Phase 1b Clinical Study to Investigate the Safety and Immunogenicity of the Bris10 (A/Brisbane/10/2007) M2SR and Sing2016 (A/Singapore/INFIMH-16-0019/2016) M2SR H3N2 Monovalent Influenza Vaccines
Phase: PHASE1
Conditions: Influenza A
Sponsor: FluGen Inc

  
 
  
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In 
any event, persons to whom the information is disclosed must be informed that the information is privileged 
or confidential and may not be further disclosed without written authorization of Sponsor’s name. 
 
 
This study will be conducted in compliance with this protocol, 
the ICH Note for Guidance on Good Clinical Practice (CMPM/ICH/135/95) 
and with the applicable regulatory requirement(s)
Phase 1b clinical study to investigate the safety and immunogenicity of 
the Bris10 (A/Brisbane/10/2007) M2SR and  
Sing2016 (A/Singapore/INFIMH-16-0019/2016)  
M2SR H3N2 monovalent influenza vaccines 
Products 
Bris10 M2SR Vaccine and 
 
Sing2016 M2SR Vaccine 
Protocol Number 
FLUGEN-H3N2-V003 
 
IND Number 
016968  
 
Clinical Phase 
1b 
 
Clinical Indication Not applicable (Healthy Volunteers) 
 
Initial Protocol Version 1.0, 30-Apr-2019 
Amendment 1 Version 2.0, 14-May-2019 
Amendment 2 Version 3.0, 17-May-2019 
Amendment 3 Version 4.0, 08-August-2019 
Amendment 4 Version 5.0, 21-August-2019 
Amendment 5 Version 6.0, 26-September-2019 
Amendment 6 Version 7.0, 28-October-2019 
Amendment 7 Version 8.0, 18-May-2020 
Sponsor FluGen Corporation 
Sponsor Representative Pamuk Bilsel 
Phone 
608-442-6562 
 
Fax 
608-260-7704 

FluGen, Inc. 
CLINICAL STUDY PROTOCOL – FLUGEN-H3N2-V003 
18MAY2020 (v8.0) 
CONFIDENTIAL 
2 
 
 
 
SIGNATURES 
 
 
Signature of FluGen, Inc. Representative 
 
 
 
Study Title: Phase 1b clinical study to investigate the safety and immunogenicity of the 
Bris10 (A/Brisbane/10/2007) M2SR and Sing2016 (A/Singapore/INFIMH-16-
0019/2016) M2SR H3N2 monovalent influenza vaccines 
Protocol Date: 30APR2019 
 
 
Name:  
 
Pamuk Bilsel, PhD 
Affiliation:  
FluGen, Inc. 
Address:   
597 Science Drive, Madison, WI USA 53711 
 
 
This Clinical Study Protocol has been reviewed and approved by the Sponsor in order 
to ensure compliance with Good Clinical Practice. 
 
 
 
 
Signature: 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FluGen, Inc. 
CLINICAL STUDY PROTOCOL – FLUGEN-H3N2-V003 
18MAY2020 (v8.0) 
CONFIDENTIAL 
3 
 
 
 
 
 
 
 
Signature of FluGen, Inc. Statistician 
 
 
 
Study Title: Phase 1b clinical study to investigate the safety and immunogenicity of the 
Bris10 (A/Brisbane/10/2007) M2SR and Sing2016 (A/Singapore/INFIMH-16-
0019/2016) M2SR H3N2 monovalent influenza vaccines 
Protocol Date: 30APR2019 
 
 
Name:  
 
Roger Aitchison 
Affiliation:  
North Rim Consulting 
Address:   
814 Plateau Road, Longmont, Colorado USA 80504 
 
 
 
This Clinical Study Protocol has been reviewed and approved by the study 
statistician in order to ensure that the protocol and any amendments cover all 
relevant statistical matters clearly and accurately, using technical terminology as 
appropriate. 
 
 
 
 
Signature: 
 
Date: 
 
 

FluGen, Inc. 
 CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003  
 
18May2020 (v8.0) 
CONFIDENTIAL 
 
 
4 
 
 
 
PROTOCOL HISTORY 
 
 
 
 
 
 
FluGen, Inc. – FLUGEN-H3N2-V003 
 
Document 
Issue Date 
Amendment Type 
Comments 
Initial Clinical Study Protocol 
30APR2019 
Not applicable 
 
Protocol V2.0 
14MAY2019 
Non-substantial amendment 
1. Statement that study is funded by US Department of Defense  
2. New exclusion: Active military personnel not allowed to participate in the 
study 
3. Subjects are not allowed to use a Legally Authorized Representative 
4. ICF must be administered individually to each subject and in a private 
setting 
5. Clarified duties and responsibilities of Medical Monitor  
6. Minor corrections and clarifications including word modification and 
administrative changes  
Protocol V3.0 
17May2019 
Non-substantial amendment 
1. Updated to reflect what information will be collected if pregnancy occurs 
during the study 
2. Expanded and added clarity on the roles and responsibilities of the Medical 
Monitor 
3. Added details on how subjects will be identified and recruited for this study 
Protocol V4.0 
08August2019 
Non-substantial amendment 
1. Updated to clarify pregnancy occurring during trial. 
2. Added further details on identifying and recruiting subjects. 
Protocol V5.0 
21August2019 
Non-substantial amendment 
1. Updated to change the Lead Principal Investigator and site PI credentials 
2. Clarified that a site-specific Informed Consent Form, not a separate 
protocol ICF, may be used for consent to assess a subject’s 
microneutralization titer to Sing2016 
3. Clarified inclusion and exclusion criteria 
4. Added a ± 1-day window to Day 4 after each dose and 90-day window for 
pre-screen 
5. Clarified study event details 
6. Minor corrections and clarifications including word modification and 
administrative changes 
 
 

FluGen, Inc. 
 CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003  
 
18May2020 (v8.0) 
CONFIDENTIAL 
 
 
5 
Protocol V6.0 
26September2019 Non-substantial amendment 
1. Corrected 60-day to 90-day for MN titers consistent with other sections of 
protocol 
2. Updated exclusion 3 to clarify that subjects with clinically significant 
abnormal screening lab values should be excluded 
Protocol V7.0 
28October2019 
Non-substantial amendment 
1. Clarified that concomitant medications are to be recorded from time of 
signing ICF to Day 57. 
2. Clarified that subjects are to be observed approximately 5 and 30 minutes 
after dosing. 
3. Clarified that subjects are to be at rest for approximately 5 minutes prior to 
measurements of vital signs. 
4. Inserted text at 6.1.3 to instruct sites in regions of increased influenza 
activity to ask subjects to report any influenza symptoms and to collect a 
nasal swab if needed for lab confirmation of influenza infection. 
Protocol V8.0 
18May2020 
Non-substantial amendment 
1. Section 9.8 was revised in protocol v4.0 08AUG2019 but the original 
language was inadvertently re-instated in v5.0 21AUG2019 and remained in 
later versions. The language from section 9.8 of protocol v4.0 is the intended 
language.  
2. Section 6.1.2.8, exclusions 6 and 15, and Table 3 were revised to allow for 
a safety phone call on Day 209 due to prevalence of COVID-19. 
3. Addition of vendors to Study Administrative Structure and Investigators. 
4. Minor corrections and clarifications including word modifications. 
 
 
 
 

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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
SIGNATURES ......................................................................................................... 2 
PROTOCOL HISTORY ......................................................................................... 4 
TABLE OF CONTENTS ........................................................................................ 6 
LIST OF TABLES ................................................................................................. 10 
LIST OF FIGURES ............................................................................................... 10 
PROTOCOL SYNOPSIS ...................................................................................... 11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................... 26 
STUDY ADMINISTRATIVE STRUCTURE AND INVESTIGATORS ......... 29 
1. 
INTRODUCTION ....................................................................................... 31 
1.1. Overview ................................................................................................... 31 
1.2. Background Information ........................................................................... 31 
1.2.1. Influenza ........................................................................................ 31 
1.2.2. Current Influenza Vaccines ........................................................... 32 
1.2.3. Live attenuated vaccines ............................................................... 32 
1.2.4. FluGen’s H3N2 (A/Brisbane/10/2007) M2SR vaccine ................ 33 
1.2.5. FluGen’s H3N2 (A/Singapore/INFIMH-16-0019/2016) M2SR 
vaccine ................................................................................. 33 
1.3. Non-Clinical Studies of M2SR ................................................................. 34 
1.3.1. Non-Clinical Safety ....................................................................... 34 
1.3.2. Non-Clinical Efficacy ................................................................... 34 
1.4. Clinical Studies ......................................................................................... 35 
1.4.1. Phase 1 Dose Escalation Study ..................................................... 35 
1.4.2. Phase 1 Study in Adolescents ....................................................... 36 
1.4.3. Phase 2a Challenge Study ............................................................. 36 
1.5. Overall Rationale for the Study ................................................................. 37 
1.6. Risk/Benefit Analysis ................................................................................ 38 
1.6.1. Potential Risks ............................................................................... 38 
1.6.2. Potential Benefits .......................................................................... 38 
2. 
STUDY OBJECTIVES AND ENDPOINTS .............................................. 39 
2.1. Study Objectives ....................................................................................... 39 
2.1.1. Primary Objectives ........................................................................ 39 
2.1.2. Secondary Objectives .................................................................... 39 
2.1.3. Exploratory Objectives .................................................................. 39 
2.2. Study Endpoints ........................................................................................ 39 
2.2.1. Primary Endpoints ......................................................................... 39 
2.2.2. Secondary Endpoints ..................................................................... 40 
2.2.3. Exploratory Endpoints .................................................................. 40 
3. 
STUDY DESIGN .......................................................................................... 41 
3.1. Overview of Study Design ........................................................................ 41 
3.2. Study Conduct and Safety Reviews .......................................................... 43 

