A Phase I Trial to Evaluate the Safety and Immunogenicity of an Influenza Vaccination Strategy Including a H3N2 M2SR Prime Followed by a Seasonal Quadrivalent Inactivated Vaccine Boost in a Pediatric Population 9-17 Years Old
Phase: PHASE1
Conditions: Influenza, Influenza Immunisation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
A Phase I Trial to Evaluate the Safety and Immunogenicity of an Influenza 
Vaccination Strategy Including a H3N2 M2SR Prime followed by a Seasonal 
Quadrivalent Inactivated Vaccine Boost in a Pediatric Population 9-17 years 
old 
 
DMID Protocol Number: 17-0012 
 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
 
Pharmaceutical Support: 
FluGen 
IND Sponsor: DMID, NIAID 
 
Principal Investigator: Daniel F. Hoft, MD, PhD 
DMID Clinical Project Manager: Tena Knudsen, RN 
DMID Scientific Lead: Chris Roberts, PhD 
DMID Medical Officer:  Francisco J. Leyva M.D., Ph.D, ScM 
DMID Medical Monitor:  Mohamed Elsafy, MD 
Version: 6.0 
3 MARCH 2020 
 
 
 
 
 

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H3N2 M2SR in Pediatric Population 
March 3, 2020 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 United States Code of Federal Regulations (CFR) 45 CFR Part 46:  Protection of 
Human Subjects 
 Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 312 
(Investigational New Drug Application, 21 CFR 812 (Investigational Device 
Exemptions) 
 
The International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) 
E6(R2) Good Clinical Practice:  Integrated Addendum to ICH E6(R1) Guidance for 
Industry, published in the Federal Register (83 Federal Register 8882 (2018)), 
including the latest finalized revision 
 International Conference on Harmonisation: Good Clinical Practice (ICH E6): 62 
Federal Register 25691 (1997); and future revisions 
 Belmont Report:  Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, Report of the National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research 
 National Institutes of Health (NIH) Office of Extramural Research, Research 
Involving Human Subjects, as applicable 
 National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of 
Award, as applicable 
 Applicable Federal, State, and Local Regulations and Guidance  
 
 

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SIGNATURE PAGE 
The signature below provides the necessary assurances that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements.   
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 
Site Investigator Signature: 
 
Signed: 
 
 
Date: 
 
 
Daniel F. Hoft, MD, PhD 
Principal Investigator 
 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................9 
LIST OF ABBREVIATIONS ........................................................................................................10 
PROTOCOL SUMMARY .............................................................................................................13 
1. 
Key Roles ...............................................................................................................20 
2. 
Background Information and Scientific Rationale ................................................21 
2.1. 
Background Information ........................................................................................21 
2.2. 
Rationale ................................................................................................................22 
2.3. 
Potential Risks and Benefits ..................................................................................23 
2.3.1. 
Potential Risks .......................................................................................................23 
2.3.2. 
Known Potential Benefits ......................................................................................26 
3. 
Objectives and Outcome Measures ........................................................................28 
3.1. 
Study Objectives ....................................................................................................28 
3.1.1. 
Primary:..................................................................................................................28 
3.1.2. 
Secondary:..............................................................................................................28 
3.1.3. 
Exploratory: ...........................................................................................................28 
3.2. 
Study Outcome Measures ......................................................................................28 
3.2.1. 
Primary:..................................................................................................................28 
3.2.2. 
Secondary:..............................................................................................................29 
3.2.3. 
Exploratory: ...........................................................................................................30 
4. 
Study Design ..........................................................................................................32 
5. 
Study Enrollment and Withdrawal.........................................................................33 
5.1. 
Subject Inclusion Criteria ......................................................................................33 
5.2. 
Subject Exclusion Criteria .....................................................................................35 
5.3. 
Treatment Assignment Procedures ........................................................................37 
5.3.1. 
Randomization Procedures ....................................................................................37 
5.3.2. 
Masking Procedures ...............................................................................................37 
5.3.3. 
Reasons for Withdrawals and Discontinuation of Study Product Administration 38 
5.3.4. 
Handling of Withdrawals and Discontinuation of Administration ........................39 
5.3.5. 
Subject Replacement ..............................................................................................40 
5.3.6. 
Termination of Study .............................................................................................40 
6. 
Study Intervention/Investigational Product ...........................................................41 
6.1. 
Study Product Description .....................................................................................41 
6.1.1. 
Acquisition .............................................................................................................42 

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6.1.2. 
Formulation, Packaging, and Labeling ..................................................................43 
6.1.3 
Product Storage and Stability.................................................................................45 
6.2. 
Dosage, Preparation, and Administration of Study Intervention/ Investigational 
Product ...................................................................................................................45 
6.3. 
Modification of Study Intervention/Investigational Product for a Subject ............48 
6.4. 
Accountability Procedures for the Study Intervention/ Investigational Product(s)
................................................................................................................................48 
6.5. 
Assessment of Subject Compliance with Study Intervention/ Investigational 
Product/Investigational Device ..............................................................................49 
6.6. 
Concomitant Medications/Treatments ...................................................................49 
7. 
Study Schedule.......................................................................................................50 
7.1. 
Recruitment ............................................................................................................50 
7.2. 
Screening Visit .......................................................................................................50 
7.2.1. 
Visit 00, Screening Visit ........................................................................................50 
7.3. 
Enrollment Visit .....................................................................................................52 
7.3.1. 
Visit 01, Enrollment and First Study Vaccination, (Dose 1), Clinic Visit.............52 
7.4. 
Follow-up ...............................................................................................................53 
7.4.1. 
Visit 02, Day 08, Clinic Visit.................................................................................54 
7.4.2. 
Visit 03, Day 22, Clinic Visit.................................................................................55 
7.4.3. 
Visit 04, Day 57, Clinic Visit.................................................................................56 
7.4.4. 
Visit 05, Day 92, Second Vaccination (Dose 2), Clinic Visit................................57 
7.4.5. 
Visit 06, Day 113, Clinic Visit...............................................................................58 
7.4.6. 
Visit 07; Day 240, Phone Call ...............................................................................59 
7.5. 
Final Study Visit, Visit 08, Day 366, Phone Call ..................................................59 
7.6. 
Early Termination Visit (if needed) .......................................................................59 
7.7. 
Unscheduled Visit (if needed) ...............................................................................60 
8. 
Study Procedures/Evaluations ...............................................................................62 
8.1. 
Clinical Evaluations ...............................................................................................62 
8.2. 
Laboratory Evaluations ..........................................................................................63 
8.2.1. 
Clinical Laboratory Evaluations ............................................................................63 
8.2.2. 
Special Assays or Procedures ................................................................................64 
8.2.3. 
Specimen Preparation, Handling, and Shipping ....................................................66 
8.2.3.1. 
Instructions for Specimen Preparation, Handling, and Storage .............................66 
8.2.3.2. 
Specimen Shipment ...............................................................................................66 
9. 
Assessment of Safety .............................................................................................67 
9.1 
Specification of Safety Parameters ........................................................................67 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
................................................................................................................................67 
9.2.1 
Adverse Events ......................................................................................................67 

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9.2.2. 
Reactogenicity........................................................................................................69 
9.2.3. 
Serious Adverse Events .........................................................................................74 
9.2.4. 
Adverse Events of Special Interest (AESI) ............................................................76 
9.2.5. 
Clinical Safety Laboratory Adverse Event Grading ..............................................76 
9.2.6. 
Respiratory Tract Assessment Grading: Erythema and Induration .......................77 
9.2.7. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings ...................................................................................78 
9.3. 
Reporting Procedures .............................................................................................79 
9.3.1 
Serious Adverse Events .........................................................................................79 
9.3.2. 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND .......80 
9.3.3. 
Reporting of Pregnancy .........................................................................................80 
9.4. 
Type and Duration of Follow-up of Subjects after Adverse Events ......................81 
9.5. 
Halting Rules .........................................................................................................81 
9.6. 
Safety Oversight.....................................................................................................82 
9.6.1 
Independent Safety Monitor (ISM) ........................................................................82 
9.6.2 
Safety Monitoring Committee (SMC) ...................................................................83 
10. 
Clinical Monitoring ................................................................................................85 
10.1 
Site Monitoring Plan ..............................................................................................85 
11. 
Statistical Considerations .......................................................................................86 
11.1 
Study Hypothesis ...................................................................................................86 
11.2. 
Sample Size Considerations ...................................................................................86 
11.3. 
Planned Interim Analyses ......................................................................................87 
11.3.1 
Interim Safety Review ...........................................................................................87 
11.3.2. 
Interim Immunogenicity Review ...........................................................................88 
11.4. 
Final Analysis Plan ................................................................................................88 
11.4.1. 
Analysis Populations ..............................................................................................89 
11.4.2. 
Primary Safety Data ...............................................................................................90 
11.4.3. 
Secondary Immunogenicity Data ...........................................................................90 
11.4.4. 
Exploratory Immunogenicity Data ........................................................................91 
11.4.5. 
Missing Values and Outliers ..................................................................................91 
12. 
source documents access to source data/documents ..............................................92 
13. 
Quality Control and Quality Assurance .................................................................93 
14. 
Ethics/Protection of Human Subjects ....................................................................94 
14.1. 
Ethical Standard .....................................................................................................94 
14.2. 
Institutional Review Board ....................................................................................94 
14.3. 
Informed Consent Process .....................................................................................95 
14.3.1 
Informed Consent/Assent Process (in Case of a Minor) ........................................97 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................98 
14.5 
Subject Confidentiality ..........................................................................................98 

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14.6 
Study Discontinuation ............................................................................................99 
14.7 
Costs, Subject Compensation, and Research Related Injuries ...............................99 
14.8 
Future Use of Stored Specimens and Data ..........................................................100 
14.9 
Disclosure of Study Related Information ............................................................102 
15. 
Data Handling and Record Keeping ....................................................................103 
15.1. 
Data Management Responsibilities......................................................................103 
15.2. 
Data Capture Methods .........................................................................................103 
15.3. 
Types of Data .......................................................................................................104 
15.4. 
Timing/Reports ....................................................................................................104 
15.5. 
Study Records Retention......................................................................................105 
15.6. 
Protocol Deviations ..............................................................................................105 
16. 
Publication Policy ................................................................................................107 
17. 
Literature References ...........................................................................................108 
APPENDIX A : SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS................110 
 
 
 

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LIST OF TABLES 
Table 1: Treatment Arms: ............................................................................................................. 18 
Table 2: Venipuncture Volumes (mL): ......................................................................................... 65 
Table 3: Power (%) to Detect Safety Events: ............................................................................... 86 
Table 4: Minimum Detectable Difference in Proportion Responders with 80% Power............... 87 
 
 

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LIST OF FIGURES 
Figure 1: Schematic of Study Design: .................................................................................... 19 
Figure 2: Image of the VaxINator Device ............................................................................... 46 
Figure 3: Image of the MAD301 Sprayer Device .................................................................. 47 
 
 

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LIST OF ABBREVIATIONS 
AdvantageEDCSM 
Electronic Data Capture System 
AE 
Adverse Event/Adverse Experience 
AESI 
Adverse Event of Special Interest 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
CAR 
Clinical Agents Repository 
CBC 
Complete Blood Count 
CFC 
Chlorofluorocarbons 
CFR 
Code of Federal Regulations 
CFSE 
Carboxyfluorescein Succinimidyl Ester 
CI 
Confidence Interval 
CMI 
Cell-Mediated Immunity 
CROMS 
Clinical Research Operations & Management Support 
CSR 
Clinical Study Report 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
DRM 
Data Review Meetings 
eCRF 
Electronic Case Report Form 
EIA 
Enzyme-Linked Immunoassay 
ELISA 
Enzyme-Linked Immunosorbent Assay 
ELISpot 
Enzyme-Linked Immunosorbent Spot  
ELLA 
Enzyme-Linked Lectin Assay 
EPT 
End Point Titer 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
g/dL 
Grams per Deciliter 
GBS 
Guillain-Barré Syndrome 
GMFR 
Geometric Mean Fold Rise 
GCP 
Good Clinical Practice 
GMT 
Geometric Mean Titer 
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition 
HGB 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 

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IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICS 
Intracellular Cytokine Staining 
IFN-γ 
Interferon Gamma 
IFU 
Instructions for Use 
IgG 
Immunoglobulin G 
IIV 
Inactivated Influenza Virus Vaccine 
IM 
Intramuscular 
IN 
Intranasal 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intent-to-Treat 
KG 
Kilogram 
LAIV 
Live Attenuated Influenza Vaccine 
mcg  
Microgram(s) 
µL 
Microliter(s) 
MDCK 
Madin Darby Canine Kidney cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/dL 
Milligram(s) per Deciliter 
mL 
Milliliter(s) 
Mm 
Millimeter(s) 
mmHg 
Millimeters of Mercury 
MOP 
Manual of Procedures 
N 
Number of Subjects 
NA 
Neuraminidase 
NACL 
Sodium Chloride 
Neut 
Neutralizing or Neutralization 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NOCMC 
New Onset Chronic Medical Conditions 
NIH 
National Institutes of Health 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
PBS 
Phosphate Buffered Saline 
PCR 
Polymerase Chain Reaction 
PHI 
Personal Health Information 

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PP 
Per Protocol 
QA 
Quality Assurance 
QC 
Quality Control 
QIV 
Quadrivalent Influenza Vaccine 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical Data Coordinating Center 
sIgA 
Secretory IgA 
SLUCVD 
Saint Louis University Center for Vaccine Development 
SMC 
Safety Monitoring Committee 
SOB 
Shortness of Breath 
SOP 
Standard Operating Procedure 
 
 
TBD 
To Be Determined 
US 
United States 
USDA 
US Department of Agriculture 
VTEU 
Vaccine and Treatment Evaluation Unit 
WB 
Whole Blood 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 

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PROTOCOL SUMMARY 
Title: 
A Phase I Trial to Evaluate the Safety and Immunogenicity of an 
Influenza Vaccination Strategy Including an H3N2 M2SR Prime 
followed by a Seasonal Quadrivalent Inactivated Vaccine Boost in 
a Pediatric Population 9-17 years old 
Phase: 
I 
Population: 
50 males and non-pregnant females, 9 to 17 years old, inclusive, 
who are in good health and meet all eligibility criteria 
PNumber of Sites: 
1 Vaccine and Treatment Evaluation Unit (VTEU) site 
Study Duration: 
Approximately 28 months 
Subject Participation 
Duration: 
Approximately 13 months 
 
 
Description of Agent: 
One dose of a monovalent live attenuated influenza H3N2 M2SR 
vaccine manufactured by FluGen or placebo administered 
intranasally (IN) followed by one dose of licensed quadrivalent 
influenza vaccine (QIV) administered intramuscularly 3 months 
later. 
Objectives: 
 
Primary: 
Safety: 
• To assess the safety and reactogenicity of a monovalent 
live attenuated influenza H3N2 M2SR vaccine. 
Secondary: 
Immunogenicity: 
• Identification of circulating and mucosal antibody 
responses induced by H3N2 M2SR vaccination. 

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• Identification of cellular immune responses induced by 
H3N2 M2SR vaccination.  
 
Exploratory: 
• Investigation of H3N2 M2SR priming effects on QIV-
induced broadly neutralizing serum antibody responses to 
HA and NA.   
 
• Investigation of H3N2 M2SR priming effects on QIV-
induced influenza-specific secretory IgA (sIgA) responses. 
 
• Investigation of H3N2 M2SR priming effects on QIV-
induced influenza-specific CD4 and CD8 T cell 
lymphoproliferative and effector cytokine responses.   
 Outcome Measures: 
 
 
Primary: 
 
Safety: 
 
• 
Frequency of solicited upper respiratory and systemic 
reactogenicity through approximately Day 8 after the first 
study vaccination.  
 
•     Frequency of unsolicited non-serious adverse events 
from the time of study vaccination through 21 days 
after the first study vaccination. 
 
•     Frequency of SAEs, regardless of seriousness or 
relationship to study vaccination, from receipt of the 
first vaccination throughout the entire study. 
 
• 
Frequency of New Onset Chronic Medical Conditions 
(NOCMC) and AESIs that develop from receipt of 
vaccination through 3 months after first study 
vaccination.  
Secondary: 

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Immunogenicity: 
 
• 
For HAI and Neutralizing antibody responses, percentage 
of subjects achieving seroconversion (defined as either a 
pre-vaccination titer <1:10 and a post-vaccination titer 
≥1:40 or a pre-vaccination titer ≥1:10 and a minimum four-
fold rise in post-vaccination antibody titer) against an 
H3N2 M2SR-like virus and H3N2 QIV-like viruses at 
approximately 7, 21, and 56 days following receipt of the 
first study vaccination and immediately prior to and 
approximately 21 days following receipt of QIV.  
 
• 
For HAI and Neutralizing antibody responses, percentage 
of subjects achieving a serum antibody titer of 1:40 or 
greater against the H3N2 M2SR-like virus and the H3N2 
QIV-like virus at baseline and approximately 7, 21, and 56 
days following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following 
receipt of QIV. 
 
• 
For HAI and Neutralizing antibody responses, the 
geometric mean titers (GMTs) and geometric mean fold 
rise (GMFR) to H3N2 M2SR-like virus and the H3N2 
QIV-like virus at baseline and approximately 7, 21, and 56 
days following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following 
receipt of QIV.   
 
• 
GMT and GMFR of nasal sIgA responses directed against 
the H3N2 M2SR virus and the H3N2 QIV virus measured 
by EPT(ELISA) with and without normalization to total 
sIgA at baseline and approximately 7, 21, and 56 days 
following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following 
receipt of QIV.  
 
• 
Frequency of influenza H3 HA-specific (H3 M2SR-like 
and QIV-like viruses) and conserved internal viral protein-

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specific IFN-γ ELISPOT responses at baseline and 
approximately 7, 21, and 56 days following receipt of the 
first study vaccination and immediately prior to and 
approximately 21 days following receipt of QIV. 
Exploratory: 
• 
GMT and GMFR of serum chimeric HA ELISA reactivity 
with Groups 1 and 2 HA stem domains of the viral 
hemagglutinin at baseline and approximately 7, 21, and 56 
days following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following 
receipt of QIV.  (Note:  These studies will be contingent 
upon seeing increased seroconversion rates and/or 4fold 
rises in either M2SR or QIV matched H3HA-specific HAI 
and/or MN assays induced by H3N2 M2SR vaccination). 
 
• 
GMT and GMFR of serum anti-NA antibody titers to N1 
and N2 Neuraminidases as determined by NA ELLA or 
ELISA at baseline and approximately 7, 21, and 56 days 
following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following 
receipt of QIV.  (Note:  These studies will be contingent 
upon seeing increased seroconversion rates and/or 4-fold 
rises in either M2SR or QIV matched H3HA-specific HAI 
and/or MN assays induced by H3N2 M2SR vaccination). 
 
• 
GMT and GMFR of nasal wash sIgA chimeric HA ELISA 
to the HA stem domains of the viral hemagglutinin (Group 
2 versus Group 1 viruses with and without normalization to 
total sIgA at baseline and approximately 7, 21, and 56 days 
following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following 
receipt of QIV.  (Note:  These studies will be contingent 
upon seeing increased GMT and/or GMFR of sIgA reactive 
with M2SR matched H3HA induced by H3N2 M2SR 
vaccination). 
 

