited injection site and 
systemic reactions from the time of the first study vaccination through Day 8. 
Unsolicited non-serious adverse events (AEs) will be collected from Day 1 through 
approximately Day 29. Serious adverse events (SAEs), Adverse Events of Special 
Interest (AESIs) including reports of tearing, dry mouth, dry eyes and medically-
attended adverse events (MAAEs), including new-onset chronic medical conditions 
(NOCMCs) and potentially immune-mediated medical conditions (PIMMCs), will be 
collected from the time of study vaccination through approximately 12 months after the 
first study vaccination. Clinical safety laboratory evaluations (hematology and 
chemistry) will be performed at screening, immediately prior to the first study 
vaccination and at approximately Day 8. 
Only pharmacy personnel, the Emmes unblinded team and an unblinded vaccinator will 
have access to the study codes; all other study personnel will be blinded. 
Immunogenicity testing will include performing serological assays to assess 
hemagglutination inhibition (HAI), neutralizing (Neut) and neuraminidase inhibition 
(NAI) titers at multiple time points following both study vaccinations. Antibody 
responses will be determined for both influenza vaccine strains and heterologous 
influenza strains.  In addition, whole blood transcriptomics and peripheral blood 
mononuclear cells (PBMCs) will be used to determine transcriptional profiling and 
broad immunologic responses and to associate these responses with serological 
antibody responses described above in each of the treatment arms.  Immunologic 
responses will include longitudinal assessments of the kinetics, magnitude, specificity, 
and/or quality of influenza-specific memory B cells, plasmablasts, and circulating T 
follicular helper (TFH) cells and non-neutralizing antibody responses to HA and NA 
antigens 

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Table 2: Study Design 
 
 
 
 
Day 1 
 
Day 90 
Study Group 
N 
Study Vaccine 
Adjuvant 
Seasonal Vaccine 
1 
40 
Fluzone 2018/2019 QIV 
None 
Fluzone 2019/2020 QIV   
2 
40 
Fluzone 2018/2019 QIV 
AF03 
Fluzone 2019/2020 QIV   
3A 
40 
Fluzone 2018/2019 QIV 
Advax-CpG55.2 
Fluzone 2019/2020 QIV   
4 
40 
Flublok 2018/2019 QIV 
None 
Flublok 2019/2020 QIV   
5 
40 
Flublok 2018/2019 QIV 
AF03 
Flublok 2019/2020 QIV   
6A 
40 
Flublok 2018/2019 QIV 
Advax-CpG55.2 
Flublok 2019/2020 QIV   
 
Total N= 240 A 
 
 
 
Note: Cohorts will be enrolled simultaneously. Randomization at each site will be stratified by prior receipt of licensed, seasonal influenza 
vaccine (defined as receipt of at least one of the 2017/2018 and/or 2018/2019 licensed, seasonal influenza vaccines). 
A If Advax-CpG55.2 is not available, the study will proceed only with groups 1, 2, 4 and 5 open for enrollment for the remaining subjects (up to 
240, 60 per group) in groups 1, 2, 4 and 5. 

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Figure 1: Schematic of Study Design 
Planned Enrollment
 Up To n=240
Men & Non Pregnant Women, 18-45 year of age
Consent and evaluate medical status, assess eligibility, 
perform screening and laboratory evaluations
Randomize and vaccinate 6 sentinel 
subjects, one from each groups 1-6
Follow Sentinel subjects for pre-defined safety signals 
through Day 8
DSMB Review 
Day 8 Post 1st Vaccination
50% of all subjects
(Enrollment will not be paused)
Complete Enrollment
Assessment of Final Outcome Measures
Randomize and vaccinate 4 sentinel 
subjects, one from each groups 1,2,4 & 5
If both adjuvants are available 
If Advax-CpG55.2 is not available
Continue Enrollment
DSMB Review
HAI, NAI and Neut data for 
Day 1 and Day 29 and safety data through Day 57
Post 1st vaccination
 

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1 
KEY ROLES 
Lead Principal Investigator: 
 
Patricia Winokur, MD 
University of Iowa Carver College of Medicine 
Iowa City, IA 
 
DMID Clinical Project Manager: 
Kathy Ormanoski, M.S., CCRA 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Medical Monitor: 
Mohamed Elsafy, MD 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Medical Officer: 
 
Mamodikoe Makhene, MD, MPH 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Scientific Lead: 
Chris Roberts, PhD 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
Safety and Pharmacovigilance: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
(CROMS) 
Site Principal Investigators 
Emmanuel (Chip) Walter, MD 
Duke University 
 
Hana El Sahly, MD 
Baylor College of Medicine 
 
Robert Frenck, MD 
Cincinnati Children’s Medical Center 
 
Sharon Frey, MD 
Saint Louis University 
 
 

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C. Buddy Creech, MD, MPH 
Vanderbilt University Medical Center 
 
Evan J. Anderson, MD 
Emory University 
 
James D. Campbell, MD, MS 
University of Maryland School of Medicine 
Statistical and Data Coordinating 
Center: 
The Emmes Company, LLC 
 
Clinical Materials Services: 
Fisher BioServices 
 
Central (Clinical) Laboratory: 
PPD Global Central Laboratories 
 
HAI, NAI, Neut Antibody, Cellular 
Immunology, Transcriptomics and 
Additional Serological Assays 
Laboratory: 
Sanofi Pasteur 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background Information 
Influenza is a common acute viral respiratory illness.  Seasonal influenza occurs annually, and in 
the United States it causes an estimated 100,000 to 600,000 hospitalizations annually and up to 
50,000 deaths a year [1].  Use of influenza vaccines is the primary means for preventing 
influenza.  Current licensed inactivated influenza vaccines (IIVs) are good for preventing 
influenza but are less effective than desirable.  Meta-analyses examining controlled trials 
comparing seasonal IIV to no vaccine for preventing laboratory-confirmed influenza illness have 
shown remarkable variability between different seasons ranging from 16%-76% with improved, 
though still imperfect, efficacy seen when the IIV strains matched the circulating strains [2].  
Others have evaluated the effectiveness of IIV in preventing severe influenza hospitalizations 
and found a pooled efficacy of 51% in adults aged 18-64 and 37% in adults 65 years of age or 
older [3]. 
Various formulations of IIV have been approved for use in the United States.  Most vaccines 
belong to the inactivated, split virus family of vaccines that are produced from influenza viruses 
grown in embryonated chicken eggs or cell lines that then undergo chemical disruption and 
purification to produce the antigens included in the vaccine. These vaccines include not only the 
immunodominant hemagglutinin protein (HA) from influenza, but also smaller quantities of 
neuraminidase proteins (NA).  Fluzone belongs to this family of IIV.  More recently FDA has 
approved Flublok, which is also a non-replicating vaccine, but the manufacturing process and 
subsequent antigen composition of the vaccine is quite different from that seen with the split 
virus family of vaccines.  Flublok contains only recombinant HA proteins (rHA) produced in an 
insect cell line using a baculovirus vector that encodes the influenza HA gene.  The rHAs are 
purified from the cells and used to create the Flublok vaccine. 
Serum IgG antibody to the influenza virus HA, the major component of inactivated subunit and 
split virus vaccines, has a major role in protective immunity to influenza virus infection [4].  
Resistance to infection with seasonal influenza virus strains correlates directly with both serum 
hemagglutination inhibition (HAI) and neutralizing (Neut) antibody levels, and measurements of 
serum HAI and Neut antibodies are used routinely to assess the immunogenicity of both seasonal 
and pandemic IIVs.  Recent data also support an important role for neuraminidase inhibiting 
(NAI) antibodies in protection against disease [4].  In a recent human influenza challenge study, 
serum NAI antibody levels were also identified as an independent correlate of protection against 

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influenza illness [5].  Cellular immunity also can have a role in preventing influenza-associated 
illness [6].
 
Several approaches have been used to increase the immunogenicity of IIVs. Standard-adult dose 
seasonal IIVs contain 15 mcg of HA antigen per seasonal influenza vaccine strain. Clinical 
studies evaluating increased HA-containing influenza vaccines have shown dose-related 
increases in serum and mucosal antibody responses [7].  In 2009, a high-dose seasonal IIV 
containing 4 times the standard HA antigen per seasonal influenza vaccine strain was approved 
in the United States (US) for use in individuals 65 years of age and older. 
The inclusion of an adjuvant provides another mechanism to improve the immune response to 
IIV antigens.  The addition of MF59, a squalene-based, oil-in-water emulsion, to IIV has been 
shown to increase HAI titers to the homologous vaccine strains and also to induce cross-reactive 
HAI antibodies that bind drifted seasonal influenza viruses. MF59-adjuvanted seasonal IIV was 
approved for use in the elderly in Italy in 1997.  Studies have typically shown the MF59 
adjuvanted groups produce more local vaccination site tenderness and inflammation, but most 
events are mild-moderate [8].  Many studies were subsequently performed in other age groups 
and led to the approval of two MF59- adjuvanted pandemic 2009 H1N1 vaccines for use in 
children and all adults in 2009 [9].  Today 38 countries have approved the use of MF59- 
adjuvanted seasonal trivalent IIV, now called Fluad® (Fluad), and many allow use in all age 
groups.  In 2015, the U.S. FDA approved Fluad, though it restricted the use to adults ages 65 and 
older. 
More recently, studies have explored the use of adjuvants to enhance the antibody responses to 
the much less immunogenic novel avian strains of influenza virus such as A/H5N1 and A/H7N9. 
AS03 is a squalene-based, oil-in-water emulsion that includes -tocopherol. Both AS03 and 
MF59 have resulted in increased antibody responses to IIVs containing novel HAs[9].  Studies 
have shown that the inclusion of these two adjuvants can reduce the antigen dose needed to 
achieve higher HAI and neutralizing titers and the titers are substantially greater than those 
generated with unadjuvanted formulations of vaccine [10]. 
Given the fact that the MF59 and AS03 adjuvants were dose-sparing and improved the antibody 
responses generated when added to otherwise poorly immunogenic influenza vaccines, they are 
considered to be of critical importance for pandemic response planning.  As part of its pandemic 
preparedness efforts, the US Government maintains stockpiles of unique HA-containing 
influenza vaccines, including those against influenza A/H7N9 and A/H5N1 viruses as well as 
AS03 and MF59 adjuvants.   
What has become apparent is that even modest changes to adjuvant formulations can modulate 
immune responses and different adjuvants work better for certain antigens.  Immunological 

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protection for some pathogens requires cellular immune responses while others respond 
predominantly to humoral immune responses. Adjuvants in development or in use include a large 
variety of compounds including aluminum salts, oil emulsions (such as MF59 and AS03 
mentioned above), saponins, immune-stimulating complexes, liposomes, microparticles, 
nonionic block copolymers, polysaccharides, cytokines and bacterial derivatives[11-16]. Given 
the relatively modest effectiveness of influenza vaccines, these vaccines serve as an important 
target for testing new adjuvants.  Clearly, both immunogenicity as well as safety will be 
important factors as new adjuvanted influenza vaccines are reviewed for licensure. 
AF03 is a squalene emulsion-based adjuvant that utilizes an alternative manufacturing process 
that involves phase inversion temperature emulsification and incorporates two non-ionic 
surfactants [17, 18].  During the 2009 H1N1 pandemic, Sanofi Pasteur created an AF03 
adjuvanted A/H1N1 pandemic influenza vaccine (Humenza™) and performed multiple clinical 
trials to support the licensure of the vaccine in the European Union. This included trials in 
children 6 months-17 years of age, adults 18-60 years of age and adults above 60 years of age. 
There is one published study that evaluated children ages 6 months to 17 years who were 
enrolled in a trial comparing AF03- adjuvanted and non-adjuvanted pandemic H1N1 influenza 
vaccine. The youngest children, those ages 6-35 months, showed significantly improved 
antibody titers with the adjuvanted vaccine compared to the unadjuvanted vaccine and the 
adjuvanted vaccine led to better antibody persistence [18].  AF03 clinical trials have also been 
performed with A/H5N1 vaccine [19] (SP AF03 IB).  
To further assess the safety of AF03 when mixed with licensed Fluzone and FluBlok QIV, 
Sanofi conducted a recent GLP toxicology study in rabbits. The objective of the GLP toxicology 
study was to determine the systemic toxicity and the local tolerance of Fluzone and Flublok 
Quadrivalent influenza vaccines adjuvanted with AF03 in New Zealand White (NZW) rabbits 
following three 0.75 mL IM administrations at 2-week intervals (on D1, D15, and D29) in the 
dorsal lumbar muscles. 
 
Three groups of 10 males and 10 females were given either Fluzone or Flublok vaccine (at 15µg 
or 45µg of HA per influenza virus strain per dose) adjuvanted with AF03 (12.5 mg squalene per 
dose), or a saline control (NaCl 0.9%). Mortality, clinical signs and local reactions, 
ophthalmology, body weight, food consumption, clinical pathology, and immunogenicity were 
investigated. Animals were euthanized either 2 or 28 days after the third injection (on D31 or 
D57). A microscopic examination was performed on the preserved tissues from all animals as 
per the WHO guidelines document on the nonclinical evaluation of vaccine adjuvants and 
adjuvanted vaccines (2013). 
AF03-adjuvanted Fluzone and Flublok vaccines were clinically well tolerated in the rabbit with 
no unscheduled deaths, no adverse clinical signs, no ophthalmological findings, and no adverse 

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effects on body weight or food intake. Immunogenicity results demonstrated a good humoral 
response after vaccination in all treated groups. Injections of both vaccines showed reversible 
minimal to moderate inflammatory changes at the injection sites associated with related 
lymphoid hyperplasia in lymph nodes and spleen, as well as increase in white blood cell counts 
and treatment-related increase in C reactive protein, fibrinogen and globulin levels. All changes 
showed either complete or partial recovery by the end of the 4-week observation period and were 
considered as related to the pharmacology activity of the adjuvanted vaccines, but non-adverse. 
Advax™ is yet another adjuvant that has been tested as a component to inactivated seasonal and 
pandemic influenza vaccines including 2009 H1N1 and H5N1 vaccine antigens.  Advax is a 
polysaccharide adjuvant that contains particles of semi-crystalline delta inulin, a plant based 
carbohydrate [13].  In the mid-1980s the studies demonstrated that semi-crystalline particles of 
inulin activated complement through the non-classical pathway and could act as a vaccine 
adjuvant [20].  Advax,  a more temperature stable delta inulin isoform created by Vaxine Pty Ltd 
has been found to have improved adjuvant potency in animal models and humans when 
combined with a number of vaccines including Japanese encephalitis, West Nile virus, HIV, 
influenza , RSV, SARS coronavirus, tuberculosis, Listeria, anthrax, chlamydia and hepatitis B 
[13],[21-34]. This adjuvant enhances both humoral and cellular immunity to co-administered 
antigens and induces a potent antigen-specific CD4+ and CD8+ memory T cell response as well 
as enhanced production of antigen specific IgM, IgG and IgA [35].  Advax adjuvant has been 
shown to enhance vaccine immunogenicity and protection through stimulation of both cellular 
and humoral immune pathways when combined with inactivated influenza virus (in mice, rats 
and sheep), inactivated avian H5N1 influenza (in mice and ferrets) and recombinant HA antigen 
from H1, H5 and H7 strains of influenza virus (in mice, rabbits, and humans) [36-42]. 
Over 10 human trials have been conducted with Advax, including several that evaluated Advax 
adjuvanted IIV for seasonal influenza and 2009 pandemic H1N1, in Australia and Europe 
involving over 2000 subjects.  The first in man Advax-adjuvanted seasonal trivalent IIV (IIV3) 
vaccine study showed that the adjuvant given with 1/10th the dose of the standard IIV vaccine 
generated equivalent seroprotection rates and GMTs compared to the full standard dose of 
unadjuvanted IIV3 vaccine [37].  There were no significant differences seen in solicited, 
unsolicited or serious adverse events, though there was a trend toward reduced incidence of fever 
and arthralgias in the reduced IIV3 dose Advax-adjuvanted arm as compared to the full dose 
standard IIV3.  A rHA vaccine from the pandemic 2009 H1N1 influenza strain adjuvanted with 
Advax also showed significantly improved HAI and Neutralising antibody titers, seroconversion 
and seroprotection rates when compared to unadjuvanted vaccine, with no increase in systemic 
adverse events when compared to the unadjuvanted vaccine, and an unexpected but significant 
reduction in post-immunization headaches in the week following immunization in the Advax-
adjuvanted arms [36]. 