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3.3. Expected Duration of a Subject’s Participation in the Entire Study ......... 44 
3.4. Total Study Duration ................................................................................. 45 
3.5. Discussion of Study Design ...................................................................... 45 
3.5.1. Rationale for Use of Bris10 M2SR (H3N2) Vaccine and Route of 
Administration ..................................................................... 45 
3.5.2. Rationale for Dose Selection ......................................................... 45 
3.5.3. Rationale for Placebo Control ....................................................... 45 
3.5.4. Rationale for Randomization and Blinding ................................... 45 
4. 
SELECTION OF STUDY POPULATION ............................................... 46 
4.1. Inclusion Criteria ...................................................................................... 46 
4.2. Exclusion Criteria ..................................................................................... 47 
4.3. Lifestyle Guidelines .................................................................................. 49 
4.3.1. Contraception ................................................................................ 50 
5. 
TREATMENTS ............................................................................................ 51 
5.1. Study Vaccines .......................................................................................... 51 
5.2. Placebo Administered in the Study ........................................................... 51 
5.3. Packaging and Labeling ............................................................................ 52 
5.3.1. Vaccines ........................................................................................ 52 
5.3.2. Placebo .......................................................................................... 53 
5.4. Storage and Drug Accountability .............................................................. 53 
5.4.1. Vaccines ........................................................................................ 53 
5.4.2. Placebo .......................................................................................... 55 
5.5. Randomization .......................................................................................... 55 
5.6. Blinding ..................................................................................................... 55 
5.7. Dose and Administration ........................................................................... 56 
5.7.1. Vaccine .......................................................................................... 56 
5.8. Treatment Compliance .............................................................................. 57 
5.9. PRIOR AND CONCOMITANT THERAPY ............................................ 57 
5.9.1. Permitted Concomitant Therapies ................................................. 57 
5.9.2. Prohibited Concomitant Therapies ................................................ 58 
6. 
ASSESSMENTS ........................................................................................... 59 
6.1. Timing of Assessments ............................................................................. 59 
6.1.1. Screening Period 1 (Days -30 to Dosing) ...................................... 62 
6.1.2. Treatment Period (Day 1 to Day 57) ............................................. 63 
6.1.2.1. Day 1 
63 
6.1.2.2. Day 4 ± 1 day ....................................................................... 63 
6.1.2.3. Day 8 ± 1 day ....................................................................... 64 
6.1.2.4. Day 29 ± 7 days ................................................................... 64 
6.1.2.5. Day 32 (3 days ± 1 day after second dose) .......................... 65 
6.1.2.6. Day 36 (7 days -1/+7 day after second dose) ...................... 65 
6.1.2.7. Day 57 (28 days ± 7 days after second dose) ...................... 65 
6.1.2.8. Day 209 (180 days ± 14 days after second dose)- on-site visit
 ............................................................................... 65 
6.1.3. Testing for Influenza ..................................................................... 66 
6.1.4. Early Termination Visit ................................................................. 66 
6.1.5. Unscheduled Visits ........................................................................ 67 
6.2. Study Assessments .................................................................................... 67 

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18May2020 (v8.0) 
 
 
 
 
 
6.2.1. Clinical Evaluations ...................................................................... 67 
6.2.1.1. Medical History ................................................................... 67 
6.2.1.2. Concomitant Medications .................................................... 67 
6.2.1.3. Demographics ...................................................................... 67 
6.2.1.4. Physical Examination .......................................................... 67 
6.2.1.5. Vital Signs ........................................................................... 68 
6.2.1.6. Symptom Memory Aids ...................................................... 68 
6.2.1.7. Urine Samples...................................................................... 69 
6.2.2. Bioanalysis .................................................................................... 69 
6.2.3. Adverse Events .............................................................................. 70 
6.2.4. Efficacy Evaluations ..................................................................... 70 
6.2.4.1. Nasal Swabs ......................................................................... 70 
6.2.4.2. Delivery Device Weights ..................................................... 71 
6.2.4.3. Blood Collection for Influenza Antibody Testing ............... 71 
6.2.4.4. PBMCs for Cell-mediated Immunity Testing ..................... 71 
6.2.4.5. Plasma for Gene Expression and Cytokine Testing ............ 71 
7. 
STUDY TERMINATION/COMPLETION ............................................... 73 
7.1. Study Completion and End of Study Definition ....................................... 73 
7.2. Termination of the Study by the Sponsor ................................................. 73 
7.3. Study Halting Rules .................................................................................. 73 
7.4. Removal of Subjects from the Study ........................................................ 74 
8. 
STATISTICAL METHODS AND CONSIDERATIONS ........................ 75 
8.1. General Considerations ............................................................................. 75 
8.2. Analysis Sets ............................................................................................. 75 
8.3. Subject Disposition and Baseline Comparability ...................................... 75 
8.3.1. Sample Size ................................................................................... 76 
8.3.2. Subject Characteristics Data Set ................................................... 76 
8.3.3. Safety Analyses ............................................................................. 76 
8.3.4. Additional Analyses ...................................................................... 77 
8.4. Appropriateness of Measurements ............................................................ 77 
9. 
ADVERSE EVENT REPORTING ............................................................. 78 
9.1. Definitions ................................................................................................. 78 
9.2. Intensity of Adverse Events ...................................................................... 79 
9.3. Causality Assessment ................................................................................ 79 
9.4. Reactogenicity ........................................................................................... 80 
9.5. Outcome .................................................................................................... 80 
9.6. Recording of Adverse Events .................................................................... 81 
9.7. Reporting of Serious Adverse Events to the Sponsor for 
Pharmacovigilance ............................................................................. 81 
9.8. Pregnancy .................................................................................................. 82 
9.9. Reporting of Serious Adverse Events to Competent Authorities/Ethics 
Committees ........................................................................................ 82 
9.10. Medical Monitor ................................................................................... 82 
9.11. Safety Review Committee .................................................................... 83 
10. 
ETHICAL ASPECTS .................................................................................. 84 
10.1. Study-Specific Design Considerations ................................................. 84 

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CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
10.2. Regulatory Ethics Compliance ............................................................. 84 
10.2.1. Investigator Responsibilities ......................................................... 84 
10.2.2. Independent Ethics Committee or Institutional Review Board 
(IEC/IRB) ............................................................................ 84 
10.2.3. Informed Consent .......................................................................... 86 
11. 
ADMINISTRATIVE REQUIREMENTS .................................................. 87 
11.1. Protocol Amendments .......................................................................... 87 
11.2. Subject Identification, Enrollment, and Screening Logs ...................... 87 
11.3. Source Documentation ......................................................................... 87 
11.4. Case Report Form Completion ............................................................. 88 
11.5. Study Monitoring ................................................................................. 88 
11.6. Data Management ................................................................................. 89 
11.7. Data Quality Assurance ........................................................................ 89 
11.8. On-Site Audits ...................................................................................... 89 
11.9. Study Termination ................................................................................ 90 
11.10. 
Record Retention ............................................................................... 90 
11.11. 
Use of Information and Publication ................................................... 90 
11.12. 
Results ................................................................................................ 92 
11.13. 
Investigator Indemnity ....................................................................... 92 
11.14. 
Confidentiality ................................................................................... 92 
12. 
REFERENCES ............................................................................................. 93 
APPENDICES ........................................................................................................ 95 
APPENDIX 1: VITAL SIGN AND SYSTEMIC TOXICITY ASSESSMENTS
 .............................................................................................................. 96 
APPENDIX 2: LABORATORY ASSESSMENTS ............................................. 99 
APPENDIX 3: REACTOGENICITY ASSESSMENTS .................................. 104 
APPENDIX 4: INVESTIGATOR SIGNATURE PAGE ................................. 106 
APPENDIX 5: SYMPTOM MEMORY AID FOR VACCINATION PERIOD
 ............................................................................................................ 107 