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• 
GMT and GMFR of sIgA anti-NA antibody titers to N1 
and N2 Neuraminidases as determined by NA ELLA or 
ELISA at baseline and approximately 7, 21, and 56 days 
following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following 
receipt of QIV.  (Note:  These studies will be contingent 
upon seeing increased GMT and/or GMFR of sIgA reactive 
with M2SR matched H3HA induced by H3N2 M2SR 
vaccination. 
 
• CD4+ and CD8+ T cell responses to the H3HA present in 
the M2SR vaccine and pools of highly conserved Influenza 
A T cell epitopes by 7 day CFSE dilution/flow cytometry 
at baseline and approximately 7, 21, and 56 days, following 
receipt of the first study vaccination and immediately prior 
to and approximately 21 days following receipt of QIV.  
(Note:  These studies will be contingent upon seeing 
increased frequencies of H3HA-specific and/or conserved 
peptide epitope-specific IFN-gamma producing T cells 
induced by M2SR vaccination in ELISPOT assays).  
 
Description of Study Design: This is a Phase I randomized, double-blind, comparison trial in 50 
children and adolescents, 9 to 17 years old, inclusive, who are in 
good health and meet all eligibility criteria.  This clinical trial is 
designed to assess the safety and immunogenicity of a monovalent 
H3N2 M2SR vaccine (manufactured by FluGen) in an older 
pediatric population.  The monovalent influenza H3N2 M2SR 
virus vaccine was derived from influenza strain 
A/Brisbane/10/2007-like H3N2 (H3N2 M2SR). 
Subjects will be enrolled in one of two groups in a 1:1 ratio as 
indicated in Table 1.  Subjects will be randomly assigned to either 
receive one dose of Saline intranasally or one dose of M2SR 
intranasally followed by one dose of licensed QIV 3 months later.   
Reactogenicity will be measured for the first vaccine (first 
vaccination) by the occurrence of solicited reactions from the time 
of study vaccination through Day 8 after vaccination.  Unsolicited 
non-serious AEs will be collected from the time of the first study 

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vaccination through approximately 21 days after the first study 
vaccination.  SAEs will be collected from the time of the first 
study vaccination throughout the entire study.  AESIs (wheezing, 
and otitis media) and NOCMC will be documented and reported 
from the time of first study vaccination through approximately 3 
months after first study vaccination. 
Immunogenicity testing will include performing HAI, HA/NA 
ELISA, neutralization, nasal secretory IgA (sIgA), IFN-γ 
ELISPOT and CFSE dilution/ICS assays.  Serum for HAI, HA/NA 
ELISA and neutralization assays will be obtained on Day 01 (pre-
vaccination), Days 08, 22, and 57 after the first vaccination, 
immediately prior to the 2nd study vaccination (Day 92), and on 
Day 22 after the 2nd vaccination.  Nasal swabs for sIgA will be 
collected on Day 01 (pre-vaccination), Days 08, 22, and 57 after 
the first vaccination, immediately prior to the 2nd vaccination (Day 
92), and on Day 22 after the 2nd vaccination.  PBMC for T cell 
functional assays will be harvested on Day 01 (pre-vaccination), 
Days 08, 22, and 57 after the first vaccination, immediately prior 
to 2nd vaccination (Day 92), and on Day 22 after the 2nd 
vaccination.   
 
Estimated Time to Complete 
Enrollment: 
Approximately 3 months 
Table 1: Treatment Arms: 
Treatment 
Arm 
Subjects 
First Study Vaccination  
Second Study Vaccination  
Group A 
25 
M2SR 
QIV 
Group B 
25 
Placebo 
QIV 
 
 
 

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1. 
KEY ROLES 
Lead Principal Investigator: 
 
 
 
Daniel F. Hoft, MD, PhD 
Saint Louis University Medical School 
 
 
DMID Clinical Project Manager: 
Tena Knudsen, RN 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
 
Statistical Data Coordinating 
Center: 
 
 
The Emmes Company, LLC 
 
 
 
 
 
 
 

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2. 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1. 
Background Information 
 
Influenza continues to be a major threat to human health.  Every year, thousands of persons in 
the US die from complications of influenza infection.  Usually the elderly, young children and 
pregnant women are particularly susceptible to severe complications, but with some pandemic 
strains, over-exuberant inflammation in response to lower respiratory infection seems to 
disproportionately affect the middle aged and younger adult populations.  Effective vaccines 
have been available for the past 50 years, but must be given annually to optimally protect against 
the diversity of new strains that circulate over time.   
The influenza genome contains 8 segments, and each is prone to high error rates during viral 
replication.  The high mutation rate results in extensive genetic diversity, especially within the 
surface proteins Hemagglutinin (HA) and Neuraminidase (NA).  These molecules are constantly 
under intense immune pressure as major targets for viral specific, immunoprotective antibodies.  
The random mutation or genetic drift, combined with the selection of immune escape variants, 
renders vaccine immunity -involving primarily HA/NA specific antibodies- of only transient 
efficacy against the seasonally emerging strains that disseminate worldwide.  Therefore, current 
vaccines targeting primarily the induction of HA-reactive antibodies specific for seasonal 
circulating strains must be administered yearly to be maximally effective.  In years when the 
vaccines poorly matches the predominantly circulating strains, significant increased influenza 
morbidity and mortality can occur.  Additionally, some groups (elderly and young children) 
respond less well than healthy adults to HA antigen when it is injected as vaccine.   
Two major types of influenza vaccines have been developed and widely utilized.  The 
inactivated influenza vaccines (IIV) contain primarily HA protein (and some variable NA protein 
levels that co-purify with HA during manufacture).  The HA is derived from 3 (trivalent vaccine) 
or 4 (quadrivalent vaccine [QIV]) strains representing the major early circulating viral pathogens 
each season.  IIV induce HA type-specific antibodies, measurable in highly standardized 
hemagglutination inhibition (HAI) in vitro assays.  An HAI titer of at least 1:40 is known to be 
associated with protection against influenza strains expressing the specifically targeted matching 
HA sequences.  IIV can be highly protective if given annually to young and middle-aged 
populations but are less effective in infants, the elderly and the immunosuppressed.  Higher dose 
IIV, IIV including adjuvants and novel vaccines have been designed to enhance immunity in 
these special populations.    

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Live attenuated influenza vaccines (LAIV) are reassortment viruses generated with genomic 
segments expressing nonstructural proteins with attenuating mutations and HA/NA-encoding 
segments from seasonally circulating viral strains.  Flumist, the only previously licensed LAIV, 
is delivered intranasally.  Work led by Dr. Belshe and our SLU Center for Vaccine Development 
(SLUCVD) demonstrated that LAIV vaccination was more effective in children than IIV 
vaccination1.  The improved efficacy in children is most likely due to the induction of a better 
combination of serum antibodies, secretory IgA (sIgA) and cell-mediated immunity (CMI); i.e., a 
more complete immune response than is seen in children given IIV.  In adults LAIV is also 
effective, however several comparative studies have suggested equal efficacy or a modest 
advantage to IIV.  Of interest, HA-specific serum HAI responses induced by LAIV in adults 
have not been highly predictive of protective immunity, further suggesting that either sIgA 
and/or CMI can be important.  In addition, inducing antibodies directed against highly conserved 
HA stem epitopes instead of highly variable HA head epitopes is another possible explanation 
for the improved protection that has been induced by LAIV.  Prime/boost strategies using 2 
different heterotypic pandemic influenza vaccines have led to more broadly reactive antibody 
responses, and is another promising area for influenza vaccine research focusing on the 
development of universally protective novel vaccines. 
The additional immune responses induced by LAIV responsible for increased protection in 
children, and protection in adults in the absence of increased serum HAI antibodies, are unclear.  
As mentioned above, LAIV has been shown to induce T cell responses and sIgA which likely are 
involved.  Dr. Hoft’s lab has recently shown that LAIV induces influenza-specific CD4+, CD8+ 
and γδ T cell responses in children not induced by IIV in children, including T cells specific for 
highly conserved epitopes encoded by internal/nonstructural viral proteins2.  In addition, because 
LAIV is given intranasally, it also induces mucosal immune responses not induced by IIV.  In 
fact, Dr. Hoft’s lab has recently shown in adults that compared with IIV, LAIV uniquely induces 
influenza-specific sIgA responses, without inducing increased serum HAI responses or increased 
T cell responses3.  Therefore, depending on the population being vaccinated, serum HAI 
antibodies, broadly protective HA stem-specific antibodies, T cell responses and/or sIgA all can 
be important for LAIV-induced protective immunity.  In contrast, single or multiple IIV 
vaccinations appear to induce predominantly serum HAI antibodies specific for highly variable 
HA head-specific epitopes in the absence of broadly protective HA stem-specific antibody, T cell 
or sIgA responses.   
2.2. 
Rationale 
 
FluGen has produced new whole influenza virus M2SR vaccines which can be safely delivered 
intranasally.  Because of M2 protein deletion, these M2SR vaccines undergo only a single 

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replication cycle after vaccination.  The pre-clinical data from mice and ferrets are very 
promising, suggesting that M2SR vaccines can induce both humoral and cellular immune 
responses important for broadly protective influenza-specific immunity4,5.  In addition, there is 
some evidence that M2SR vaccines may work better than Flumist vaccines for inducing broadly 
protective immune responses against antigenically-drifted viruses and heterotypic viruses 
expressing different HA subtypes.  The fact that the immunogenicity of the M2SR vaccines does 
not appear to depend on sustained in vivo replication suggests that these vaccines could be more 
effective than Flumist in partially immune individuals.   
The first in human phase 1 dose escalation trial of a monovalent H3N2 M2SR vaccine conducted 
in healthy adult subjects has demonstrated that the vaccine is generally safe and well-tolerated 
and that it is immunogenic.  This protocol is a phase 1 study of the monovalent H3N2 M2SR 
vaccine in an older pediatric population, one of the most important vaccine targets for limiting 
influenza transmission from a public health point of view.  In addition, we propose to study 
whether H3N2 M2SR priming elicits broadly protective HA stem-specific antibodies, NA 
antibodies, T cell responses and sIgA responses that are readily boosted by a seasonal QIV 
vaccine.  Our hypotheses are that pediatric subjects primed with the M2SR vaccine will have 
more robust serum HAI and NA antibody responses, broadly neutralizing serum antibody 
responses, sIgA responses and cell-mediated immunity directed against both matched and 
unmatched influenza viruses.  These immune responses could greatly advance public health 
protection against pandemic influenza, bringing us much closer to universal influenza vaccine-
induced protection. 
2.3. 
Potential Risks and Benefits 
2.3.1. 
Potential Risks 
The potential risks of this trial are those associated with having blood drawn, possible reactions 
to the monovalent influenza H3N2 M2SR virus vaccine or the licensed inactivated QIV, and 
breach of confidentiality. 
H3N2 M2SR Vaccine 
Intranasal LAIV vaccines have induced nasal edema, nasal dryness, nasal pain/irritation, nasal 
congestion, rhinorrhea, decreased appetite, irritability, decreased activity, fatigue, malaise, sore 
throat (pharyngitis), difficulty swallowing, headache, arthralgia, myalgia, fever, feverishness 
(chills, shivering, sweating), cough, abdominal pain, nausea, vomiting, diarrhea, ear infections, 
conjunctivitis, itchy eyes, flushing, sinusitis, sneezing, nasal bleeding, shortness of breath, 
allergy, and wheezing/rhonchi in young children.  Rarely, nosebleeds can occur after intranasal 

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vaccinations.  Because H3N2 M2SR vaccine is a live attenuated vaccine given intranasally 
similar to other LAIV, we will specifically study these symptoms as solicited AEs. 
 
Placebo 
 
The placebo is physiological saline or 0.9% sodium chloride for injection.  Side effects do not 
typically occur from administration of this solution to the nasal passages.  If the subject’s nasal 
passages are extremely dry or irritated it is possible they may experience a stinging sensation or 
have some mild rhinitis.   
Licensed QIV 
Occasionally, recipients of unadjuvanted licensed, QIVs may develop influenza-like reactions, 
such as fever, feverishness (chills/shivering/sweating), fatigue (tiredness), malaise (general 
unwell feeling), myalgia (body aches/muscular pain), arthralgia (joint pain), headache, and/or 
nausea.  Some subjects may develop reactions at the injection site, including pruritus (itching), 
ecchymosis (bruising), erythema (redness), induration (hardness)/swelling, pain, and/or 
tenderness.  Most of these reactions peak in intensity in the first 24 hours after vaccination and 
disappear without treatment within 1 or 2 days.  Analgesics (e.g., acetaminophen, or ibuprofen or 
similar non-steroidal anti-inflammatory drugs (NSAIDs) and rest may generally relieve or lessen 
these reactions.  Bruising can sometimes occur due to the vaccination procedure. 
In addition, post-marketing surveillance indicates AESIs (autoimmune, auto-inflammatory and 
immune-mediated diseases) as potential risks identified for the seasonal influenza vaccines 
including, but not limited to, neuritis, convulsions, severe allergic reactions, syncope, 
encephalitis, thrombocytopenia, vasculitis, and Guillain-Barré syndrome.  Reports of these 
reactions were rare; however, exact incidence rates cannot be precisely calculated. 
Allergic Reaction 
Acute and potentially life-threatening allergic reactions are also possible.  Very rarely, occurring 
in about 1 in 4 million people given a vaccination, there can be a serious allergic reaction to a 
vaccine.  These reactions can manifest as skin rash (hives), swelling around the mouth, throat or 
eyes (angioedema), difficulty breathing (bronchospasm), a fast pulse (tachycardia), or loss of 
blood pressure (hypotension).  If these reactions occur, they can usually be stopped by the 
administration of emergency medications by the study personnel.  As with any vaccine or 
medication, there is a very small chance of a fatal reaction (death), although researchers do not 
expect this to occur. 
Blood Draw 

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Drawing blood may cause transient discomfort and fainting.  Fainting is usually transient and 
managed by having the subject lie down and elevate his/her legs.  Bruising at the blood draw site 
may occur, but can be prevented or lessened by applying pressure to the blood draw site for a 
few minutes after the blood is taken.  
Intramuscular Injection 
Intramuscular injection may also cause transient discomfort and fainting.  Giving an IM injection 
may also 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. 
Nasal Swabs 
Obtaining a nasal swab may cause mild discomfort and on rare occasions may cause a nosebleed. 
Pregnancy 
It is unknown if this vaccine poses any risks to an unborn child.  As such, female adolescents of 
childbearing potential, i.e., women who have started menses, must agree to use an effective 
method of birth control for at least 30 days prior to first study vaccination and for at least 30 days 
following the second vaccination.  Males who are sexually active with a female of childbearing 
potential must agree not to father a child for 30 days after receipt of the first study vaccination. 
Other Risks 
In addition, post-marketing surveillance of seasonal influenza vaccines identified other adverse 
events including, but not limited to, neuritis, convulsions, severe allergic reactions, syncope, 
encephalitis, thrombocytopenia, vasculitis, and Guillain-Barré syndrome.  Reports of these 
reactions were rare; however, exact incidence rates cannot be precisely calculated. 
During the swine influenza (H1N1) vaccine campaign of 1976, some recipients developed a 
paralytic illness called Guillain-Barré syndrome (GBS).  GBS is an acute inflammatory 
neuropathy characterized by weakness, hyporeflexia or areflexia, and elevated protein 
concentrations in cerebrospinal fluid.  The rate of GBS was significantly increased in individuals 
receiving the 1976 swine influenza (H1N1) vaccine at about 1 per 100,000 vaccine recipients.  
This syndrome has not been seen consistently with other influenza vaccines.  Most persons who 
develop GBS recover completely, although the recovery period may be as little as a few weeks 
or as long as a few years.  About 30% of those with GBS still have residual weakness after 3 
years and about 3% may suffer a relapse of muscle weakness and tingling sensations many years 
after the initial attack.  Intensive surveillance of GBS after administration of inactivated 
influenza vaccines since 1976 has shown a slight increase in risk over background cases (more 

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than one additional case of GBS per million persons) following vaccination, typically with onset 
within 6 weeks after vaccination6.  Interestingly, although vaccination rates have increased in the 
last 10 years the numbers of reported cases of vaccine-associated GBS have declined7.  A recent 
study in Canada showed that the 2009 H1N1 vaccine was associated with a small but significant 
risk of GBS in persons 50 years and older8.  An active, population-based surveillance study 
conducted in the United States during the 2009-2010 influenza season found less than 1 excess 
GBS case per million doses of 2009 H1N1 vaccine administered – a rate similar to that 
associated with some previously administered annual influenza vaccines9-11.  Another study 
using the Medicare system showed an elevated risk of GBS with 2009 monovalent H1N1 
vaccination (incidence rate ratio = 2.41, 95% confidence interval: 1.14, 5.11; attributable risk = 
2.84 per million doses administered, 95% confidence interval: 0.21, 5.48)12.  An international 
collaboration study also supported a conclusion of an association between 2009 H1N1 
vaccination and GBS13.  It is unknown if the administration of the H3N2 M2SR and seasonal 
vaccines to be used in this study will result in the incidence of GBS as high as that seen with the 
1976 vaccine product as the mechanism leading to this response has not been completely 
elucidated. 
PHI 
Subjects will be asked to provide personal health information (PHI).  All attempts will be made 
to keep this PHI confidential within the limits of the law.  However, there is a chance that 
unauthorized persons will see the subjects’ PHI.  All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating VTEU site.  Electronic files will be 
password-protected.  Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this trial will be allowed access to the PHI that is collected.  Any publications from 
this trial will not use information that will identify subjects by name.  Organizations that may 
inspect and/or copy research records maintained at the participating VTEU site for quality 
assurance and data analysis include groups such as the local Institutional Review Board (IRB) 
NIAID and FDA. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law.  This web site will not include information that can identify subjects.  At most, this 
web site will include a summary of the results. 
There may be other risks, discomforts, or side effects that are unknown at this time. 
2.3.2. 
Known Potential Benefits 
There are no known benefits attributable to the receipt of the monovalent live attenuated H3N2 
M2SR virus vaccine.  It is anticipated that vaccination using the monovalent live attenuated 

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H3N2 M2SR may result in some protection against infection caused by the influenza H3N2 
virus.  The duration and type of protection elicited in humans is currently unknown.  The 
monovalent live attenuated H3N2 M2SR virus vaccine may offer protection against circulating 
seasonal influenza viruses, but this has not yet been demonstrated in humans.  It is likely that the 
subject will develop at least partial protective immunity from receiving the licensed QIV 
depending on the match between vaccine virus and circulating viruses. It is also possible that if 
the subject gets sick from flu infection, symptoms or complications would be less severe than if 
they had not been vaccinated.  Society might benefit in the future from the information gathered 
during this study as it may help researchers better understand how to improve influenza vaccines. 

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3. 
OBJECTIVES AND OUTCOME MEASURES 
3.1. 
Study Objectives 
3.1.1. 
Primary: 
Safety: 
• To assess the safety and reactogenicity of a monovalent live attenuated influenza H3N2 
M2SR vaccine. 
3.1.2. 
Secondary: 
Immunogenicity: 
• Identification of circulating and mucosal antibody responses induced by H3N2 M2SR 
vaccination.  
• Identification of cellular immune responses induced by H3N2 M2SR vaccination. 
3.1.3. 
Exploratory: 
 
• Investigation of H3N2 M2SR priming effects on QIV-induced broadly neutralizing 
antibody responses to HA and NA.   
 