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Unmethylated CpG oligonucleotides have been found to serve as Toll-like Receptor (TLR) 9 
agonists that enhance antigen-specific immune responses and induce pro-inflammatory cytokines 
particularly IL-12, which can enhance downstream production of Th1 cytokines that promote 
survival and proliferation of Th1 cells and can activate TFH, which enhance B cell 
immunoglobulin production.  Thus, CpG enhances both cellular and humoral immune responses. 
A range of CpG oligonucleotides have been evaluated as adjuvants either alone or in 
combination with alum adjuvants, in human trials of vaccines against infectious disease 
(hepatitis B, influenza, anthrax, malaria, and HIV), cancer and allergy.  
Studies have been performed to determine whether the addition of CpG to Advax can improve 
immune responses to various vaccine antigens.  In a mouse study evaluating a candidate 
Mycobacterium tuberculosis vaccine, the addition of CpG246.1 to Advax enhanced the 
generation of chemoattractants and resulted in a rapid influx of monocytes and neutrophils to the 
site of vaccination with significant early priming of vaccine antigen specific CD4+ T cells [33].  
A ferret study evaluated Advax-CpG246.1 and Advax-alone adjuvanted H5N1 vaccine.  Advax-
CpG246.1 adjuvant enhanced HAI titers and protection from influenza virus challenge over and 
above Advax adjuvant alone when combined with influenza H5N1 vaccine [42].  Phase I trials 
have been conducted to evaluate Panblok-H5® vaccine alone or in combination with Advax-
CpG246.1 adjuvant.  An interim analysis was performed on subjects who completed both 
immunizations and had blood samples drawn at 4 weeks.  The highest levels of H5 HAI titers 
were in the Advax-CpG246.1 group; these were statistically improved over unadjuvanted 
vaccine (see Advax-CpG IB).  A similar Phase 1 trial was conducted evaluating Panblok-H7® 
alone or with Advax or Advax-CpG246.1 adjuvant.  The preliminary data indicates that the 
immune responses are similar to those seen in the H5 rHA vaccine trial, with the highest HAI 
titers against H7 in the Advax-CpG246.1 adjuvanted arm, versus very low or undetectable HAI 
titers in the Panblok-H7® alone arm and intermediate results in the Advax arm (see Advax-CpG 
IB).  The version of CpG oligonucleotide that Vaxine used in Advax-CpG clinical trials to date is 
a 24-mer class B CpG oligonucleotide with a phosphorothioate backbone called CpG246.1. 
Vaxine has subsequently further optimized the CpG nucleotide sequence to maximize its activity 
for both human and mouse TLR9, resulting in the oligonucleotide CpG55.2. CpG55.2 is also a 
24-mer class B CpG oligonucleotide with a phosphorothioate backbone, however, the sequence 
order of the nucleotides is different between CpG55.2 and CpG246.1. 
To further assess safety of the Advax-CpG55.2 combination adjuvant when mixed with licensed 
Fluzone and FluBlok QIV, Sanofi conducted a recent GLP toxicology study in rabbits. The 
objective of the GLP toxicology study was to determine the systemic toxicity and local tolerance 
of Fluzone and Flublok Quadrivalent influenza vaccines adjuvanted with Advax-CpG55.2 in 
NZW rabbits following three 1 mL IM administrations at 2-week intervals (on D1, D15, and 
D29) in the dorsal lumbar muscles. 

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Four groups of 10 males and 10 females were given either Fluzone or Flublok vaccine (at 15 µg 
or 45 µg of HA per influenza virus strain per dose) adjuvanted with Advax-CpG55.2 (20 and 0.2 
mg per dose, respectively), Advax-CpG55.2 alone at the same dose level or a saline control 
(NaCl 0.9%). Mortality, clinical signs and local reactions, ophthalmology, body weight, food 
consumption, clinical pathology, and immunogenicity were investigated. Animals were 
euthanized either 2 or 28 days after the third injection (on D31 or D57). A microscopic 
examination was performed on the preserved tissues from all animals as per WHO guidelines 
(2013). 
Advax-CpG55.2-adjuvanted Fluzone and Flublok vaccines were clinically well tolerated in the 
rabbit with no unscheduled deaths, no adverse clinical signs, ophthalmological findings, and no 
effects on body weight or food intake. Immunogenicity results demonstrated a good humoral 
response after vaccination in all vaccinated groups. Injections of both vaccines showed reversible 
inflammatory changes at the injection sites associated with related lymphoid hyperplasia in 
lymph nodes and spleen, as well as increase in C-Reactive Protein and fibrinogen levels. All 
changes showed either complete or partial recovery by the end of the 4-week observation period 
and were considered as related to the pharmacology activity of the adjuvanted vaccines, but non-
adverse. 
The proposed trial will be the first time that an Advax-CpG formulation incorporating CpG55.2 
in place of CpG246.1 will be tested in humans. 
 
Scientific Rationale 
Seasonal influenza vaccines have variable efficacy.  Efficacy can be reduced when the vaccine 
strains have mismatched antigenic profiles as compared to the circulating strains of influenza 
virus. Additionally, populations can have variable efficacy based on the immunological sequence 
of prior exposure to influenza infections or vaccines.  Adjuvants provide a promising strategy to 
enhance the humoral immune responses to influenza proteins and may enhance the cellular 
memory responses, as well.  Two new adjuvants are being evaluated that show promise in animal 
studies (Advax-CpG55.2 and AF03) and early human trials (AF03).  These two products have 
been tested predominantly as adjuvants for novel avian influenza strains that show poor 
immunogenicity.  However, there is great need to improve vaccine efficacy that can overcome 
the problems of antigenic drift, immunosenescence and prior immunological priming.   
The goal of this clinical trial is to assess in healthy adults, 18-45 years of age, the safety, 
reactogenicity and immunogenicity of one dose of 2018/2019 Quadrivalent Influenza Vaccine 
(either Fluzone or Flublok) administered intramuscularly (IM) with or without one of two 
adjuvants (AF03 or Advax-CpG55.2).  The study will evaluate the traditional HAI and Neut 

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responses among groups, but also will explore additional immunological parameters.  Since 
antibodies targeting the NA may represent an independent correlate of protection against 
influenza infection [43] [5], we plan to assess the NAI responses in each group.  The longitudinal 
kinetics and durability of HAI, Neut, and NAI responses will be evaluated for one year following 
vaccination.   
This clinical trial will also assess cellular correlates of immunity to influenza including memory 
B cell populations, plasmablasts, TFH cells, functional non-neutralizing Fc-effector antibodies, as 
well as determine the transcriptional profiling responses following vaccination. 
 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
The potential risks of participating in this trial are those associated with having blood drawn, the 
IM injection, possible reactions to the Fluzone or Flublok QIV, with or without AF03 or Advax- 
CpG55.2 adjuvant, and breach of confidentiality. 
Drawing blood may cause transient discomfort and fainting and lead to or exacerbate iron 
deficiency in those who are not anemic. Fainting is usually transient and managed by having the 
subject lie down and elevating his/her legs. Bruising at the blood draw site may occur but can be 
prevented or lessened by applying pressure to the blood draw site for a few minutes after the 
blood is taken. IM injection may also cause transient discomfort and fainting. Drawing blood and 
IM injection may cause infection. The use of aseptic (sterile) technique will make infection at the 
site where blood will be drawn or where the study vaccination will be given extremely unlikely.  
There is a small amount of risk to subjects who report that they are in good health but who have 
an unknown health problem at the time of screening. This trial will screen by physical exam, 
history, vital signs and erythrocyte sedimentation rate (ESR) and clinical safety labs for white 
blood cells (WBC), hemoglobin (Hgb), platelets (PLT), alanine aminotransferase (ALT), total 
bilirubin (T. Bili), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), 
alkaline phosphatase (ALP) serum lipase and serum amylase and creatinine (Cr).  Only subjects 
with a stable health history, physical exam and laboratories that fall within acceptable range (see 
Section 5.1.1) will proceed to vaccination.  
Fluzone and Flublok Vaccines 
The 2018/2019 and 2019/2020 QIV products used in this study are approved by the FDA for 
active immunization against disease caused by influenza viruses contained in the vaccine.  

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Occasionally, adult recipients of unadjuvanted licensed, inactivated influenza vaccines (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, ecchymosis, erythema, induration, edema, pain, and/or tenderness. Most of 
these reactions peak in intensity in the first 24 hours after vaccination and disappear without 
treatment within 1 or 2 days. Analgesics (e.g., acetaminophen, ibuprofen or similar non-steroidal 
anti-inflammatory drugs (NSAIDs) and rest may generally relieve or lessen these reactions. 
Bruising can sometimes occur due to the vaccination procedure.  
 
During the clinical development of Flublok, which is a recombinant influenza vaccine (RIV), 
both local and systemic reactogenicity symptoms were generally similar in frequency and 
severity to those observed with the active control vaccines (trivalent or quadrivalent influenza 
vaccines, TIV or QIV) in adults. The only SAEs that were considered related or possibly related 
to Flublok in any of the trials were one case of vasovagal syncope (quadrivalent RIV, within 20 
minutes post-vaccination, attributed to the injection process rather than the vaccine material) and 
one case of non-infectious pericardial effusion (trivalent RIV, 11 days post-vaccination). 
Serious immediate reactions, such as hypersensitivity, or delayed reactions, such as Guillain-
Barré syndrome, have not been observed in the clinical trials with any formulations of rHA 
vaccines. 
In addition, post-marketing surveillance of the seasonal IIVs indicates autoimmune and other 
disorders as potential risks; these may also include, but are not limited to, neuritis, convulsions, 
severe allergic reactions, syncope, encephalitis, thrombocytopenia, vasculitis, and Guillain-Barré 
syndrome (GBS). Reports of these reactions were rare; however, exact incidence rates cannot be 
precisely calculated. 
Acute and potentially life-threatening allergic reactions (i.e., anaphylaxis) are also possible. 
These reactions occur in about 1 in 4 million people given a vaccination. These reactions can 
manifest as 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 (A/H1N1) vaccine campaign of 1976, some recipients developed a 
paralytic illness called GBS. GBS is an acute inflammatory neuropathy characterized by 
weakness, hyporeflexia or areflexia, and elevated protein concentrations in cerebrospinal fluid. 
The rate of GBS was significantly increased in individuals receiving the 1976 swine influenza 
(A/H1N1) vaccine at about 1 per 100,000 vaccine recipients. This syndrome has not been seen 
consistently with other influenza vaccines. Most persons who develop GBS recover completely, 

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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 [44]. Interestingly, although 
vaccination rates have increased in the last 10 years, the numbers of reported cases of vaccine-
associated GBS have declined [45].  A recent study in Canada showed that the 2009 A/H1N1 
vaccine was associated with a small but significant risk of GBS in persons 50 years of age and 
older [46].  An active, population-based surveillance study conducted in the US during the 2009-
2010 influenza season found less than 1 excess GBS case per million doses of 2009 A/H1N1 
vaccine administered – a rate similar to that associated with some previously administered 
annual influenza vaccines [47-49].   Another study using the Medicare system showed an 
elevated risk of GBS with monovalent 2009 A/H1N1 vaccination (incidence rate ratio = 2.41, 
95% confidence interval (CI): 1.14, 5.11; attributable risk = 2.84 per million doses administered, 
95% CI: 0.21, 5.48) [50].  An international collaboration study also supported a conclusion of an 
association between 2009 A/H1N1 vaccination and GBS [51].    
AF03 
Over 1500 people have been evaluated in clinical trials conducted in the European Union and the 
US evaluating inactivated, monovalent H5N1 or H1N1 influenza vaccine adjuvanted with AF03. 
(SP AF03 IB) 
In Phase I and Phase II clinical trials in adults, the most frequently observed local reactions were 
pain, induration and erythema and the most frequently reported solicited systemic reactions in all 
groups and for each injection were headache and myalgia. Most local and systemic reactions 
generally appeared on the day following vaccination and disappeared within 3 days without 
medication use. The addition of AF03 has been associated with a higher incidence of local 
reactions, mainly characterized by injection site pain and induration, compared to non-
adjuvanted vaccine. The addition of AF03 was associated with an increased incidence of 
systemic reactions when compared to unadjuvanted vaccine in adults. 
Some systemic adverse events have been rarely observed concomitantly with the administration 
of vaccines from other manufacturers containing oil-in-water adjuvants similar to AF03. These 
systemic adverse events include autoimmune diseases and demyelinating neurological disorders. 
No causal relationship has been established between these observations and oil-in-water 
adjuvants. To date, these events have not been observed with AF03 adjuvanted vaccines.  
 
Animal toxicology studies following administration of high doses of AF03 and AF04 have 
shown increased single cell apoptosis or necrosis in acinar tissues including the lacrimal gland 

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and the exocrine pancreas in the rabbit model and the parotid glands in rats. These findings were 
observed only at high doses, of low severity and reversible, they were therefore not considered 
clinically significant.  
 
Advax-CpG55.2  
The clinical experience with combination adjuvants combining Advax and TLR9 agonist 
oligonucleotides such as CpG remains limited.  However, approximately 400 exposures in 
approximately 160 adult humans to an earlier generation combined formulation of Advax with 
CpG246.1, a class B CpG oligonucleotide similar to CpG55.2, have been evaluated in Phase I 
trials with various investigational vaccines. When formulated with influenza vaccines Advax-
CpG246.1 induced similar types of local and systemic reactions to those seen in subjects 
receiving unadjuvanted IIV’s which mimicked influenza-like reactions, with symptoms such as 
feverishness, fatigue, malaise, myalgia, arthralgia, headache, and/or nausea. An increase in local 
injection site reactions, including pruritus, ecchymosis, erythema, induration, edema, pain, 
and/or tenderness is typically seen when using vaccine adjuvants, and was similarly observed in 
trials of Advax-CpG246.1 adjuvanted vaccines, but these local reactions were predominantly 
mild in severity and were self-limiting. Most of these reactions peaked in intensity in the first 24 
hours after vaccination and resolved without treatment within 1 or 2 days. The most common 
solicited systemic adverse reaction in the first seven days post-immunization was headache, 
which affected 20-35% of participants. The next most common solicited systemic adverse 
reactions in the first seven days post- immunization were muscle ache (~20%), fatigue (~10%) 
and shivering and chills (~5%). The frequency of unsolicited adverse events was not 
significantly different between the Advax-CpG, Advax and non-adjuvanted groups. Analgesics 
(e.g., acetaminophen, ibuprofen or similar NSAIDs) and rest generally relieved or lessened these 
reactions 
 
Risks of Genetic Testing 
Genetic data and health information will be stored and shared with other researchers through a 
controlled-access repository, such as dbGaP. There may be a risk that information resulting from 
research genetic testing could be misused for discriminatory purposes. However, state and 
federal laws provide protections against genetic discrimination. Researchers will need to 
maintain confidentiality in order to be granted access to genetic information.   
2.3.2 
Known Potential Benefits 
The unadjuvanted seasonal QIVs are known to stimulate HAI antibody titers that can reduce the 
likelihood of influenza virus infection and/or reduce the likelihood of severe influenza illness.  

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The inclusion of an adjuvant, either AF03 or Advax-CpG55.2, could improve the titers of 
protective antibodies.  However, the timing of the start of this study is designed to coincide with 
a time when influenza virus is unlikely to be circulating so it is not clear that an individual would 
receive any benefit to receiving 2018/2019 QIV. All participants will receive a dose of 
2019/2020 QIV which may provide protection from influenza for the 2019/2020 influenza 
season. There may also   be benefits to society through the improvement of our understanding of 
these two new adjuvants and how they affect the immune response to seasonal influenza vaccine. 

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3 
STUDY OBJECTIVES AND OUTCOME MEASURES 
Refer to Table 1: Study Objectives and Outcome Measures 

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4 
STUDY DESIGN 
This is a Phase I, randomized, double blinded, clinical trial in up to 240 males and non-pregnant 
females, 18-45 years of age, inclusive, who are in good health and meet all eligibility criteria. 
This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of either 
the 2018/2019 seasonal Fluzone or Flublok QIV manufactured by Sanofi Pasteur (SP) given 
without adjuvant or with one of two adjuvant formulations, AF03 (SP) or Advax-CpG55.2 
(Vaxine Pty Ltd as manufactured by Sypharma and Nikko Denka Avecia). Fluzone is a 
quadrivalent split virion inactivated vaccine, whereas Flublok is a quadrivalent influenza vaccine 
that contains recombinant hemagglutinin proteins.  AF03 is a squalene-based emulsion adjuvant, 
whereas Advax-CpG55.2 is a combination adjuvant comprised of Advax (delta inulin) and the 
oligonucleotide, CpG55.2.  Enrollment will occur in the second and third quarters of calendar 
year 2019 to allow antibody titers to previous doses of 2018/2019 IIV to wane.   
Subjects will be stratified by prior receipt of licensed, seasonal influenza vaccine (defined as 
receipt of at least one of the 2017/2018 and/or 2018/2019 influenza vaccines) and will be 
randomly assigned to 1 of 6 treatment arms to receive a single dose of one of the two seasonal 
2018/2019 QIV vaccine formulations with or without one of the two adjuvants (Day 1). On 
approximately Day 90, each subject will receive a single dose of the seasonal 2019/2020 QIV.  
Groups 1, 2 and 3 will receive 2019/2020 Fluzone QIV and Groups 4, 5 and 6 will receive 
2019/2020 Flublok QIV.  
To determine early safety signals for this Phase I study, enrollment will proceed in a staged 
fashion for the first 6 sentinel subjects. The first six subjects will be randomized and vaccinated 
with one each from Groups 1-6.  These six subjects will be followed through Day 8. If any of the 
pre-specified halting rules occur, the study will be halted and reviewed by the DSMB.  If no pre-
specified safety signals are encountered enrollment will proceed. 
It is anticipated that both adjuvant formulations (AF03 and Advax-CpG55.2) will be available at 
the start of study enrollment.  However, if the Advax-CpG55.2 is not available, the study will 
proceed only with groups 1, 2, 4 and 5 open for enrollment for the remaining subjects (up to 240, 
60 per group). For the sentinel subjects, one subject from groups 1, 2, 4 and 5 will be enrolled 
and followed through Day 8. If any of the pre-specified halting rules occur, the study will be 
halted and reviewed by the DSMB.  If no pre-specified events occur, randomization will proceed 
in groups 1, 2, 4 and 5 for the remaining subjects. 
The DSMB will review the data when the 8-day reactogenicity and clinical safety laboratory data 
following the first study vaccination is available for 50% of study subjects.  Enrollment will not 
be paused for this review. An additional scheduled DSMB review will occur when all HAI, NAI 
and Neut data for Day 1, and Day 29 and safety data through Day 57 following the first study 
vaccination, are available. 

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Reactogenicity will be measured by the occurrence of solicited injection site and systemic 
reactions from the time of the first study vaccination through Day 8. Unsolicited non-serious 
adverse events (AEs) will be collected from Day 1 through approximately Day 29. Serious 
adverse events (SAEs), AESIs including reports of tearing, dry mouth, dry eyes and MAAEs, 
including NOCMCs and PIMMCs, will be collected through approximately 12 months after the 
first study vaccination. Clinical safety laboratory evaluations (hematology and chemistry) will be 
performed at screening, immediately prior to the first study vaccination and approximately Day 
8. 
Only pharmacy personnel, the Emmes unblinded team and an unblinded vaccinator will have 
access to the study codes all other study personnel will be blinded.  Immunogenicity testing will 
include performing serological assays to assess hemagglutination inhibition (HAI), neutralizing 
(Neut) and neuraminidase inhibition (NAI) titers at multiple time points following study 
vaccination. Antibody responses will be determined for both influenza vaccine strains and 
heterologous influenza strains.  In addition, whole blood transcriptomics and peripheral blood 
mononuclear cells (PBMCs) will be used to determine transcriptional profiling and broad 
immunologic responses and to associate these responses with serological antibody responses 
described above in each of the treatment arms. Immunologic responses will include longitudinal 
assessments of the kinetics, magnitude, specificity, and/or quality of influenza-specific memory 
B cells, plasmablasts, and circulating T follicular helper (TFH) cells. 
For additional details on study procedures and evaluations and study schedule by study 
visits/days, see Sections 7 and 8 as well as Appendix A: Schedule of Study Procedures and 
Evaluations and Appendix B: Adverse Events of Special Interest. 
 