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CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
 
LIST OF TABLES 
Table 1: 
Dose Cohorts ........................................................................................ 41 
Table 2: 
Dosing and Safety Reviews .................................................................. 42 
Table 3: 
Schedule of Events ............................................................................... 60 
 
LIST OF FIGURES 
 
Figure 1: 
Sample labels for drug product and SPG-NaCl buffer. ........................ 53 
Figure 2: 
Image of the MAD301 Sprayer Device Fitted to a Syringe ................. 56 
 
 

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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
PROTOCOL SYNOPSIS 
Study Title 
Phase 1b clinical study to investigate the safety and immunogenicity of 
the Bris10 (A/Brisbane/10/2007) M2SR and Sing2016 
(A/Singapore/INFIMH-16-0019/2016) M2SR H3N2 monovalent 
influenza vaccines 
Product 
Bris10 M2SR Vaccine 
(Lot#10250) 
Sing2016 M2SR 
Vaccine 
(Lot# 19097) 
Clinical 
Phase 
1b 
Protocol 
Number 
FLUGEN-H3N2-V003 
Indication Prophylactic H3N2 monovalent 
influenza vaccines, Bris10 
(A/Brisbane10/2007) M2SR and 
Sing2016 (A/Singapore/INFIMH-
16-0019/2016) M2SR, for 
protection against influenza 
disease caused by seasonal 
influenza A viruses. 
IND 
Number 
IND# 016968 
 
 
 
 
 
Sponsor 
FluGen Corporation 
597 Science Drive 
Madison, WI USA 53711 
 
Funded by: United States Department of Defense (DoD) 
Sponsor Representative Pamuk Bilsel, PhD 
Principal 
Investigator(s) 
(*Lead PI) 
1. Carlos Fierro, MD* 
2. Howard Schwartz, MD 
3. Mark Adams, MD 
4. Kimberly J. Ellis, DO 
Clinical Center(s) 
1. Johnson County Clin-Trials 
2. Research Centers of America 
3. Alliance for Multispecialty Research, Lexington 
4. Alliance for Multispecialty Research, Norfolk 
Study Period  
Initiation:     August 2019  
Completion: April 2020 
Number of Subjects 
Approximately 250 evaluable subjects 

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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
Introduction: 
FluGen, Inc., a biotech company based in Madison WI, USA, is developing a novel 
M2-deficient single replication live influenza vaccine platform M2SR to provide safe, 
effective protection against seasonal influenza strains. The vaccine virus does not express 
an essential viral protein (influenza M2), restricting it to a single replication cycle in the 
host. The initial (prototypical) product, designated as Bris10 M2SR vaccine, was intended 
to elicit an immune response to the vaccine virus, A/Brisbane/10/2007 (H3N2). Available 
data from Phase 1 and 2a studies have shown that a single intranasal dose of Bris10 M2SR 
vaccine is safe, immunogenic, and provided protection against a highly drifted H3N2 
influenza challenge agent among adult subjects who demonstrated a serum immune 
response following vaccination. Ultimately the vaccine development program aims to 
evaluate a quadrivalent M2SR vaccine containing two influenza A subtypes (H1N1-like 
and H3N2-like viruses) and two influenza B types.  
Previous clinical experience with the M2SR vaccine platform includes a First Time in 
Human (FTIH) Phase 1 dose escalation study in healthy adults, an on-going Phase 1 safety 
and immunogenicity study in adolescents and a Phase 2a challenge study in healthy adults 
using the H3N2 vaccine Bris10 M2SR.  
Between the FTIH Phase 1 and the Phase 2a challenge studies, a total of 72 adult subjects 
have been exposed to the highest dose of Bris10 M2SR tested (108 TCID50) with no SAEs 
or AEs of clinical significance or observations that would halt these studies. In addition, 
in the challenge study, 48 subjects who received the live, single-replication M2SR virus 
were subsequently challenged with a live, replicating influenza virus. A portion of those 
individuals experienced infection and symptoms consistent with influenza (e.g., nasal 
congestion, runny nose, sore throat, cough, tiredness, headache), but at frequency less 
than observed among individuals in the same study who did not receive vaccine prior to 
challenge. Of the 19 adolescents enrolled in the ongoing second Phase 1 study, while the 
randomization was set at 1:1 active to placebo, it is not known exactly how many received 
active investigational vaccine (M2SR), but in blinded review no safety concerns related 
to the M2SR vaccine have been reported. Combined, these findings indicate that the 
vaccine is safe and generally well tolerated as a single 108 TCID50 dose.  
The purpose of this Phase 1b dose escalation clinical study is to assess the safety, 
tolerability/reactogenicity, and immunogenicity of M2SR vaccines when delivered at 
higher dosages or in two doses to increase the proportion of subjects responding 
serologically to the vaccine. For this study, an updated vaccine, Sing2016 M2SR, has 
been prepared that will provide the HA and NA components from A/Singapore/INFIMH-
16-0019/2016, the H3N2 strain recommended for the 2018-2019 influenza season. 
Due to the COVID-19 pandemic, local governments may issue stay-at-home orders which 
prevent centers from conducting on-site Day 209 visits. This protocol allows for Day 209 
visit to be a safety follow-up phone call.  
Objectives: 
Primary Objectives: 
The primary objectives are: 
1. To assess the safety and tolerability of one and two administrations of the Bris10 
M2SR influenza vaccine each at 108 TCID50 delivered intranasally to healthy adult 
subjects. 

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CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
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2. To assess the safety and tolerability of one and two administrations of the 
Sing2016 M2SR influenza vaccine each at 108, 108.5 and 109 TCID50 delivered 
intranasally to healthy adult subjects 
Secondary Objectives: 
The secondary objectives are: 
1. To assess the immunogenicity (serum antibody, mucosal antibody and cellular 
immune responses) of one and two administrations of Bris10 M2SR vaccine at 
108 TCID50. 
2. To assess the immunogenicity (serum antibody, mucosal antibody and cellular 
immune responses) of one and two administrations of Sing2016 M2SR vaccine at 
108, 108.5 and 109 TCID50. 
3. To evaluate vaccine virus shedding after intranasal delivery. 
Exploratory Objectives: 
The exploratory objectives are: 
1. To evaluate cell mediated immunity for up to 2 months after the last vaccination. 
2. To evaluate additional vaccine-related immune responses during the period of 
study participation. 
 
Criteria for Evaluation: 
Primary endpoints: 
The primary endpoints are: 
1. The number and percentage of study participants who experience any vaccine-
associated adverse events (AEs) or serious adverse events (SAEs) after Bris10 
M2SR or placebo administration. 
2. The number and percentage of study participants who experience any vaccine-
associated AEs or SAEs after Sing2016 M2SR or placebo administration. 
Secondary endpoints: 
The secondary endpoints are:  
1. The number and percentage of study participants who after one or two doses of 
Bris10 M2SR or placebo demonstrate: 
i. Influenza-specific serum antibody responses measured at specified time 
points; 
ii. Influenza-specific mucosal IgA antibody responses measured at specified 
time points;  
iii. Influenza-specific cellular immune responses measured by cytokine 
enzyme-linked immunospot (ELISPOT) at specified time points.  
2. The number and percentage of study participants who after one or two doses of 
Sing2016 M2SR or placebo demonstrate: 
▪ Influenza-specific serum antibody responses measured at specified time 
points;  
▪ Influenza-specific mucosal IgA antibody responses measured at specified 
time points;  
▪ Influenza-specific cellular immune responses measured by ELISPOT at 
specified sampling time points.  

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3. Vaccine virus shedding evaluated by influenza A-specific qPCR on day 7 post IP 
administration. 
 
 
Exploratory endpoints: 
The exploratory endpoints are: 
1. Cell-mediated immunity (CMI) assessed by frequencies and fold increases 
of antigen-specific T-lymphocytes. 
2. Additional influenza-specific immunological assays may be performed.  
 