• Investigation of H3N2 M2SR priming effects on QIV-induced influenza-specific 
secretory IgA (sIgA) responses. 
 
• Investigation of H3N2 M2SR priming effects on QIV-induced influenza-specific CD4 
and CD8 T cell lymphoproliferative and effector cytokine responses. 
 
3.2. 
Study Outcome Measures 
3.2.1. 
Primary: 
Safety: 
 
•  Frequency of solicited upper respiratory and systemic reactogenicity through approximately 
Day 8 after the first study vaccination. 
 

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• 
Frequency of unsolicited non-serious adverse events from the time of study 
vaccination through 21 days after the first study vaccination. 
 
• 
Frequency of SAEs, regardless of seriousness or relationship to study vaccination, 
from receipt of the first vaccination throughout the entire study. 
 
• 
Frequency of New Onset Chronic Medical Conditions (NOCMC) and AESIs that 
develop from receipt of vaccination through 3 months after first study vaccination.  
3.2.2. 
Secondary: 
Immunogenicity: 
• 
For HAI and Neutralizing antibody responses, percentage of subjects achieving 
seroconversion (defined as either a pre-vaccination titer <1:10 and a post-vaccination titer 
≥1:40, or a pre-vaccination titer ≥1:10 and a minimum four-fold rise in post-vaccination 
antibody titer) against H3N2 M2SR-like and H3N2 QIV-like viruses at approximately 7, 
21, and 56 days following receipt of the first study vaccination and immediately prior to 
and approximately 21 days following receipt of QIV.  
 
• 
For HAI and Neutralizing antibody responses, percentage of subjects achieving a serum 
antibody titer of 1:40 or greater against the H3N2 M2SR-like virus and the H3N2 QIV-
like virus at baseline and approximately 7, 21, and 56 days following receipt of the first 
study vaccination and immediately prior to and approximately 21 days following receipt 
of QIV. 
 
• 
For HAI and Neutralizing antibody responses, the geometric mean titers (GMTs) and 
geometric mean fold rise (GMFR) to H3N2 M2SR-like virus and H3N2 QIV-like virus at 
baseline and approximately 7, 21, and 56 days following receipt of the first study 
vaccination and immediately prior to and approximately 21 days following receipt of 
QIV. 
 
• 
GMT and GMFR of nasal sIgA responses directed against the H3N2 M2SR virus and the 
H3N2 QIV virus measured by EPT(ELISA) with and without normalization to total sIgA 
at baseline and approximately 7, 21, and 56 days following receipt of the first study 
vaccination and immediately prior to and approximately 21 days following receipt of 
QIV.  
 
• 
Frequency of influenza H3 HA-specific (H3 M2SR-like and QIV-like viruses) and 
conserved internal viral protein-specific IFN-γ ELISPOT responses at baseline and 

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approximately 7, 21, and 56 days following receipt of the first study vaccination and 
immediately prior to and approximately 21 days following receipt of QIV. 
3.2.3. 
Exploratory: 
• 
GMT and GMFR of serum chimeric HA ELISA reactivity with Groups 1 and 2 HA stem 
domains of the viral hemagglutinin at baseline and approximately 7, 21, and 56 days 
following receipt of the first study vaccination and immediately prior to and 
approximately 21 days following receipt of QIV.  (Note:  These studies will be 
contingent upon seeing increased seroconversion rates and/or 4-fold rise as measured by 
GMFR in either M2SR or QIV matched H3HA-specific HAI and/or MN assays induced 
by H3N2 M2SR vaccination.)  
 
• 
GMT and GMFR of serum anti-NA antibody titers to N1 and N2 Neuraminidases as 
determined by NA ELLA or ELISA at baseline and approximately 7, 21, and 56 days 
following receipt of the first study vaccination and immediately prior to and 
approximately 21 days following receipt of QIV.  (Note:  These studies will be 
contingent upon seeing increased seroconversion rates and/or 4-fold rises in either M2SR 
or QIV matched H3N2-specific HAI and/or MN assays induced by H3N2 M2SR 
vaccination). 
 
• 
GMT and GMFR of nasal wash sIgA chimeric HA ELISA to the HA stem domains of the 
viral hemagglutinin (Group 2 versus Group 1 viruses with and without normalization to 
total sIgA at baseline and approximately 7, 21, and 56 days following receipt of the first 
study vaccination and immediately prior to and approximately 21 days following receipt 
of QIV.  (Note:  These studies will be contingent upon seeing increased GMT and/or 
GMFR of sIgA reactive with M2SR matched H3HA induced by H3N2 M2SR 
vaccination). 
 
• 
GMT and GMFR of sIgA anti-NA antibody titers to N1 and N2 Neuraminidases as 
determined by NA ELLA or ELISA at baseline and approximately 7, 21, and 56 days 
following receipt of the first study vaccination and immediately prior to and 
approximately 21 days following receipt of QIV.  (Note:  These studies will be 
contingent upon seeing increased GMT and/or GMFR of sIgA reactive with M2SR 
matched H3HA induced by H3N2 M2SR vaccination). 
 
• 
CD4+ and CD8+ T cell responses to the H3HA present in the M2SR vaccine and pools of 
highly conserved Influenza A T cell epitopes by 7 day CFSE dilution/flow cytometry at 
baseline and approximately 7, 21, and 56 days following receipt of the first study 
vaccination and immediately prior to and approximately 21 days following receipt of 

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QIV.  (Note:  These studies will be contingent upon seeing increased frequencies of 
H3HA-specific and/or conserved peptide epitope-specific IFN-gamma producing T cells 
induced by M2SR vaccination in ELISPOT assays). 

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4. 
STUDY DESIGN 
This is a Phase I double-blind, randomized, placebo-controlled study in 50 healthy adolescents 
and children, 9-17 years of age, who are in good health and meet all eligibility criteria.  The 
study is designed to assess the safety and immunogenicity of a prime-boost regimen of H3N2 
M2SR intranasal influenza vaccine followed by licensed inactivated QIV boost administered IM.  
Group A will receive one dose of M2SR intranasally on Day 1 and one dose of QIV on Day 92.  
Group B will receive one dose of saline intranasally on Day 1, and one dose of QIV on Day 92.  
See Table 1 for the randomization scheme for this trial.   
The two treatment arms will be enrolled and vaccinated concurrently.  
Reactogenicity will be measured by the occurrence of solicited upper respiratory, respiratory 
tract assessment, and systemic reactions from the time of the experimental (first) study 
vaccination through 7 days after vaccination.  Unsolicited non-serious AEs will be collected 
from the time of the first study vaccination through approximately 21 days after the first study 
vaccination.  SAEs will be collected from the time of the first study vaccination throughout the 
entire study.  AESIs (wheezing, and otitis media) and NOCMC will be documented and reported 
from the time of first study vaccination through approximately 3months after first study 
vaccination.      
Immunogenicity testing will include performing HAI, HA/NA ELISA, neutralization, nasal 
secretory IgA (sIgA), IFN-γ ELISPOT and CFSE dilution/ICS assays.  Serum for HAI, HA/NA 
ELISA and neutralization assays will be obtained on Day 01 (pre-vaccination), Days 08, 22, and 
57 after the first vaccination, immediately prior to the 2nd study vaccination (Day 92), and on 
Day 22 after the 2nd vaccination.  Nasal swabs for sIgA will be collected on Day 01 (pre-
vaccination), Days 08, 22, and 57 after the first vaccination, immediately prior to the 2nd 
vaccination (Day 92, and on Day 22 after the 2nd vaccination.  PBMC for T cell functional assays 
(IFN-γ ELISPOT and CFSE dilution/ICS assays) will be harvested on Day 01 (pre-vaccination), 
Days 08, 22, and 57 after the first vaccination, immediately prior to 2nd vaccination (Day 92), 
and on Day 22 after the 2nd vaccination.   
The duration of this study for each subject will be approximately 13 months.   

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5. 
STUDY ENROLLMENT AND WITHDRAWAL 
Approximately 50 males and non-pregnant females, 9 to 17 years old, inclusive, who are in good 
health and meet all eligibility criteria, will be enrolled from 1 VTEU site participating in this 
trial.  The target population should reflect the community at large at the participating VTEU site. 
Estimated time to complete enrollment in this trial is approximately 3 months for the 2018/2019 
season and 3 months for the 2019/2020 season. Information regarding this trial may be provided 
to potential subjects who have previously participated in vaccine trials conducted at the 
participating VTEU site.  Other forms and/or mechanisms of recruitment may also be used. The 
local Institutional Review Board (IRB) will approve all materials prior to use. 
Subject Inclusion and Exclusion Criteria must be assessed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or sub-
investigator. 
No exemptions are granted on Subject Inclusion or Exclusion Criteria in DMID-sponsored 
studies. Questions about eligibility should be directed toward the DMID Medical Officer. 
5.1. 
Subject Inclusion Criteria 
Subjects eligible to participate in this trial must meet all of the following inclusion criteria: 
1. 
Parent(s)/legal guardian(s) must provide written informed consent prior to initiation of 
any study procedures, and subject must provide assent. 
2. 
Are able to understand and comply with planned study procedures and be available for 
all study visits. 
3. 
Are males or non-pregnant females, 9-17 years old, inclusive at the time of enrollment.  
4. 
Are in good health1. 
 
1As determined by medical history and physical examination to evaluate acute or currently ongoing 
chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, 
which would affect the assessment of the safety of subjects or the immunogenicity of study vaccinations. 
Chronic medical diagnoses or conditions should be stable for the last 60 days (no hospitalizations, ER, or 
urgent care for condition and no adverse symptoms that need medical intervention).  This includes no 
change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic 
medical diagnosis or condition in the 60 days prior to enrollment.  Any prescription change that is due to 
change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in 
the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in 
prescription medication due to improvement of a disease outcome, as determined by the site principal 
investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. 
Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site principal 

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investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of 
reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition.  
Similarly, medication changes subsequent to enrollment and study vaccination are acceptable provided 
there was no deterioration in the subject’s chronic medical condition that necessitated a medication 
change, and there is no additional risk to the subject or interference with the evaluation of responses to 
study vaccination. Note: Low dose topical steroids, herbals, vitamins, and supplements are permitted. 
5. 
Oral temperature is less than 100.0°F. 
 
6. 
For female adolescent of child-bearing potential2 must agree to correctly use an 
acceptable method of contraception3 from 30 days prior to vaccination until 30 days 
after the last study vaccination. 
2Defined by the onset of menses, and not sterilized via tubal ligation, bilateral oophorectomy, 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 l). 
3Includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous 
relationship with a vasectomized partner, and correct use of male condoms with the use of applied spermicide, 
intrauterine devices, NuvaRing®, and licensed hormonal methods such as implants, injectables, contraceptive 
patches or oral contraceptives (“the pill”). Method of contraception will be captured on the appropriate data collection 
form. 
 
7. 
Female adolescent of childbearing potential must have a negative urine pregnancy test 
within 24 hours prior to study vaccination. 
8. 
Males who are sexually active with a female of childbearing potential must agree not to 
father a child for 30 days after receipt of the first study vaccination. 
9. 
Agrees not to participate in another clinical trial during the study period. 
10. 
Agrees not to donate blood or blood products to a blood bank for 12 months after 
receiving the investigational vaccine. 
 
11. 
Weight > 34 kg or 75 pounds. 
 
12. 
Hemoglobin > 11.5 g/dL. 
 
13. 
Hematocrit > 35%. 
 
14. 
Ferritin level > 15 ng/mL. 
 
15. 
Parent/legal guardian must provide consent to future use of stored samples. 
 
 
 

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5.2. 
Subject Exclusion Criteria 
Subjects eligible to participate in this study 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 each 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 or chronic medical disease or condition, defined as persisting for at least 90 days, that 
 would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the 
protocol, or may interfere with the evaluation of responses or the subject’s successful completion of this study. 
 
3. 
Have immunosuppression as a result of an underlying illness or treatment, or use of 
anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to 
study vaccination. 
 
4. 
 Have known active neoplastic disease or a history of any hematologic malignancy. 
Non- melanoma skin cancers that are not active are permitted. 
5. 
Have known HIV, hepatitis B, or hepatitis C infection.  
6. 
Have a history of severe reactions following previous immunization with licensed 
or unlicensed influenza vaccines. 
7. 
History of anatomic disorder of the nares or nasopharynx (Deviated septum is allowed). 
8. 
History of chronic sinus infections. 
9. 
Have a history of Guillain-Barré Syndrome. 
10. 
Have a history of alcohol or drug abuse prior to study vaccination.  
11. 
Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other 
psychiatric diagnosis that may interfere with subject compliance or safety evaluations. 
12. 
Have been hospitalized for psychiatric illness, history of suicide attempt, or 
confinement for danger to self or others prior to study vaccination. 
13. 
Have taken oral and/or nasal corticosteroids of any dose within 30 days prior to each 
study vaccination or plan to take in the 30 days following the first study vaccination. 

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14. 
Have taken high-dose7,8 inhaled corticosteroids within 30 days (prior to study 
vaccination). 
7High-dose defined as per age as using inhaled high dose per reference chart  
8https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf.   
15. 
Use of aspirin or salicylate-containing products 30 days prior to the first vaccination. 
16. 
Recurring or active wheezing or diagnosis of asthma, or history of significant wheezing9  
9Medically significant wheezing: defined as wheezing on physical exam plus sign of respiratory distress (tachypnea, 
retractions, or dyspnea), hypoxemia (02 saturation < 95%), or new bronchodilator prescription, or use of daily 
bronchodilator therapy (not on an “as needed” basis). 
17. 
Received any licensed live or inactivated vaccine within 30 days prior to or plan to 
receive any licensed live or inactivated vaccine within 30 days after each study 
vaccination. 
 
18. 
Received any influenza vaccine (inactivated or live) within 6 months prior to the first 
study vaccination and until the end of the study. 
19. 
Received immunoglobulin or other blood products within 6 months prior to study 
vaccination. 
20. 
Received an experimental agent10 within 30 days prior to the first study  
vaccination, or expects to receive an experimental agent11 during the 12-month trial-
reporting period. 
10Including vaccine, drug, biologic, device, blood product, or medication. 
11Other than from participation in this study. 
21. 
Are participating or plan to participate in another clinical trial with an  
interventional agent12 that will be received during the 12-month trial-reporting 
period. 
12Including agent (licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication) 
during the 12- month study period. 
 
22. 
Prior history of H3N2 actual or potential exposure or infection prior to the first study 
vaccination, or receipt of experimental vaccines within the past year prior to the first 
study vaccine. 
 
23. 
Female adolescent subject who is breastfeeding or plans to breastfeed at any  
given time from the first study vaccination until 30 days after the last study 
vaccination. 
 
24. 
Blood donation within 30 days prior to the study vaccination through 30 days after the 
last blood drawn for this study. 
 

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25. 
Have signs or symptoms that could confound or confuse assessment of study 
vaccine reactogenicity13. 
 
13The study vaccination should be postponed/deferred until signs or symptoms have resolved and if within the 
acceptable protocol-specified window for that visit. 
 
26. 
Have received any antiviral drug within 3 days of study vaccination. 
5.3. 
Treatment Assignment Procedures 
5.3.1. 
Randomization Procedures 
Conformity with the ICHE6; and per FDA Guidance for Industry E6: Good Clinical Practice 
(GCP), Consolidated Summary; screening records will be kept at the participating VTEU site to 
document the reason why an individual was screened, but failed trial entry criteria.  The reasons 
why individuals failed screening will be recorded in the Statistical Data Coordinating Center’s 
(SDCC) AdvantageEDCSM (Electronic Data Capture System). 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled.  Fifty subjects will be randomly assigned to one of two treatment 
arms, as shown in Table 1.  The list of randomized treatment assignments will be prepared by 
statisticians at the SDCC and included in the enrollment module for this trial.  AdvantageEDCSM 
will assign each subject to a treatment arm after the demographic and eligibility data have been 
entered into the system.  A designated individual at the VTEU site will be provided with a code 
list for emergency unblinding purposes, which will be kept in a secure place. 
Instructions for use of the enrollment module are included in the AdvantageEDCSM User’s 
Guide.  Manual back-up procedures and instructions are provided for use in the event that the 
VTEU site temporarily loses access to the Internet or the online enrollment system is 
unavailable. 
Subjects who are randomized but do not receive study vaccine may be replaced.  Subjects who 
are randomized and vaccinated, and subsequently withdraw, or are withdrawn or terminated from 
this trial, or are lost to follow-up will not be replaced. 
See Table 1 for the randomization scheme for this trial. 
5.3.2. 
Masking Procedures 
This is a double-blind clinical trial. 

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Subjects, investigators, study personnel performing any study-related assessments following 
study vaccine administration will be blinded to treatment assignment, laboratory personnel 
performing immunologic and future-use research assays will be blinded to treatment assignment, 
subject ID, and visit number.   
The randomization scheme will be generated by the SDCC and provided to unblinded study 
personnel (i.e., research pharmacists performing study vaccination preparations and unblinded 
study vaccine administrators) at the participating VTEU site. 
The unblinded study vaccine administrator is a study personnel licensed, registered, or certified 
to administer medications/vaccines, but will not be involved in study-related assessments or have 
subject contact for data collection following study vaccine administration. 
The Safety Monitoring Committee (SMC) may receive data in aggregate and presented by 
treatment arm.  The SMC may also be provided with expected and observed rates of the expected 
AEs in an unblinded fashion, and may request the treatment arm be unblinded for an individual 
subject if required for safety assessment.  The SMC will review grouped and unblinded data in 
the closed session only. 
5.3.3. 
Reasons for Withdrawals and Discontinuation of Study Product Administration 
Parent(s)/legal guardian(s) may voluntarily withdraw their consent for trial participation at any 
time and for any reason, without penalty. 
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 principal investigator 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. 
• Subject no longer meets eligibility criteria (see Section 5.1).  
• As deemed necessary by the site principal investigator or appropriate sub-investigator for 
noncompliance or other reasons. 
• Withdrawal of consent. 
• Lost to follow-up. 

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• Termination of this trial. 
• New information becomes available that makes further participation unsafe. 
The second study vaccination will not be administered to a subject if any of the following 
criteria are met: 
• 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/parent(s)/legal guardian(s) 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. 
5.3.4. 
Handling of Withdrawals and Discontinuation of Administration 
The primary reason for withdrawal from this trial will be recorded on the Study Status data 
collection form.  Subjects will be encouraged to complete the Early Termination Visit. The Early 
Termination Visit procedures are listed in Section 8. 
Although subjects are free to withdraw at any time or may be withdrawn by the site principal 
investigator or appropriate sub-investigator at any time (see Section 5.3.3), those subjects who 
receive only one dose of study vaccine will be encouraged to remain in this trial for follow-up 
safety assessments (may be conducted by phone call/electronic communication (e.g., email, text 
message) rather than in person) continuing through approximately 3 months after their first study 
vaccination.  These subjects will also be encouraged to provide a venous blood sample for 
immunogenicity and future-use research assays on all follow-up study visits.  See the protocol-
specific Manual of Procedures (MOP) for alternate follow-up requirements. 
Every attempt will be made to follow all AEs, including solicited dose site and systemic 
reactions, unsolicited non-serious AEs, SAEs ongoing at the time of early withdrawal through 
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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, emails, text messages, etc., 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. 
5.3.5. 
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, randomization, and receipt of study vaccine will not be 
replaced.  Over enrollment (randomized per the study design) may be allowed if any subjects 
withdraw, or are withdrawn or terminated from this trial, or are lost to follow-up after signing the 
informed consent form and randomization but before receipt of study vaccine.  Over enrollment 
must be approved by the sponsor. 
5.3.6. 
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 SMC review and recommendation and at the 
discretion of DMID. 