 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Up to 240 males and non-pregnant females, 18 to 45 years of age, inclusive, who are in good 
health and meet all eligibility criteria will be enrolled at up to 8 VTEU sites (and their 
subcontractors) participating in this trial. The target population should reflect the community at 
large at each of the participating VTEU sites. Estimated time to complete enrollment in this trial 
is approximately 9 weeks. Information regarding this trial may be provided to potential subjects 
who have previously participated in vaccine trials conducted at each of the participating VTEU 
sites. Other forms and/or mechanisms of recruitment may also be used. The IRB will approve the 
recruitment process and 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 
5.1.1 
Subject Inclusion Criteria 
Subjects eligible to participate in this trial must meet all of the following inclusion criteria: 
1. Provide written informed consent prior to initiation of any study procedures. 
2. Are able to understand and comply with planned study procedures and be available for all 
study visits. 
3. Must agree to the collection of venous blood per protocol. 
4. Are males or non-pregnant females, 18 to 45 years of age, inclusive at time of enrollment. 
5. Are in good health1. 
1As determined by medical history and physical examination to evaluate acute or currently ongoing chronic medical or 
psychiatric diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the 
assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or 
conditions should be stable for the last 60 days (no hospitalizations, emergency room or urgent care for condition, or 
invasive medical procedure and no adverse symptoms that need medical intervention such as medication 
change/supplemental oxygen). This includes no change in chronic prescription medication, dose or 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 

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inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site PI or 
appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and 
immunogenicity and do not indicate a worsening or treatment of continued symptoms of medical diagnosis or 
condition. Note: Low dose topical, corticosteroids as outlined in the Subject Exclusion Criteria (see Section 5.1.2) as 
well as herbals, vitamins and supplements are permitted. 
6. Oral temperature is less than 100.0°F. 
7. Pulse is 47 to 100 beats per minute, inclusive. 
8. Systolic blood pressure is 85 to 140 mmHg, inclusive. 
9. Diastolic blood pressure is 55 to 90 mmHg, inclusive. 
10. Screening laboratories (ESR, WBC, Hgb, PLTs, ALT, T. Bili, AST, GGT, ALP serum lipase, 
serum amylase and Cr) are within acceptable parameters %  
% ESR must be below 30 mm/hr; WBC >3.90 K/MM3 and <10.60 K/MM3; Hgb ≥11.5 g/dl (women) or ≥12.5 g/dl 
(men); PLTs (EDTA) 140-415 K/MM3;PLTs (Citrate) 125-325 K/MM3 ALT ≤43U/L (women) or ≤60 U/L (men); T Bili 
≤1.20 mg/dl; Cr <1.1mg/dl (women) or < 1.4 mg/dl (men); AST 10-36 U/L (women) or 10-43 U/L (men); GGT 5--32 
U/L (women) or 10-49 U/L (men); ALP 30-115 U/L (women) or 43-115 U/L (men); lipase 13-60 U/L; amylase (Total) 
35-121 U/L, for subjects to qualify for randomization and vaccination. 
11. Women of childbearing potential2 must use an acceptable contraception method3 from at 
least 30 days before the first study vaccination until 60 days after the second study 
vaccination. 
2Not sterilized via bilateral oophorectomy, tubal ligation/salpingectomy, hysterectomy, or successful Essure® 
placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at 
least 90 days after the procedure, and still menstruating or <1 year has passed since the last menses if menopausal. 
3Includes non-male sexual relationships, full abstinence from sexual intercourse with a male partner, monogamous 
relationship with vasectomized partner who has been vasectomized for 180 days or more and shown to be azoospermic 
prior to the subject receiving the study vaccination, barrier methods such as condoms or diaphragms/cervical cap with 
spermicide, effective intrauterine devices, NuvaRing®, , and licensed hormonal methods such as implants, injectables 
or oral contraceptives (“the pill”). 
12. Women of childbearing potential must have a negative urine or serum pregnancy test 
within 24 hours prior to the first study vaccination. 
13. For a woman with potential to become pregnant, she understands that in the event of 
pregnancy during the study she will be approached to enroll in the Sanofi Pregnancy 
Registry. 
14. Must agree to have residual specimens (i.e. residual/excess of per protocol specifications) 
(see Section 14.8). 

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5.1.2 
Subject Exclusion Criteria 
Subjects eligible to participate in this trial must not meet any of the following exclusion criteria: 
1. Have an acute illness4, as determined by the site PI or appropriate sub-investigator, 
within 72 hours prior to study vaccination. 
4An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion 
of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety 
parameters as required by the protocol. 
2. Have any medical disease or condition that, in the opinion of the site PI or appropriate 
sub-investigator, is a contraindication to study participation5. 
5Including acute, subacute, intermittent or chronic medical disease or condition 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 or recently active (12 months) neoplastic disease or a history of any 
hematologic malignancy. Non-melanoma, treated, skin cancers are permitted. 
6. Have known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. 
7. Have known hypersensitivity or allergy to eggs, egg or chicken protein, squalene-based 
adjuvants, or other components of the study vaccine. 
8. Have a history of severe reactions following previous immunization with licensed or 
unlicensed influenza vaccines. 
9. Have a history of GBS. 
10. Have a history of convulsions or encephalomyelitis within 90 days prior to study 
vaccination. 
11. Have a history of PIMMCs6. 

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6Refer to Appendix B: Adverse Events of Special Interest  
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 interfere7 with subject compliance or safety evaluations. 
7As determined by the site PI or appropriate sub-investigator. 
14. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement 
for danger to self or others within 5 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 corticosteroids8 within 30 days prior to study vaccination. 
8High-dose defined as per age as using inhaled high-dose per reference chart in the National Heart, Lung and Blood 
Institute Guidelines for the Diagnosis and Management of Asthma (EPR-3) or other lists published in UPTODATE. 
17. Received or plan to receive a licensed, live vaccine (excluding all licensed, seasonal LAIVs) 
within 30 days before or after the study vaccination. 
18. Received or plan to receive a licensed, inactivated vaccine (excluding all licensed, 
seasonal IIVs) within 14 days before or after each study vaccination. 
19. Have received any 2018/2019 seasonal influenza vaccine within the 6 months prior to 
enrollment.   
20. Plans to receive any 2019/2020 seasonal influenza vaccine within approximately 90 days 
of receipt of the first study vaccination. 
21. Have a known history of documented influenza infection within the past 6 months. 
22. Received immunoglobulin or other blood products (except Rho D immunoglobulin) 
within 90 days prior to study vaccination. 
23. Received an experimental agent9 within 30 days prior to the study vaccination or expect 
to receive another experimental agent10 during the trial-reporting period11. 
9Including vaccine, drug, biologic, device, blood product, or medication. 
10Other than from participation in this trial. 

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11Approximately 12 months after the first study vaccination. 
24. Are participating or plan to participate in another clinical trial with an interventional 
agent12 that will be received during the trial-reporting period13. 
12Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication. 
13Approximately 12 months after the first study vaccination. 
25. Female subjects who are breastfeeding or plan to breastfeed from the time of the first 
study vaccination through 30 days after the last study vaccination. 
26. Plan to travel outside the US (continental US, Hawaii and Alaska) from the time of study 
vaccination through approximately 90 days after the first study vaccination. 
27. Planning to donate blood within 4 months following first vaccination.   
5.1.3 
Exclusion Criteria for Second Study Vaccination 
All study participants will be expected to receive the second study vaccination   except under the 
circumstances listed below. The second study vaccination will not be administered to a subject if 
any of the following criteria are met: 
• Meets the contraindication on the package insert to receipt of licensed influenza vaccine. 
• As deemed necessary by the site principal investigator or appropriate sub-investigator for 
noncompliance or other reasons. 
• Subject refusal of further study vaccination. 
• Withdrawal of consent. 
• Subject is lost to follow-up. 
• Termination of this trial. 
• New information becomes available that makes further participation unsafe. 

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Treatment Assignment Procedures 
5.2.1 
Enrollment and Randomization Procedures 
Per ICH E6 GCP, screening records will be kept at each participating VTEU site to document the 
reason why an individual was screened, but failed trial entry criteria. The reasons why 
individuals failed screening will be recorded in the Statistical and Data Coordinating Center’s 
(SDCC) Advantage eClinicalSM (Electronic Data Capture System). 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled in the electronic data capture system.  If all study adjuvants are 
available at the time of study start, the subject will be enrolled and randomly assigned with equal 
allocation (1:1:1:1:1:1) to 1 of 6 treatment arms, stratified by the participating VTEU site and 
prior receipt of licensed, seasonal influenza vaccine (defined as receipt of at least one of the 
2017/2018 and/or 2018/2019 licensed, seasonal influenza vaccines).  All subjects will receive a 
licensed 2019/2020 QIV on approximately Day 90.  
If the Advax-CpG55.2 components are not available groups 1, 2, 4, and 5 will be enrolled, and 
subjects (up to 240) will be randomized with equal allocation (1:1:1:1) to these 4 arms, stratified 
by the participating VTEU site and prior receipt of licensed, seasonal influenza vaccine (defined 
as receipt of at least one of the 2017/2018 and/or 2018/2019 licensed, seasonal influenza 
vaccines).  Enrollment of subjects will be done online using the enrollment module of Advantage 
eClinicalSM. The randomization code will be prepared by statisticians at the SDCC and included 
in the enrollment module for this trial. Advantage eClinicalSM 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 Advantage eClinicalSM 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. 
5.2.2 
Masking Procedures 
This is a double-blinded clinical trial. 
Subjects, site investigators and study personnel performing any study-related assessments 
following study vaccine administration to the subject are blinded to vaccination and adjuvant 

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received. Laboratory personnel performing immunological assays will receive serum and cell 
specimens blinded to subject ID number and specimen visit number and allocation group. 
Unblinding by allocation group may occur after data lock. 
The randomization scheme will be generated by the SDCC and provided to unblinded study 
personnel (i.e., research pharmacists performing study vaccination preparations and unblinded 
study vaccine administrators) at the participating VTEU sites. 
The unblinded study vaccine administrator is a study personnel member credentialed to 
administer vaccines and may also participate in dose preparation but will not be involved in 
study-related assessments or have subject contact for data collection following study vaccine 
administration to the subject. 
The Data and Safety Monitoring Board (DSMB) may receive data in aggregate and presented by 
treatment arm. The DSMB may also be provided with expected and observed rates of the 
expected AEs in an unblinded fashion and may request the treatment assignment be unblinded 
for an individual subject if required for safety assessment. The DSMB will review grouped and 
unblinded data in the closed session only. 
5.2.3 
Reasons for Withdrawals and Discontinuation of Study Product Administration 
Subjects may voluntarily withdraw their consent for trial participation at any time and for any 
reason, without penalty or loss of benefits to which they are otherwise entitled. 
The site PI or appropriate sub-investigator may also withdraw a subject from receiving the study 
vaccine for any reason. 
A subject may withdraw or be withdrawn from this trial for any of the following reasons: 
• Medical disease or condition, or any new clinical finding for which continued 
participation, in the opinion of the site PI or appropriate sub-investigator, would 
compromise the safety of the subject, or would interfere with the subject’s successful 
completion of this trial, or would interfere with the evaluation of responses (for example, 
has baseline significant laboratory abnormalities). 
• Subject withdrawal of consent. 
• Subject lost to follow-up. 
• Termination of this trial. 

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• As deemed necessary by the site PI or appropriate sub-investigator for noncompliance or 
other reasons. 
• New information becomes available that makes further participation unsafe. 
 
5.2.4 
Handling of Withdrawals and Discontinuation of Study Product Administration 
The primary reason for withdrawal from this trial will be recorded on the Study Status data 
collection form (DCF). Subjects will be encouraged to complete the Early Termination Visit. 
The Early Termination Visit procedures are listed in Section 8.4. 
Every attempt will be made to follow all AEs, including solicited injection site and systemic 
reactions, unsolicited non-serious AEs, SAEs, AESIs (including Protocol Specified AESIs, 
MAAEs, NOCMCs and PIMMCs) ongoing at the time of early withdrawal through resolution as 
per applicable collection times defined for the specific type of AE. 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort (i.e., 
three documented contact attempts via phone calls made on separate occasions and followed by a 
certified letter) will be made to locate or recall them, or at least to determine their health status. 
These efforts will be documented in the subject’s study records. 
The site PI or appropriate sub-investigator will inform the subject that already collected data will 
be retained and analyzed even if the subject withdraws or is withdrawn from this study. 
5.2.5 
Subject Replacement 
Subjects who withdraw, or are withdrawn or terminated from this trial, or are lost to follow-up 
after signing the informed consent form (ICF), randomization and receipt of study vaccine will 
not be replaced. However, if a subject withdraws after signing the ICF, but before randomization 
and/or receipt of study vaccine, they may be replaced. 
5.2.6 
Termination of Study 
Although the sponsor has every intention of completing this trial, it reserves the right to 
terminate this trial at any time for clinical or administrative reasons. Reasons for termination 
include, but are not limited to, study closure due to DSMB review and recommendation, and at 
the discretion of DMID. 

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If this trial is prematurely terminated by the sponsor, any regulatory authority, the site PI, or 
appropriate sub-investigator for any reason, the site PI or appropriate sub-investigator will 
promptly inform the subjects and assure appropriate therapy or follow-up for the subjects, as 
necessary. The site PI or appropriate sub-investigator will provide a detailed written explanation 
of the termination to the IRB. 
 

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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
 
Study Product Description 
2018/2019 and 2019/2020 Fluzone Quadrivalent Influenza Vaccine (QIV) 
The Sanofi Pasteur manufactured Fluzone Quadrivalent is an FDA approved vaccine 
indicated for active immunization in persons 6 months of age and older for the prevention of 
influenza disease caused by influenza viruses contained in the vaccine. Fluzone QIV is 
propagated in embryonated chicken eggs, chemically inactivated, disrupted and purified to 
yield a split virus vaccine.   
2018/2019 and 2019/2020 Flublok Quadrivalent Influenza Vaccine (QIV) 
The Sanofi Pasteur (Protein Sciences Corporation) manufactured FluBlok Quadrivalent is an 
FDA approved recombinant HA protein vaccine indicated for active immunization in persons 
18 years of age and older for the prevention of influenza disease caused by influenza viruses 
contained in the vaccine. It contains purified HA proteins produced in a Sf9 insect cell line 
derived from the fall armyworm, Spodoptera frugiperda.   
2018/2019 Fluzone and 2018/2019 Flublok Vaccine Expiry 
The 2018/2019 Fluzone and Flublok are labeled to expire on June 30, 2019. The expiration 
date that is present on the label of licensed seasonal influenza vaccine is to ensure the 
product made for previous years’ influenza strains are not still available for general licensed 
use when new seasonal vaccine becomes available against the most recent circulating 
strains. Historical data exists indicating that flu vaccine maintains potency for a period well 
beyond its expiration date. For this clinical trial, the 2018/2019 Fluzone and Flublok will be 
used beyond the labeled expiration date. 
AF03 Adjuvant  
The Sanofi Pasteur adjuvant formulation AF03 is a squalene-in-PBS emulsion stabilized by non-
ionic surfactants, sorbitan oleate and macrogol cetostearyl ether prepared by the "Phase Inversion 
Temperature” (PIT) method. 
Advax-CpG55.2 Adjuvant 

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The Vaxine adjuvant Advax-CpG55.2 is a combination adjuvant supplied as two separate 
components, Advax (delta inulin) and CpG55.2, in individual aseptic glass vials.  
Advax (Delta Inulin) 
Inulin is a natural storage polysaccharide of plants of the Compositae family, such as 
dahlias, artichoke and chicory. Inulin exists in different polymorphic forms. Advax is 
manufactured from highly purified inulin that is subsequently crystallized into microscopic 
particles of known as delta inulin and then formulated in an aqueous phosphate buffer.  
Advax adjuvant appears as a milky white non-viscous suspension and if left undisturbed on 
a stable surface for several days to weeks the delta inulin particles will slowly sediment to 
the bottom of the vial, leaving a clear slightly off white solution above them. The particles 
can be resuspended easily by simple repeated inversion of the vial several times.  
CpG55.2 
CpG55.2 is a completely synthetic Class B CpG oligonucleotide of 24 nucleotides in 
length with a full phosphorothioate backbone for increased stability. It is presented as a 
clear solution in an aqueous buffer. 
Acquisition 
2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV and the AF03 adjuvant will be 
provided by Sanofi Pasteur. 
Advax and CpG55.2 adjuvants, the individual components of Advax-CpG55.2 adjuvant will be 
provided by Vaxine. 
Sterile Water for Injection (SWI) will be provided by DMID Clinical Materials Services 
Contract. 
Upon request by DMID, 2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV, AF03 and 
Advax and CpG55.2 adjuvants will be transferred to the following address: 
DMID Clinical Materials Services Contract 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com 