Overview of Study Design: 
This is a randomized, double-blind, placebo-controlled Phase 1 study evaluating the 
safety and immunogenicity of the Bris10 M2SR and Sing2016 M2SR H3N2 influenza 
vaccines delivered intranasally to healthy adults.  
Eligible subjects will be screened and randomized to receive two administrations 28 days 
apart of Sing2016 at three dose levels, Bris10 at one dose level, or placebo in a 1:1:1:1:1 
ratio. An overview of the planned dose cohorts is presented in (Table 1).  
Table 1: Dose Cohorts 
Dose Cohort 
Number of 
Subjects 
Number in 
Sentinel Group 
Number in 
Expansion Group 
1. 108   TCID50 Sing2016 
M2SR 
50 
9 
41 
2. 108.5 TCID50 Sing2016 
M2SR 
50 
9 
41 
3. 109   TCID50 Sing2016 
M2SR 
50 
9 
41 
4. 108   TCID50 Bris10 
M2SR 
50 
9 
41 
5. Placebo 
50 
9 
41 
Total 
250 
45 
205 
 
As shown in Table 2, three sentinel groups will be vaccinated first, each containing 
15 subjects (9 subjects receiving escalating doses of Sing2016 M2SR, 3 subjects 
receiving Bris10 M2SR, and 3 subjects receiving placebo), followed by the remainder of 
the subjects in an expansion group. Cohorts are split into multiple groups to alleviate 
PBMC processing issues of large numbers of samples. Dosing will be staggered to allow 
for review of AEs through Day 3 post-administration for each sentinel group prior to 
dose escalation. A Safety Review Committee (SRC) will review available safety data 
from all sentinel subjects after subjects have completed 7 days after vaccination, prior to 
dosing of the expansion group. A comprehensive list of safety parameters collected 
during the study are described in Table 3.  

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CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
Table 2: Dosing and Safety Reviews 
 
*Dose Cohort 1 = Sing2016 M2SR 108, Dose Cohort 2 = Sing2016 M2SR 108.5, Dose Cohort 3 = 
Sing2016 M2SR 109, Dose Cohort 4 = Bris10 M2SR108, Dose Cohort 5 = saline placebo 
Notes: Safety indicates a review by the Lead PI and/or Medical Monitor as detailed below in Study 
Conduct. SRC indicates a review by the SRC as detailed below in Study Conduct. The Expansion Group 
schedule may be extended based on speed of enrollment.  
 
Using one nasal sprayer per nare, up to 0.5 mL of the Sing2016 M2SR vaccine or placebo 
(a total of up to 1.0 mL) and up to 0.2 mL of the Bris10 M2SR vaccine (a total of up to 
0.4 mL), will be delivered per subject per administration. The study will administer 
escalating doses of Sing2016 M2SR vaccine, with a starting dose of 108 TCID50 
increasing in half log (3-fold) increments to a maximum dose of 109 TCID50. Controls 
will be saline placebo and a 108 TCID50 dosage of Bris10 M2SR.  
Five (5) dose cohorts of 50 subjects each will be enrolled, for a total of approximately 250 
subjects randomized 1:1:1:1:1 to receive either Sing2016 M2SR 108, Sing2016 M2SR 
108.5, Sing2016 M2SR 109, Bris10 M2SR or saline placebo. A sentinel group of 9 subjects 
(~18% of each escalating dose cohort) will be vaccinated first, followed by the remainder 
of the dose cohort in an expansion group. Subjects in each sentinel group will be actively 
followed for 3 days and if the Medical Monitor and/or Lead PI determine that no halting 
rules have been met, the next sentinel group will be enrolled. After all sentinel subjects 
have completed 7 days following vaccination, a Safety Review Committee (SRC) will 
review available safety data prior to enrollment and vaccination of the expansion groups. 
All dosed subjects will receive a second dose of the assigned investigational product (IP) 
approximately 28 days after receiving the first dose. The SRC review of sentinel data prior 
to enrollment of expansion subjects may occur concurrently with or following the 
administration of second doses of vaccine to sentinel subjects.  
SAEs occurring at any time during the study will be recorded. Administration site and 
solicited AEs will be recorded through 7 days after each vaccination (Days 8 and 29) and 
unsolicited AEs will be recorded through 28 days after the last vaccination (Day 57). An 
SRC, comprised at a minimum of two independent physicians experienced in vaccine 

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research and a biostatistician, will be available to review safety data at specified time 
points and as needed. 
Based on the safety reviews, an intermediate or lower dose may be chosen to replace the 
planned dose for a dose cohort. If a lower or intermediate dose is chosen that dose will be 
used for an entire dose cohort. Should dosing be delayed for safety review or enrollment 
issues, subjects may receive their second dose at a time later than defined in the proposed 
dosing window. 
While safety and tolerability are the primary objectives, this clinical study is also designed 
to assess the immune response to one and two doses of each of the investigational vaccines 
at each of the designated dose levels. Immunogenicity will be assessed by measuring 
serum 
antibody 
responses 
by 
hemagglutination 
inhibition 
(HAI) 
and/or 
microneutralization (MN) assay. Additional immune parameters will be assessed 
including mucosal antibody titers and cell-mediated immunity. Subjects will be pre-
screened, under a site-specific Informed Consent Form (ICF), to avoid enrollment of 
individuals 
with 
high 
MN 
titers 
(> 1:20) 
against 
the 
target 
component 
(A/Singapore/INFIMH-16-0019/2016 [H3N2]). 
Study Conduct 
After subjects have signed an informed consent and have met the inclusion /exclusion 
criteria, healthy adults will receive a single administration of the IP (active M2SR or 
placebo) delivered intranasally as a liquid formulation. The Phase 1 and Phase 2a trials in 
adults and the ongoing Phase 1 trial in adolescents have demonstrated that a single dose 
of Bris10 M2SR at 108 TCID50 with and without a subsequent administration of a live, 
replicating influenza virus is generally safe and well tolerated with no shedding of 
infectious vaccine virus. Hence, the study will be conducted in an outpatient setting and 
with safety reviews as shown in Table 2 and summarized here: 
1. Deliver first dose to sentinel group 1 on Day 1. Lead PI reviews AEs through 3 
days post-administration of first dose (Day 4), confirms that no halting rules have 
been met, and communicates this to the Sponsor. 
2. If no safety concerns in sentinel group 1, deliver first dose to sentinel group 2. 
Lead PI reviews AEs for sentinel group 2 through Day 4, and cumulative AEs for 
sentinel group 1, confirms that no halting rules have been met, and communicates 
this to the Sponsor. 
3. If no safety concerns in sentinel groups 1 and 2, deliver first dose to sentinel 
group 3. Lead PI reviews AEs for sentinel group 3 through Day 4 and cumulative 
AEs for sentinel groups 1 and 2, confirms that no halting rules have been met, and 
communicates this to the Sponsor. 
4. If no halting rules are met, second doses are administered to sentinel subjects in 
all groups at Day 29 according to the study schedule. 
5. Safety reviews through 3 days post administration of the second dose (Day 32) are 
conducted in the same manner as outlined above for second doses of sentinel 
groups. 

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18May2020 (v8.0) 
 
 
 
 
 
6. After sentinel subjects have completed 7 days following first vaccination (Day 8), 
SRC reviews available safety data for sentinel groups 1-3. If no safety concerns 
are identified, deliver first dose to expansion group subjects.  
7. After all sentinel subjects have completed 7 days following second vaccination 
(Day 36), SRC reviews cumulative safety data. If no safety concerns are identified, 
deliver second dose to expansion group subjects.    
8. During enrollment of the expansion cohorts, the occurrence of events which could 
prompt a study halt will be reviewed weekly by the Medical Monitor, until all 
subjects have completed 7 days following second vaccination (Day 36).  
Each subject will undergo the following testing (also depicted in Table 3): [Note that a 
Pre-screen with blood draw to assess the subject’s microneutralization (MN) titer to 
Sing2016 may be conducted under a site-specific ICF in the period spanning 90 calendar 
days before enrollment in this study.] Subjects who meet eligibility criteria will be 
enrolled in the proposed Phase 1b study, have a baseline blood draw, be randomized to a 
dose cohort and administered IP of either active M2SR vaccine or placebo on Days 1 
(Visit 01) and 29 (Visit 04). For 7 days following each dose the subjects will record 
symptoms in a Symptom Memory Aid (Appendix 5) and after 3 days (Days 4 and 32) will 
be contacted via phone call by the site staff representative to report symptoms and AEs. 
Subjects will attend the investigational site for follow-up on Days 8, 29, 36, 57 and 209 
(Visits 03, 04, 06, 07 and 08, respectively) for a limited physical exam, safety evaluation, 
nasal swabs and blood draws. Day 209 will also be the end of study visit for each subject 
in the study. Serum samples for analysis of anti-HA antibody titers for the H3N2 antigen 
in Sing2016 and Bris10 will be collected at baseline and on Days 8, 29, 36, 57 and 209. 
PBMC samples for analysis of cell-mediated immunity and/or innate transcriptome gene 
expression will be collected at baseline and on Days 4 (optional), 8, 29, 32 (optional), 36 
and 57 from select sites. Nasal swabs will be collected on Days 1, 8, 29, 36, 57 and 209 
for analysis of IgA-specific anti-HA antibody titers. Nasal swabs will be collected at Days 
1, 8, 29, and 36 to evaluate shedding of vaccine virus. A nasal swab collected at Day 1 
may be evaluated for presence of respiratory pathogens. Safety clinical laboratory testing 
will be performed at screening, and on Days 1, 8, 29, and 36. During the treatment period 
(Day 1 – Day 57), subjects will be asked to notify the site immediately if symptoms of 
influenza (fever, chills, sore throat, rhinorrhea, cough, muscle/body aches) occur. When 
increased influenza infections are being reported in the geographic region of the 
investigational site, subjects will additionally be contacted at Days 15±2, 21±2, 43±2, and 
50±2 by phone or messaging. If influenza is suspected the subject will be asked to return 
to the site for laboratory confirmation of influenza using nasal swabs.  
Halting Rules 
Vaccination of subjects will be suspended until after review of safety data by the SRC if 
any of the following halting rules are met:  
1. One or more subjects experience a Grade 4 AE, vital sign or laboratory AE that 
cannot be clearly attributed to another cause. 
2. Three or more subjects within a single sentinel group or ten or more subjects 
within the expansion group experience the same Grade 3 AE, vital sign or 
laboratory AE that cannot be clearly attributed to another cause.  
3. One or more subjects experiences a SAE assessed as related to IP.  