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These cells were adapted to grow freely in suspension in culture medium. The virus is 
inactivated with β-propiolactone, disrupted by the detergent, cetyltrimethylammonium bromide 
and purified through several process steps.  Each of the 4 virus strains is produced and purified 
separately then pooled to formulate the quadrivalent vaccine. 
Placebo (Normal Saline)  
The 0.9% sodium chloride for injection, USP, is a sterile, nonpyrogenic, isotonic solution of 
sodium chloride.  It is preservative-free and supplied in a single-dose container.  The placebo 
will be aseptically transferred by the pharmacist into the nasal spray Vaxinator or into the 
MAD301 nasal sprayer device (provided by FluGen) for administration to the subject.  
Additional detail is supplied in the MOP. 
VaxINator 
The VaxINator™ is made from radiation-stable medical-grade polycarbonate material and is 
compliant with USP Class VI and ISO 10993 requirements.  Investigational vaccine or placebo 
will be administered nasally via the VaxINator atomization device attached to a 1 mL syringe. 
The VaxINator is manufactured by Teleflex Medical.  The VaxINator is a conical shape plastic 
component that Luer-locks onto a standard syringe.  The VaxINator atomizes the liquid vaccine 
as it exits the syringe.  The conical shape forms a plug in the nostril and high applied-pressure 
atomizes the liquid into a fine mist. 
MAD301 Sprayer Device  
The MAD301 atomization device is made from radiation-stable medical-grade polycarbonate 
material and is compliant with USP Class VI and ISO 10993 requirements.  Investigational 
vaccine or placebo will be administered nasally via the MAD301 atomization device attached to 
a 1 mL syringe. The MAD301 sprayer is manufactured by Teleflex Medical.  The MAD301 is a 
conical shape plastic component that Luer-locks onto a standard syringe.  The MAD301 
atomizes the liquid vaccine as it exits the syringe.  The conical shape forms a plug in the nostril 
and high applied-pressure atomizes the liquid into a fine mist. 
6.1.1. 
Acquisition 
Bris10 M2SR vaccine is manufactured and provided by FluGen.   
VaxINator kits and the MAD301 sprayer devices will be shipped from FluGen Inc (Madison, 
WI) to the Fisher BioServices repository for distribution to the clinical site. 

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Upon DMID authorization, the M2SR vaccine, 
diluent, and the VaxINator and the 
MAD301 sprayer devices 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 
Normal saline and FLUCELVAX® will be obtained by the DMID Clinical Materials Services 
(CMS), Fisher BioServices.  
All study products (i.e., M2SR, 
buffer, normal saline, the VaxINator and the 
MAD301 sprayer devices) will be shipped to the participating VTEU site prior to the start of this 
study upon request and with prior approval from DMID.  FLUCELVAX® will be shipped to the 
participating VTEU site once available.  Should the site principal investigator require additional 
study vaccine or study products during this trial, further instructions are provided in the protocol-
specific MOP. 
6.1.2. 
Formulation, Packaging, and Labeling 
Investigational Vaccine (Bris10 M2SR) 
The investigational vaccine, Bris10 M2SR, is provided at a
 
 
Each vial is a single-use vial. The vaccine is an 
infectious but non-replicating influenza virus.  
 
 
 
 
 
 Refer to the 
Investigator’s Brochure and supplements for the M2SR as well as in the protocol specific MOP.  
Vaccine Diluent 
 
The vaccine diluent,
 
 is used to prepare dilutions of the investigational 

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vaccine for the active dose treatments.  Each vial is a single-use vial.  The unblinded pharmacist 
will remove a vial from 
 
 
 will be used to prepare the diluted vaccine 
stock solutions for the H3N2 M2SR treatment group.  
Vials (used and unused) will be 
 and retained until after accountability is completed 
by the Sponsor for disposal.  
Licensed Inactivated QIV 
FLUCELVAX® Quadrivalent Influenza Vaccine from Seqirus Inc. is a sterile, slightly opalescent 
suspension in phosphate buffered saline and will be provided in 0.5 mL single-dose prefilled 
Luer Lock syringes that contain no preservatives or antibiotics.  It is stored at refrigerator 
temperature 2° to 8°C (35° to 46°F).  Do not freeze.   
Used syringes will not be retained after administration. 
Refer to the FLUCELVAX® package insert as well as the protocol specific MOP. 
Placebo (Normal Saline) 
The placebo consists of physiological saline (containing no preservatives and suitable for 
intranasal administration) and is a clear, colorless solution.  It will be sourced by DMID CMS in 
single-use containers.  It is stored at ambient temperature 20°C to 25°C (68°F to 77°F) (See USP 
Controlled Room Temperature).  The unblinded pharmacist will aseptically withdraw volumes of 
the placebo as needed to fill the nasal spray devices.  
The placebo container(s) will be retained until after accountability is completed by the Sponsor 
for disposal.  
VaxINator 
VaxINator kits are supplied in individual sterile pouches containing a VaxINator atomization 
device, a 1-mL single-use syringe, and a dose divider (not utilized in the current protocol and 
will be discarded).  VaxINator devices are stored at 20°C to 25°C (68°F to 77°F) (See USP 
Controlled Room Temperature). 
MAD301 sprayer devices 

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MAD301 atomization devices are supplied in individual non-sterile pouches and are attached to 
sterile 1-mL single-use syringes before use (see below).  MAD301 sprayer devices are stored at 
20°C to 25°C (68°F to 77°F) (See USP Controlled Room Temperature). 
 
 
Refer also to the VaxINator Kit and the MAD301 sprayer device Instructions For Use (IFU) as 
well as in the protocol-specific MOP. 
 
Each of these study products except the VaxINator and the MAD301 nasal sprayer, will be 
labeled according to manufacturer specifications and include the statement “Caution: New Drug 
– Limited by Federal Law to Investigational Use.” 
6.1.3 
Product Storage and Stability  
The temperature of the storage unit must be manually recorded daily (excluding non-business 
days and holidays as applicable), continuously monitored and recorded during the duration of 
this trial per the participating VTEU site’s standard operating procedures, and documentation 
will be maintained.  If the temperature fluctuates outside of the required range, the affected study 
product(s) must be quarantined at the correct storage temperature and labeled as ‘Do Not Use’ 
(until further notice).  The research pharmacist must alert the site principal investigator 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 
principal investigator or responsible person should immediately contact the DMID Product 
Support Team at DMIDProductSupportTeam@niaid.nih.gov for further instructions before any 
additional study vaccinations are administered.  Based on the information collected, DMID 
and/or the manufacturer will determine whether the affected study product(s) can be used.  If it 
cannot be used, the site will receive specific instructions on how to return the affected study 
product(s) to the DMID CMS or destroy it on site.  Additional instructions for quarantine are 
provided in the protocol-specific MOP. 
6.2. 
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 group.  Study vaccine preparation will be 
performed by the participating VTEU site’s pharmacist on the same day of study vaccine 
administration.  

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Investigational Vaccine (Bris10 M2SR) 
Visually inspect the study vaccine (Bris10 M2SR, vaccine diluent and placebo [normal saline]) 
upon receipt and prior to preparation and use.  If the study vaccine appear(s) to have been 
damaged, contaminated or discolored, or if there are any concerns regarding its integrity, do 
NOT use the affected study vaccine.  The affected study vaccine must be quarantined and labeled 
as “Do Not Use (until further notice).”  The Site Principal Investigator or responsible person 
should immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager for further 
instructions before any additional study vaccinations are administered.  Based on the information 
collected, DMID and/or the manufacturer will determine whether the affected study vaccine can 
be used.  If it cannot be used, the site will receive specific final disposition instructions from 
DMID.  If the study vaccine is unusable, the participating VTEU site’s pharmacist will prepare 
another dose. Replacement vials may be requested by contacting DMID.  Additional instructions 
for quarantine and DMID contact information are provided in the protocol-specific MOP.  
Depending on randomization, each subject will be randomized to receive a one-time intranasal 
administration of a priming vaccine either: 
Bris10 M2SR vaccine at 108 virus particles OR placebo (normal saline) at Day 1 followed by a 
one-time intramuscular administration of quadrivalent inactivated vaccine at Day 92.   
The Bris10 M2SR vaccine will be diluted on-site as needed by the Pharmacist.  The Pharmacist 
will also fill vaccine and placebo into nasal spray devices.   
Study vaccine administration will be performed by an unblinded study vaccine administrator 
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.  On the assigned days, each dose of study vaccine or placebo will 
be administered to subjects via the nasal spray devices into each nostril. 
Filling and masking the nasal spray device 
M2SR vaccine and placebo will be prepared and filled into a Teleflex VaxINator nasal spray 
device (Figure 2) by the unblinded pharmacist. For both Groups A and B, two devices will be 
filled per subject to deliver 150 µl volume to each nare; a total of 300 µl.  
Figure 2: Image of the VaxINator Device 

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M2SR vaccine and placebo will be prepared and filled into a sterile 1 mL polypropylene syringe 
that is fitted with a Teleflex MAD301 sprayer for intranasal delivery (Figure 3) by the 
unblinded pharmacist. For both Groups A and B, two devices will be filled per subject to deliver 
150 µl volume to each nare; a total of 300 µl.  
Figure 3: Image of the MAD301 Sprayer Device 
 
 
To fill the device, the contents are drawn into the syringe barrel via a draw-up tube.  For the 
Teleflex VaxINator the draw-up tube is removed and replaced with the nose cone via a Luer lock 
fitting.  For the MAD301, the draw-up tube is removed and replaced with the MAD301 sprayer 
via a Luer lock fitting. The device is then primed.  Further details for filling and actuating the 
device are provided in the MOP. The pharmacist will wrap an opaque label completely around 
the circumference of the syringe barrel to conceal any color of the liquid contents and will use an 
indelible marker to record the subject’s ID and device number (#1 or #2) on the label.  The 
pharmacist or other clinic staff will then use the masked, filled device #1 to administer the first 
half of the dose (active or placebo) to the subject, followed by use of the masked, filled device #2 
to administer the second half of the dose to the same subject.  The device number will be 
provided by the research pharmacist. 
Short-term Stability 
Stability of the M2SR product has been tested and informs the following conditions: 
• 
 
 
 

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• 
 
 
 
  
 
6.3. 
Modification of Study Intervention/Investigational Product for a 
Subject 
 
There will be no dose modifications.  If a subject’s second study vaccination is deferred, it 
should be rescheduled to occur within the acceptable protocol-specified window for that visit 
(Day 92±14 days post first study vaccination).  If a protocol deviation occurs due to unforeseen 
circumstances related to the second vaccination window and the QIV cannot be given within the 
protocol window, the DMID Medical Officer must approve the second vaccination and the 
documentation of approval should be filed in the subject’s chart. 
 
Subjects who do not receive the second study vaccination will be encouraged to provide a 
venous blood sample for immunogenicity and future research testing.  See Sections 5.3.3 and 
5.3.4 for reasons for and handling of withdrawals and discontinuation of treatment. See the 
protocol-specific MOP for alternate follow-up requirements. 
6.4. 
Accountability Procedures for the Study Intervention/ 
Investigational Product(s) 
After receipt of the Bris10 M2SR vaccine, 
diluent, QIV, and normal saline placebo, 
the site principal investigator is responsible for study product distribution and disposition, and 
has ultimate responsibility for study product accountability.  The site principal investigator 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).  The study product 
accountability records and dispensing logs will also capture vial numbers, date of study vaccine 
preparation/administration, time of study product removal from storage freezer, time of study 
vaccine preparation, expiration of study vaccine preparation, time study vaccine is drawn into the 
syringe, and amount of study vaccine withdrawn for administration.  Time of study vaccine 
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product(s), including the amount of Bris10 M2SR, 
 diluent, QIV and normal saline, 
whether administered or not, must be documented on the appropriate study product 
accountability record or dispensing log.  The sponsor's monitoring staff will verify the 
participating VTEU site’s study product accountability records and dispensing logs per the site 
monitoring plan. 
Used and unused vials of Bris10 M2SR and 
diluent, and normal saline will be 
retained until monitored and released for disposition as applicable.  After dosing subjects, 
remnants of Bris10 M2SR vaccine doses 
 
 until returned to FluGen for dose confirmation.  Unused syringes 
of QIV will be stored at recommended temperature for neuraminidase quantitation. Dose 
confirmation and quantitation can occur on an ongoing basis for used vials of Bris10 M2SR and 
QIV. Final disposition of the unused Bris10 M2SR, QIV, and normal saline will be determined 
by DMID and communicated to the participating VTEU site by the DMID Clinical Project 
Manager. 
6.5. 
Assessment of Subject Compliance with Study Intervention/ 
Investigational Product/Investigational Device 
Study product will be administered to subjects by an unblinded study vaccine administrator via 
intranasal route for Dose 1 and IM injection for Dose 2 according to subject treatment 
assignment and as described in Section 6.4.  Thus, subject compliance is not anticipated to be an 
issue.  
6.6. 
Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
data collection form.  Concomitant medications will include all current medications and 
medications taken in the 30 days prior to signing the informed consent form through 
approximately 21 days after the first study vaccination, early termination or unscheduled visits 
(if prior to 21 days after the first study vaccination), whichever occurs first.  Medications 
reported in the electronic case report form (eCRF) are limited to those taken within 30 days prior 
to the first study vaccination through approximately 21 days after the first study vaccination. 
Prescription and over-the-counter drugs will be included as well as herbals, vitamins, and 
supplements.  In addition, receipt of non-study influenza vaccines will be solicited through 
approximately 21 days after the first study vaccination, and reported in the eCRF. The use of 
aspirin or salicylate containing products will be solicited from 30 days prior to the first 
vaccination through 21 days after the last vaccination and reported in the eCRF.  

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7. 
STUDY SCHEDULE 
Complete study schedule details listed by type of visit are described below. Refer also to 
Sections 4 and 7 and Appendix A: Schedule of Study Procedures and Evaluations. 
7.1. 
Recruitment 
The targeted/planned enrollment of subjects by gender and ethnicity/race will be distributed 
appropriately based on the Inclusion/Exclusion criteria of the protocol and will also be 
representative of the population of the region.  The VTEU is committed to accessing the diverse 
population of the region for enrollment into the study while taking into account the protocol 
specific criteria.   
Subjects will be recruited actively and prospectively.  Methods of recruitment may include but 
are not limited to letters, postcards, email messages, handouts, brochures, websites, 
posters/flyers, public service announcements, press releases, interviews with the media, 
Facebook posts, Twitter feeds, contact by telephone, lectures, announcements, and discussions 
held in groups or individually. 
IRB approved recruitment materials will be posted to the SLU Media Relations and Center for 
Vaccine Development Facebook Page and SLU Media Relations Twitter Feed.  For those 
parents/legal guardians who follow our Facebook page and Twitter feed, they will see the posted 
recruitment information.  Our email address will be provided so they can contact us for more 
information if interested. 
7.2. 
Screening Visit 
7.2.1. Visit 00, Screening Visit 
(Window:  Day -28 to -1) 
• 
Parent(s)/legal guardian(s) will be provided with a description of this trial (purpose and 
study procedures) and asked to read and sign the informed consent form.  The informed 
consent form will be signed prior to performing any study procedures. Subject will be 
provided with an age appropriate assent information sheet that includes a description of the 
trial (purpose and study procedures).  The information will be reviewed with the subject and 
the subject must provide assent prior to performing any study procedures. 
• 
Demographic information will be obtained by interview of parent(s)/legal guardian(s). 
• 
Eligibility criteria will be reviewed with parent(s)/legal guardian(s). 

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• 
Complete medical history will be obtained by interview of parent(s)/legal guardian(s) to 
ensure eligibility. 
• 
All concomitant medications taken within 30 days prior to signing the informed consent 
form will be reported on the eCRF. 
• 
Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any 
aspirin or salicylate containing products for 30 days prior to receipt of the first vaccination 
through 21 days after the last vaccination. 
• 
Subject receipt of licensed seasonal influenza vaccine over the previous two seasons, what 
type (inactivated or live attenuated), and approximate date of vaccination will be recorded 
on the appropriate data collection form, if known.  Prior receipt of licensed seasonal 
influenza vaccine is not exclusionary, as long as it has been administered within the 
allowable window (see Section 5.2). 
• Subject receipt of non-seasonal influenza vaccines, including those that are experimental, 
what type (inactivated or live attenuated), what subtype (e.g., A/H3, A/H5, A/H9) and 
approximate date of vaccination will be recorded on the appropriate DCF, if known. Prior 
receipt of non-seasonal influenza vaccines are not exclusionary, except influenza A/H7 
vaccines (see Section 5.2).  
• Weight will be obtained. 
• Oral temperature 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. 
• 
A physical examination will be performed on all subjects to include the following organs 
and organ systems: skin, head and neck including upper respiratory tract (nares and 
nasopharynx), lungs including wheezing, heart, liver, spleen, extremities, lymph nodes, and 
nervous system, by a study clinician licensed to make medical diagnoses and listed on the 
Form FDA 1572 as the site principal investigator or sub-investigator.  
• 
Age and developmentally appropriate counseling about pregnancy prevention may be 
provided. 
• 
A urine pregnancy test will be performed on all female adolescent subjects of childbearing 
potential and must be negative to ensure eligibility. 
• 
Approximately 14 mL of venous blood will be collected for clinical evaluation and safety 
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and aPTT. 
7.3. 
Enrollment Visit 
7.3.1. Visit 01, Enrollment and First Study Vaccination, (Dose 1), Clinic Visit 
• Eligibility criteria will be reviewed with parent(s)/legal guardian(s). 
• Interim medical history, including an assessment for new medical conditions will be obtained 
by interview of parent(s)/legal guardian(s) and any changes since the previous clinic visit or 
contact will be noted.  
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate data collection form prior to the second study 
vaccination.  
• Subject receipt of licensed seasonal influenza vaccine over the previous two seasons, what 
type (inactivated or live attenuated), and approximate date of vaccination will be recorded on 
the appropriate data collection form, if known.  Prior receipt of licensed seasonal influenza 
vaccine is not exclusionary, as long as it has been administered within the allowable window 
(see Section 5.2). 
• Subject receipt of non-seasonal influenza vaccines, including those that are experimental, 
what type (inactivated or live attenuated), what subtype (e.g., A/H3, A/H5, A/H9) and 
approximate date of vaccination will be recorded on the appropriate DCF, if known. Prior 
receipt of non-seasonal influenza vaccines are not exclusionary, except influenza A/H7 
vaccines (see Section 5.2).  
• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination. 
• Oral temperature 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. 
• A limited physical examination to specifically include the nares (including edema), throat, 
and lungs (including evaluation for wheezing) will be performed and a targeted physical 
examination may be performed on the other body systems 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 principal investigator or sub-investigator. 