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2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV, AF03 and Advax and CpG55.2 
adjuvants, and SWI 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 2018/2019 and 2019/2020 Fluzone QIV and 
Flublok QIV, AF03 and Advax and CpG55.2 adjuvants, or SWI during this trial, contact the 
DMID CPM. 
6.1.1 
Formulation, Storage, Packaging, and Labeling 
2018/2019 and 2019/2020 Fluzone QIV  
Fluzone QIV is a sterile clear and slightly opalescent in color suspension of inactivated split 
virus for IM use. It is prepared from seasonal influenza virus candidate vaccine strains 
propagated in embryonated chicken eggs. The single-dose, pre-filled syringes (0.5 mL) are 
formulated without thimerosal or any other preservative and do not contain natural latex rubber.  
2018/2019 Fluzone QIV single dose pre-filled syringes are formulated  to contain 60 µg of HA 
per 0.5 mL dose with 15 µg of HA from each of the following four influenza virus strains 
recommended for the 2018/2019 influenza season:  A/Michigan/45/2015 X-275 (H1N1); 
A/Singapore/INFIMH-16-009/2016 IVR-186 (H3N2); B/Maryland/15/2016 BX-
69A(B/Colorado/06/2017-like;Victoria lineage) and B/Phuket/3073/2013 (Yamagata lineage).   
The pre-filled syringes must be stored at 2°C to 8°C (36°F to 46°F). Do not freeze. 
Detailed mixing instructions and necessary supplies to prepare adjuvanted 2018/2019 QIV are 
described in the protocol-specific MOP. 
2018/2019 and 2019/2020 Flublok QIV  
Flublok QIV is a sterile, clear, colorless solution of recombinant HA proteins from four influenza 
viruses for IM use. Vaccine may also contain residual amounts of baculovirus and Spodoptera 
frugiperda cell proteins, baculovirus and cellular DNA and Triton X-100.  This vaccine contains 
no preservative (thimerosal), antibiotics or egg proteins.  
2018/2019 FluBlok QIV single dose pre-filled syringes are formulated to contain 180 µg of HA 
per 0.5 mL dose, with 45 µg of HA derived from each of four influenza virus strains 
recommended for the 2018/2019:  A/Michigan/45/2015 (H1N1); A/Singapore/INFIMH-16-
009/2016 (H3N2); B/Maryland/15/2016 (a B/Colorado/06/2017-like virus; Victoria lineage) and 
B/Phuket/3073/2013 (Yamagata lineage).  The pre-filled syringes must be stored protected from 

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light at 2°C to 8°C (36°F to 46°F). Do not freeze. Detailed mixing instructions to prepare 
adjuvanted 2018/2019 QIV are included in the protocol-specific MOP. 
AF03 
The AF03 adjuvant is a sterile injectable suspension containing 5% squalene (50 mg/mL), free 
from preservatives, and provided in amber glass vials containing 0.7 mL. Each 0.25 mL dose of 
AF03 that will be administered admixed with vaccine contains approximately 12.5 mg of 
squalene. 
The adjuvant should be stored at a temperature ranging from +2°C to +8°C (36°F to 46°F).  
Detailed mixing instructions to prepare AF03-adjuvanted 2018/2019 QIV are included in the 
protocol-specific MOP. 
Advax-CpG55.2 
Advax-CpG55.2 is a combination adjuvant formulation comprised of two components, Advax 
and the CpG55.2 oligonucleotide, that will be extemporaneously mixed with QIV on the day of 
administration in accordance with the mixing instructions detailed in the protocol-specific MOP.  
Each 0.5 mL dose of Advax-CpG55.2 that will be administered admixed with vaccine contains 
approximately 15 mg of Advax and 0.15 mg of CpG55.2. 
Advax  
 
Advax adjuvant is a sterile injectable suspension, free from preservatives, provided in 2.0 mL 
clear glass vials.  Each 2.0 mL vial contains 0.5 mL of a 50 mg/mL suspension of delta inulin 
in phosphate buffered saline.  
 
The Advax adjuvant will be stored refrigerated, protected from light at a temperature ranging 
from +2°C to +8°C (36°F to 46°F). Do not freeze. 
CpG55.2 
CpG55.2 adjuvant is a sterile injectable solution and provided in clear glass vials containing 
0.5 mL of a 2 mg/ml solution of CpG55.2. 
The CpG55.2 adjuvant will be stored refrigerated, protected from light at a temperature 
ranging from +2°C to +8°C (36°F to 46°F). 
The CpG55.2 and Advax adjuvant components should be extemporaneously mixed with the 
appropriate investigational vaccine, and then stored at +2°C to +8°C (36°F to 46°F) until use. 

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Detailed mixing instructions to prepare Advax-CpG55.2-adjuvanted 2018/2019 QIV are included 
in the protocol-specific MOP. 
Sterile Water for Injection (SWI)  
• 
Sterile Water for Injection, USP, is sterile, nonpyrogenic, distilled water in a single dose 
container for intravenous administration after addition of a suitable solute. It may also be 
used as a dispensing container for diluent use. No antimicrobial or other substance has been 
added. The pH is 5.5 (5.0 to 7.0). The osmolarity is 0.  
• Sterile Water for Injection (SWI) must be stored at room temperature 20°C to 25°C (68°F to 
77°F) (USP Controlled Room Temperature). Avoid storing SWI in any excessive heat. For 
SWI, excursions between 15-30°C (59°F to 86°F) the product can continue to be used (no 
quarantine) but the site needs to complete the DMID Study Product Support Team Temperature 
Excursion Reporting Form and submit to PSTBased on UPS guidelines, excursions between 
15°C and 30°C are allowed and will not be considered deviations.. 
• 
SWI will be used to prepare the Advax-CpG55.2 adjuvant prior to admixing with the 2018/2019 
QIVs.   
Each of the adjuvant 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 manufacturers’ package inserts for the 2018/2019 
and 2019/2020 (when available) Fluzone and Flublok QIVs and the manufacturers’ 
Investigator’s Brochures for both adjuvants. 
Sterile empty vials (2-mL or 5-mL) will be provided with latex-free stoppers. 
6.1.2 
Study Product Storage and Stability Procedures 
The temperature of the storage unit must be manually recorded daily (excluding non-business 
days and holidays, as applicable) and continuously monitored and recorded during the course of 
this trial per the participating VTEU site standard operating procedures (SOPs), and 
documentation will be maintained. If the temperature fluctuates outside of the required range, the 
affected study product(s) must be quarantined at the correct storage temperature and labeled as 
‘Do Not Use’ (until further notice). The participating VTEU site’s research pharmacist must alert 
the site PI and study coordinator, if the temperature fluctuates outside of the required range. In 
the event the temperature fluctuates outside of the required range, including accidental deep-
freezing or disruption of the cold chain, the affected study product(s) must not be administered. 
The site PI or responsible person should immediately contact the DMID Product Support Team 

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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. Additional instructions for quarantine and DMID contact 
information are provided in the protocol-specific MOP. 
 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
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 sites’ research pharmacist on the same day of study 
vaccine.  
Visually inspect the Fluzone QIV, Flublok QIV, AF03 adjuvant and the Advax-CpG55.2 
adjuvant individual components, Advax and CpG55.2, and SWI upon receipt and prior to use. If 
the study product(s) appear(s) to have been damaged, contaminated, discolored, contain(s) 
visible particulate matter, or if there are any concerns regarding the integrity, do NOT use the 
affected study product(s). The affected study product(s) must be quarantined at 2°C to 8°C (36°F 
to 46°F) for Fluzone QIV, Flublok QIV, AF03 adjuvant and the Advax-CpG55.2 adjuvant 
individual components, Advax and CpG55.2, and at 20-25°C (68°F to 77ºF, USP Controlled 
Room Temperature) for SWI and labeled as ‘Do Not Use’ (until further notice). The site PI or 
responsible person should immediately contact the DMID Product Support Team at and DMID 
Clinical Project Manager for further instructions before any additional study vaccinations are 
administered. Based on the information collected, DMID and/or the manufacturer will determine 
whether the affected study product(s) can be used. If the affected study product(s) cannot be 
used, the site will receive specific instructions on how to return the affected study product(s) to 
the DMID CMS or destroy the affected study product(s) on site. If the Fluzone QIV, Flublok 
QIV, AF03 adjuvant or Advax-CpG55.2 individual components, Advax and CpG55.2, and SWI 
are unusable, study personnel will use another vial from the study supply. Replacement vials 
may be requested by contacting DMID. Additional instructions for quarantine and DMID contact 
information are provided in the protocol-specific MOP. 
For those doses that must be admixed visually inspect the Fluzone QIV or Flublok QIV plus 
adjuvant admixture (final mixed syringe depending on treatment arm) prior to use. The 
admixtures will be white cloudy suspension or milky in appearance. If the admixture(s) appear(s) 
to have been damaged, contaminated or discolored, contain(s) visible particulate matter, or if 
there are any concerns regarding the integrity, do NOT use the affected admixture(s). The 

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affected admixture(s) must be quarantined at 2°C to 8°C (36°F to 46°F) for the Fluzone QIV or 
Flublok QIV plus adjuvant admixture and labeled as ‘Do Not Use’ (until further notice). The site 
PI or responsible person should immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager for further 
instructions before any additional study vaccinations are administered. Based on the information 
collected, DMID and/or the manufacturer will determine whether the affected admixture(s) can 
be used. If the affected admixture(s) cannot be used, the site will receive specific instructions on 
how to send the affected admixture(s) to the DMID CMS or destroy the affected admixture(s) on 
site. If the affected admixture is unusable, the participating VTEU site’s research pharmacist will 
prepare another admixture. Additional instructions for quarantine and DMID contact information 
are provided in the protocol-specific MOP. 
Each dose of study vaccine, including those doses that must be admixed, the Fluzone QIV or 
Flublok QIV plus adjuvant admixture, once mixed, must be administered as soon as possible (not 
to exceed 30 minutes total since admixing at room temperature.   
Only one dose of study vaccine should be administered. For those doses of 2018/2019 Fluzone 
QIV or 2018/2019 Flublok QIV that must be admixed with adjuvant gently invert the final mixed 
syringe 4 times immediately before the single dose of adjuvanted study vaccine is administered. 
Do not shake the final mixed syringe.  
Study vaccine administration to the subject will be performed by an unblinded study personnel 
member who is credentialed to administer vaccines and may also participate in dose preparation, 
but will not be involved in study-related assessments or have subject contact for data collection 
following study vaccine administration to the subject. One dose of study vaccine (volumes may 
vary depending on study arm) will be administered to the subject via a single IM injection into 
the deltoid muscle of the subject’s preferred arm on the day of study vaccine administration to 
the subject. See the protocol-specific MOP for information on how to administer IM injections. 
The site of injection (right or left arm) and time of study vaccine administration to the subject 
will be recorded on the appropriate DCF. Study vaccinations subsequent to the first study 
vaccination may be given in the same preferred arm as long as there is no interference with the 
reactogenicity assessment. 
Aseptic technique will be used for the admixture preparation of vaccine with adjuvant using 
disposable, sterile needles appropriate in length for each subject and a 1-mL disposable, sterile 
syringe.   
 

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Accountability Procedures for the Study Intervention/Investigational 
Product 
The site PI is responsible for study product distribution and disposition and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating 
VTEU site’s research pharmacist responsibility for study product accountability. The 
participating VTEU site’s research pharmacist will be responsible for maintaining complete 
records and documentation of study product receipt, accountability, dispensation, storage 
conditions, and final disposition of the study product(s). Study product accountability records 
and dispensing logs should include, but are not limited to the following: DMID protocol number; 
name, dosage form, strength of the study product; capture vial numbers (optional) and pre-filled 
syringe number (optional) assigned sequentially by the pharmacists as vials/syringes are used 
(number uniquely, do not start over at 1 or repeat numbers),  , manufacturer or other source; 
control, lot number or other identification number; expiration or retest date (memo from DMID 
or noted on the protocol indicating that the expiration is centrally managed is acceptable); date of 
receipt of the study product; quantity received from supplier; subject identification number, 
quantity dispenses as amount or dose per subject, balance of study product currently available, 
disposition of drug if not dispensed to a study subject (e.g. disposed/destroyed or retuned to 
supplier as per protocol or MOP or as directed by DMID), date of study vaccine 
preparation/administration, time of study vaccine preparation, expiration of study vaccine 
preparation, and amount of study vaccine withdrawn for administration. Time of study vaccine 
administration to the subject will be recorded on the appropriate DCF. All study product(s), 
including the amount of 2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV, vials of AF03 
and Advax-CpG55.2 (Advax and CpG55.2 individual components) adjuvants, SWI and syringe 
and vial admixtures, whether administered or not, must be documented on the appropriate study 
product accountability record or dispensing log. The sponsor’s monitoring staff will verify the 
participating VTEU site’s study product accountability records and dispensing logs per the site 
monitoring plan. 
Used syringes of 2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV may be destroyed in 
accordance with site-specific SOPs.   
There are three options for documenting product accountability and dispensation: 
 
 
  
 

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Option 1:  Retained until monitored and released for disposition 
Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual components) 
adjuvants, SWI and vial admixtures will be retained until monitored and released for 
disposition, as applicable. This can occur on an ongoing basis for vials of AF03 and 
Advax-CpG55.2 (Advax and CpG55.2 individual components) adjuvants, SWI and vial 
admixtures. Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual 
components) adjuvants, SWI and vial admixtures may be destroyed in accordance with 
site-specific SOPs following each monitoring visit where study product accountability is 
monitored, and resolution of any discrepancies.   
 Option 2: Counted and verified by two personnel before disposition 
Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual components) 
adjuvants, SWI and vial admixtures will be retained until counted and verified by two 
pharmacy personnel before being released for disposition.  The documentation for the 
verification performed by two pharmacy personnel needto be retained for sponsor’s 
monitoring staff for review.  This can occur on an ongoing basis for vials of AF03 and 
Advax-CpG55.2 (Advax and CpG55.2 individual components) adjuvants, SWI and vial 
admixtures. After the used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 
individual components) adjuvants, SWI and vial admixtures are counted and verified the 
vials may be destroyed in accordance with site-specific SOPs.   
Option 3:  Use of an Electronic Data Capture system 
 Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual components) 
adjuvants, SWI and vial admixtures can be captured in an Electronic Data Capture system 
which is 21 CFR Part 11 compliant. Used vials of AF03 and Advax-CpG55.2 (Advax and 
CpG55.2 individual components) adjuvants, SWI and vial admixtures may be destroyed 
on an ongoing basis in accordance with site-specific SOPs. Spornsor’s monitoring staff 
will be provided with access to the data for verification.     
Upon study completion, for all options listed above, unused syringes of 2018/2019 and 
2019/2020 Fluzone QIV and Flublok QIV, unused or expired vials of AF03 and Advax-CpG55.2 
(Advax and CpG55.2 individual components) adjuvants, and SWI will be retained until 
monitored and released for destruction. 

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Assessment of Subject Compliance with Study 
Intervention/Investigational Product 
Study vaccine will be administered to the subject by an unblinded study vaccine administrator 
via IM injection at all dosing times per the subject’s randomized treatment assignment and as 
described in Section 6.2. Noncompliance from the dose schedule may occur. Study vaccine 
administration to the subject and noncompliance with the dose schedule will be recorded on the 
appropriate DCF. 
 
Concomitant Medications/Treatments 
Administration of any medications, therapies or vaccines will be recorded on the appropriate 
DCF. Concomitant medications will include all current medications and medications taken in the 
60 days prior to signing the ICF through approximately Day 29 after first study vaccination or 
early termination, whichever occurs first. Receipt of any influenza vaccine during the 2018/2019 
influenza vaccine season prior to receipt of the study vaccine (regardless of the date of receipt) 
will be documented. 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 28 days 
after the first study vaccination. Prescription and over-the-counter drugs will be included as well 
as herbals, vitamins and supplements.  
In addition, receipt of any non-study influenza vaccines will be solicited through approximately 
365 days after the first 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 first 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 
STUDY PROCEDURES/EVALUATIONS 
 
Clinical Evaluations 
A complete medical history will be obtained by interview of subjects at the screening visit. 
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 all subsequent visits an interim medical history will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. The interim 
medical history should include an assessment for new medical conditions and symptoms 
suggestive of AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs). 
 
Concomitant medications and influenza vaccination history will be collected as described in 
Section 6.5. 
 
At the screening visit a physical examination will be performed on all subjects, by a study 
clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator, to include the following organs and organ systems: skin, head and neck, lungs, 
heart, liver, spleen, extremities, lymph nodes, and nervous system.. At the vaccination visit and 
at follow-up visits after each 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. 
 
Height, weight will be collected at the screening visit, and vital signs (oral temperature, pulse 
and blood pressure) will be collected at the screening visit and prior to the 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. 
 
Reactogenicity assessments will include an assessment of solicited AEs occurring from the time 
of first study vaccination through Day 8, which includes an assessment of injection site reactions 
including pruritus, ecchymosis, erythema, induration, edema, pain, and tenderness as well as 
systemic reactions including fever, feverishness, fatigue, malaise, myalgia (exclusive of the 

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injection site), arthralgia, headache, and nausea. Pre-administration reactogenicity assessments 
will be performed immediately prior to first 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 the first study vaccination 
only (administered during visit 1). Following the first study vaccination, the vaccination site will 
be examined, post-administration reactogenicity assessments will be performed, and any 
AE/SAEs will be recorded on the appropriate DCF prior to discharge from the clinic. The study 
vaccination site will also be examined on approximately Day 2 and Day 8. 
 
All subjects will complete a Memory Aid from the time of first study vaccination through Day 8. 
Memory Aids will be reviewed with the subjects for any AEs (solicited injection site and 
systemic reactions as well as unsolicited AEs), SAEs and concomitant medications (including 
solicitation for receipt of any non-study influenza vaccines) at clinic study visits on 
approximately Day 2 and Day 8. 
 
Laboratory Evaluations 
Clinical laboratory evaluations and special assays are described below. Refer also to Sections 4 
and 8 as well as Appendix A: Schedule of Study Procedures and Evaluations and Appendix B: 
Adverse Events of Special Interest. 
7.2.1 
Clinical Laboratory Evaluations 
Urine or serum pregnancy tests will be performed locally by the site at the screening visit 
(optional) and within 24 hours prior to first study vaccination for all women of childbearing 
potential. Results must be negative and known prior to randomization on Day 1 and 
administration of first study vaccination to be eligible for participation in this trial and receipt of 
study vaccination. 
 