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4. One or more subjects has laryngospasm, bronchospasm, or anaphylaxis associated 
with the study product within 72 hours of product administration. 
Any AE or SAE that falls into the above criteria for suspending or terminating the study 
(including the occurrence of any Grade 3 AE, vital sign or laboratory AE that cannot be 
clearly attributed to another cause) must be reported by the investigator to the Sponsor 
immediately (within 24 hours). 
In the case of halting rules being met, the SRC will be convened as quickly as possible. 
After review of the safety data the SRC will make a recommendation to the Sponsor 
whether to resume, suspend or terminate the study. The Sponsor will communicate a 
decision to suspend or terminate the study to the Investigators. 
Subsequent review of serious, unexpected, and related AEs by the Medical Monitor, 
SRC, IRB, the Sponsor(s), or the FDA or relevant local regulatory authorities may also 
result in suspension of further trial interventions/administration of study product at a 
site. The FDA and study Sponsor(s) retain the authority to suspend additional 
enrollment and study interventions/administration of study product for the entire study, 
as applicable. 
Safety Parameters 
Visual assessment of the nose on the day of IP administration (pre-dose, 5 minutes 
post-dose and at 30 minutes post-dose) and at follow-up assessments along with exam 
of throat and lungs on Patient Days 8, 29, 36, 57 and 209 will be part of a limited 
physical exam. Note: Appropriate medical treatment and supervision must be available 
to manage possible anaphylactic reactions following administration of the vaccine. 
Clinical pathology will be evaluated at screen, Day 1 pre-dose, Day 8, Day 29 pre-dose 
and Day 36 and at additional time points as judged by the Investigator for safety 
evaluation.  
Unsolicited local and systemic adverse events for 28 days post-dose. 
Solicited AEs using a symptom memory aid for 7 days post-dose. 
SAEs from vaccination until Day 209.  
Changes in physical examination, vital signs, laboratory safety tests, lung function and 
pregnancy tests over the course of the study. 
Study Population: 
Healthy male and non-pregnant/lactating female subjects ages 18-49 years old. 
The study plans to enroll approximately 250 subjects who will receive two doses of 
experimental Bris10 or Sing2016 M2SR vaccine or placebo (physiological saline) on 
Study Days 1 and 29. Subjects will be randomized 1:1:1:1:1 (Sing2016 M2SR 108, 
Sing2016 M2SR 108.5, Sing2016 M2SR 109, Bris10 M2SR or Saline placebo). 
Inclusion Criteria:  
1. Give written informed consent to participate; a legally authorized representative 
(LAR) may not be used. 
2. Age 18 – 49 years old, inclusive. 
3. Judged suitable by the PI, as determined by medical history, physical examination, 
vital signs, and clinical safety laboratory examinations. 

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CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
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4. Negative test for pregnancy at screening visit and on Day 1. A positive test on 
Patient Day 29 will exclude subject from a second dose. 
5. Negative test (urine) for drugs of abuse at screening. Patients who are on stable (6 
months or longer) medications prescribed by their physician which result in a 
positive screen for that substance are allowed at the discretion of the investigator. 
6. Female subjects should fulfill one of the following criteria: 
a. Post-menopausal status defined as no menses for 12 consecutive months 
without an alternative medical cause. 
b. Surgically sterile. 
c. Willing to use oral, implantable, transdermal or injectable contraceptives, 
or sexual abstinence as outlined in inclusion criteria 7, from screening and 
until 28 days after second vaccine dose (Patient Day 57). 
7. Female subjects of childbearing potential must agree to sexual abstinence, use a 
reliable form of contraception approved by the Investigator (e.g., oral, 
implantable, transdermal, or injectable contraception, combined oral, intrauterine 
device [IUD], or a sterile sexual partner) from screening and until 28 days after 
the second vaccine dose (Patient Day 57). Non-surgically sterile male subjects 
who are sexually active with a female partner(s) of childbearing potential (i.e. 
males who have not been sterilized by vasectomy for at least 6 months prior to 
screening) must be willing to use condoms from screening and until 28 days after 
the second vaccine dose (Patient Day 57).  
8. Willing to adhere to the requirements of the study and willing and able to 
communicate with the Investigator and understand the requirements of the study. 
9. Non-smoker (defined as no use of tobacco products and no use of inhaled non-
tobacco products in the past 30 days prior to Study Day 1; nicotine patches and 
gum are allowed). Subject must also agree to restrict the use of these products until 
7 days after last vaccine administration. 
10. H3N2 Sing2016 MN titers ≤1:20 (determination within 90 calendar days of study 
enrollment is acceptable and does not need to be repeated for entry to this study). 
Exclusion Criteria:  
1. Any subject who is a family member of a) study site personnel and other personnel 
directly involved in conduct or monitoring of study, or b) the Sponsor. 
2. Any condition that would limit the subject’s ability to complete the study based 
on the opinion of the Investigator (for example, a recent surgical procedure). 
3. Clinically significant abnormal screening hematology or chemistry value, as 
assessed by the investigator. 
4. Pulse rate or blood pressure outside the reference range for this study population 
and considered as clinically significant by the Investigator.  
5. Has an acute or chronic medical condition or history of a medical condition that, 
in the opinion of the Investigator, would render the study procedures unsafe or 
would interfere with the evaluation of the responses, including but not limited to, 
respiratory, autoimmune, or immune suppression conditions, neuroinflammatory 
conditions, mental illness (including depression), active hematological, renal, 
hepatic, pulmonary, central nervous, neurological, cardiovascular, endocrine 
(including diabetes mellitus) or gastrointestinal disorders. 

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CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
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6. Has been vaccinated against influenza within the last 6 months or plans to be 
inoculated with an influenza vaccine (other than study vaccine) until one month 
after completion of follow up on Patient Day 209. 
7. Had a flu-like illness (i.e., fever, chills and myalgia), influenza treatment (i.e., 
commercial drug such as Oseltamivir, etc.), or prophylactic influenza viral drug 
administered in the previous 6 months before screening.  
8. Positive screening test or known infection with human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). 
9. History of cancer within 5 years prior to screening (except basal cell carcinoma 
and cervical carcinoma in situ). 
10. Presence or clinically significant history of lung disease, asthma, chronic 
obstructive pulmonary disease (COPD), or otherwise poor lung function. 
Childhood asthma that resolved by age 12 years is not criteria for exclusion.  
11. Any significant abnormality altering the anatomy of the nose or nasopharynx. A 
test swabbing by mock swab may be performed at screening at the Investigator’s 
discretion. 
12. Any confirmed or suspected immunosuppressive or immunodeficient state 
including: asplenia, recurrent severe infections and chronic (more than 14 days) 
immunosuppressant medication (such as systemic corticosteroids at a dose of 
≥ 0.5 mg/kg/day for longer than 1 week, or immunosuppressants such as cytotoxic 
drugs) within the last 6 months (topical steroids are permitted). Use of 
immunosuppressive medications, such as allergy shots, immune globulin, 
interferon, or immunomodulators in the past 6 months or planned to be used during 
the course of the trial. Use of intranasal corticosteroids within the last 7 days 
before screening. 
13. Significant adulthood history of seasonal hay fever, a seasonal allergic rhinitis, 
perennial allergic rhinitis, chronic nasal or sinus condition such as sinusitis, at the 
discretion of the investigator. 
14. Received any licensed vaccine within 1 month before screening and during the 
course of the study.  
15. Received or planned administration of another investigational vaccine or drug 
during the period from 90 days prior to Day 1 to one month after completion of 
Day 209 follow up  
16. History of allergy/hypersensitivity to any vaccine component (sucrose, sodium 
chloride, phosphate, glutamate), or material in nasal delivery device 
(polycarbonate, polypropylene, synthetic rubber). 
17. Experienced a life-threatening reaction(s) after a previous administration of any 
vaccine or experienced an allergic reaction after a previous administration of any 
influenza vaccine or component. 
18. A history or prior diagnosis of Guillain-Barré Syndrome.  
19. Living in the same household with any person with a non-functional or suppressed 
immune system, or with a confirmed influenza infection or febrile illness within 
the previous two weeks. 
20. History of drug or alcohol abuse in the 6 months before the study. 