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• A nasal swab for sIgA will be obtained. 
• Age and developmentally appropriate counseling about pregnancy prevention may be 
provided. 
• Approximately 6 mL of venous blood will be collected for serum HAI, HA/NA ELISA and 
neutralization assays. 
• Approximately 16 mL of PBMCs will be collected for IFN-γ ELISPOT and CFSE 
dilution/ICS assays.  
• A urine pregnancy test will be performed on all female adolescent subjects of childbearing 
potential and must be negative to ensure eligibility. 
• Subjects will be enrolled in AdvantageEDCSM and assigned randomly to a treatment arm 
prior to the first study vaccination. 
• Pre-administration reactogenicity assessments will be performed prior to the first study 
vaccination to establish baseline.  Subjects will then receive a single dose of study product or 
placebo intranasally.  Subjects will be observed in the clinic for at least 30 minutes after the 
first study vaccination.  Post-administration reactogenicity assessments will be completed, 
and any AE/SAEs will be recorded on the appropriate data collection form prior to discharge 
from the clinic. 
• Parent(s)/legal guardian(s) will be provided with a memory aid and other study-related 
materials to record daily oral temperature, solicited systemic reactions, any unsolicited AEs, 
and concomitant medications.  Parent(s)/legal guardian(s) will be encouraged to take child’s 
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.  Parent(s)/legal 
guardian(s) will be instructed on how to use their memory aid and how to measure and record 
AEs prior to discharge from the clinic.  Parent(s)/legal guardian(s) will be instructed to notify 
the study center if they develop any severe reactions after the first study vaccination.  If the 
site principal investigator or appropriate sub-investigator deems the reaction severe enough, 
further instructions will be given to the parent(s)/legal/guardian(s) on the proper course of 
action, including a return to the clinic for immediate evaluation if appropriate. 
7.4. 
Follow-up  
Follow-up visits are scheduled in reference to study vaccination dates as indicated for each visit 
window. 

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7.4.1. Visit 02, Day 08, Clinic Visit 
(Window: 7±1 days post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions will be obtained 
by interview of parent(s)/legal guardian(s) and any changes since the previous clinic visit or 
contact will be noted.  
• Subject’s parent(s)/legal guardian(s) will be asked if the subject had any additional blood 
taken for medical reasons. 
• Memory aid information will be reviewed with parent(s)/legal guardian(s). 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate data collection form prior to the second study 
vaccination. 
• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination.  
• All AE/AESIs/NOCMCs/SAEs will be recorded on the appropriate data collection form.  
• In the event that the subject attends the visit without a parent/legal guardian, the parent/legal 
guardian will be called to collect updated medical history, concomitant medications, and will 
be reminded that the subject is to avoid any aspirin or salicylate containing products for 30 
days prior to receipt of the first vaccination through 21 days after the last vaccination. 
• A limited physical examination to specifically include the nares (including edema), throat, 
and lungs (including evaluation for wheezing) will be performed and a targeted physical 
examination may be performed on the other body systems 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 principal investigator or sub-investigator. 
• A nasal swab for sIgA will be obtained. 
• Approximately 14 mL of venous blood will be collected for safety labs including WBC, 
HGB, Platelet Count, ALT, AST, Serum Creatinine, PT and aPTT. 
• Approximately 6 mL of venous blood will be collected for serum HAI, HA/NA ELISA and 
neutralization assays. 

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• Approximately 16 mL of PBMCs will be collected for IFN-γ ELISPOT and CFSE 
dilution/ICS assays.  
7.4.2. Visit 03, Day 22, Clinic Visit 
(Window:  21±2 days post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions will be obtained 
by interview of parent(s)/legal guardian(s) and any changes since the previous clinic visit or 
contact will be noted.  
• Subject or subject’s parent(s)/legal guardian(s) will be asked if the subject had any additional 
blood taken for medical reasons. 
• 
All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate data collection form prior to the second study 
vaccination.  
• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination. All AE/AESIs/NOCMCs/SAEs will be recorded on the 
appropriate data collection form.  
• In the event that the subject attends the visit without a parent/legal guardian, the parent/legal 
guardian will be called to collect updated medical history, concomitant medications, and will 
be reminded that the subject is to avoid any aspirin or salicylate containing products for 30 
days prior to receipt of the first vaccination through 21 days after the last vaccination. 
• A targeted physical examination 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 principal investigator or sub-investigator. 
• A nasal swab for sIgA will be obtained. 
• Approximately 6 mL of venous blood will be collected for serum HAI, HA/NA ELISA and 
neutralization assays. 
• Approximately 16 mL of PBMCs will be collected for IFN-γ ELISPOT and CFSE 
dilution/ICS assays.  
• Approximately 4 mL of venous blood will be collected if Hgb drops > 0.5g/dL or < lower 
limits of normal from screen to Day 8, draw repeat Hgb. 

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7.4.3. Visit 04, Day 57, Clinic Visit 
(Window:  56±3 days post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions will be obtained 
by interview of parent(s)/legal guardian(s) and any changes since the previous clinic visit or 
contact will be noted.  
• Subject or subject’s parent(s)/legal guardian(s) will be asked if the subject had any additional 
blood taken for medical reasons. 
• AEs limited to AESIs, NOCMCs, and SAEs will be recorded on the appropriate data 
collection form.  
• A targeted physical examination 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 principal investigator or sub-investigator. 
• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination.  
• In the event that the subject attends the visit without a parent/legal guardian, the parent/legal 
guardian will be called to collect updated medical history, concomitant medications, and will 
be reminded that the subject is to avoid any aspirin or salicylate containing products for 30 
days prior to receipt of the first vaccination through 21 days after the last vaccination. 
• A nasal swab for sIgA will be obtained. 
• Approximately 6 mL of venous blood will be collected for serum HAI, HA/NA ELISA and 
neutralization assays. 
• Approximately 16 mL of PBMCs will be collected for IFN-γ ELISPOT and CFSE 
dilution/ICS assays.  
• Approximately 4 mL of venous blood will be collected if Hgb level at Day 22 has dropped 
0.5 g/dL or more from baseline or is < lower limit of normal.  If results at Day 57 still meet 
that criteria (>0.5 g/dL drop from baseline or < lower limit of normal), no further PBMC 
collection will be done.  If results have recovered to within 0.4 g/dL of baseline at Day 57,  
resume blood collection plan for the rest of the study. 

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7.4.4. Visit 05, Day 92, Second Vaccination (Dose 2), Clinic Visit 
 (Window: 91±14 days post first study vaccination) 
• Interim medical history, including an assessment for new medical conditions will be obtained 
by interview of parent(s)/legal guardian(s) and any changes since the previous clinic visit or 
contact will be noted. 
• Criteria for administering QIV will be reviewed with parent(s)/legal guardian(s).  
• Concomitant medications (limited to aspirin or salicylate containing products) will be 
recorded on the appropriate data collection form. 
• All AESIs/NOCMCs/SAEs will be recorded on the appropriate data collection form. 
Reporting of AEs occurring since previous visit but before 2nd vaccination is limited to 
AESIs, NOCMCs, and SAEs.  
• A targeted physical examination may be performed prior to the second study vaccination, if 
indicated based on review of interim medical history, by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or sub-
investigator. 
• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination.  
• Oral temperature 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. 
• A urine pregnancy test will be performed on all female adolescent subjects of childbearing 
potential and must be negative to ensure eligibility. 
• A nasal swab for sIgA will be obtained. 
• Approximately 6 mL of venous blood will be collected for serum HAI, HA/NA ELISA and 
neutralization assays. 
• Approximately 16 mL of PBMCs will be collected for IFN-γ ELISPOT and CFSE 
dilution/ICS assays. Note: PBMCs will not be collected if the HgB was consistently low 
through Day 57. 
• Subjects will receive their second vaccination IM in whichever deltoid they prefer. 

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• Subjects will receive a single dose of study vaccine via IM injection into the deltoid muscle 
of the preferred arm.  The site of injection and time of administration will be recorded on the 
appropriated data collection form.  Subjects will be observed in the clinic for at least 30 
minutes after the second study vaccination.  
7.4.5. Visit 06, Day 113, Clinic Visit 
 
(Window:   21±2 days post second study vaccination) 
• Interim medical history, including an assessment for new medical conditions will be obtained 
by interview of parent(s)/legal guardian(s) and any changes since the previous clinic visit or 
contact will be noted. 
• Concomitant medications (limited to aspirin or salicylate containing products) will be 
recorded on the appropriate data collection form. 
• All SAEs will be recorded on the appropriate data collection form.  
• A targeted physical examination 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 principal investigator or sub-investigator. 
• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination.  
• In the event that the subject attends the visit without a parent/legal guardian, the parent/legal 
guardian will be called to collect updated medical history, concomitant medications, and will 
be reminded that the subject is to avoid any aspirin or salicylate containing products for 30 
days prior to receipt of the first vaccination through 21 days after the last vaccination. 
• A nasal swab for sIgA will be obtained. 
• Approximately 6 mL of venous blood will be collected for serum HAI, HA/NA ELISA and 
neutralization assays. 
• Approximately 16 mL of PBMCs will be collected for IFN-γ ELISPOT and CFSE 
dilution/ICS assays. Note: PBMCs will not be collected if the HgB was consistently low 
through Day 57. 
 

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• Approximately 8 mL of venous blood will be collected for Hgb and Ferritin level. If the 
ferritin level is < 15 ng/mL and/or the Hgb is less than the lower limits of normal, 
recommend  follow-up with primary care provider for consideration of multivitamins with 
iron. 
7.4.6. Visit 07; Day 240, Phone Call 
 
(Window:   148±14 days post second vaccination) 
• Study personnel will contact parent(s)/legal guardian(s) by phone to solicit any SAEs, 
medical history information that have occurred since the previous clinic visit will be 
solicited.  Based on the information, subjects may be asked to return to the clinic for 
evaluation. 
7.5. 
Final Study Visit, Visit 08, Day 366, Phone Call 
(Window:  274±14 days post second vaccination) 
• Study personnel will contact parent(s)/legal guardian(s) by phone to solicit any SAEs, 
medical history information that have occurred since the previous clinic visit will be 
solicited.  Based on the information, subjects may be asked to return to the clinic for 
evaluation. 
7.6. 
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 will be obtained 
by interview of parent(s)/legal guardian(s) and any changes since the previous clinic visit or 
contact will be noted. 
• Memory aid information will be reviewed with parent(s)/legal guardian(s) (if within 8 days 
after the last study vaccination). 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate data collection form (if within 21 days after the 
first study vaccination). If within 30 days of either vaccination through 21 days after the last 
vaccination, aspirin or salicylate containing products will be recorded. 

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• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination.  
• All AE/AESIs/NOCMCs/SAEs will be recorded on the appropriate data collection form. AEs 
will be limited to AESIs and SAEs if after 21 days the first study vaccination.  AESIs and 
NOCMCs will be collected until 3 months and SAEs will be collected throughout the entire 
study. 
• In the event that the subject attends the visit without a parent/legal guardian, the parent/legal 
guardian will be called to collect updated medical history, concomitant medications, and will 
be reminded that the subject is to avoid any aspirin or salicylate containing products for 30 
days prior to receipt of the first vaccination through 21 days after the last vaccination. 
• Oral temperature 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 limited physical examination to specifically include the nares (including edema), throat, 
and lungs will be done if within 8 days after first vaccination. 
• A targeted physical examination may be performed prior to the second study vaccination, if 
indicated based on review of interim medical history, by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or sub-
investigator. 
• A nasal swab for sIgA will be obtained. 
• Approximately 6 mL of venous blood will be collected for serum HAI, HA/NA ELISA and 
neutralization assays. 
• Approximately 16 mL of PBMCs will be collected for IFN-γ ELISPOT and CFSE 
dilution/ICS assays.  Note: PBMCs will not be collected if the HgB was consistently low 
through Day 57. 
7.7. 
Unscheduled Visit (if needed) 
Unscheduled visits may occur at any time during this trial.  Any of the following activities may 
be performed: 
• Interim medical history will be obtained by interview of parent(s)/legal guardian(s) and any 
changes since the previous clinic visit or contact will be noted (if indicated). 

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• Memory aid information will be reviewed with parent(s)/legal guardian(s) (if within 8 days 
after the first study vaccination). 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate data collection form (if within 21 days after the 
first study vaccination). If within 30 days of either vaccination through 21 days after the last 
vaccination, aspirin or salicylate containing products will be recorded. 
• Subject’s/parent(s)/legal guardian(s) will be counseled on the avoidance of taking any aspirin 
or salicylate containing products for 30 days prior to receipt of the first vaccination through 
21 days after the last vaccination.  
• All AE/AESIs/NOCMCs/SAEs will be recorded on the appropriate data collection form. AEs 
will be limited to AESIs, NOCMCs, and SAEs if after 21 days after the first study 
vaccination.  AESIs and NOCMCs will be collected until 3 months and SAEs will be 
collected throughout the entire study. 
• In the event that the subject attends the visit without a parent/legal guardian, the parent/legal 
guardian will be called to collect updated medical history, concomitant medications, and will 
be reminded that the subject is to avoid any aspirin or salicylate containing products for 30 
days prior to receipt of the first vaccination through 21 days after the last vaccination. 
• Oral temperature 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 limited physical examination to specifically include the nares (including edema), throat, 
and lungs will be performed if within 7 days after vaccination. 
• A targeted physical examination may be performed prior to the second study vaccination, if 
indicated based on review of interim medical history, by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or sub-
investigator. 

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8. 
STUDY PROCEDURES/EVALUATIONS 
8.1. 
Clinical Evaluations 
Complete medical history will be obtained by interview of subjects, parent(s) and/or legal 
guardian(s) on the Screening visit. Subjects, parent(s) and/or legal guardian(s) will be queried 
regarding a history of significant medical disorders of the head, eyes, ears, nose, throat, mouth, 
cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, kidney, urologic system, 
nervous system, blood, lymph nodes, endocrine system, musculoskeletal system, skin, and 
genital/reproductive tract.  A history of any allergies, cancer, immunodeficiency, psychiatric 
illness, substance abuse, and autoimmune disease will be solicited at follow-up visits after the 
first study vaccination, an interim medical history will be obtained by interview of subjects, 
parent(s) and/or legal guardian(s) noting any changes since the previous clinic visit or contact.  
See section 6.6 for the collection of medication history.  Use of new medication should prompt 
evaluation for the occurrence of any AESIs or NOCMC.  Assessment of eligibility will include a 
review of all permitted and prohibited medications per the Subject Inclusion and Exclusion 
Criteria (see Sections 5.1and 5.2).  In addition, the site principal investigator or appropriate sub-
investigator may identify other medications that should not be used due to a risk to subject safety 
or assessment of reactogenicity and immunogenicity. 
• At the screening visit a physical examination will be performed on all subjects to include 
the following organs and organ systems: including skin, head and neck including upper 
respiratory tract (nares and nasopharynx), lungs, heart, liver, spleen, extremities, lymph 
nodes, and nervous system, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  At 
Visit 01, 02 and Early Termination or Unscheduled Visits if they occur within 8 days of 
vaccination after the first study vaccination, a limited physical examination to include the 
nares (including edema), throat, and lungs will be performed and a targeted physical 
examination may be performed on the other body systems, 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 principal investigator or sub-
investigator.  At all other follow-up visits, a targeted physical examination 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 
principal investigator or sub-investigator. 
Oral temperature will be collected prior to each study vaccination.  Subjects must not eat or drink 
anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 

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Reactogenicity assessments will include an assessment of solicited AEs occurring from the time 
of experimental (first) study vaccination through Day 8 after vaccination.  For upper respiratory 
symptoms, this includes an assessment of runny nose, stuffy nose/ congestion, sneezing, nasal 
pain/irritation/nasal dryness, nasal bleeding/epistaxis, sinus pressure/pain, sore 
throat/sore/scratchy, itchy or painful throat, cough, trouble breathing/shortness of breath.  For 
general systemic symptoms, this includes an assessment of reactions including fever, 
feverishness (chills/shivering/sweating), fatigue (tiredness), malaise, myalgia (body 
aches/muscular pain), arthralgia (joint pain), headache, flushing, decreased activity, decreased 
appetite, abdominal pain, nausea, vomiting, diarrhea, eye pruritus, eye redness (conjunctivitis), 
and allergy.  For respiratory tract symptoms, this will include an assessment of nares’ erythema 
and induration. 
Memory Aids:  All parent(s)/legal guardian(s) will complete a subject memory aid from the time 
of the first study vaccination Day 01 (Visit 01) through 7 days after the first study vaccination. 
Memory aids will be reviewed with the parent(s)/legal guardian(s) for AEs at the clinic visit 
following receipt of first study vaccination.  If a subject noted ongoing local (nasal or injection 
site) or systemic reactogenicity on the 7th day following the study vaccination (study Day 8), the 
memory aid will continue to be reviewed until resolved.  The memory aids will not be retained as 
a source document. 
Subjects will be observed in the clinic for at least 30 minutes after each study vaccination.  Any 
AE/SAEs will be recorded on the appropriate data collection form prior to discharge from the 
clinic.  
8.2. 
Laboratory Evaluations 
8.2.1. 
Clinical Laboratory Evaluations 
Urine pregnancy tests will be performed locally by site laboratory at the Screening visit and 
within 24 hours prior to each study vaccination (Day 01 (Visit 01) and Day 92 (Visit 05) on all 
female adolescents of childbearing potential.  Results must be negative and known prior to 
randomization on Day 1 and administration of each study vaccination to be eligible for 
participation in this study and receipt of each study vaccination.   
• Clinical laboratory parameters to be evaluated at the Screening Visit (Visit 00) and on Day 
08 (Visit 02) will include a White Blood Cell Count (WC), HGB, HCT (only at Visit 00), 
Platelet Count, ALT, AST, Serum Creatinine, Ferritin (at Visit 00), Prothrombin Time (PT) 
and Activated Partial Thromboplastin Time (aPTT). The results from the clinical safety 
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vaccination.  Results of the HGB and HCT must be within normal limits, and Ferritin must 
be > 15 ng/mL for enrollment. HGB will also be repeated at Day 22 and/or Day 57 if HGB is 
below the lower limit of normal or ≥0.5g/dL below the baseline screening level at the day 8 
follow up safety.  HGB and Ferritin will be drawn at Day 113.  
All other results can be and will serve as a Grade 1 or normal. 
8.2.2. 
Special Assays or Procedures 
Immunogenicity 
Immunogenicity testing will include performing HAI, HA/NA ELISA, neutralization, nasal 
sIgA, IFN-γ ELISPOT and CFSE dilution/ICS assays and will be done by the Saint Louis 
University laboratory.  Serum for HAI, HA/NA ELISA and neutralization assays will be 
obtained on Day 01 (pre-vaccination), Days 08, 22, and 57 after the first vaccination, 
immediately prior to the 2nd study vaccination (Day 92), and on Day 22 after the 2nd vaccination.  
Nasal swabs for sIgA will be collected on Day 01 (pre-vaccination), Days 08, 22, and 57 after 
the first vaccination, immediately prior to the 2nd vaccination (Day 92), and on Day 22 after the 
2nd vaccination.  PBMC for T cell functional assays will be harvested on Day 01 (pre-
vaccination), Days 08, 22, and 57 after the first vaccination, immediately prior to 2nd vaccination 
(Day 92), and on Day 22 after the 2nd vaccination.  Subjects who withdraw early will have HAI 
and Neut antibody assays completed on available samples. 
The volumes of venous blood to be collected for HAI, ELISA, neutralization assays, IFN-γ 
ELISPOT CFSE dilution/ICS assays, and future use assays are presented in the table below. 
 