The ESR evaluation will be performed locally by the site at the screening visit and confirmed as 
less than 30 mm per hour to be eligible for participation in this trial and receipt of the first study 
vaccination. 
 
Clinical safety laboratory parameters (WBC, Hgb, PLT, ALT, AST, GGT, ALP, Bilirubin (total), 
serum lipase and serum amylase and Cr) will be collected at the screening study visit and will be 
sent to the Central Clinical Laboratory. The results from the clinical safety laboratory parameters 
collected at the screening visit must be reviewed prior to the first study vaccination and must be 

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within acceptable ranges to be eligible for receipt of the first study vaccination (see Section 
5.1.1).  The safety laboratories will be repeated prior to receipt of the first study vaccination.  
However, the results from the clinical safety laboratory parameters collected prior to the study 
vaccination will not be available or reviewed prior to the study vaccination.  Clinical safety 
laboratory parameters collected immediately prior to the first study vaccination will serve as the 
baseline and will be repeated on approximately Day 8. 
 
The volume of venous blood to be collected for ESR and clinical safety laboratory evaluations is 
presented in Table 3. 
7.2.2 
Special Assays or Procedures 
Serological Assays 
Serum will be collected for HAI, Neut, NAI, multiplex HA ELISA, NA ELISA and non-
neutralizing Fc-effector antibody studies.  Once the last subject completes the visits that occur 
through approximately 28 days after the first study vaccination, serum specimens collected for 
D1 and Day 29 visits will be shipped from the DMID CMS to Sanofi Pasteur specified research 
laboratories for final serological analyses. Subsequent shipments will occur once the last subject 
completes the visits that occur through approximately Day 118 (inclusive of D8, D57, Day 90 
and Day 118), once the last subject completes the Day 180 and again once the last subject 
completes the Day 365 visit. Preparation of blood samples and shipping instructions for cellular 
immunology assays are outlined in the MOP. 
Cellular Immunology Assays 
This clinical trial will also investigate B cell memory responses using a multiplexed B cell 
FluroSpot assay evaluating IgG, IgM and IgA specific B cells.  Multiparametric flow cytometry 
will be used to identify plasmablast/Tfh cells. PBMCs will be collected and shipped from the 
DMID CMS to Sanofi Pasteur specified research labs to conduct the cellular immunological 
assays. Preparation of blood samples and shipping instructions for cellular immunology assays 
are outlined in the MOP. 
Transcriptomic Analyses 
Whole blood transcriptomics will be done using RNA sequencing. Samples collected will be 
shipped from the DMID CMS to Sanofi Pasteur specified research labs to conduct transcriptomic 
analyses. Preparation of the blood samples and shipping instructions for transcriptomic are 
outlined in the MOP.  

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The volume of venous blood to be collected for serological, cellular immunology assays and 
transcriptomics is presented in Table 3. 
 
Table 3: Venipuncture Volumes  
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Cumulative Blood Volume 
Total (mL) 
Study Day post first 
study vaccination 
Screening 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2 +1 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90 +/-14 d  
D118 +/-3 d 
D180 +/- 14d 
D365-14/+35d 
Study Vaccination 
 
X 
 
 
 
 
X 
 
 
 
 
ESR 
4^ 
 
 
 
 
 
 
 
 
 
4 
Clinical Safety 
Laboratory Evaluations 
6^ 
6#† 
 
6 
 
 
 
 
 
 
18 
Serological Assays 
 
20† 
 
20 
20 
20 
20† 
20 
20 
20 
160 
Cellular Immunology 
Assays 
 
80† 
 
48 
80 
 
48† 
 
 
 
256 
Tempus RNA Tube 
 
3† 
3 
3 
 
 
 
 
 
 
9 
Per Visit Blood 
Volume Total (mL) 
10 
109 
3 
77 
100 
20 
68 
20 
20 
20 
 
Running Blood Volume 
Total (mL) 
10 
119 
122 
199 
299 
319 
387 
407 
427 
447 
447 
^ Drawn up to 28 days prior to the first study vaccination. The ESR value must be confirmed as less than 30 mm per 
hour prior to randomization and prior to first study vaccination. Screening WBC, Hgb, PLT, ALT, T. Bili, AST, 
GGT, ALP and serum lipase and serum amylase and Cr must be within the accepted ranges outlined in the 
inclusion criteria prior to randomization and study vaccination. 
# Clinical safety laboratory evaluations collected on Day 1 prior to first study vaccination will be considered as 
baseline. 
† Blood must be drawn immediately prior to each study vaccination. 
 
 
 

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7.2.3 
Specimen Preparation, Handling and Shipping 
7.2.3.1 
Instructions for Specimen Preparation, Handling and Storage 
Instructions for specimen preparation, handling and storage are included in the Central Clinical 
Laboratory manual and protocol-specific MOP as appropriate. 
7.2.3.2 
Specimen Shipment 
Specimen shipment will occur at intervals during the course of this trial following all applicable 
International Air Transport Association (IATA) requirements and according to the specifics for 
storage temperature and documentation as detailed in the central (clinical) laboratory manual and 
protocol-specific MOP as appropriate. 
 
Specimens for clinical safety laboratory evaluations will be shipped from the participating VTEU 
sites to the central (clinical) laboratory except those done locally. 
 
Specimens for antibody, cellular and transcriptomic assays will be shipped from the participating 
VTEU as outlined in the MOP. 
 
Further instructions for specimen shipment are included in the central (clinical) laboratory 
manual and protocol-specific MOP, as appropriate. 

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8 
STUDY SCHEDULE 
Complete study schedule details listed by type of visit are described below. Refer also to 
Sections 4 and 7 as well as Appendix A: Schedule of Study Procedures and Evaluations and 
Appendix B: Adverse Events of Special Interest. 
 
Screening and Enrollment Visits 
8.1.1 
Visit 00, Screening (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 study vaccination. 
• Demographic information will be obtained by interview of subjects. 
• Eligibility criteria will be reviewed with subjects to ensure eligibility. 
• Complete medical history will be obtained by interview of subjects to ensure eligibility. 
• All concomitant medications taken within 60 days prior to signing the ICF will be 
reviewed with subjects to determine stability of chronic diseases and eligibility. 
Medications reported in the eCRF are limited to those taken within 30 days prior to the 
first study vaccination. 
• Subject receipt of licensed, seasonal influenza vaccine over the current (2018-2019), 
what type (inactivated or live attenuated) and approximate date of vaccination will be 
recorded on the appropriate DCF, if known. Prior receipt of licensed, seasonal influenza 
vaccine is not exclusionary, as long as it has been administered within the allowable 
window (see Section 5.1.2). 
• Subject receipt of non-seasonal influenza vaccine, including those that are experimental, 
what type (inactivated or live attenuated), what subtype (e.g., A/H3, A/H5, A/H9) and 
approximate date of vaccination will be recorded on the appropriate DCF, if known. Prior 
receipt of non-seasonal influenza vaccine is not exclusionary (see Section 5.1.2). 
• Vital signs, including oral temperature, pulse and BP, will be obtained to ensure 
eligibility. Subjects must not eat or drink anything hot or cold, or smoke within 10 
minutes prior to taking oral temperature. 

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• Height and weight will be collected for the calculation of BMI. 
• A physical examination will be performed on all subjects to include the following organs 
and organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph 
nodes, and nervous system, and as an assessment for signs suggestive of PIMMCs, by a 
study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• A urine or serum pregnancy test may be performed locally by the site for all women of 
childbearing potential. Women of childbearing potential must have a negative urine or 
serum pregnancy test within 24 hours prior to the first study vaccination. Counsel on 
need for avoidance of pregnancy during the study.  
• Approximately 4 mL of venous blood will be collected for ESR and performed locally by 
the site. The ESR value must be confirmed as less than 30 mm per hour to ensure 
eligibility. 
• Approximately 6 mL of venous blood will be collected for WBC, Hgb, PLT, ALT, T. 
Bili, AST, GGT, ALP, serum lipase and amylase and Cr for transport to the Central 
Clinical Laboratory.  The results must be within the acceptable range as outlined in the 
eligibility criteria to be eligible for randomization and vaccination. 
8.1.2 
Visit 01, Day 1, Enrollment (Vaccination), 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 study vaccination. 
• Eligibility criteria, including results from Screening of the ESR, WBC, Hgb, PLT, ALT, T. 
Bili, AST, GGT, ALP, serum lipase and amylase and Cr evaluation, will be reviewed with 
subjects prior to the first study vaccination to ensure continued eligibility. (The ESR 
value must be confirmed as less than 30 mm per hour prior to randomization and study 
vaccination.  The remaining laboratories must be within acceptable parameters as 
outlined in the inclusion 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 study vaccination. Any changes in medical history since the screening 
visit will be reviewed with subjects prior to study vaccination to ensure continued 
eligibility. 

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• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be reviewed with subjects prior to study vaccination for accuracy and 
completeness. Any new concomitant medications taken since the screening visit will be 
reviewed with subjects prior to study vaccination to ensure continued eligibility. 
Medications reported in the eCRF are limited to those taken within 30 days prior to the 
first study vaccination. 
• Vital signs, including oral temperature, pulse and BP, will be obtained prior to study 
vaccination to ensure continued eligibility. Vital signs assessed on Day 1 prior to 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 performed prior to study vaccination, including an 
assessment for signs suggestive of PIMMCs, may be performed prior to study 
vaccination, if indicated based on review of complete medical history and any updates 
obtained by interview of subjects since the screening visit, by a study clinician licensed to 
make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
investigator. 
• A urine or serum pregnancy test will be performed locally by the site within 24 hours 
prior to study vaccination for all women of childbearing potential. Results must be 
negative and known prior to randomization and study vaccination.   
• Approximately 6 mL of venous blood will be collected immediately prior to study 
vaccination for baseline clinical safety labs (WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, 
ALP, serum lipase and serum amylase and Cr) to be performed by the Central Clinical 
Laboratory. The results from these evaluations will not be available or reviewed prior to 
the study vaccination and will serve as a baseline safety assessment only. 
• Approximately 20 mL of venous blood will be collected immediately prior to study 
vaccination for baseline serological assays. 
• Approximately 80 mL of venous blood will be collected immediately prior to study 
vaccination for baseline cellular immunology assays. 
• Approximately 3 mL of venous blood will be collected immediately prior to study 
vaccination for transcriptomic evaluations. 
• Subjects will be enrolled in Advantage eClinicalSM and randomly assigned to a treatment 
arm prior to study vaccination. 

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• Pre-administration reactogenicity assessments will be performed immediately prior to 
study vaccination to establish baseline. 
• Subjects will then receive one dose of study vaccine via a single IM injection into the 
deltoid muscle of the subject’s preferred arm. The site of injection (right or left arm) and 
time of study vaccine administration to the subject will be recorded on the appropriate 
DCF. Subjects will be observed in the clinic for at least 20 minutes after study 
vaccination. The study vaccination site will be examined, post-administration 
reactogenicity assessments will be performed, and any AE/SAEs will be recorded on the 
appropriate DCF prior to discharge from the clinic. 
• Subjects will be provided with a Memory Aid and other study-related materials to record 
daily oral temperature, solicited injection site and systemic reactions, unsolicited AEs, 
and concomitant medications. Subjects will be encouraged to take their oral temperature 
around the same time each day. Subjects must not eat or drink anything hot or cold, or 
smoke within 10 minutes prior to taking oral temperature. Subjects will be instructed on 
how to use their Memory Aid and how to measure and record AEs prior to discharge 
from the clinic. Subjects will be instructed to notify the study center if they develop any 
severe reactions after 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. 
• Counsel on avoidance of pregnancy.  
 
Follow-up Visits 
Follow-up visits are scheduled in reference to study vaccination date as indicated for each visit 
window. 
8.2.1 
Visit 02, Day 2, Clinic Visit  
(Window: Day 2 +1 day post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 

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• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and 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. 
• Approximately 3 mL of venous blood will be collected for transcriptomic assays. 
• Counsel on avoidance of pregnancy.  
8.2.2 
Visit 03, Day 8, Clinic Visit 
(Window: Day 8 +/- 1 day post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 

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• The study vaccination site will be examined. 
• Counsel on avoidance of pregnancy.  
• Approximately 6mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase and amylase and Cr) to be 
performed by the Central Clinical Laboratory. 
• Approximately 20 mL of venous blood will be collected for serological assays. 
• Approximately 48 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 3 mL of venous blood will be collected for transcriptomic analyses. 
Note: Subjects that complete this visit on Day 7 will be reminded to complete their Memory Aid 
through the end of Day 8, and study personnel will contact these subjects by phone to review 
their Memory Aid information and solicit any AE/SAEs and concomitant medications (including 
solicitation for receipt of any non-study influenza vaccines). 
8.2.3 
Visit 04, Day 29, Clinic Visit 
(Window: Day 29, +/-2 days post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and 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. 
• Counsel on avoidance of pregnancy.  

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• Approximately 20 mL of venous blood will be collected for serological assays. 
• Approximately 80 mL of venous blood will be collected for cellular immunology assays. 
8.2.4 
Visit 05, Day 57, Clinic Visit 
(Window: Day 57 +/- 3 days post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
•  SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) 
will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and 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. 
• Counsel on avoidance of pregnancy.  
• Approximately 20 mL of venous blood will be for serological assays. 
8.2.5 
Visit 06, Day 90, Clinic Visit 
(Window: Day 90 +/- 14d) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 

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• SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) 
will be recorded on the appropriate DCF. 
• A targeted physical examination performed prior to study vaccination, including an 
assessment for signs suggestive of AESIs (including Protocol Specified AESIs, MAAEs, 
NOCMCs and 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 20 mL of venous blood will be collected immediately prior to study 
vaccination for serological assays. 
• Approximately 48 mL of venous blood will be collected immediately prior to study 
vaccination for immunological assays.  
• Subjects will then receive one 0.5 mL dose of 2019-2020 Fluzone or Flublok QIV study 
vaccine via a single IM injection into the deltoid muscle of the subject’s preferred arm. 
Subjects who received 2018-2019 Fluzone QIV will receive 2019-2020 Fluzone QIV. 
Subjects who received 2018-2019 Flublok QIV will receive 2019-2020 Flublok QIV. The 
site of injection (right or left arm) and time of study vaccine administration to the subject 
will be recorded on the appropriate DCF.  Any SAE’s will be recorded on the appropriate 
DCF prior to discharge.   
8.2.6 
Visit 07, Day 118, Clinic Visit 
(Window: Day 118 +/- 3d) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
• SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) 
will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 

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licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• Approximately 20 mL of venous blood will be collected for serological assays. 
8.2.7 
Visit 08, Day 180, Clinic Visit 
(Window: Day 180+/- 14d) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
• Only SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and 
PIMMCs), will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and 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 20 mL of venous blood will be collected for serological assays. 
 
Final Visit 
8.3.1 
Visit 09, Day 365, Clinic Visit 
(Window: Day 365-14/+35)  
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 

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• Only SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and 
PIMMCs) will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and 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 20 mL of venous blood will be collected for serological assays. 
 
Early Termination Visit (if needed) 
The following activities will be performed at the Early Termination Visit on subjects who 
withdraw, or are withdrawn or terminated from this trial: 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• All concomitant medications will be recorded on the appropriate DCF (if prior to 28 days 
after the first study vaccination). Receipt of any non-study influenza vaccines will also be 
recorded on the appropriate DCF (if within 365 days after first study vaccination). 
• All AE/SAEs will be recorded on the appropriate DCF. Unsolicited AEs (if occurs within 
28 days of the first study vaccination). SAEs and AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) that have occurred since the previous clinic 
visit will be solicited (if within 365 days after first study vaccination). 
• Memory Aid information will be reviewed with subjects (if within 7 days after the first 
study vaccination). 
• Vital signs, including oral temperature, pulse and BP, may be obtained if indicated. 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking oral temperature. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) may be 
performed, if indicated based on review of interim medical history, by a study clinician 

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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 first study 
vaccination). 
• Post administration reactogenicity assessment will be performed (if within 7 days after 
the first study vaccination).  
• Approximately 6 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase and amylase and Cr) to be 
performed by the Central Clinical Laboratory (if within 7 days after the first study 
vaccination). 
• Approximately 20 mL of venous blood will be collected for serological assays. 
• Approximately 80 mL of venous blood will be collected for cellular immunology assays 
(if prior to or at the Day 90 visit). 
• Approximately 3 mL of venous blood will be collected for transcriptomic assays (if prior 
to or at the Day 8 visit). 
 
Unscheduled Visit (if needed) 
An Unscheduled Visit may occur at any time during this trial. Any of the following activities 
may be performed: 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) will be obtained by interview of subjects and 
any changes since the previous clinic visit or phone call will be noted (if indicated). 
• All concomitant medications will be recorded on the appropriate DCF (if within 28 days 
after first study vaccination). Receipt of any non-study influenza vaccines will also be 
recorded on the appropriate DCF (if within 365 days after first study vaccination). 
• All AE/SAEs will be recorded on the appropriate DCF. Unsolicited AEs (if occurs within 
28 days of the first study vaccination). SAEs and AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) that have occurred since the previous clinic 
visit will be solicited (if within 365 days after first study vaccination). 

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• Memory Aid information will be reviewed with subjects (if within 7 days after the first 
study vaccination). 
• Vital signs, including oral temperature, pulse and BP, may be obtained if indicated. 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking oral temperature. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and 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 study vaccination). 
• Post administration reactogenicity assessment will be performed (if within 7 days after 
the first study vaccination).  
• Site investigators have the discretion of administering 2019/2020 Fluzone or Flublok 
QIV earlier than the Day 90 window (i.e. earlier than Day 76) if 10% of more of 
surveillance samples in the CDC geographic region surrounding the local site test 
positive for influenza.  
• Approximately 6 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, AST, GGT, ALP serum lipase and amylase and Cr) to be 
performed by the Central Clinical Laboratory (if indicated). 
• Approximately 20 mL of venous blood will be collected for serological assays. 
 