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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
21. Current use of any new prescription or new over-the-counter (OTC) medications 
starting within 1 month of vaccination, except for contraceptive pills, implants, 
transdermal or injections in female subjects, which may have been started within 
the previous 1 month. Herbal medications and supplements other than vitamins 
are prohibited.  
22. Receipt of blood products or immunoglobulin within 6 months before study entry 
or planned for within 180 days after the last vaccination. 
23. Donation of blood or blood products within 30 days before study entry or planned 
donation at any time during the 30 days post last vaccination. 
24. Females who are pregnant or lactating (i.e., a nursing mother). 
25. Acute febrile illness within 72 hours prior to vaccination, defined as the presence 
of a moderate or severe illness with or without fever (as determined by the 
Investigator through medical history and physical examination), or presence of a 
fever >38ºC orally. Vaccination (or administration of the second dose of vaccine) 
should be delayed until the subject has recovered. Persons with a minor illness, 
such as diarrhea, or mild upper respiratory tract infection with or without low-
grade fever, may be enrolled after resolution of the illness.  
26. Any condition, in the opinion of the Investigator, (such as subjects who have 
medically high-risk conditions) that might interfere with the primary study 
objectives for safety of the study subject. 
27. Previous exposure to M2SR investigational vaccine. 
28. Any active military personnel/member. 
 
Exclusions at Day 29: 
Pregnancy, receipt of a prohibited medication, or new prohibited diagnosis, including 
laboratory confirmed influenza and or treatment for influenza, or high-risk condition are 
exclusions for second vaccination. 
 
Note: At the discretion of the investigator, subjects may be rescreened; out-of-range 
clinical laboratory tests may be repeated twice, and vital signs may be repeated three 
times. Results of any retest must be available prior to enrollment. 
Test Product, Dose, Mode of Administration: 
Bris10 M2SR Vaccine: One IP is termed Bris10 M2SR and is a recombinant, 
monovalent influenza A virus that encodes the viral antigens, hemagglutinin (HA) 
and neuraminidase (NA) from Influenza A/Uruguay/716/2007, an 
A/Brisbane/10/2007-like H3N2 virus strain. Bris10 M2SR has been initially tested in 
the Phase 1, first-time-in-humans (FTIH) study FluGen-H3N2-V001 under US IND 
016968 (also see ClinicalTrials.gov identifier NCT02822105), in a Phase 1 
adolescent study in the US (BB-IND 18170) and in a Phase 2a virus challenge study 
in Belgium (EudraCT 2017-004971-30). The vaccine (Lot# 15100251) for these three 
studies was manufactured using a master virus stock and working cell bank at 
Meridian Life Sciences (Memphis, Tennessee, USA) under current Good 
Manufacturing Practice (cGMP) in a liquid formulation.  
Sing2016 M2SR Vaccine: The second IP is termed Sing2016 M2SR and is a 
recombinant, monovalent influenza A virus that provides the HA and NA components 

CONFIDENTIAL 
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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
from A/Singapore/INFIMH-16-0019/2016 that were recommended for the 2018-2019 
influenza season. 
The Bris10 M2SR vaccine (Lot# 10250) and the Sing2016 M2SR (Lot# 19097) for 
this Phase 1b study were manufactured at Ology Bioservices (Alachua, Florida, USA) 
under current Good Manufacturing Practice (cGMP) in a liquid formulation. The 
Bris10 M2SR vaccine and the Sing2016 M2SR vaccine will be provided frozen and 
in single-use. A pharmacist or designee will thaw the vial contents to room 
temperature just prior to dose administration. The contents will be diluted to the 
target dosing concentration with provided SPG diluent for each subject. The final 
diluted product will be drawn into two 1 mL disposable polypropylene syringes each 
fitted with a mucosal atomization device (MAD301; Teleflex, Salt Lake City, Utah, 
USA) for intranasal delivery. 
For delivery, on each of Days 1 and 29, subjects will receive a single intranasal dose 
of vaccine (or placebo) via two nasal spray devices. Subjects will be in a semi-
recumbent position and receive approximately two administrations of ~50% volume 
per nasal cavity by employing two spray devices. Devices will be weighed pre- and 
post-dose to allow calculation of dose eliminated from the devices. Subjects will 
remain semi-recumbent and under observation for thirty (30) minutes and will not be 
allowed to blow their noses, eat or drink during this time.  
Reference Product, Dose, Mode of Administration: 
The reference product (placebo) is a physiological saline suitable for intranasal delivery. 
The placebo will be provided as a liquid and in single-use vials. The placebo will be 
drawn into two 1 mL disposable syringes that are fitted with a Teleflex MAD301 
sprayer for intranasal delivery. Administration will be as described for the M2SR 
vaccines. 
The placebo is a clear solution whereas the M2SR vaccines are a light yellowish color. 
The unblinded pharmacy staff will prepare the vaccine and placebo doses, fill delivery 
devices and apply an opaque label to the device barrel to obscure any coloration of the 
contents or volume differences and maintain the blind. 

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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
Study/Treatment Duration: 
All subjects will receive either active vaccine or placebo on Days 1 and 29.    
Eligible subjects will be enrolled and receive a first dose on Day 1, be contacted by the 
site on Day 4 for report of symptoms/AEs (or optionally may attend the clinic if 
consenting to PBMC collection at select sites) and will attend the clinic on Day 8 for 
safety follow-up. Subjects will return to the site for a second dose administration on Day 
29, be contacted by the site on Day 32 for report of symptoms/AEs and will attend the 
clinic on Day 36 for safety follow-up. Subjects return to the clinic on Day 57 and then 
on Day 209 (180 days after the last dose) for the final study follow-up visit. If Day 209 
visit cannot be conducted in person, a safety follow-up call will be conducted. Duration 
of participation for each subject is anticipated to be 7 months. 
Sentinel subjects will be treated in three staggered groups of approximately 15. After 
subjects in all sentinel groups have completed 7 days following first vaccination 
(Day 8), SRC will review available safety data for sentinel groups 1-3 and the expansion 
subjects may be enrolled. It is anticipated that a total study length of 8-9 months will be 
required.  
The study will be subject, investigator and sponsor blinded. However, after all sentinel 
subjects have completed study visits through day 28 after the second dose (Day 57) 
and/or after all study subjects have completed study visits through 28 days after the 
second dose administration (Day 57), the study sponsor may be unblinded. Study 
subjects, blinded investigational site personnel and blinded study monitors will remain 
blinded until all subjects have completed the study.  
For vaccine program planning purposes, an early review of partial data may occur prior 
to all subjects completing the day 57 visit. In such case, to maintain the overall study 
blind, minimize operational bias, and protect trial integrity, the majority of operational 
team members will remain fully blinded to individual subject treatment. Specified team 
members (as defined in a Blinding Plan) will receive the datasets unblinded by treatment 
group only with no subject identifiers. This will allow for summary tables to be 
generated by placebo versus active yet will not unblind individual subject treatment. The 
data will not be used to make decisions about the dis/continuation of or alterations to the 
trial. 
 
Statistical Methods: 
The Statistical Analysis Plan (SAP), including table shells will be finalized prior to 
database lock.  
The final analysis will be done after the last subject has had the day 57 visit and the data 
base has been locked. The day 209 data will be included as a supplemental analysis.  
Analyses will be done using SAS software version 9.4 or higher. 
 