 

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Table 2: Venipuncture Volumes (mL): 
Study Visit Number 
 
VS00 
V01 
V02 
V03 
 
V04 
V05 
 
V06 
 
V07 
 
V08 
Study Day post 1st 
study vaccination 
 
Screen 
D01 
Dose
#1 
 
D08 
D22 
D57 
D92 
Dose 
#2 
 
 
D 
113 
 
 
 
D  
240 
 
 
D 
366 
Study Day post 2nd 
study vaccination 
 
 
 
 
 
D01 
 
 
D22 
 
 
D 
149 
 
 
D 
275 
Clinical Screening 
and Safety Laboratory 
Evaluations 
 
 
 
14 
mL2,3,4, 
 
14mL3 
4mL5 
 
 
4mL5 
 
 
 
8mL4,6 
 
 
Serum for HAI, 
HA/NA ELISA, 
Neutralization Assays 
 
6 mL 
 6 mL 
6 mL 
6 mL 
6 mL  
6 mL 
 
 
 
Nasal Swab sIgA 
 
X 
X 
X 
X 
X 
X 
 
 
PBMC for IFN-γ 
ELISPOT CFSE 
Dilution/ICS Assays 
 
16 mL 
16 mL 
16 mL 
16 mL 
16 mL 
16 mL 
 
 
Total (mL) 
14 mL  
22mL1 
36 mL1 
26mL1 
26mL1 
22mL1 
30mL1 
0 
0 
Cumulative Total 
(mL) 
 
14 mL 
 
36 mL 
72 mL 
98 mL 
124 mL 
146 mL 
176 mL 
 
176 mL 
 
 
176 mL 
1 Verify that for pediatric patients, no more than 5 mL/kg may be drawn for research purposes in a single day, and 
no more than 9.5 mL/kg may be drawn over any eight-week period.  (NIH blood draw policy) or institutional policy 
is followed. 
2 Includes HCT.  
3 Includes WBC, Hgb, Platelet Count, ALT, AST, Serum Creatinine, PT, and aPTT 
4Includes Ferritin Level. 
5 Includes Hgb; Draw if Hgb drops >0.5 g/dL or < lower limits of normal at previous visit. 
6Includes Hgb.. 

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8.2.3. 
Specimen Preparation, Handling, and Shipping 
8.2.3.1. 
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. 
8.2.3.2. 
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 protocol-specific MOP. 
Specimens for HAI and Neut antibody assays will be shipped from the participating VTEU site 
to the DMID CMS. 
Further instructions for specimen shipment are included in the protocol-specific MOP, as 
appropriate. 

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9. 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
1. SAEs occurring from the time of the first study vaccination through 12 months after the first 
vaccination. 
2. AESIs (wheezing, otitis media) and NOCMCs occurring from the time of the first study 
vaccination through 3 months after the first vaccination. 
3. Solicited Adverse Events – reactogenicity events occurring from the time of experimental 
(first) study vaccination through 7 days after the first study vaccination.  See tables listed in 
section 9.2.2 and 9.2.6 for local upper respiratory, respiratory tract assessment, and systemic 
symptoms: 
4. Unsolicited Non-Serious Adverse Events –non-serious AEs occurring from the time of the 
first study vaccination through approximately 21 days after the first study vaccination. 
5. Clinical safety laboratory AEs occurring at approximately 7 days after the first vaccination.  
Parameters to be evaluated include a WBC, HGB, Platelet Count, ALT, AST, Serum 
Creatinine, Ferritin level, PT and aPTT. HGB will also be repeated at Day 22 if there is a 
drop in HGB level from screen to Day 8 of > 0.5 g/dL or results are < lower limits of normal.  
If unable to collect at Day 22, collect at Day 57.  If drawn at Day 22 and the results are still 
low, repeat at Day 57.  If HGB results are still low at Day 57, no further PBMC collection 
will be done.  HGB and Ferritin level will be drawn at Day 113.  If the ferritin is < 15 ng/mL 
and/or the HGB is less than the lower limits of normal, will recommend follow-up with 
primary care provider for consideration of multivitamins with iron. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 
Adverse Events 
Adverse Event (AE): ICH E6 defines an AE as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product regardless of its causal 
relationship to the study treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 

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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 local (respiratory) and systemic (subjective and quantitative) reactions, 
not meeting the protocol-defined criteria for SAEs will be captured on the appropriate data 
collection form and 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 and 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 principal investigator or sub-investigator), date of resolution of the event, 
seriousness, and outcome.  AEs occurring during the trial collection and reporting period will be 
documented appropriately regardless of relationship.  AEs will be followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE.  However, if the severity of any pre-existing medical 
condition increases, it will be recorded as an AE. 
AEs must be graded for severity and assessed for 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 data 
collection form and eCRF. 
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
New-Onset Chronic Medical Conditions (NOCMCs):  NOCMCs are defined as any new ICD-
10 diagnosis that is applied to the subject during the duration of the study, after receipt of the 
study agent, that is expected to continue for at least 3 months and requires continued health care 
intervention. 
Severity of Event:  AEs will be assessed by a licensed study physician listed on the Form FDA 
1572 as the site principal investigator or appropriate 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. 

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• 
Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures.  Moderate events may cause some interference with functioning 
and daily activities. 
• 
Severe (Grade 3): Events interrupt the subject’s daily activities and may require systemic 
drug therapy or other treatment.  Severe events are usually incapacitating. 
Relationship to Study Product:  The licensed study physician’s assessment of an AE's 
relationship to study product is part of the documentation process, but it is not a factor in 
determining what is or is not reported in this trial.  If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported.  The relationship to study product must be 
assessed for AEs using the terms: related or not related.  In a clinical trial, the study product must 
always be suspect.  To help assess, the following guidelines are used: 
• Related – There is a reasonable possibility that the study product caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2. Reactogenicity  
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine.  The following Toxicity Grading Scales will be used to grade solicited 
local (upper respiratory) and systemic (subjective and quantitative) reactions: 
Local (Upper Respiratory) Reactogenicity Grading 
Local (Nasal) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Runny Nose 
Noticeable but does 
not interfere with 
daily activity  
Moderate 
discomfort/interferes 
with daily activity 
Significant 
discomfort/prevents 
daily activity or seeks 
medical encounter 

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Local (Nasal) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Stuffy 
Nose/Congestion 
Noticeable but does 
not interfere with 
daily activity 
Moderate 
discomfort/interferes 
with breathing from 
nose 
not being able to breath 
from nose, or prevents 
daily activity or seeks 
medical encounter 
Sneezing 
Noticeable but does 
not interfere with 
daily activity 
Moderate discomfort. 
Interferes with daily 
activity 
Significant 
discomfort/prevents 
daily activity 
Nasal Pain/Irritation  
Noticeable but does 
not interfere with 
daily activity 
Moderate 
discomfort/interferes 
with daily activity 
Significant 
discomfort/prevents 
daily activity or seeks 
medical encounter 
Nasal 
Bleeding/Epistaxis  
Total duration of all 
episodes in a 24 hour 
period <30 minutes 
Total duration of all 
episodes in a 24 hour 
period > 30 minutes  
Any bleeding that 
required visit for 
medical encounter 
Sinus Pressure/Pain 
Noticeable but does 
not interfere with 
daily activity 
Moderate discomfort. 
Interferes with daily 
activity 
Significant 
discomfort/prevents 
daily activity 
Sore 
Throat/Sore/Scratch
y/ 
Itchy or Painful 
Throat 
Noticeable but does 
not interfere with 
eating and/or 
drinking 
Moderate discomfort. 
Interferes with eating 
and/or drinking 
Significant 
discomfort/prevents 
eating and/or drinking 
or seeks medical 
encounter 
Cough 
Noticeable but does 
not interfere with 
daily activity or 
sleeping 
Moderate 
discomfort/interferes 
with daily activity or 
sleeping 
Significant 
discomfort/prevents 
daily activity or seeks 
medical encounter 
Trouble 
breathing/Shortness 
of Breath 
Noticeable but does 
not interfere with 
daily activity or not 
Moderate 
discomfort/interferes 
with daily activity or 
Significant 
discomfort/prevents 
daily activity or seeks 

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Local (Nasal) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
troubled by 
breathlessness except 
on vigorous exercise  
short of breath with 
regular movement 
activities such as 
when hurrying on the 
level or walking up a 
slight incline and 
need to stop 
medical encounter or 
TOO breathless to 
leave the house, or 
breathless when 
undressing, preventing 
normal activities 
 
 

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Subjective Systemic Reactogenicity Grading 
 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Feverishness 
(Chills/Shivering/Sweati
ng) 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 
Fatigue (Tiredness) 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 
Malaise (General Unwell 
Feeling) 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 
Myalgia (Body 
Aches/Muscular Pain) 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 
Arthralgia (Joint Pain) 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity  
Headache 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity and/or 
seeks medical 
encounter 
Flushing 
Asymptomatic 
flushing 
Symptoms, some 
interference with 
daily activity 
Symptomatic, 
significant 
interference, prevents 
daily activity 
Decreased Activity 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 

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Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Decreased Appetite 
Loss of appetite 
without decrease 
in oral intake  
Loss of appetite 
associated with 
decreased oral 
intake  
Loss of appetite 
without oral intake, 
seek medical care 
Abdominal Pain 
No interference 
with daily 
activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 
Nausea  
Transient (<24 
hours) or 
intermittent 
AND No or 
minimal 
interference 
with oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours  
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR Rehydration 
indicated (e.g., IV 
fluids)  
Vomiting 
Transient or 
intermittent 
AND no 
interference 
with daily 
activity; 
minimal 
interference 
with oral intake 
Frequent episodes 
with no dehydration 
and interferes with 
some daily activity 
Persistent vomiting, 
resulting in orthostatic 
hypotension or 
aggressive rehydration 
(e.g., IV fluids) or 
prevents normal daily 
activity 
Diarrhea 
Transient or 
intermittent 
AND no 
interference 
with daily 
activity; 
minimal 
interference 
with oral intake 
Frequent episodes 
with no dehydration 
and interferes with 
some daily activity 
Persistent diarrhea, 
resulting in orthostatic 
hypotension or 
aggressive rehydration 
(e.g., IV fluids) or 
prevents normal daily 
activity 

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Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Eye Pruritus 
Transient of 
intermittent or 
minimal 
interference and 
no intervention 
Persistent or 
frequent episodes, 
some interference 
with daily activity 
Significant symptoms, 
prevents daily activity, 
or seeks medical 
attention 
Eye Redness 
(Conjunctivitis) 
Asymptomatic 
eye redness 
Symptomatic eye 
redness, some 
interference with 
daily activity 
Eye redness prevents 
daily activity or seeks 
medical encounter 
Allergy 
Pruritus with or 
without rash, no 
medical 
intervention 
Localized urticaria, 
with intervention 
Generalized Urticaria,  
Anaphylaxis, or 
Angioedema 
 
Oral temperature# will be graded as follows: 
Quantitative Systemic Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* - oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as 
baseline. 
* A fever can be considered not related to the study product if an alternative etiology can be 
documented. 
† Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking 
oral temperature. 
9.2.3. 
Serious Adverse Events 
Serious Adverse Event (SAE):  

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An AE or suspected adverse reaction is considered “serious” if, in the view of either the site 
principal investigator or sponsor, it results in any of the following outcomes: 
• Death, 
• A life-threatening AE*, 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
* Life-threatening AE. An AE is considered “life-threatening” if, in the view of either the site 
principal investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death.  It does not include an AE that, had it occurred in a more severe form, might have caused 
death. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology. 
• 
Recorded on the appropriate SAE data collection form and eCRF. 
• 
Followed through resolution. 
• 
Reviewed and evaluated by an Independent Safety Monitor (ISM) (as deemed necessary), 
the SMC (periodic review unless related), DMID, and the IRB. 
At any time after protocol follow up period or completion of this study, if the site principal 
investigator or appropriate sub-investigator becomes aware of an SAE that is suspected to be 

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related to study product, the site principal investigator or appropriate sub-investigator will report 
the event to the DMID Pharmacovigilance Group. 
9.2.4. 
Adverse Events of Special Interest (AESI) 
• Medically significant wheezing:  defined as wheezing on physical exam sign of respiratory 
distress (tachypnea, retractions, or dyspnea), hypoxemia (O2 saturation < 95%), or new 
bronchodilator prescription, or use of daily bronchodilator therapy (not on an “as needed” 
basis) from receipt of the first vaccination through 3 months after the first vaccination.  Will 
record presence or absence of any wheezing after V02 and whether wheezing is diffuse or 
localized, respiratory rate, oxygen saturation, medications associated with wheezing, and 
physician’s description on auscultation. 
 
• Otitis Media and Wheezing at V02 only will be graded as follows: 
 
Systemic 
(Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Otitis Media 
No interference with 
daily activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 
Wheezing 
No interference with 
daily activity 
Some interference 
with daily activity 
Significant 
interference, prevents 
daily activity 
9.2.5. 
Clinical Safety Laboratory Adverse Event Grading 
 
Note: Ranges have been modified to reflect local laboratory normal ranges for the site conducting this study 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC cells/mm3; 103 cells/µL 
(Decrease) 
 
2.0 – 2.4 
1.50 – 1.0 
<1.5 
HgB g/dL 
9-12 years of age  
9.5-10.4  
8.5-9.4  
<8.5  

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HgB g/dL   
Males > 13 years of age 
10.0 – 10.9 
9.0 - < 10.0 
< 9.0 
HgB g/dL 
Females > 13 years of age  
 
9.5 – 10.4 
8.5 - < 9.5 
< 8.5 
Platelets cell/mm3/UL  
 
100- < 125 
50- < 100 
< 50 
PT 
 
1.1 - <1.25 x ULN 1.25 - < 1.50  x 
ULN 
> 1.50 x ULN 
aPTT 
 
1.1  - < 1.66 x  
ULN 
1.66 - <2.33 x 
ULN 
> 2.33 x ULN 
 
 
 
 
Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
ALT  
1.25 – < 2.5 x 
ULN 
>2.5 –  <5.0 x 
ULN 
>5.0 x ULN 
AST 
1.25 – < 2.5 x 
ULN 
>2.5 –  <5.0 x 
ULN 
>5.0 x ULN 
Creatinine mg/dL  
1.1 – 1.3 x ULN  
>1.3 – 1.8 OR 
Increase to 1.3 to 
< 1.5 x subject’s 
baseline 
>1.8 x ULN OR 
Increase to > 1.5 x 
subject’s baseline  
 
9.2.6. 
Respiratory Tract Assessment Grading: Erythema and Induration 
Erythema and Induration of the nasal cavity will be graded as follows: 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Erythema 
(Redness) 
Very slight or 
barely perceptible 
redness 
Well defined redness 
Moderate to severe beet 
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Parameter 
Grade 1 
Grade 2 
Grade 3 
Induration 
(Swelling or 
edema) 
Very slight or 
barely perceptible 
swelling 
Slight swelling (edges 
of area well-defined by 
definite raising) 
Moderate swelling (edges 
raised approximately 1 
mm) 
9.2.7. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
The site principal investigator or appropriate sub-investigator is responsible for recording all 
AE/SAEs that are observed or reported during this trial, regardless of the relationship to study 
product. AE/SAEs, abnormal laboratory test values, or abnormal clinical findings will be 
collected, assessed, documented, reported, and followed appropriately. 
 
 

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9.3. 
Reporting Procedures 
Solicited upper respiratory assessment, respiratory tract assessment, and systemic reactogenicity 
events will be documented and reported from the time of experimental (first) study vaccination 
through 7 days after vaccination. 
Unsolicited non-serious AEs will be documented and reported from the time of the first study 
vaccination through approximately 21 days after the first study vaccination. 
SAEs will be documented and reported from the time of the first study vaccination through 12 
months after the first vaccination. 
AESIs (wheezing and otitis media) and NOCMCs will be documented and reported from the 
time of first study vaccination through approximately 3 months after first study vaccination. 
9.3.1 
Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group at the following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, selected SAE data fields must also be entered into 
AdvantageEDCSM. Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. 
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary) when they are 
provided to the DMID Pharmacovigilance Group.  The DMID Medical Monitor and DMID 

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Clinical Project Manager will be notified of the SAE by the DMID Pharmacovigilance Group. 
The DMID Medical Monitor will review and assess the SAE for regulatory reporting and 
potential impact on study subject safety and protocol conduct. 
At any time after completion of this trial, if the site principal investigator or appropriate sub-
investigator becomes aware of an SAE that is suspected to be related to study product, the site 
principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group. 
9.3.2. 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site principal investigator 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 FDA and all participating site principal investigators (i.e., all principal investigators to 
whom the sponsor is providing drug under its IND(s) or under any principal investigator’s 
IND(s)) in an IND safety report of potential serious risks from clinical trials or any other source, 
as soon as possible, but in no case later than 15 calendar days after the sponsor determines that 
the information qualifies for reporting as specified in 21 CFR Part 312.32.  DMID will also 
notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as 
possible, but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information.  Relevant follow up information to an IND safety report will be submitted as soon 
as the information is available.  Upon request from FDA, DMID will submit to FDA any 
additional data or information that the agency deems necessary, as soon as possible, but in no 
case later than 15 calendar days after receiving the request. 
All serious events designated as “not related” to study product(s), will be reported to the FDA at 
least annually in a summary format. 
9.3.3. 
Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported via AdvantageEDCSM on the Pregnancy 
Report form.  No further study vaccinations will be administered to pregnant subjects, but with 
the subject’s permission all protocol-required venous blood samples will be obtained and the 
subject will continue to be followed for safety for the duration of this trial.  Efforts will be made 
to follow all pregnancies reported during the course of this trial to pregnancy outcome pending 
the subject’s permission. 

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9.4. 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be collected, assessed, and followed through resolution from the time of each study 
vaccination through approximately 21 days after the first study vaccination. 
AESIs and NOCMCs will be collected, assessed, and followed through resolution from the time 
of the first study vaccination through approximately 3 months after the first study vaccination.  
SAEs 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 (through 12 months after 
the first 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. 
If the site principal investigator or appropriate sub-investigator becomes aware of an acute 
febrile illness and the site principal investigator or appropriate sub-investigator decides to bring 
the subject in for an evaluation to determine etiology, then the site principal investigator or 
appropriate sub-investigator, at their own discretion, can determine if specific viral testing should 
be done by either culture or polymerase chain reaction (PCR) to determine if the infectious agent 
was influenza and what strain. 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate data 
collection form. 
9.5. 
Halting Rules 
Further enrollment and study vaccinations will be halted for SMC review/recommendation if any 
of the following are reported following experimental (first) vaccination: 
• Any subject experiences laryngospasm, bronchospasm, or anaphylaxis within 1 day after 
administration of study product that is considered related to study product. 
• Two or more subjects experience the same grade 3 Adverse Event of any kind after 
administration of study product through day 8 that is considered related to study product 
• Two or more subjects experience generalized urticaria (defined as occurring at more than two 
body parts) within 3 days after administration of study product that is considered related to 
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• Any subject experiences a study vaccine-related SAE from the time of the first study 
vaccination through the subject’s last study visit. 
Grading scales for solicited upper respiratory and systemic (subjective and quantitative) 
reactions are included in Section 9.2.2. 
If any of the halting rules are met following any subject receipt of the first study vaccination, 
then this trial will not continue with the remaining enrollments or study vaccinations without a 
review by and recommendation from the SMC to proceed. 
DMID retains the authority to suspend additional enrollment and study interventions/ 
administration of study product during the entire trial, as applicable. 
9.6. 
Safety Oversight 
9.6.1 
Independent Safety Monitor (ISM) 
The ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion.  The ISM will review SAEs in real 
time and other AEs as needed and provide a written report to DMID.  Participation is for the 
duration of the DMID study.  The ISM must meet the requirements of the NIAID conflict of 
interest polity. 
The ISM: 
• Is in close proximity to the study site and has the authority and ability to readily access 
study participant records in real time. 
• May be a member of the participating institution’s staff but preferably be from a different 
organizational group within the institution. 
• Should not be in a direct supervisory relationship with the investigator. 
• Should have no direct involvement in the conduct of the study. 
The ISM will: 
• Sign a Conflict of Interest (COI) certification at the time they are asked to participate and 
provide updates to this information as needed. 