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9 
ASSESSMENT OF SAFETY 
 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
1. SAEs occurring from the time of the first study vaccination through approximately 12 
months after the first study vaccination. 
2. Solicited AEs – reactogenicity events occurring from the time of the first study 
vaccination through 7 days after the first study vaccination: 
a) Injection site reactions including pruritus, ecchymosis, erythema, induration, edema, 
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 the first study vaccination 
through approximately 7 days after the first study vaccination. Parameters to be evaluated 
include WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum amylase, 
and Cr. 
4. Unsolicited AEs –non-serious AEs occurring from the time of the first study vaccination 
through approximately Day 29. 
5. AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) occurring 
from the time of the study vaccination through approximately 12 months after the first 
study vaccination. 
 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
9.2.1 
Adverse Events 
Adverse Event (AE): ICH E6 GCP defines an AE as any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product regardless of its 
causal relationship to the study treatment. The FDA defines an AE as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related. 

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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. 
AEs, including solicited injection site and systemic (subjective and quantitative) reactions, not 
meeting the protocol-defined criteria for SAEs, will be recorded on the appropriate DCF and 
entered into the eCRF. Information to be collected for unsolicited non-serious AEs includes 
event description, date of onset, licensed study physician’s assessment of severity and 
relationship to study product or alternate etiology (if not related to study product) (assessed only 
by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as 
the site PI or sub-investigator), date of resolution, seriousness, and outcome. AEs occurring 
during the trial-collection and reporting period will be documented appropriately regardless of 
relationship to study product. AEs will be followed through resolution. 
 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it will be recorded as an AE. 
 
AEs must be assessed for severity and relationship to study product (see definitions below). AEs 
characterized as intermittent require documentation of onset and duration of each episode. The 
start and stop date of each reported AE will be recorded on the appropriate DCF and entered into 
the eCRF. 
 
Adverse Events of Special Interest (AESI): An adverse event of special interest 
(serious or nonserious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (e.g., regulators) might 
also be warranted.  
 
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. 
 

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New-Onset Chronic Medical Conditions (NOCMCs): NOCMCs are defined as any 
new ICD-10 diagnosis (10th revision of the International Statistical Classification of 
Diseases and Related Health Problems) that is applied to the subject during the course of 
the study, after receipt of the study agent, that is expected to continue for at least 3 
months and requires continued health care intervention. 
 
Potentially Immune-Mediated Medical Conditions (PIMMCs): PIMMCs constitute a 
group of AEs that includes diseases which are clearly autoimmune in etiology and other 
inflammatory and/or neurologic disorders which may or may not have autoimmune 
etiologies. PIMMCs currently in effect are presented in Appendix B: Adverse Events of 
Special Interest. 
 
Protocol Specified AESIs: Dry Eye, Dry Mouth and Tearing 
 
Severity of Event: AEs will be assessed by a licensed study physician listed on the Form FDA 
1572 as the site PI or sub-investigator using a protocol-defined grading system (see Sections 
9.2.2 and 9.2.3). For events not included in the protocol-defined grading system, the following 
guidelines will be used to quantify severity: 
• 
Mild (Grade 1): Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures. Moderate events may cause some interference with functioning and 
daily activities. 
• 
Severe (Grade 3): Events interrupt the subject’s daily activities and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Relationship to Study Product: The licensed study physician’s assessment of an AE’s 
relationship to study product is part of the documentation process, but it is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. The relationship to study product must be 
assessed for AEs using the terms: related or not related. In a clinical trial, the study product must 
always be suspect. To help assess, the following guidelines are used: 
• Related – There is a reasonable possibility that the study product caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the AE. 

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• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2 
Reactogenicity 
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine. The following Toxicity Grading Scales will be used to grade solicited 
injection site and systemic (subjective and quantitative) reactions: 
 
Table 4: 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-experienced 
with touching the 
injection site 
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 
Pruritus 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity or 
requires prescription 
medication 
Ecchymosis (Bruising)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema (Redness)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration 
(Hardness)/Edema 
(Swelling)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
* Will also be measured in mm but size will not be used as halting criteria. 

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Ecchymosis, erythema and induration/edema as analyzed by measurement will be graded as 
follows: 
 
Table 5: Injection Site Reactogenicity Measurements 
Injection Site Reaction 
Small 
Medium 
Large 
Ecchymosis (Bruising)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema (Redness)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration (Hardness)/Edema 
(Swelling)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
* Will not be used as halting criteria. 
Table 6: 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 
Headache 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity or 
headache requires 
prescription medication 
Nausea 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity or 
nausea requires prescription 
medication 
* Not at injection site. 

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Oral temperature# will be graded as follows: 
Table 7: Quantitative Systemic (Oral Temperature) Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* – oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
* A fever can be considered not related to the study product if an alternative etiology can be documented. 
† Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
9.2.3 
Additional Adverse Event Severity Grading 
Pulse and BP# will be graded as follows: 
Table 8: Pulse and BP Adverse Event Grading 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia – beats per minute 
45 – 46 
40 – 44 
<40 
Tachycardia – beats per minute 
101 – 130 
131 – 155 
>155 
Hypotension (systolic) mmHg 
80 – 84 
75 – 79 
<75 
Hypotension (diastolic) mmHg 
50 – 54 
45 – 49 
<45 
Hypertension (systolic) mmHg 
141 – 155 
156 – 160 
>160 
Hypertension (diastolic) mmHg 
91 – 100 
101 – 110 
>110 
# Pulse and BP assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
Clinical safety laboratory values# will be graded as follows: 
Table 9: Clinical Safety Laboratory Adverse Event Grading 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/µL (Decrease) 
2.50 – 3.90 
1.50 – 2.49 
<1.50 
WBC 103/µL (Increase) 
10.60 – 15.00 
15.01 – 20.00 
>20.00 

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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) EDTA 
125 – 139 
100 – 124 
<100 
Platelets 103/µL (Increase) EDTA 
416 – 550 
551– 750 
>750 
Platelets K/cu mm (Decrease) Citrate 
115-124 
100-114 
<100 
Platelets K/cu mm (Increase) Citrate 
376-550 
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 
Aspartate Amino Transferase IU/L 
(Increase) (Female) 
37-90 
91-180 
> 180 
Aspartate Amino Transferase IU/L 
(Increase) (Male) 
44-108 
109-215 
> 215 
Total Bilirubin mg/dL (Increase) – 
when accompanied by any increase in 
ALT 
1.30 – 1.59 
1.60 – 1.80 
> 1.80 
Total Bilirubin mg/dL (Increase) – 
when ALT is normal 
1.30 – 1.89 
1.90 – 2.40 
> 2.40 
Gamma-Glutamyl Transferase IU/L 
(Increase) (Female) 
33-80 
81-160 
> 160 
Gamma-Glutamyl Transferase IU/L 
(Increase) (Male) 
50-123 
124-245 
> 245 
Alkaline Phosphatase IU/L (Increase) 
(Female) 
116-230 
231-345 
> 345 
Alkaline Phosphatase IU/L (Increase) 
(Male) 
116-230 
231-345 
> 345 
Serum Amylase 
122-182 
183-242 
>243 
Serum Lipase 
61-90 
91-180 
> 181 
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 safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered 
as baseline. 

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

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• 
Reviewed and evaluated by the DSMB (periodic review unless related), DMID, and IRB. 
9.2.5 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
The site PI or appropriate sub-investigator is responsible for recording all AE/SAEs that are 
observed or reported during this trial, regardless of relationship to study product. AE/SAEs, 
abnormal laboratory test values or abnormal clinical findings will be collected, assessed, 
documented, reported, and followed appropriately, using a local laboratory as necessary. In 
determining eligibility, refer to Section 5.1 and the protocol-specific MOP. 
 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be documented and reported from 
the time of the first study vaccination through 7 days after the first study vaccination. 
 
Clinical safety laboratory AEs will be documented and reported from the time of the first study 
vaccination through approximately 7 days after the first study vaccination. 
 
Unsolicited non-serious AEs will be documented and reported from the time of the first study 
vaccination through approximately Day29. 
 
SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) will 
be documented and reported from the time of the first study vaccination through approximately 
12 months after the first study vaccination. 
9.3.1 
Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group, at the 
following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 

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

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9.3.3 
Reporting of Pregnancy 
Upon awareness, pregnancies occurring in subjects will be recorded on the Pregnancy Report 
DCF. All pregnancies reported during the course of this trial will be followed to pregnancy 
outcome. With the subject’s permission, a venous blood sample(s) for serological assays will be 
collected per protocol though large volume blood samples for cellular immunological assays will 
be discontinued. Subjects who become pregnant will not be excluded from receiving the seasonal 
flu vaccine at Day 90, unless there are contraindications. Subjects will be followed for safety as 
per the protocol.  
Pregnant subjects will be contacted at least once every 12-16 weeks during pregnancy, following 
delivery, and at approximately one month following birth (if live birth) or one to two months 
following still birth.  
Subjects who become pregnant will be approached regarding their interest to enroll in the Sanofi 
Pregnancy Registry. This Registry program is not a part of this research study. Participation is 
completely voluntary. If subjects choose to enroll they can contact Sanofi via email at 
USPVmailbox@sanofi.com or call Customer Service at 1-800-633-1610 option#2 to discuss 
enrollment in the Pregnancy Registry for Influenza.  
 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be collected, assessed and followed through resolution from the time of first study 
vaccination through approximately 28 days after the first study vaccination. 
 
SAEs and AESIs (including Protocol Specified AESIs, MAAEs, 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 first study vaccination). 
 
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
 
Follow-up procedures, evaluations and outcomes will be recorded on the appropriate DCF and 
entered into the eCRF. 

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Halting Rules 
Enrollment will start with 6 sentinel subjects, one each from each study group (groups 1-6).  
Subjects will be followed through Day 8.  If any of the pre-specified events outlined in Section 
9.5.1 occur, the study will be halted and reviewed by the DSMB.  If no prespecified events 
occur, randomization and vaccination can proceed. All 6 subjects will then be followed 
according to protocol.   
 
It is anticipated that both adjuvant formulations (AF03 and Advax-CpG55.2) will be available at 
the start of study enrollment.  However, if the Advax or CpG55.2 components for Advax-
CpG55.2 are not available, the study will proceed only with groups 1, 2, 4 and 5 open for 
enrollment for the remaining subjects (up to 240) in groups 1, 2, 4 and 5. For the sentinel 
subjects, one subject from groups 1, 2, 4 and 5 will be enrolled and followed through Day 8. If 
any of the pre-specified halting rules occur, the study will be halted and reviewed by the DSMB. 
If no pre-specified events occur, randomization will proceed in groups 1, 2, 4 and 5 and 
enrollment will continue for the remaining subjects in groups 1, 2, 4 and 5. 
 
9.5.1 
Halting Rules for the Sentinel Subjects 
• Any subject experiences ulceration, abscess or necrosis at the injection site. 
• Any subject experiences laryngospasm, bronchospasm or anaphylaxis within 24 hours 
after administration. 
• Any subject experiences generalized urticaria (defined as occurring at more than two 
body parts) within 72 hours after administration of study product. 
• Any subject experiences an SAE (except for accident or trauma) after administration of 
the study product. 
• Any subject experiences acute weakness of limbs and/or cranial nerve innervated muscles 
(description of potential signal of GBS) after administration of study product. 
• Any subject that experiences grade 3 AE including lab, local or systemic solicited 
reactogenicity events (excluding measured grades of erythema and induration alone) 

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• Two or more subjects experience the same grade 2 (same HLGT by MedDRA coding) 
AE including local or systemic solicited reactogenicity events (excluding measured 
grades of erythema and induration alone) 
9.5.2 
Halting for Study 
 
Additional enrollment and study interventions/administration of study products in this trial will 
be halted for DSMB review/recommendation if any of the following are reported after the first 
study vaccination: 
• Any subject experiences ulceration, abscess or necrosis at the injection site that is 
considered related to study product administration. 
• Any subject experience laryngospasm, bronchospasm or anaphylaxis within 24 hours 
after administration of study product that is considered related to study product. 
• Two or more subjects experience generalized urticaria (defined as occurring at more than 
two body parts) within 72 hours after administration of study product that is considered 
related to study product. 
• Any subject experiences an SAE after administration of study product that is considered 
related to study product. 
• Any subject experiences acute weakness of limbs and/or cranial nerve innervated muscles 
(description of potential signal of GBS) after administration of study product. 
• Any subject develops a PIMMC after administration of study product. 
• 10% of subjects (minimum 3 subjects) experience a grade 3 injection site or systemic 
solicited adverse event (excluding measured grades of erythema and induration alone).   
• 10% of subjects (minimum 3 subjects) experience same grade 3 AE (unsolicited and 
laboratory abnormality), in the same HLGT by MedDRA coding, considered related to 
study product. 
Grading scales for solicited injection site and systemic (subjective and quantitative) reactions are 
included in Section 9.2.2. 
Grading scales for clinical safety laboratory AEs are included in Section 9.2.3. 

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If any of the halting rules are met following any subject receipt of study vaccination, then this 
trial will not continue with the remaining enrollments or study vaccinations without a review by 
and recommendation from the DSMB to proceed. 
 
DMID retains the authority to suspend additional enrollment and study 
interventions/administration of study products during this trial, as applicable. 
 
The DMID Medical Monitor is empowered to stop enrollment and study vaccinations if AEs that 
meet the halting criteria are reported. 
 
Safety Oversight 
9.6.1 
Independent Safety Monitor (ISM) 
An ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion. This is a voluntary position that 
does not receive payment. The ISM must meet the requirements of the NIAID Conflict of 
Interest (COI) policy. 
 
For this clinical trial an ISM is not required. However, at each participating VTEU site, upon 
DMID Medical Monitor request, the site PI will identify a physician with relevant expertise, to 
act as a Secondary Medical Assessor (SMA). The SMA will examine a subject and/or medical 
records and provide to DMID a medical assessment (or second medical opinion) of the safety 
event in question. The site PI or appropriate sub-investigator will send to the DMID Medical 
Monitor, a summary of the event and include the site PI or appropriate sub-investigator and SMA 
assessments. 
 
Note: In the case that DMID has requested this type of evaluation multiple times, DMID may 
request the participating VTEU site(s) identify an ISM to assist DMID with safety oversight. 
Data and Safety Monitoring Board (DSMB) 
 
9.6.2 
Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 

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or other COI related to this trial. The DSMB will consist of members with appropriate expertise 
to contribute to the interpretation of the data from this trial. 
 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. Procedures for DSMB reviews/meetings will be defined in the 
charter. The DSMB will review applicable data to include, but not limited to, study progress and 
subject, clinical, safety, reactogenicity, and immunogenicity data. Reports may include 
enrollment and demographic information, medical history, concomitant medications, physical 
assessments, clinical laboratory values, dosing compliance, solicited and unsolicited AE, SAEs, 
AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) and HAI and 
Neut antibody assay results. The DSMB will review SAEs on a regular basis and ad hoc during 
this trial. The DMID Medical Monitor and the ISM (as deemed necessary) will be responsible for 
reviewing SAEs in real time. 
The DSMB will review the data when the 8-day reactogenicity and clinical safety laboratory data 
following the first study vaccination is available for 50% of study subjects.  Enrollment will not 
be paused for this review.     
The DSMB will conduct the following reviews: 
• An Organizational Meeting that occurs prior to subject enrollment 
• Scheduled Data Review Meeting when 50% of the subjects reach Day 8 post first 
injection and all clinical safety laboratory data following the first study vaccination are 
available.  
• Scheduled Data Review Meeting when an expedited report containing safety and 
immunogenicity analyses for HAI, NAI and Neut antibody assays unblinded by group 
has been created by the SDCC after the interim clinical database is cleaned, monitored 
and locked and all HAI, NAI, and Neut data for Day 1 and Day 29 and safety date 
through Day 57 after the first study vaccination have been received.  If other 
immunological analyses are available, these data may be reviewed at this meeting.  
• Ad hoc when a halting rule is met, or DMID/DSMB chair may convene an ad hoc 
meeting if there are immediate concerns regarding observations during the course of this 
trial. The DMID Medical Monitor is empowered to stop enrollment and study 
vaccinations if AEs that meet the halting criteria are reported. 
• Final review meeting may be conducted: 6 to 8 months after clinical database lock to 
review the cumulative unblinded safety and immunogenicity data for this trial. If a final 
meeting is held, the data may be provided in a standard summary format, or provided as 

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the CSR. The DSMB may be asked to provide recommendations in response to questions 
posed by DMID. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion and may request the treatment assignment be 
unblinded for an individual subject if required for safety assessment. The DSMB will review 
grouped and unblinded data in the closed session only. As an outcome of each review/meeting, 
the DSMB will make a recommendation as to the advisability of proceeding with study 
vaccinations, as applicable, and to continue, modify or terminate this trial. 

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

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11 
STATISTICAL CONSIDERATIONS 
 
Introduction  
The goal of this clinical study is to assess, in healthy adults ages 18-45, the safety, reactogenicity 
and immunogenicity of either the 2018/2019 seasonal Fluzone or Flublok QIV manufactured by 
Sanofi Pasteur administered intramuscularly given without adjuvant or with one of two 
adjuvants, AF03 or Advax-CpG55.2.  These study arms are included to allow evaluation of the 
potential of each of the two adjuvants to enhance the immune response to either the 2018/2019 
seasonal Fluzone QIV or the 2018/2019 seasonal Flublok QIV. 
 
Study Hypotheses 
This Phase I 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 either the 
2018/2019 seasonal Fluzone or Flublok QIV administered without adjuvant or with AF03 or 
Advax-CpG55.2 adjuvants, and to uncover any safety issues that occur at a sufficiently high rate 
that they might be observed in a study of this size. The sample size facilitates formal testing of 
selected hypotheses as discussed in Section 11.4.3, along with the probability of observing safety 
outcomes and the precision of immunogenicity outcomes. 
    
 
Study Outcome Measures 
Please refer to Study Outcome Measures outlined in Table 1. 
 