Safety Analyses 
Safety and tolerability of the Bris10 M2SR and Sing2016 M2SR influenza vaccines will 
be assessed using subject diaries, solicited and unsolicited AEs, vaccine -associated AEs, 
SAEs, safety labs, vital signs, and physical examinations. 
 

CONFIDENTIAL 
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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
Exposure  
Vaccine exposure will be summarized by actual dose, % of expected dose, and % of 
subjects receiving the expected dose. 
 
Adverse Events 
Treatment-emergent AEs (local and systemic) will be summarized as N (%) with AEs, 
with related AEs, and by worst severity. 
Incidence of TEAEs will be reported by Medical Dictionary for Regulatory Activities 
(MedDRA)-coded System Organ Class (SOC), Preferred Term (PT) and maximum 
severity. 
Incidence of most frequent TEAEs and most frequent treatment-related TEAEs will be 
reported by SOC and PT  
Listings of subjects who died, discontinued the study due to an AE, or experienced an 
SAE will be provided. 
Dose-site reactions will be presented by reaction and severity. 
Post-administration symptoms (memory aid) will be summarized by timepoint, worst 
occurrence, and days with symptoms.  
 
Clinical Laboratory Tests 
Biochemistry and hematology laboratory results and change from baseline results will be 
summarized by timepoint using descriptive statistics.  
Shift tables of maximum grade compared to baseline tabulated according to the FDA 
guidance: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials, or in accordance with the normal ranges of the 
clinical laboratory (below, within, or above normal range) for parameters for which no 
toxicity grades are defined. 
A listing of clinical laboratory test results outside the reference ranges will be provided.  
 
Vital Signs 
Vital sign results and change from baseline results will be summarized by timepoint using 
descriptive statistics.  
 
Limited Physical Examination 
Abnormal findings in physical examination will be listed. 
 
Pregnancy 
A listing of pregnant subjects will be displayed. 
 
Additional Analyses (descriptive only; p-values are descriptive and not corrected for 
multiple testing) 
 
Immunogenicity 
Serum antibody, mucosal antibody and cellular immune response will be summarized 
using descriptive statistics by sampling timepoint for all subjects and by baseline values. 

CONFIDENTIAL 
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FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
 
 
 
 
 
Seroconversion rates will be presented by timepoint and by baseline starting values. 
 
Vaccine virus detection 
Viral shedding will be summarized using descriptive statistics. 
 
Additional (exploratory) endpoints may be analyzed. 
 
Sample size  
The sample size of 50 subjects per group was chosen based on reports of studies of other 
vaccines in early stage development. This study is not powered for any formal 
comparisons.  
 
Subject Characteristics Data Set 
Demographics will include by-treatment summaries of age, height, weight, BMI, race, 
and gender. 
Other baseline characteristics may be summarized. 
 
Analysis Datasets 
The Safety set will include any subject who receives at least one administration of IP. 
The full analysis set (FAS) will include all subjects randomized, received IP and had at 
least one post baseline assessment.  
If necessary, a per protocol set (PPS) will include all subjects in the FAS with no major 
protocol violations or deviations. 
 
Issue Date (Version) 
18May2020 (v8.0) 
 
 

FluGen, Inc. 
CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
26 
CONFIDENTIAL 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
List of Abbreviations 
ACIP 
Advisory Committee on Immunization Practices 
AE 
adverse event 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practice 
CI 
confidence interval 
CMI 
cell-mediated immunity 
CoA 
certificate of analysis 
COPD 
chronic obstructive pulmonary disease 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunoSpot 
eTMF 
electronic Trial Master File 
FACS 
fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
FTIH 
first time in human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HA 
hemagglutinin 
HAI 
hemagglutination inhibition 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRPO 
Human Research Protection Office 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICS 
intracellular cytokine staining 
IEC 
Independent or Institutional Ethics Committee 
IgA 
immunoglobulin A  
IgG 
immunoglobulin G 
IN 
intranasal(ly) 
IND 
Investigational New Drug Application 
IP 
investigational product 
IRB 
Institutional Review Board 

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CLINICAL STUDY PROTOCOL - FLUGEN-H3N2-V003 
18May2020 (v8.0) 
27 
CONFIDENTIAL 
 
 
 
 
 
 
IUD 
intrauterine device 
LAR 
Legal Authorized Representative 
M2SR 
M2-deficient Single Replication vaccine  
MAD 
mucosal atomization device 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
mM 
millimolar 
MMWR 
Morbidity and Mortality Weekly Report 
MN 
microneutralization 
MNT 
microneutralization test 
N 
number (typically refers to subjects) 
NA 
neuraminidase 
NAI 
neuraminidase inhibition assay 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over the counter 
PBMC 
peripheral blood mononuclear cell 
PE 
physical exam 
PCR 
polymerase chain reaction 
PI 
Principal Investigator 
PP 
Per-protocol Set 
PT 
Preferred Term 
QIV 
quadrivalent influenza vaccine 
qRT-PCR 
real-time quantitative reverse transcription PCR 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SE 
standard error 
SRC 
Safety Review Committee 
SPG-NaCl 
sucrose phosphate glutamate with sodium chloride 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SUSAR 
suspected unexpected serious adverse reaction 
TCID  
50% tissue culture infective dose 
TEAE 
treatment-emergent adverse event 
TIV 
trivalent influenza vaccine 
US DoD 
United States Department of Defense 
US 
United States 
VE 
vaccine effectiveness 
 

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Definitions of Terms 
Baseline 
Day of vaccine/placebo administration; typically last measurement taken 
prior to initiating treatment, determined at the record, not the visit level. 
BMI 
Weight in kilogram divided by the square of height in meters 

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STUDY ADMINISTRATIVE STRUCTURE AND INVESTIGATORS 
 
Sponsor: 
FluGen Corporation 
597 Science Drive 
Madison, WI 53711 USA 
Funded by: United States Department of Defense (DoD) 
Lead Principal 
Investigator:   
 
Dr Carlos Fierro 
Johnson County Clin-Trials 
16300 College Blvd  
Lenexa, KS 66219 
Medical Monitor:   
 
Ruth D. Ellis, MD, MPH 
Biologics Consulting, Inc. 
Mobile: 1-703-401-8189   
Email: rellis@biologicsconsulting.com 
Sponsor Clinical Project 
Manager: 
Renee Herber 
FluGen Corporation 
597 Science Drive 
Madison, WI 53711 USA 
Clinical Laboratories:  
LabCorp 
4200 N 29th Avenue  
Hollywood, FL 33020-1017 
 
5610 W Lasalle Street 
Tampa. FL 33607 
 
7800 W 110th St  
Overland Park, KS  66210 
 
6370 Wilcox Road  
Dublin, OH 43016-1269 
 
1447 York Court  
Burlington, NC 27215-3361 
Bioanalytical Laboratory: 
Viroclinics Biosciences 
Marconistraat 16, 3029 AK  
Rotterdam, Netherlands 
FluGen 
597 Science Drive 
Madison, WI 53711 USA 
 
Southern Research Institute  

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Drug Development Division  
2000 Ninth Avenue South  
Birmingham, Alabama 35205 
 
Vismederi Srl 
Strada del Petriccio e Belriguardo, 35 
53100 Siena, Italy 
 
Q Squared Solutions LLC  
33608 Ortega Highway  
San Juan Capistrano, CA 92690 
 
Cellular Technology, Ltd. 
20521 Chagrin Blvd 
Shaker Heights, OH 44122 
 
Saint Louis University 
Doisy Research Center, 8th floor 
1100 S. Grand Blvd. 
St. Louis, MO  63104 
 
Storage: 
Brooks Life Sciences 
2910 Fortune Circle West, Suite E 
Indianapolis, IN 46241 USA 
Pharmacovigilance: 
Ruth D. Ellis, MD, MPH 
Biologics Consulting, Inc. 
Mobile: 1-703-401-8189   
Email: rellis@biologicsconsulting.com 
FluGen, Inc. 
597 Science Drive 
Madison, WI 53711 USA 