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• Receive reports of Serious Adverse Events (SAEs) from the site investigator and will be 
notified by email when DMID is notified of the SAE. 
• Evaluate the SAE and report their clinical assessment to DMID, through DMID-CROMS 
SOCS in a timely manner using the report form and email the report to DMID-CROMS 
SOCS. 
• Communicate with the investigator at the participating site as needed. 
• Review additional safety related events at the request of DMID. 
• Provide additional information to DMID and/or the DSMB by teleconference as 
requested. 
9.6.2 
Safety Monitoring Committee (SMC) 
This study will utilize an SMC, which is an independent group of experts that advises DMID.  
The primary responsibility of the SMC is to monitor subject safety.  The SMC is external to 
DMID and comprises at least 3 voting members.  The SMC will consist of members with 
appropriate phase 1 study expertise to contribute to the interpretation of the data from this trial.  
Its activities will be delineated in a SMC charter that will describe the membership, 
responsibilities, and the scope and frequency of data reviews.  The SMC will operate on a 
conflict-free basis independently of the study team.  The DMID or the SMC may convene ad hoc 
meetings of the SMC according to protocol criteria or it there are concerns that arise during the 
study.  
The SMC will review the safety data at the following milestones: 
• Organizational meeting (prior to start of the study) 
• Data Review Meetings (DRM) will be held during the study.  The SMC will review and 
evaluate accumulated trial data for subject safety, trial conduct, and trial progress at the 
below time points.  Unless a halting rule has been met or there is a safety concern, 
screening, enrollment, and vaccination will continue while the data is being prepared and 
reviewed by the SMC for these DRMs. 
o For Dose 1 – all available safety data through Day 8 after all subjects have 
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• An ad hoc SMC meeting will be convened when a halting rule is met, or at the request of 
the investigator and/or DMID if there are safety concerns during the course of the study. 
 
• Early analysis review: After clinical database lock on day 57 to review the cumulative 
unblinded safety data for this trial.  The data will be provided in a standard summary 
format. 
 
• Final Data Review Meeting: May be held 6 to 8 months after final clinical database lock 
to review the cumulative unblinded safety and immunogenicity data for this trial.  If a 
final review meeting is held, the data will be provided in a standard summary format.  
The SMC may be asked to provide recommendations in response to questions posed by 
DMID. 
 
All reviews by the SMC will be performed using unblinded data.  Study drug administration 
data, including dose interruptions, modifications, and the associated reason(s), will be reported to 
the SMC. 
The DMID Medical Monitor is empowered to stop study enrollment and vaccine administration 
if adverse events that meet the halting criteria are reported or if any serious safety concerns arise.  
The DMID Medical Monitor and the ISM will be responsible for reviewing SAEs in real time.  
The SMC will review SAEs on a regular basis and ad hoc during the study. 
 

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10. 
CLINICAL MONITORING 
10.1 
Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subjects protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, informed consent forms, medical and laboratory 
reports, and protocol and GCP compliance.  Site monitors will have access to the participating 
site, study personnel, and all study documentation according to the DMID-approved site 
monitoring plan.  Study monitors will meet with site principal investigators to discuss any 
problems and actions to be taken, and will document site visit findings and discussions. 

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11. 
STATISTICAL CONSIDERATIONS 
11.1 
Study Hypothesis 
This Phase I study is exploratory, rather than confirmatory and not designed to test a formal null 
hypothesis.  Rather, it is intended to obtain preliminary data in a pediatric population to estimate 
the immune response induced by this vaccine and to uncover any safety issues that occur at a 
sufficiently high rate that they might be observed in a study of this size.    
11.2. 
Sample Size Considerations 
This study is planned to enroll approximately 25 subjects in each treatment arm (Table 1).  The 
sample size for this study was selected to obtain preliminary estimates in a pediatric population. 
While this study is not designed to test any specific null hypothesis, the following tables 
illustrate the precision and power available for select estimates and comparisons of interest. 
Table 3 indicates the probability of observing one or more safety events, such as solicited local 
or systemic reactogenicity events or an unsolicited AE of a particular type, for a single treatment 
arm (N=25), and for all enrolled subjects (N=50).  
Table 3: Power (%) to Detect Safety Events: 
Event 
Frequency 
Single 
Treatment 
Arm 
N=25 
All 
Enrolled 
Subjects 
N=50 
10% 
Very Common 
93 
>99 
1% 
Common 
22 
40 
0.1% 
Uncommon 
3 
5 
0.01% 
Rare 
<1 
<1 

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Table 4 illustrates the minimum detectable differences in the proportion of subjects responding 
(e.g., attaining seroconversion or a titer ≥1:40) between two treatment arms for a range of 
possible response rates in the comparator arm, using a Chi-Square Test and alpha = 0.05.  In a 
Previous DMID trial (12-0016) in this population approximately 8% of subjects did not have 
available immunogenicity data at Day 42.  Table 4 is presented for the planned enrollment (N = 
25 per group) and accounting for 10% drop out (N = 22 per group). 
Table 4: Minimum Detectable Difference in Proportion Responders with 80% Power 
Assumed Proportion 
of Responders in 
Comparator Arm 
N = 25 
N = 22 
0.20 
0.36 
0.40 
0.40 
0.36 
0.40 
0.60 
0.31 
0.33 
0.80 
0.20 
0.20 
11.3. 
Planned Interim Analyses 
Immunogenicity and safety results will be provided for the purpose of planning subsequent trials 
as described in Sections 11.3.1 and 11.3.2. Interim analyses would 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.  An SMC 
will be convened by DMID to review study progress and participant, clinical, safety, and 
reactogenicity data.  
11.3.1 
Interim Safety Review 
Reports for interim safety review may include enrollment, and demographic information, dosing, 
solicited and unsolicited AE/SAE data, and clinical laboratory results.  Additional data may be 
requested by the SMC, and interim statistical reports may be generated as deemed necessary and 
appropriate by DMID.  The SMC may receive data in aggregate and presented by treatment arm.  
The SMC may also be provided with expected and observed rates of the expected AEs, and may 
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assessment.  The SMC will meet and review this data at scheduled time points or ad hoc as 
needed during the study as defined in the SMC charter.  As an outcome of each review/meeting, 
the SMC will make a recommendation as to the advisability of proceeding with study 
vaccinations (as applicable), and to continue, modify, or terminate this trial. 
Additional safety data may be requested by the vaccine partner during study follow-up for the 
purpose of planning future trials. Interim statistical reports may be generated as deemed 
necessary and appropriate by DMID. Reports may include data summarized by unblinded 
treatment arm; if so, the presentation will be in a format that prevents inadvertent unblinding of 
any individual subject. Such reports will be made available to the sponsor and vaccine partner for 
planning subsequent trials. These analyses will not be used to make any decisions concerning the 
conduct of this trial. No hypothesis testing will be included in any interim report. Additionally, 
the study will be monitored to determine if any of the halting rules described in Section 9.5 are 
met. 
11.3.2. 
Interim Immunogenicity Review 
An interim report of blinded MN results will be provided after the 19 subjects enrolled in 2018 
have completed the Day 113 visit. This streamlined report will be made available to the sponsor 
and vaccine partner for planning subsequent trials. These results will not be used to make any 
decisions concerning the conduct of this trial. No hypothesis testing will be included in any 
interim analysis. 
11.4. 
Final Analysis Plan 
Once the last subject completes the last immunogenicity outcome visit (approximately 21 days 
after the second study vaccination), all serum samples will be sent for secondary immunogenicity 
assays (HAI, MN, and sIgA). 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 on an expedited timeline. 
Once the last subject completes the last clinical visit (approximately 275 days after the second 
study vaccination), the clinical database will be cleaned, monitored and locked. Unblinded 
analyses of safety, reactogenicity, and immunogenicity will be performed by the SDCC after the 
primary clinical database is locked and all immunogenicity data are received.   
Analysis of exploratory immunogenicity endpoints may be performed and released as the data 
are available from the research laboratory.  Any such analyses would be considered the final 
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endpoint data not available at the time of CSR preparation may be included in an addendum to 
the CSR.  A formal statistical analysis plan will be developed and finalized prior to clinical and 
laboratory database freeze for the interim analysis, which will define the analyses to be included 
in the interim analysis and the final CSR. 
11.4.1. 
Analysis Populations 
The Safety Analysis population includes all subjects who received at least one dose of study 
vaccine. 
The modified intent-to-treat (mITT) population includes all subjects who received at least one 
dose of study vaccine and contributed both pre- and at least one post-study vaccination venous 
blood samples for immunogenicity testing (HAI antibody assays) for which valid results were 
reported. For analyses using the mITT population, subjects will be grouped based on randomized 
treatment arm.   
The per protocol (PP) population includes all subjects in the mITT subset with the following 
exclusions: 
• 
Data from all available visits for subjects found to be ineligible at baseline. 
• 
Data from all visits subsequent to major protocol deviations, such as: 
• 
Second study vaccination not received, 
• 
Second study vaccination received out of window, 
• 
Receipt of non-study licensed live or inactivated vaccine within 30 days prior to the first 
study vaccination,  
• 
Receipt of influenza vaccine (live or inactivated) within 6 months prior to the first study 
vaccination. 
• 
Receipt of immunosuppressive therapy (e.g., corticosteroids)  
• 
Receipt of aspirin or salicylate-containing products 
• 
Receipt of antiviral therapy 
• 
Data from any visit that occurs substantially out of window, such that in the opinion of 
the study investigator could affect the scientific goals of this protocol. 

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For analyses using the PP population, subjects will be grouped based on study vaccinations 
received.  
11.4.2. 
Primary Safety Data 
Summaries and analysis of safety data will be presented for the Safety Analysis Population.   
Solicited AEs will be summarized by severity for each day after the first study vaccination (Days 
1-8 post 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 number and percentage of subjects 
reporting each symptom, any upper respiratory symptom and any systemic symptom by 
treatment arm.  
Unsolicited AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA®) for 
preferred term and system organ class (SOC).  The number of SAEs, AESIs, and NOCMCs is 
expected to be small in this trial and will be reported by detailed listing showing the event 
description, MedDRA preferred term and SOC, relevant dates (study vaccinations and AEs), 
severity, relatedness, and outcome for each event.  If more than 5% of subjects report SAEs, and 
AESIs, and NOCMCs then the number and percentage of subjects reporting each type of event 
will be reported by treatment arm and compared using Fisher’s Exact test.  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. 
11.4.3. 
Secondary Immunogenicity Data  
Summaries and analysis of secondary immunogenicity data will be presented for the mITT and 
PP populations. 
Immune responses in terms of strain-specific (A/Brisbane/10/2007-like H3N2 (H3N2 M2SR) 
present in QIV, HAI and neutralization antibody titers will be summarized by treatment arm at 
each time point. Analyses will include number and proportion of subjects with a titer ≥1:40, 
number and proportion of subjects achieving seroconversion (defined as either a pre-vaccination 
titer <1:10 and a post-vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and a minimum 
four-fold rise in post-vaccination y titer), Geometric Mean Titers (GMTs) and Geometric Mean 
Fold Rise (GMFR) along with corresponding 95% confidence intervals (CIs).  

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Strain specific nasal sIgA responses with and without normalization to total sIgA at baseline will 
be summarized as the GMT and GMFR with corresponding 95% CIs.  Descriptive summaries of 
the frequency of influenza H3 HA-specific (H3 M2SR-like and QIV-like viruses) and conserved 
internal viral protein-specific IFN-gamma ELISPOT will be provided. 
Plots such as reverse cumulative distributions or longitudinal presentations of GMTs will be 
presented.  Regression models of immune response controlling for baseline titers may be 
considered. 
11.4.4. Exploratory Immunogenicity Data 
Exploratory studies will be performed contingent on the results of the secondary immunogenicity 
analysis as noted in Section 3.2; additional details will be provided in the statistical analysis plan.  
Summaries and analysis of exploratory immunogenicity data will be descriptive, including 
summary statistics and 95% CIs for each assay at each time point.  Correlations between HAI 
and exploratory immune response outcomes will be evaluated.  Graphical presentations may 
include plots such as reverse cumulative distributions or longitudinal presentations of GMTs will 
be presented. 
11.4.5. 
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. 
SOURCE DOCUMENTS ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records in compliance 
with ICH E6, section 4.9, and regulatory and institutional requirements for the protection of 
confidentiality of subjects.  Each site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, 
to copy) clinical trial records for the purposes of quality assurance reviews, audits, evaluation of 
the study safety and progress.  These representatives will be permitted access to all source data 
and source documents, which include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, copies of 
transcriptions certified after verification as being accurate and complete, microfiches,  
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
 
 

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

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14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1. 
Ethical Standard 
The site principal investigator (PI) 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 PI will also ensure conformity with ICH E6 Good Clinical Practice, and 
applicable federal regulations, guidance, and guidelines for Good Clinical Practice and Clinical 
Trials with humans. 
14.2. 
Institutional Review Board 
Each site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s), 
and send supporting documentation to the DMID before initiating recruitment of subjects.  The 
investigator will submit applicable information to the IRB/IEC on which it relies for the review, 
to conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as applicable, 21 CFR 
56 (Institutional Review Boards) and 21 CFR 50 (Protection of Human Subjects), other federal, 
state, and local regulations.  The IRB/IEC must be registered with OHRP as applicable to the 
research.  DMID must receive the documentation that verifies IRB/IEC-approval for this 
protocol, associated informed consent documents, and upon request any recruitment material and 
handouts or surveys intended for the subjects, prior to recruitment and enrollment of subjects. 
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before 
they are implemented.  IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects, and may cease if annual review is no longer required by 
applicable regulations.  The investigator will notify the IRB/IEC of deviations from the protocol 
and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federal Wide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research.  
The IRB/IEC will determine that adequate provisions are made for soliciting the permission of 
each child’s parent(s) or legal guardian, including whether permission of one parent is sufficient 
for research or whether permission is to be obtained from both parents.  The IRB/IEC will 
determine how consent from subjects will be obtained when participating in the study is ongoing, 
and the subject has reached the age of majority. 

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14.3. 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation.  Before any study procedures 
are performed, informed consent will be obtained and documented from the subject, 
parent(s)/legal guardian(s) of the minor subject.  Subjects, parent(s)/legal guardian(s) will 
received a concise and focused presentation of key information about the clinical trial, verbally 
and with a written consent form.  The explanation will be organized, and presented in lay 
terminology and language that facilitates understanding why one might or might not want to 
participate.   
An investigator or designee will describe the protocol to potential face to face with the subject, 
parent(s)/legal guardian(s).  The key information about the purpose of the study, the procedures 
and experimental aspects of the study, risks and discomforts, any expected benefits to the 
subject, and alternative treatment will be presented first to the subject, parent(s)/legal 
guardian(s). 
Subjects, parent(s)/legal guardian(s) will also receive an explanation that the trial involves 
research, and a detailed summary of the proposed study procedures and study 
interventions/products.  This will include aspects of the trial that are experimental, the 
probability for random assignment to treatment groups, any expected benefits, all possible risks 
(including a statement that the particular treatment or procedure may involve risks to the subject 
or to the embryo or fetus, if the subject is or may become pregnant, that are currently 
unforeseeable), the expected duration of the subject’s participation in the trial, alternative 
procedures that may be available and the important potential benefits and risks of these 
alternative procedures. 
Subjects, parent(s)/legal guardian(s) will be informed that they will be notified in a timely 
manner if information becomes available that may be relevant to their willingness for the subject 
to continue participating in the trial.  Subjects, parent(s)/legal guardian(s) will receive an 
explanation as to whether any compensation and any medical treatments are available if injury 
occurs, and, if so, what they will consist of, or where further information may be obtained.  
Subjects, parent(s)/legal guardian(s) will be informed of the anticipated financial expenses, if 
any, to the subject for participating in the trial, as well as any anticipated prorated payments, if 
any, to the subject for participating in the trial.  They will be informed of whom to contact (e.g., 
the investigator) for answers to any questions relating to the research project.   
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated.  The subject, parent(s)/legal guardian(s) 

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will be informed that the subject’s participation is voluntary and they are free to withdraw from 
the study for any reason at any time without penalty or loss of benefits to which the subject is 
otherwise entitled. 
The extent of the confidentiality of the subjects’ records will be defined, and parent(s)/legal 
guardian(s) will be informed that applicable data protection legislation will be followed.  
Subjects, parent(s)/legal guardian(s) will be informed that the monitor(s), auditor(s), IRB, 
NIAID, and regulatory authority(ies) will be granted direct access to the subject’s original 
medical records for verification of clinical trial procedures and/or data without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and regulations, and 
that, by signing a written informed consent form, the subject, parent(s)/legal guardian(s) is 
authorizing such access. 
Subjects, parent(s)/legal guardian(s) will be informed that records identifying the subject will e 
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, parent(s)/legal guardian(s) will be informed whether private 
information, collected from this research and/or specimens will be used for additional research, 
even if identifiers are removed. 
Subjects, parent(s)/legal guardian(s) will be allowed sufficient time to consider their minor 
child’s participating in this research trial, and have the opportunity to discuss this trial with their 
family, friends or legally authorized representative, or think about the process prior to agreeing 
to participate. 
Informed consent forms will be IRB-approved and parent(s)/legal guardian(s) will be asked to 
read and review the consent form.  Subjects, parent(s)/legal guardian(s) must sign the informed 
consent form prior to starting any study procedures being done specifically for this trial. 
Once signed, a copy of the informed consent form will be given to the parent(s)/legal guardian(s) 
for their records.  The subjects, parent(s)/legal guardian(s) may withdraw consent at any time 
throughout the course of the trial.  The rights and welfare of the subject(s) will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-
specific screening consent is on record or if the IRB has agreed that chart review is allowed 
without a fully executed screening consent.  In cases where there is not a patient-specific 
screening consent on record, site Clinical staff may pre-screen via chart review and refer 

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potential subjects to the Research staff.  Research staff would obtain written consent per the 
standard informed consent process before conducting protocol-specific screening activities. 
New information will be communicated by the site principal investigator to subjects, 
parent(s)/legal guardian(s) who consent to their minor child to participate in this trial in 
accordance with IRB requirements.  The informed consent document will be updated and 
subject, parent(s)/legal guardian(s) will be re-consented per IRB requirements, if necessary.  
Subjects, parent(s)/legal guardian(s) will be given a copy of all informed consent forms that they 
sign. 
14.3.1 
Informed Consent/Assent Process (in Case of a Minor) 
Investigators will follow IRB/IEC requirements for enrollment of minors in this study.  Minors 
will be informed about the study to the extent understandable to the minor.  Investigators or 
designee will conduct the consent process with the parent(s)/legal guardian, who will be given 
an IRB/IEC-approved permission form, which may be referred to as a consent form, to read, 
review, and sign prior to any study procedures.  The parent(s)/legal guardian will be provided 
meaningful study information including a statement that this study involves research, the child 
may not benefit from the trial, and the study involves risk.  The required elements will be clearly 
presented, including the purpose of the study, the experimental procedures, the potential risks 
and discomforts, known adverse effects, possible benefits of the study for the subject, alternative 
therapies that may be beneficial, use and disclosure of private information, and other elements 
that are part of obtaining proper consent.  The subject’s parent(s)/legal guardian will be allowed 
sufficient time to discuss questions with the investigator. 
The investigator or designee will describe in simplified terms the details of the study 
intervention/product, study procedures, risks and discomforts, benefits, and other consent 
elements, as appropriate.  A separate IRB/IEC-approved assent form will be used for the minor, 
who may read and sign the form, or have it read to him/her prior to participating in study 
procedures.  Assent may be obtained verbally or waived when approved by the IRB/IEC as 
appropriate to age.  If a child declines to participate in the trial when assent is required by the 
IRB/IEC, the subject will not be enrolled even though the parents have provided permission.  To 
ensure that consent is an ongoing process throughout the subject’s participation in the study, the 
investigator and staff will review information as needed with the subject and the parent(s)/legal 
guardian and confirm that assent and permission are continuing.  The permission and assent 
documents will be updated when new information is acquired that may impact the decision to 
continue in the study, and the subject’s assent and the parent(s)/legal guardian’s permission is 
obtained, as applicable. 