Sample Size Considerations 
Please refer to Study Design outlined in Section 4. 
11.4.1 
Study Population 
The study population for this clinical trial includes males and non-pregnant females, 18-45 years 
of age, who are in good health and meet all eligibility criteria. The subjects will be recruited 
from the general population at each of the participating VTEU sites that have substantial 
experience conducting large influenza vaccine studies. 

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11.4.2 
Subject Enrollment and Follow-up 
Based on the accrual rates observed in similar studies, it seems reasonable to expect that the 
participating VTEUs will be able to enroll this trial in a timely fashion. In a previous DMID trial 
(DMID 15-0064, NCT02624219), 4 VTEUs recruited 275 healthy subjects, 19 to 64 years of 
age, in 20 weeks. In this trial, approximately 3% of subjects, 19 to 64 years of age, were 
excluded from the per protocol (PP) analysis for the Day 22 primary immunogenicity outcome 
either because they were lost-to-follow-up or because they had a protocol deviation requiring 
their exclusion from the PP analysis. The rate of per protocol exclusions for the Day 29 visit in 
this protocol is expected to follow a similar trend. 
A total of 40 subjects will be enrolled and randomized in each group. Assuming up to 3% drop 
out by Day 29, it is expected that at least 38 subjects per group will be available for the primary 
immunogenicity analysis. If Advax-CpG55.2 is not available, the study will proceed only with 
groups 1, 2, 4 and 5 open for enrollment for the remaining subjects (up to 240 or 60 per group) in 
groups 1, 2, 4 and 5. In this case, assuming the same dropout rate of 3%, it expected that at least 
58 subjects per group will be available for the primary immunogenicity analysis. 
Follow-up will consist of 2 segments. The first encompasses the core data for this trial and will 
consist of results for all study visits through approximately 28 days after study vaccination. The 
second segment consists of a 6-month immunogenicity assessment and follow-up safety 
assessments through approximately 12 months after study vaccination. 
11.4.3 
Sample Size 
This study is planned to enroll 40 subjects per group. If Advax-CpG55.2 is not available, the 
study will proceed only with groups 1, 2, 4 and 5 open for enrollment for the remaining subjects 
(up to 240 or 60 per group) in groups 1, 2, 4 and 5. This study is not designed to test a formal 
null hypothesis. Rather, it is intended to obtain sufficient data to obtain meaningful estimates of 
the immune response and to uncover any safety issues that occur at a sufficiently high rate that 
they might be observed in a study of this size. For the purposes of summarizing we will assume a 
type one error rate, alpha = 0.05, and will not adjust for multiple comparisons. The following 
tables illustrate the precision and power for select estimates and comparisons of interest. Table 
10 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 
sentinel subjects (N=4 or 6), for a single adjuvanted/ unadjuvanted treatment arm/stratum (N = 
40 or 60), for all subjects receiving the same seasonal QIV (N= 120), for all subjects in the trial 
(N=240). 

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Table 10: Probability (%) to Detect Safety Events 
Event 
Frequency 
N = 4 
N = 6 
N = 40 
N = 60 
N = 120 
N = 240 
≥10% 
Very Common 
34 
46 
98 
>99 
>99 
>99 
≥1% 
Common 
3 
5 
33 
45 
70 
91 
≥0.1% 
Uncommon 
<1 
<1 
3 
5 
11 
21 
≥0.01% 
Rare 
<1 
<1 
<1 
<1 
1 
2 
 
Binomial confidence intervals (CI) are widest (have the least precision) when the response rate is 
50%. Table 11 is presented to indicate the worst-case scenario for precision of observed exact 
(Clopper-Pearson) binomial confidence intervals. 
 
Table 11: Precision of Binomial Confidence Intervals 
For each of the primary immunogenicity objectives, a power analysis is provided below for 
testing the following hypotheses with the planned sample size, where pc = proportion of 
responders in comparator arm; where pe = proportion of responders in experimental arm.  
Test for difference in proportion responders: 
H0: pc – pe = 0 – No difference in proportion responders 
H1: pc – pe ≠ 0 – difference in response rates 
Table 12 illustrates the minimum detectable differences in the proportion of subjects responding 
(e.g., attaining seroconversion or a titer ≥1:40) between two adjuvanted treatment arms using a 
two-sided Likelihood Ratio Test and alpha = 0.05. It is assumed that approximately 3% of the 
N 
95% CI 
4 
6-94 
6 
11-89 
40 
33 -67 
60 
36-64 
120 
40-60 
240 
43-57 

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subjects (N=2) in each treatment arm will be excluded from the per protocol analysis of primary 
immunogenicity endpoints leaving N=38 subjects per treatment arm.  If Advax-CpG55.2 is 
unavailable, approximately 3% of the subjects (N=2) in each treatment arm will be excluded 
from the per protocol analysis of primary immunogenicity endpoints leaving N=58 subjects per 
treatment arm. Seroconversion rates of 40% to 90% are considered. 
Table 12: Minimum Detectable Difference in Proportion Responders with 80% Power 
Assumed Proportion of 
subjects with titer ≥ 40 in 
comparator arm (pc) 
Minimum detectable 
difference in response rate 
(pc-pe), 
N=38 per group 
Minimum detectable 
difference in response rate 
(pc-pe), 
N=58 per group 
0.40 
  0.32  
0.26 
0.50 
  0.30 
0.25 
0.60 
  0.28 
0.23 
0.70 
  0.24 
0.20 
0.80 
  0.18 
0.16 
0.90 
  0.10 
0.10 
  
 
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 9.6.2. 
 
Clinical, safety, and reactogenicity data through approximately 56 days after study vaccination 
will represent the interim clinical database for this trial. Once the last subject completes the visit 
that occurs approximately 56 days after first study vaccination, the interim clinical database will 
be cleaned, monitored and locked. Upon receipt of immunogenicity data for Day 1 and Day 29 
(HAI, NAI, and Neut data) and safety data through Day 57, the sponsor will authorize the DCC 
to transfer to Sanofi Pasteur a copy of this unblinded data set. An expedited report containing 
analyses of safety data through Day 57 and HAI, NAI, and Neut data from baseline (Day 1) and 
Day 29 unblinded by treatment group only will be prepared by the SDCC. These analyses may 
be made available to the sponsor and pharmaceutical partners for planning subsequent trials as 

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well as the DSMB for review. Other immunological analyses that are available may also be 
included in the expedited report and may also be reviewed by the DSMB.  
 
The analyses performed for the expedited report or using the data set provided to Sanofi Pasteur 
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 AESIs (including Protocol 
Specified AESIs, MAAEs, NOCMCs and PIMMCs) until all subjects have completed the final 
follow-up visit.  
11.5.1 
Interim Safety Review 
An interim safety review may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 
and solicited and unsolicited AE/SAEs. Additional data may be requested by the DSMB, and 
interim statistical reports may be generated as deemed necessary and appropriate by DMID. The 
DSMB may receive data in aggregate and presented by treatment arm, including expected and 
observed rates of the expected AEs. The DSMB will review grouped data in the closed session 
only. The DSMB will meet and review these 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 9.5 are met. 
 
 
Final Analysis Plan 
Subject unblinding will occur and the final CSR will be completed after the last subject’s last 
visit is completed, the final clinical database including all long-term safety follow-up data is 
cleaned, monitored and locked, and all primary and secondary immunogenicity data are 
available. After such data are reported in the database and the data are considered clean and 
complete, a “topline” subset of the immunogenicity tables planned for the CSR will be provided 
to DMID and Sanofi Pasteur.  Additional exploratory immunogenicity endpoint data not 
available at the time of CSR preparation may be included in an addendum to the CSR, 
manuscript(s), or other report. 

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A formal statistical analysis plan which defines the analyses to be included in the expedited 
report and the final CSR will be developed, finalized, and submitted to the FDA, prior to 
unblinding for any analysis. 
11.6.1 
Analysis Populations 
The Safety Analysis population includes all subjects who received the first dose of study 
vaccine. 
The modified intent-to-treat (mITT) population includes all randomized subjects who received 
the first dose of study vaccine and contributed at least one post-first study vaccination venous 
blood samples for immunogenicity testing (HAI, NAI 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 with the following 
exclusions: 
• 
Data from all available visits for subjects found to be ineligible at baseline. 
• 
Data from all visits for subjects that did not contribute venous blood samples for 
immunogenicity testing (HAI, NAI or Neut antibody assays) at baseline (Day 1). 
• 
Data from all visits subsequent to major protocol deviations, such as:  
o Receipt of non-study licensed live vaccine within 30 days before or after the 
first study vaccination, 
o Receipt of non-study licensed inactivated vaccine within 14 days before or after 
the first study vaccination, 
o Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days 
before or after the first 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. 

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11.6.2 
Safety Data 
Summaries and analysis of safety data will be presented for the Safety Analysis Population. All 
summaries and analyses will be presented for all subjects. 
 
Solicited AEs will be summarized by severity after the first study vaccination (1-7 days post 
study vaccination) and as the maximum severity over all 8 days. Additionally, solicited AEs will 
be analyzed by taking the most severe response over the follow-up period, dichotomizing into a 
binary variable (none versus mild, moderate, or severe) and using standard techniques, such as 
exact 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 for the first study vaccination by treatment arm. The proportion of subjects reporting 
symptoms may be compared between treatment arms using Chi-square or Fisher’s exact test.  
Unsolicited AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) for 
preferred term and system organ class (SOC). The numbers of SAEs and AESIs (including 
Protocol Specified AESIs, MAAEs, 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. 
Clinical laboratory data will be summarized by severity for each visit and as the maximum over 
all post-study vaccination visits. Graphical presentations may include box plots. 
11.6.3 
Humoral Immunogenicity Data 
Summaries and analysis of immunogenicity data will be presented for the mITT and PP 
populations. 
 
Immune responses in terms of strain-specific HAI, NAI, and Neut antibody titers will be 
summarized by treatment arm at each time point. Analyses will include GMTs, ratio of GMTs 
between adjuvanted and unadjuvanted study arms, percentage of subjects achieving 
seroconversion (as defined in Table 1) and percentage of subjects with a titer ≥1:40 (HAI and 
Neut only) along with corresponding 95% confidence intervals. Descriptive summary statistics 
will be provided for all assays and time points. These immune responses against vaccine strains 
will also be presented by serostatus and previous influenza vaccination. The correlation between 

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HAI, NAI and Neut antibody titers will be evaluated. Plots such as reverse cumulative 
distributions or longitudinal presentations of GMTs will be presented. 
 
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. 
11.6.4 
Exploratory Cellular Immunogenicity Data 
Summaries of exploratory cellular immunology assays will be presented for the Per Protocol 
Population and will be presented overall as well as by treatment arm. 
 
Analysis of the exploratory cellular immunogenicity data will be primarily descriptive.  
Association of exploratory endpoints with HAI, NAI, and Neut antibody titers will be assessed. 
11.6.5 
Exploratory Transcriptomics Data 
For the transcriptomics exploratory analysis, RNA-Seq data will be pre-processed by removing 
adapters and low-quality reads and mapping sequences to the latest human reference genome 
using splice-aware alignment software such as HISAT2[52]. Gene expression quantification will 
be carried out by using the Subread software [53] using the latest Ensembl  [54] gene model 
annotations as a reference. Systematic differences in sequence coverage between samples will be 
accounted for using the TMM normalization method [55] as implemented in the edgeR R 
package [56]. Principal component analysis, non-metric multidimensional scaling, and 
hierarchical clustering analysis will be used to identify potential outliers and systematic batch 
effects. Negative binomial models as implemented in edgeR [56] will be used to identify genes 
for each study group and post-vaccination day (Day 2 and 8) that were differentially expressed 
(DE) compared to pre-vaccination. If the analysis reveals a systematic batch effect that is not 
associated with study group or study visit, it will be accounted for by adding a batch blocking 
factor as part of the negative binomial models. To control for testing multiple genes, the false-
discovery rate (FDR) based on the Benjamini-Hochberg procedure [57] as implemented in the 
p.adjust R function will be applied. The pvclust R package [58] will be used to identify co-
expressed DE gene clusters. Mean cluster log2 fold change time trends and associated 95% 
bootstrap CIs will be presented by group across post-vaccination days. To functionally 
characterize DE genes, pathway enrichment analysis based on the latest MSigDB [59] and 
KEGG [60] databases as well as Blood Transcription Modules [61] will be carried out using the 
implementation provided by the goseq R package [62] which accounts for gene length bias. 
Pathway maps color-coded by treatment effect (log2 fold change compared to pre-vaccination) 

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will be visualized for significantly enriched KEGG pathways. Pathway enrichment trends by 
group across post-vaccination days will be visualized using heatmaps and time trend plots of 
median pathway responses (based on median average log2 fold changes of all pathway members) 
and associated 95% bootstrap CIs. Regularized linear regression analysis as implemented in the 
glmnet R package [63] will be utilized to identify gene expression changes that are predictive of 
later adaptive humoral immune response. Cross-validation will be used to select optimal models. 
11.6.6 
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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12 
DATA COLLECTION FORMS AND ACCESS TO 
SOURCE DATA/DOCUMENTS 
Each participating VTEU site will maintain appropriate medical and research records for this 
clinical trial, in compliance with ICH E6 GCP Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects. Each participating VTEU site will 
permit the study monitor or other authorized representatives of DMID as well as governmental 
regulatory agencies, such as the FDA, to examine (and when required by applicable law, to copy) 
clinical trial records for the purposes of quality assurance reviews, audits, monitoring and 
evaluation of the study safety and progress. These representatives will be permitted access to all 
source data, which include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files, and records kept at the pharmacy, at the laboratories and medico-technical 
departments involved in this clinical trial. Source data are all information, original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
 
Interview of subjects is sufficient for obtaining medical history. Solicitation of medical records 
from the subject’s primary care provider is not required. 
 

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

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

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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. During recruitment, potential 
subjects may be screened for eligibility by phone or email before obtaining written consent, per 
an IRB-approved process that ensures confidentiality.  At the first clinic visit before any study 
procedures are performed, informed consent will be obtained and documented. Subjects will 
receive a concise and focused presentation of key information about the trial, verbally and with a 
written ICF. The explanation will be organized and presented in lay terminology and language 
that facilitates understanding why one might or might not want to participate. The ICF must not 
include any exculpatory statements. 
 
The site PIs or their designees will describe the protocol to potential subjects face-to-face. The 
key information about the purpose of the trial, the procedures and experimental aspects of the 
trial, risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject.  The subject will be asked to consent specifically to genetic testing 
(transcriptomics) planned for this study. 
 
Subjects will also receive an explanation that the trial involves research and a detailed summary 
of the proposed study procedures and study interventions/study products. This will include 
aspects of the trial that are experimental, the probability for random assignment to treatment 
arms, any expected benefits, all possible risks (including a statement that the particular treatment 
or procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), the expected duration of the subject’s 
participation in the trial, alternative treatment/procedures that may be available, and the 
important potential benefits and risks of these available alternative treatment/procedures. 
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the site PI) for 
answers to any questions relating to the research project. 
 
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 

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The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitors, auditors, IRB, NIAID, and regulatory authorities will be granted direct access 
to the subject’s original medical records for verification of trial procedures and/or data without 
violating the confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations, and that, by signing a written ICF, the subject is authorizing such access. 
Subjects will be informed that records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws and/or regulations, will not be made publicly available 
and, if the results of the trial are published, the subject’s identity will remain confidential. 
Subjects will be informed whether private information collected from this research and/or 
samples/specimens will be used for additional research, even if identifiers are removed. 
Subjects will be allowed sufficient time to consider participation in the trial and have the 
opportunity to discuss the trial with their family, friends or legally authorized representative, or 
think about it prior to agreeing to participate. 
 
ICFs will be IRB-approved and subjects will be asked to read and review the ICF. Subjects must 
sign the ICF prior to starting any study procedures being done specifically for the trial. 
Once signed, a copy of the ICF will be given to the subjects for their records. The subject(s) may 
withdraw consent at any time throughout the course of the trial. The rights and welfare of the 
subjects will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in or withdraw from the trial. 
 
New information that significantly impacts the subject’s risk of receiving the study 
interventions/study products will be communicated by the site PIs or their designees to the 
subjects who consent to participate in the trial in accordance with IRB requirements. The ICF 
will be updated and subjects will be re-consented in accordance with IRB requirements, if 
necessary. Subjects will be given a copy of all ICFs that they sign. 
 
 
Exclusion of Women, Minorities and Children (Special Populations) 
This trial will be inclusive of all subjects, 18 to 45 years of age, who meet the Subject Inclusion 
Criteria (see Section 5.1.1) and do not meet the Subject Exclusion Criteria (see Section 5.1.2), 
regardless of religion, sex or ethnic background. Should the outcome of this trial be deemed 
acceptable, additional trials may be initiated including those in other populations. 
 
It is unknown if Fluzone QIV or Flublok QIV with AF03 or Advax-CpG55.2 adjuvant pose any 
risks to an unborn child. However, the unadjuvanted QIVs are recommended for pregnant 

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women and have not shown safety signals.  Women of childbearing potential must utilize a 
highly effective method of contraception that is defined as one that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly (effective methods of birth 
control are outlined in the inclusion criteria, section 5.1.1). 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 the first study vaccination. Female subjects who become pregnant 
while participating in this trial will be provided information to enroll in the Sanofi Pregnancy 
Registry, if they so choose. This registry program is not a part of this research study and 
participation in the registry program is completely voluntary.   
 
Children will not be included in this trial as presently there are no safety or efficacy data in 
adults. 
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the site PIs, other study personnel, the sponsor, 
and their agents. This confidentiality includes documentation, investigation data, subject’s 
clinical information, and all other information generated during participation in this trial. No 
information concerning this trial, or the data generated from this trial will be released to any 
unauthorized third party without written consent of the subject and approval by DMID. 
 
Subject confidentiality will be maintained when trial results are published or discussed in 
conferences and is extended to cover testing of samples/specimens. The study monitor or other 
authorized representatives of DMID as well as governmental regulatory agencies, such as the 
FDA, may inspect all documents and records required to be maintained by the site PIs. This 
includes, but is not limited to, medical records (office, clinic or hospital) and pharmacy records 
for the subjects in this trial. The participating VTEU sites will permit access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password-protected systems. All non-clinical 
samples/specimens, evaluation forms, reports, and other records that leave the site will be 
identified only by a coded number and will not be identified by the subject’s name. 
 
To protect privacy, we have received a Certificate of Confidentiality. With this Certificate, the 
researchers cannot be forced to release information that may identify the subject, even by a court 
subpoena, in any federal, state or local civil, criminal, administrative, legislative, or other 
proceedings. The researchers will use the Certificate to resist any demands for information that 
would identify the subject, except as explained below. 
 

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The Certificate cannot be used to resist a demand for information from personnel of the US 
Government that is used for auditing or evaluation of federally funded projects, like this trial, or 
for information that must be released in order to meet the requirements of the FDA. 
 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information. 
 
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse or wanting to harm themselves or others. 
 
Study Discontinuation 
If this trial is prematurely terminated by the sponsor, any regulatory authority, the site PI, or 
appropriate sub-investigator for any reason, the site PI or appropriate sub-investigator will 
promptly inform the subjects and assure appropriate therapy or follow-up for the subjects, as 
necessary. The site PI or appropriate sub-investigator will provide a detailed written explanation 
of the termination to the IRB. If any subject’s private information will continue to be collected 
for this trial, the IRB must approve an ICF with the study procedures, any risks and discomforts 
as well as applicable elements, and the site PI or designee will re-consent the subjects as 
approved by the IRB. 
 
If this trial is discontinued, subjects, who have signed the ICF, and are randomized and 
vaccinated, will continue to be followed for safety for the duration of the prescribed safety 
follow-up period. No further study vaccinations will be administered. 
 
Costs, Subject Compensation and Research Related Injuries 
There is no cost to subjects for the research tests, study procedures/evaluations or study vaccines 
while taking part in this trial. 
 
Subjects may be compensated for their participation in this trial. Compensation will be in 
accordance with local IRB requirements, and subject to local IRB approval. 
 

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If it is determined by the participating VTEU site and the site PI that an injury occurred to a 
subject as a direct result of the tests or treatments that are done for this trial, then referrals to 
appropriate health care facilities will be provided to the subject. Study personnel will try to 
reduce, control and treat any complications from this trial. Immediate medical treatment may be 
provided by the participating VTEU site, such as giving emergency medications to stop 
immediate allergic reactions to the study vaccine. No financial compensation will be provided to 
the subject by NIAID, NIH or the participating VTEU site for any injury suffered due to 
participation in this trial. 
 
Future Use of Stored Specimens 
Subjects who agree to participate in this trial will have venous blood collected for ESR and 
clinical safety laboratory evaluations, serological and cellular immunology assays, as well as for 
transcriptomic profiling assessments, a form of genetic testing. Subjects will be asked to give 
explicit consent to participate in the per protocol defined transcriptomics study.  
 
Subjects will be asked to consent to the future research use of excess/residual specimens and the 
sharing of genetic information and samples. If they choose to not provide permission for excess 
blood and future use, they will not be eligible for randomization and enrollment into the study.  
To maintain statistical power in follow-on analyses it is important that excess/residual blood 
collection be included in as many subjects as possible, due to the limited sample size per 
treatment arm.  
 
The amount of venous blood collected for serological and cellular immunology assays exceeds 
the amount of blood required to perform per protocol (PP) defined immunologic assays by 
approximately 175 mL collected across the study. This excess/residual blood and corresponding 
serum, plasma and PBMCs will be used as back-up specimens for PP defined assays or 
designated for future research use and stored indefinitely at a central storage facility. Collection 
of excess/residual samples during the course of the study will help facilitate rapid follow-on 
analyses, if warranted, to provide more comprehensive scientific insights into the impact (safety 
and immunological) of two novel adjuvants on the host response to vaccination.  
 
To maintain statistical power in follow-on analyses it is important that excess/residual blood 
collection be included in as many subjects as possible, due to the limited sample size per 
treatment arm. Samples designated for future research use may be used for additional 
immunological assessments that may include but are not limited to antibody epitope mapping, B 
and T cell repertoire determination, non-traditional immune assay development, determination of 
innate immune factors and the ability of vaccine-induced antibodies to cross-react to different 

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influenza proteins and virus strains. These blood samples might be used in new or different 
immunological laboratory tests, to provide information for the development of new vaccines, or 
for the studies of influenza or other infections. Future use DNA testing may also be warranted to 
understand genetic factors involved in vaccination failures, despite the presence of a specific 
adjuvant.  
 
Future research use specimens, upon written request and approval from DMID, may be shared    
with investigators at the participating VTEU sites, with other investigators or company 
designated research laboratories for purposes of conducting additional immunological 
assessments other than PP analysis. DMID would authorize shipment from the DMID CAR. 
There are no benefits to subjects in the collection, storage and future research use of their 
samples/specimens. Risks for excess blood drawn may include anemia, however the risk is low 
since the total amount drawn for this study and future use does not exceed a unit of blood.  
 
Future research use samples/specimens will not be sold or used directly for production of any 
commercial product.   Each sample/specimen will be encoded (labeled) only with a barcode and 
a unique tracking number to protect subject confidentiality. Reports from future research studies 
performed using subjects’ samples/specimens will NOT be kept in their health records. 
  
  
Subjects may withdraw permission to use samples for future use at any time.  They will need to 
contact the study site and the samples will be removed from the study repository after this study 
is completed and documentation will be completed that outlines the reason for withdrawal of 
permission for future use of samples. Subjects who withdraw consent before the last visit will not 
have the excess blood drawn for future use. 
 

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

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range checks, to identify data that appear inconsistent, incomplete or inaccurate. Clinical and 
reactogenicity data will be entered directly from the DCFs completed by the study personnel. 
 
Types of Data 
Data for this trial will include clinical, safety and outcome measures (e.g., clinical laboratory 
values, and reactogenicity and immunogenicity data). 
 
Timing/Reports 
Clinical, safety and reactogenicity data through approximately 56 days after the first study 
vaccination will represent the interim clinical database for this trial. Once the last subject 
completes the visit that occurs approximately 56 days after the first study vaccination, the 
primary clinical database will be cleaned, monitored and locked. Upon receipt of 
immunogenicity data for Day 1 and Day 29 (HAI, NAI, and Neut data) and safety data through 
Day 57, the sponsor will authorize the DCC to transfer to Sanofi Pasteur a copy of this unblinded 
data set.  
 
An expedited report containing immunogenicity analyses for HAI, NAI, and Neut antibody 
assays unblinded by treatment group only will be created by the SDCC after the interim clinical 
database is cleaned, monitored and locked and all HAI, NAI, and Neut data for Day 1 and Day 
29 after the first study vaccination have been received. Other immunological analyses that are 
available may also be included in the expedited report. These analyses may be made available to 
the sponsor and pharmaceutical partners for planning subsequent trials and the DSMB for 
review. 
 
 The analyses performed for the expedited report or the data set provided to Sanofi Pasteur 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, AESIs (including Protocol 
Specified AESIs, MAAEs, NOCMCs and PIMMCs) until all subjects have completed the final 
follow-up visit. All analyses of data included in the expedited report for early release will be 
included in the final clinical study report (CSR). 
 
The final CSR will be completed after the last subject’s last visit is completed, the final clinical 
database including all long-term safety follow-up data is cleaned, monitored and locked, and all 
primary and secondary immunogenicity data are available. After such data are reported in the 

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database and the data are considered clean and complete, a “topline” subset of the 
immunogenicity tables planned for the CSR will be provided to DMID and Sanofi Pasteur.  
Additional exploratory immunogenicity endpoint data not available at the time of CSR 
preparation may be included in an addendum to the CSR, manuscript(s), or other report. 
 
A formal statistical analysis plan will be developed, finalized, and submitted to the FDA, prior to 
unblinding for any analysis, which defines the analyses to be included in the expedited report and 
the final CSR. 
 
Additional statistical reports may be generated as deemed necessary and appropriate by DMID. 
Safety and immunogenicity summary reports may be generated for the DSMB. 
 
After the final CSR is complete, and upon request and DMID approval, the SDCC will provide 
the participating VTEU sites with a summary of results by treatment arm and/or subject 
treatment assignment. In this regard, the participating VTEU sites requesting such information to 
share with subjects must do so in accordance with IRB requirements. 
 
Study Records Retention 
Study records and reports, including, but not limited to, eCRFs, source documents, ICFs, and 
study drug disposition records shall be maintained for 2 years after a marketing application is 
approved for the drug for the indication for which it is being investigated; or, if no application is 
to be filed or if the application is not approved for the drug, until 2 years after the investigation is 
discontinued and the FDA has been notified. These documents will be retained for a longer 
period, however, if required by local regulations. ICFs for future research use will be maintained 
as long as the sample/specimen exists. 
 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site PI when these documents no longer need to be retained. The 
participating VTEU sites must contact DMID for authorization prior to the destruction of any 
study records. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the study protocol, GCP or protocol-specific 
MOP requirements. The noncompliance may be either on the part of the subject, the site PI or 
other study personnel. As a result of protocol deviations, corrective actions are to be developed 
by the site and implemented promptly. 

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These practices are consistent with ICH E6 GCP guidelines: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2 and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1 and 5.20.2 
It is the responsibility of the site PI and other study personnel to use continuous vigilance to 
identify and report protocol deviations within five working days of identification of the protocol 
deviation, or within five working days of the scheduled protocol-required activity. Protocol 
deviations must be promptly reported to DMID, via the SDCC’s Advantage eClinicalSM. 
 
Protocol deviations, as defined above, must be addressed on the appropriate DCF. A completed 
copy of the Protocol Deviation DCF must be maintained in the regulatory file as well as in the 
subject’s chart. Protocol deviations must be sent to the IRB in accordance with IRB 
requirements. The site PI and other study personnel are responsible for knowing and adhering to 
IRB requirements. 
 

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

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121 
17 
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123 
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[34] Menon V, Ayala VI, Rangaswamy SP, Kalisz I, Whitney S, Galmin L, et al. DNA 
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Affinity Maturation in Human Subjects Receiving Seasonal Influenza Vaccine. PloS one. 
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[42] Layton RC, Petrovsky N, Gigliotti AP, Pollock Z, Knight J, Donart N, et al. Delta inulin 
polysaccharide adjuvant enhances the ability of split-virion H5N1 vaccine to protect against 
lethal challenge in ferrets. Vaccine. 2011;29:6242-51. 
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[58] Suzuki R, Shimodaira H. Pvclust: an R package for assessing the uncertainty in hierarchical 
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18 
APPENDICES 
Appendix A: Schedule of Study Procedures and Evaluations 
Appendix B: Adverse Events of Special Interest 
 
 
 

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 SCHEDULE OF STUDY PROCEDURES AND 
EVALUATIONS 
Table 13: Schedule of Study Procedures and Evaluations 
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Early Termination  
Unscheduled 
Screening, 
Enrollment/Study 
Day and post first 
study vaccination 
Screening 
D-28 to -1 
Enrollment 
D1 
D2+1d 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90+/-14d 
Day118+/-3d 
D180 +/-14d 
D365 -14/+35 
Informed Consent∞ 
X∞ 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
Information 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X†¬
1 
 
 
 
 
 
 
 
 
 
 
Medical History@ 
X 
X†¬ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X†¬ 
X 
X 
X 
 
 
 
 
 
X6  
X6 
Vital Signs (Oral 
Temperature%, Pulse 
and BP) 
X 
X$ 
 
 
 
 
 
 
 
 
X  
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X2 
{X} 
{X} 
{X} 
{X} 
{X} 
{X}
†  
{X} 
{X} 
{X} 
{X} 
{X} 
Urine or Serum 
Pregnancy Test 
X^ 
X†^ 
 
 
 
 
 
 
 
 
 
 
Venous Blood 
Collection for 
Screening Laboratories 
X≠ 
 
 
 
 
 
 
 
 
 
 
 
Enrollment in 
Advantage eClinicalSM 
and Randomization 
 
X† 
 
 
 
 
 
 
 
 
 
 
Venous Blood 
Collection for Clinical 
Safety Laboratory 
Evaluations~ 
 
X†,~ 
 
X~ 
 
 
 
 
 
 
X7 
X  
Venous Blood 
Collection for 
Serological Assays 
 
X† 
 
X 
X 
X 
X† 
X 
X 
X 
X 
X 
Venous Blood 
Collection for Cellular 
Immunology Assays 
 
X† 
 
X 
X 
 
X† 
 
 
 
X8 
 
Venous Blood 
Collection for 
Transcriptomics 
 
X† 
X 
X 
 
 
 
 
 
 
X9 
 
Pre-Administration 
Reactogenicity 
Assessments 
 
X† 
 
 
 
 
 
 
 
 
 
 

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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Early Termination  
Unscheduled 
Screening, 
Enrollment/Study 
Day and post first 
study vaccination 
Screening 
D-28 to -1 
Enrollment 
D1 
D2+1d 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90+/-14d 
Day118+/-3d 
D180 +/-14d 
D365 -14/+35 
Study Vaccination 
 
X 
 
 
 
 
X* 
 
 
 
 
 
20-minute Evaluation 
After Study 
Vaccination 
 
X 
 
 
 
 
 
 
 
 
 
 
Examine Study 
Vaccination Site 
 
X 
X 
X 
 
 
  
 
 
 
X7 
X7 
Post-Administration 
Reactogenicity 
Assessments 
 
X 
 
 
 
 
 
 
 
 
X7 
X7 
Distribute Memory Aid 
and Study-Related 
Materials 
 
X 
 
 
 
 
 
 
 
 
 
 
Review Memory Aid 
 
 
X 
X 
 
 
 
 
 
 
X7  
X7 
AE/SAE Assessment 
 
X&,3 
X&,3 
X&,3 
X3 
X 
X4 
X4 
X4 
X4 
X3,6  
X3,6 
 
∞ Prior to study procedures. 
¬ Review/confirm information or activity in subjects previously consented and screened. 
† Prior to study vaccination. 
1 Review results of ESR and clinical safety laboratory evaluations. 
@ Complete medical history (including solicitation for receipt of any non-study influenza vaccine) will be obtained 
by interview of subjects at the screening visit  and interim medical history will be obtained by interview of 
subjects on Day 1 prior to study vaccination and at follow-up visits after study vaccination. 
$ Vital signs assessed on Day 1 prior to the 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 At the 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, and nervous system.  
{} Targeted physical examination if indicated based on review of interim medical history. 
^ Performed locally by the site at the screening visit (optional); Must be performed within 24 hours prior to study 
vaccination for all women of childbearing potential. Results must be negative and known prior to randomization 
on Day 1 and administration of study vaccination. 
≠ ESR Performed by local laboratory, WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum 
amylase and Cr will be sent to the central clinical laboratory.  
~ Includes, WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum amylase and Cr. 
& Inclusive of reactogenicity assessments performed on the day of study vaccination through 7 days after study 
vaccination. 
3  AEs (if visit occurs on or before Day 29), SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs 
and PIMMCs), for subjects who are being followed for safety. 
4 SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), for subjects who are 
being followed for safety. 

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5 Investigators have the discretion of administering 2019/2020 Fluzone or Flublok earlier than the Day 90 window 
(i.e earlier than Day 76) if 10% of more of surveillance samples in the CDC geographic region surrounding the 
local site test positive for influenza. 
6If within 365 after first study vaccination 
7 If within the first 7 days after the first study vaccination 
8 If prior to or at the D90 visit 
9 If prior to or at the D8 visit 
* Seasonal QIV 2019/2020 
 

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 ADVERSE EVENTS OF SPECIAL INTEREST 
 
MAAEs 
NOCMCs 
PIMMCs: 
Gastrointestinal disorders 
• 
Celiac disease 
• 
Crohn’s disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
Liver disorders 
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
Metabolic diseases 
• 
Addison’s disease 
• 
Autoimmune thyroiditis (including Hashimoto thyroiditis) 
• 
Diabetes mellitus type I 
• 
Grave’s or Basedow’s disease 
Musculoskeletal disorders 
• 
Antisynthetase syndrome 
• 
Dermatomyositis 
• 
Juvenile chronic arthritis (including Still’s disease) 
• 
Mixed connective tissue disorder 
• 
Polymyalgia rheumatic 
• 
Polymyositis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Rheumatoid arthritis 
• 
Scleroderma, including diffuse systemic form and CREST syndrome 

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• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s 
Syndrome) and undifferentiated spondyloarthritis 
• 
Systemic lupus erythematosus 
• 
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 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse myelitis 
• 
Myasthenia gravis, including Eaton-Lambert syndrome 
Skin disorders 
• 
Alopecia areata 
• 
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis 
herpetiformis 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Morphoea 
• 
Lichen planus 
• 
Psoriasis 
• 
Sweet’s syndrome 
• 
Vitiligo 
Vasculitides 
• 
Large vessels vasculitis including: giant cell arteritis such as Takayasu’s arteritis and 
temporal arteritis 
• 
Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, 
Kawasaki’s disease, microscopic polyangiitis, Wegener’s granulomatosis, Churg-
Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease 
thromboangiitis obliterans, necrotizing vasculitis and anti-neutrophil cytoplasmic 

DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
132 
antibody (ANCA) positive vasculitis (type unspecified), Henoch- Schonlein purpura, 
Behcet’s syndrome, leukocytoclastic vasculitis 
Others 
• 
Antiphospholipid syndrome 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis 
rapidly progressive, membranous glomerulonephritis, membranoproliferative 
glomerulonephritis, and mesangioproliferative glomerulonephritis) 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Autoimmune parotitis 
• 
Autoimmune thrombocytopenia 
• 
Good pasture syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Pernicious anemia 
• 
Raynaud’s phenomenon 
• 
Sarcoidosis 
• 
Sjögren’s syndrome 
• 
Stevens-Johnson syndrome 
• 
Uveitis 
 
Protocol Specified AESIs 
• Dry Eyes 
• Tearing  
• Dry Mouth