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The subject who reaches the age of majority will be consented at the next visit prior to study 
procedures.  When no further visits are planned but the subject’s participating is ongoing, the 
consent will be obtained via IRB/IEC-approved processes. 
 
A minor’s signature is not required on the assent form.  Parental consent will be documented on 
the ICF document.  In addition, the parent/legal guardian will sign under the assent section of the 
ICF that their child appears to understand the research to the best of their ability and agreed to 
participate. 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will be inclusive of all children and adolescents ages 9-17 years who meet the Subject 
Inclusion Criteria (see Section 5.1) and do not meet the Subject Exclusion Criteria (see Section 
5.2), regardless of religion, sex, or ethnic background.  Should the outcome of this trial be 
deemed acceptable, additional trials may be initiated. 
14.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents.  This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study.   
No information concerning the study or the data generated from the study will be released to any 
unauthorized third party without prior written approval of DMID and the subject.  Subject 
confidentiality will be maintained when study results are published or discussed in conferences. 
The study monitor or other authorized representatives of the sponsor or governmental regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the subjects in this study.  The clinical study site will permit access to such records.  All 
records will be kept locked and all computer entry and networking programs will be carried out 
with coded numbers only and with password protected systems.  All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number.   
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 

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researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the Federal 
Food and Drug Administration (FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including:  child and elder abuse, sexual 
abuse, or wanting to harm themselves or others.   
14.6 
Study Discontinuation 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary.  The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC.  If the subject’s private 
information will continue to be collected for this study, the IRB/IEC must approve a consent 
form with the study procedures, any risks and discomforts, and applicable elements, and the 
investigator or designee will re-consent the subjects as approved by the IRB/IEC. 
14.7 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial. Procedures and treatment for clinical care may be billed to the subject, subject’s 
insurance or third party.  Subjects may be compensated for their participation in this trial. 
Compensation will be in accordance with the local IRB’s policies and procedures, and subject to 
IRB approval. 
If it is determined by the site principal investigator 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 

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facilities will be provided to the subject.  Study personnel will try to reduce, control, and treat 
any complications from this trial. Immediate medical treatment may be provided by the 
participating site.  No financial compensation will be provided to the subject by the NIAID, NIH 
to the subject, or by the participating site for any injury suffered due to participation in this trial. 
14.8 Future Use of Stored Specimens and Data 
Residual samples/specimens are those that are left over after the study has been completed. 
Parent(s)/legal guardian(s) of minor subjects must give consent to keep any remaining (residual) 
specimens (serum, PBMCs, plasma) derived from venous blood samples for possible use in 
future research studies, such as examining additional immunological assessments or testing for 
antibodies against other viruses or bacteria. These residual clinical samples will be stored 
indefinitely at a central clinical storage facility and may be shared with investigators at the 
participating VTEU site and with other investigators at other institutions once the clinical study 
report has been finalized. The recipients of specimens will be informed that these specimens 
have a NIH certificate of confidentiality.  An IRB will review future research prior to the use of 
identifiable specimens or data. 
Parent(s)/legal guardian(s) of minor subjects must give consent to keep samples/specimens 
collected into a PAXgene tube during the study specifically for future use, including but not 
limited to future research studies that may test for other immune responses such as natural or 
antibodies from the vaccine to act against other bacterial or viruses.  The future research clinical 
samples will be stored indefinitely at a central storage facility.  
Residual specimens will be available upon the completion of this trial.  Extra samples/specimens 
collected during the study may be requested from DMID and shipped from the DMID CMS 
while this study is ongoing or after the study, after IRB review. 
There are no benefits to subjects in the collection, storage and subsequent future use of their 
samples/specimens.  Future research tests may benefit others by leading to new approaches in the 
development of vaccines or treatments for influenza. Future 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 that connects to a code 
key at the study site.  Restricted access to the code key is maintained by the PI to protect subject 
confidentiality.   
Reports from future research studies performed using subjects’ samples/specimens will NOT be 
kept in their health records and results will not be shared with subjects.  

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For 19 subjects enrolled in the 2018-2019 influenza season, PAXgene tubes were obtained. 
These samples/specimens might be used for genetic testing, 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. Parent(s)/legal guardian(s) of minor subjects will be contacted 
for re-consent for genetic testing. If the subject reached the age of 18, he/she will be contacted to 
give consent for genetic testing, as well as re-consent for all future research, as they have reached 
the age of adulthood.  
After all subjects had enrolled, it was determined that genetic testing may be performed on 
residual specimens and samples/specimens collected during this trial specifically for the purpose 
of future use, under a secondary research protocol. Secondary research is research that is not part 
of this trial and will be performed in the future. Subjects will be informed and asked for their 
consent to use their residual specimens and samples/specimens collected during this trial 
specifically for the purpose of future research and information for genetic testing for “secondary 
research”. Genetic testing could include transcriptomics, whole genome or exome sequencing, or 
other types of genetic testing. This could contribute to identifying genetic factors involved in 
vaccine responses. Genetic testing results (data) may be shared broadly with other researchers 
but will not be shared with subjects. Individual results will be stored indefinitely in an NIH 
restricted-access database, and a summary of results may be placed in an unrestricted (open) 
database. 
The samples/specimens will be labeled as above for storage. The genetic data in the NIH 
database will be coded in such a way that information will be considered de-identified. Subjects 
will be informed of the risks, including potential for re-identification and possible harm from the 
mis-use of data, however, NIH will require researchers to not re-identify the subjects. 
Subjects will have the right to withdraw consent for the use of their samples/specimens and/or 
data without penalty at any time. Samples/specimens and data that have already been used for 
secondary research may not be able to be withdrawn. 
"Written", or "signed", refers to the use of or writing on a paper or an electronic ICF. Re-consent 
(revised or separate consent form) for secondary research using samples/specimens and 
information, such as for genetic testing, may use paper or electronic ICFs to obtain the subject’s 
written consent. The subject will have a discussion with study staff, who is able to answer the 
subject’s questions, including if re-consent is obtained off-site. A paper copy of the signed ICF 
will be given to the subject in person or mailed. 

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14.9 
Disclosure of Study Related Information 
Parent(s)/legal guardian(s) can choose to receive written disclosure of their minor subject’s 
treatment assignment after the database has been locked.  

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15. 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported.  All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  Blue or black permanent ink is required to ensure clarity of 
reproduced copies.  When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source data collection forms 
and maintained for recording data for each subject enrolled in the study.  Data reported in the 
eCRF derived from source data collection forms should be consistent or the discrepancies should 
be explained.   
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the data collection forms and eCRF. 
15.1. 
Data Management Responsibilities 
Data collection is the responsibility of the study personnel at each participating VTEU site under 
the supervision of the respective site principal investigator.  During this trial, the site principal 
investigator must maintain complete and accurate documentation for this trial. 
The data coordinating center for this study will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
15.2. 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, and 
physical assessments, and clinical laboratory values), and reactogenicity will be collected on data 
collection forms by study personnel than entered into a eCRF via a 21 CFR 11-compliant 
internet data entry system provided by the study data coordinating center.  The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate.  

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15.3. 
Types of Data 
Data for this trial will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values, reactogenicity, and immunogenicity data). 
15.4. 
Timing/Reports 
An interim report of blinded MN results will be provided after the 19 subjects enrolled in 2018 
have completed the Day 113 visit. This streamlined report will be made available to the sponsor 
and vaccine partner for planning subsequent trials. These analyses will not be used to make any 
decisions concerning the conduct of this trial.  
Additional safety data may be requested by the vaccine partner during study follow-up for the 
purpose of planning future trials. Interim statistical reports may be generated as deemed 
necessary and appropriate by DMID. Reports may include data summarized by unblinded 
treatment arm; if so, the presentation will be in a format that prevents inadvertent unblinding of 
any individual subject. Such reports will be made available to the sponsor and vaccine partner for 
planning subsequent trials. These analyses will not be used to make any decisions concerning the 
conduct of this trial. No hypothesis testing will be included in any interim report. 
Once the last subject completes the last immunogenicity outcome visit (approximately 21 days 
after the second study vaccination), all serum samples will be sent for secondary immunogenicity 
assays (HAI, MN, and sIgA). 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 on an expedited timeline. 
Analysis of exploratory immunogenicity endpoints may be performed and released as the data 
are available from the research laboratory.  Any such analyses would be considered the final 
analysis for the endpoint, and included in the CSR.  The final CSR will be completed after the 
last subject’s last visit is completed, and the final clinical database including all long-term safety 
follow-up data is cleaned, monitored and locked and all secondary immunogenicity endpoint 
data are received.  Additional exploratory immunogenicity endpoint data not available at the time 
of CSR preparation may be included in an addendum to the CSR. 
Interim statistical reports may be generated as deemed necessary and appropriate by DMID. 
Safety and immunogenicity summary reports may be generated for the SMC. 

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After full analysis and final reporting is complete, and upon request and DMID approval, the 
SDCC will provide the participating VTEU site with a summary of results by treatment arm 
and/or subject treatment assignments.  In this regard, the participating VTEU site requesting such 
information to share with study subjects must do so in compliance with their respective IRB 
guidelines. 
15.5. 
Study Records Retention 
Study documents will be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there is no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents will be retained for a 
longer period, however, if required by local regulations.  No records will be destroyed without 
written consent of the sponsor.  It is the responsibility of the sponsor to inform the investigator 
when these documents no longer need to be retained.  
15.6. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, or protocol-specific 
MOP requirements.  The noncompliance may be either on the part of the subject, the site 
principal investigator, or the site personnel.  As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1, and 5.20.2 
It is the responsibility of the site principal investigator and personnel to use continuous vigilance 
to identify and report deviations within five working days of identification of the protocol 
deviation, or within five working days of the scheduled protocol-required activity.  All 
deviations must be promptly reported to DMID per the SDCC protocol deviation reporting 
procedures. 
All deviations, as defined above, must be addressed in study subject data collection forms.  A 
completed copy of the DMID Protocol Deviation Form must be maintained in the Regulatory 
File as well as in the subject's chart. Protocol deviations must be sent to the local IRB per its 

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guidelines.  The site principal investigator and personnel are responsible for knowing and 
adhering to their 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 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 ClinicalTrials.gov. 
The responsible party does not plan to request certification of delayed posting.   
 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
NIH NOT-OD-16-149 
 
 

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17. 
LITERATURE REFERENCES 
 
1. Longini, I.M., Halloran, M.E., Nizam, A., Wolff, M., Mendelman, P., Fast, P., Belshe, R.  
Estimation of the efficacy of live, attenuated influenza vaccine from a two-year, multi-center 
vaccine trial: Implications for influenza epidemic control.  Vaccine 2000; 18:1902-9.  
 
2. Hoft DF, et al.  Live and inactivated influenza vaccines induce similar humoral responses, 
but only live vaccines induce diverse T-cell responses in young children.  JID 2011 Sep 15; 
204(6):845-53. 
 
3. Hoft DF, et al.  Comparisons of the Humoral and Cellular Immune Responses Induced by 
Live Attenuated Influenza Vaccine an Inactivated Influenza Vaccine in Adults. Clin Vaccine 
Immunol 2017 Jan 5; 24:1-9. 
 
4. Sarawar, S., et al., M2SR, a novel live single replication influenza virus vaccine, provides 
effective heterosubtypic protection in mice. Vaccine 2016; 34(42): 5090-8. 
 
5. Hatta, Y., et al., M2SR, a novel live influenza vaccine, protects mice and ferrets against 
highly pathogenic avian influenza. Vaccine 2017; 35(33):  4177-4183. 
 
6. Lasky T, Tarracciano GJ, Magder L, Koski CL, Ballesteros M, Nash D, Clark S, Haber P, 
Stolley PD, Schonberger LB and Chen RT. The Guillain-Barré syndrome and the 1992-1993 
and 1993-1994 influenza vaccines. N Engl J Med 1998 Dec 17; 339(25):1797-1802. 
 
7.   Haber P, DeStefano F, Angulo FJ, Iskander J, Shadomy SV, Weintraub E and Chen RT.  
Guillain-Barré syndrome following influenza vaccination. JAMA 2004; 292:2478-2481. 
 
8.   De Wals P et al. Risk of Guillain-Barré syndrome following H1N1 influenza vaccination in 
Quebec. JAMA 2012; 308(2):175-181. 
 
9.   Wise ME, Viray M, Sejvar JJ, et al. Guillain-Barré syndrome during the 2009-2010 H1N1 
influenza vaccination campaign: population-based surveillance among 45 million Americans. 
Am J Epidemiol 2012; 175:1110-9. 
 
10.  Juurlink DN, Stukel, TA, Kwong, J, et al. Guillain-Barré syndrome after influenza 
vaccination in adults: a population-based study. Arch Intern Med 2006 Nov 13; 
166(20):2217-21. 
 

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11.  Salmon DA, et al. Association between Guillain-Barré syndrome and influenza A (H1N1) 
2009 monovalent inactivated vaccines in the USA: a meta-analysis. Lancet 2013; 
318(9876):1461-1468. 
 
12. Polakowski LL, et al. Chart-confirmed Guillain-Barré syndrome after 2009 H1N1 influenza 
vaccination among the medicare population, 2009-2010. Am J Epidemiol 2013 May 6. 
 
13. Dodd CN, et al. International collaboration to assess the risk of Guillain-Barré syndrome 
following Influenza A (H1N1) 2009 monovalent vaccines. Vaccine 2013 Jun 13. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A : SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS 
Study Visit Number 
 
V00 
V01 
V02 
 
 
V03 
 
 
V04 
V05 
V06 
 
V07 
 
 
V08 
Early  
Term 
Unsched- 
uled 
Study Day post first 
study vaccination 
Screen 
-28 to  
-1 
Dose 
1*  
D1 
D8 
±1 
 
 
D22 
±2 
 
 
D57 
±3 
Dose 
2* 
D92 
±14 
D 
113 
 
D 
240 
 
D 
366 
Study Day post second 
study vaccination 
 
 
 
 
 
D1 
D22 
±2 
 
 
 
D149
±14 
 
 
D275
±14 
 
 
Obtain Informed 
Consent/Assent 
 
X 
 
 
 
 
 
 
 
 
 
 
Collect Demographic 
Information 
 
X 
 
 
 
 
 
 
 
 
 
 
Review Eligibility Criteria 
X 
X 
 
 
 
X 
 
 
 
 
 
Medical History 
X 
X 
X1 
X1 
X1 
X 
X 
X 
 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X2 
X2 
X2 
 
 
X#3 
X#3 
Counsel about avoidance of 
taking aspirin and salicylate 
containing products 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 Oral Temperature  
 
X 
 
 
 
X 
 
 
 
X 
X 

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Study Visit Number 
 
V00 
V01 
V02 
 
 
V03 
 
 
V04 
V05 
V06 
 
V07 
 
 
V08 
Early  
Term 
Unsched- 
uled 
Study Day post first 
study vaccination 
Screen 
-28 to  
-1 
Dose 
1*  
D1 
D8 
±1 
 
 
D22 
±2 
 
 
D57 
±3 
Dose 
2* 
D92 
±14 
D 
113 
 
D 
240 
 
D 
366 
Study Day post second 
study vaccination 
 
 
 
 
 
D1 
D22 
±2 
 
 
 
D149
±14 
 
 
D275
±14 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
Limited Physical 
Examination 
 
X 
X 
 
 
 
 
 
 
X@ 
X@ 
Age and developmentally 
appropriate counseling 
about pregnancy prevention  
 
X 
X 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
 
 
 
{X} 
 
{X} 
 
{X} 
 
{X} 
 
{X} 
 
 
 
X 
X 
Urine Pregnancy Test 
X^ 
X^ 
 
 
 
X^ 
 
 
 
 
 

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Study Visit Number 
 
V00 
V01 
V02 
 
 
V03 
 
 
V04 
V05 
V06 
 
V07 
 
 
V08 
Early  
Term 
Unsched- 
uled 
Study Day post first 
study vaccination 
Screen 
-28 to  
-1 
Dose 
1*  
D1 
D8 
±1 
 
 
D22 
±2 
 
 
D57 
±3 
Dose 
2* 
D92 
±14 
D 
113 
 
D 
240 
 
D 
366 
 
 
Study Day post second 
study vaccination 
 
 
 
 
 
D1 
D22 
±2 
 
 
 
D149
±14 
 
 
D275
±14 
 
 
 
 
WBC, HGB, HCT, Platelet 
Count, ALT, AST, Serum 
Creatinine, PT, and aPTT 
 
X 
 
X 
X4,5 
X4,6 
 
X4 
 
 
 
 
Ferritin Level 
X 
 
 
 
 
 
X 
 
 
 
 
Serum (HAI, HA/NA 
ELISA, Neutralization 
Assays) 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Nasal Swab sIgA 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
PBMC (IFN-γ ELISPOT 
and CFSE Dilution/ICS 
Assays) 
 
X 
X 
 
X 
 
X 
X7 
X7 
 
 
X7 
 
Enrollment in 
AdvantageEDCSM and 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Pre-Administration 
Reactogenicity 
 
X 
 
 
 
X 
 
 
 
 
 
 

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{}Targeted physical examination if indicated based on review of complete or interim medical history 
^Will be performed on all female adolescents of childbearing potential at screening and within 24 hours prior to each study vaccination 
and results must be negative and known prior to each study vaccination. 
#If within 21 days post first study vaccination. 
*On dose dates, samples must be collected pre-dose 
@If within 8 days after 1st vaccination 
!If within 3 months post first study vaccination 
1Subject’s parent(s)/legal guardian(s) will be asked if the subject had any additional blood taken for medical reasons. 
subject’s blood taken for medical reasons 
2Concomitant medications will be limited to collecting aspirin and salicylate containing products 
3Aspirin or salicylate containing products will be collected if within 30 days of the first vaccination through 21 days after the last vaccination 
4Hemoglobin only 
5Collect at Day 22 if Hgb results from screen to Day 8 drop >0.5 g/dL or < lower limits of normal 
6If Hgb is not collected at Day 22 or low at Day 22, collect at Day 57 
7Will not collect PBMCs if Day 57 HgB is low