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1. 
INTRODUCTION 
1.1. 
Overview 
FluGen, Inc. is developing Bris10 M2SR and Sing2016 M2SR, two novel M2-deficient single 
replication live influenza vaccines, to provide safe, effective protection against seasonal 
influenza strains. The vaccine virus does not express an essential viral protein (influenza M2), 
restricting it to a single replication cycle in the host. Bris10 M2SR has been tested in a 
Phase 1, first-time-in-humans (FTIH) study FluGen-H3N2-V001 (ClinicalTrials.gov 
identifier NCT02822105) under United States (US) Investigational New Drug (IND) 
Application 016968, and in a Phase 2a Challenge Study FluGen-H3N2-V002 under EudraCT 
2017-004971-30. A Phase 1 study in adolescents (BB-IND 18170; sponsored by DMID and 
NIAID; NCT03553940) is also underway. The proposed study will be a FTIH study for 
Sing2016 M2SR. 
This Phase 1b dose escalation study is to assess the safety, tolerability/reactogenicity, and 
immunogenicity of M2SR vaccines when delivered at higher dosages or in two doses to 
increase the proportion of subjects responding serologically to the vaccine. For this study, an 
updated vaccine, Sing2016 M2SR, has been prepared that will provide the hemagglutinin 
(HA) and neuraminidase (NA) components from A/Singapore/INFIMH-16-0019/2016, the 
H3N2 strain recommended for the 2018-2019 influenza season.  
1.2. 
Background Information 
1.2.1. 
Influenza 
Influenza viruses typically circulate widely in the US annually from the late fall through early 
spring. Although most persons who become infected will recover without sequelae, influenza 
can cause serious illness and death, particularly among persons age ≥ 65 years, children 
< 2 years, and individuals with underlying medical conditions that confer an increased risk 
of influenza-related complications (Centers for Disease Control and Prevention [CDC] 2013). 
Over the past 40 years, estimated influenza-associated deaths have ranged from 3,000 to 
49,000 annually, with approximately 200,000 hospitalizations in the US annually (CDC 
2015).  
Annual influenza vaccination has long remained the primary means of preventing influenza 
infection and its complications, and has been consistently recommended by various advisory 
bodies over the past 60 years. Although routine vaccination was initially recommended only 
for high-risk populations in the US, the CDC and the Advisory Committee on Immunization 
Practices (ACIP) have recommended since 2010 that all persons aged ≥ 6 months who do not 
have contraindications should be vaccinated (CDC 2015). Recent evaluations conducted by 
a US government-supported network of large clinics (US Flu-VE Network; Treanor 2012), 
have demonstrated an overall vaccine effectiveness (VE) of at most 60% (95% confidence 
interval [CI], 53-66) for prevention of laboratory-confirmed, medically attended influenza 
illness due to any influenza virus, even in years in which there was a good match between 
vaccine and circulating strains (Treanor 2012). VE estimates in the US among individuals 

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age ≥ 65 years have been consistently lower than in younger age groups, which is consistent 
with the well-documented reduction in immunogenicity of influenza vaccine in older adults 
(Osterholm 2012). Given the substantial and further increasing resource allocations to the US 
influenza vaccination programs, the continued search for more effective vaccines to further 
improve the population-level impact of the program ‒ and particularly among older adults 
and others at high risk of serious influenza complications ‒ remains a critically important 
public health challenge. 
1.2.2. 
Current Influenza Vaccines 
Currently available inactivated and recombinant influenza vaccines primarily aim to induce 
neutralizing antibodies that recognize the virus envelope protein HA. These antibodies can 
provide effective immunity, but they depend on a close match between the vaccine 
immunogen and circulating viruses. Such vaccines are therefore relatively ineffective against 
newly emerging viruses or viruses that have drifted away from the vaccine strain. 
Conventional egg-derived inactivated vaccines, which currently comprise approximately 
90% of the US market, generally provide limited or no broadly cross-reactive 
(heterosubtypic) immunity needed to protect against divergent strains. Currently available 
trivalent (TIV) or quadrivalent (QIV) preparations provide only the HA antigen and either 
none or limited and non-standardized amounts NA antigen. Moreover, at least one HA 
component of these vaccines must often be updated due to accumulated point mutations in 
the HA protein that allow the viruses to evade the human immune response. In addition, while 
a strong relationship has been established between pre-existing T cell immunity and illness 
severity in subjects seronegative for influenza virus-specific antibody (Wilkinson 2012), no 
or minimal cellular immune responses have been shown to be elicited following vaccination 
with these conventional preparations. 
1.2.3. 
Live attenuated vaccines 
In contrast to conventional inactivated and recombinant vaccines, live influenza virus 
vaccines are generally believed to offer broad-spectrum immune responses because they 
induce diverse types of adaptive responses, including serum antibodies, mucosal immunity, 
and induction of cytotoxic T lymphocytes, which target conserved virus epitopes (Clements 
1986, Tamura 2005, Zhu 2010; Lanthier 2011, Ambrose 2012, Jin 2015). Only one such live 
vaccine, (FluMist®), which has been attenuated empirically by cold-adaptation, has been 
approved in the US, and is presently indicated only for persons 2-49 years of age. However, 
immune mechanisms conferring protection against influenza following receipt of FluMist 
vaccine are not fully understood; serum antibodies, mucosal antibodies, and influenza-
specific T cells may play a role but there is no established surrogate of efficacy. Accumulating 
data also indicate that pre-existing cross-reactive immunity present in most adults limits 
vaccine virus replication, which in turn reduces a consistently effective immune response 
(Eick 2009, Ohmit 2006, Wang 2009, Monto 2009). This in part explains the observation that 
young, seronegative children are the population in which FluMist vaccination is typically 
most effective. 

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1.2.4. 
FluGen’s H3N2 (A/Brisbane/10/2007) M2SR vaccine 
FluGen is developing a novel live virus vaccine platform known as “M2SR” to address the 
need for more effective influenza vaccines that will provide more consistent and broad-
spectrum immunity for adults, and especially the elderly. The product is a live virus vaccine 
for intranasal administration that has been shown to provide protection against multiple 
influenza A subtypes in animal models (see below). The vaccine is a replication-defective 
recombinant influenza virus that does not express the essential M2 protein (and hence, the 
derivation of the “M2SR” naming convention [Single Replication phenotype due to lack of 
M2]). The M2SR vaccine virus backbone is comprised of (1) five of the six internal proteins 
of the donor virus Influenza A/Puerto Rico/8/34 (PR8), a strain that has been used for decades 
in traditional inactivated influenza vaccine manufacturing; (2) the sixth internal protein, M2, 
which is acquired from the cell substrate used to grow the vaccine virus, M2 Vero cells, which 
stably express and supply M2 protein for vaccine virus growth; and (3) the two influenza 
virus surface protein antigens, HA and neuraminidase (NA), which can be derived from any 
selected Type A influenza strain. The resulting vaccine virus can infect normal cells in the 
respiratory epithelium of the vaccine recipient and then uncoat and initiate infection similar 
to a wild-type influenza virus, thereby evoking an immune response. However, because the 
M2SR genome does not encode for M2 protein, no viral progeny are subsequently produced 
after the initial (single round) infection, such that no cell-to-cell spread or subsequent 
shedding of virus occurs. The HA and NA of an A/Brisbane/10/2007-like H3N2 virus was 
chosen as the prototype monovalent vaccine to be initially tested in humans and is further 
referred to here as “Bris10 M2SR”.  
Like FluMist, Bris 10 M2SR is administered intranasally and is intended to mimic a naturally 
acquired, wild-type infection and to induce broad-spectrum immunity, including mucosal and 
cell-mediated responses. However, unlike FluMist, Bris 10 M2SR can still infect respiratory 
epithelial cells and induce immune responses in preclinical animal models in the presence of 
pre-existing antibody. In addition to eliciting neutralizing antibody responses to HA, M2SR 
induces antibody responses against the highly conserved stem region of the HA, as well as 
the NA surface protein in animal studies. Moreover, M2SR-based vaccines have induced 
strong cross-reactive T cell responses against the highly conserved internal viral antigens that 
have been recalled after heterosubtypic challenge. Flow cytometric analyses of CD8+ T cells 
in bronchoalveolar lavage studies in animals have also revealed that the majority of these 
cells have an effector/memory or effector phenotype, the presence of which has been shown 
in humans to reduce influenza related symptoms upon exposure to wild-type influenza 
(Wilkinson 2012). By contrast, cell-mediated responses (either effector or memory) are 
generally not elicited by current split or subunit vaccines (Hoft 2017, He 2006). These 
properties suggest that vaccines based on this approach may potentially confer additional 
advantages over currently available influenza vaccines, including FluMist, and are intended 
to model natural (wild-type) infection, while at the same time incorporate the critical safety 
feature of only precipitating a single round of virus replication. 
1.2.5. 
FluGen’s H3N2 (A/Singapore/INFIMH-16-0019/2016) M2SR vaccine 
Sing2016 M2SR and is a recombinant, monovalent influenza A virus that was generated as 
described above for Bris10 M2SR. It contains a similar PR8 backbone but with nine amino 

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acid changes distributed over five genes (PB1, PB2, PA, NP and NS1) that facilitate growth 
in the production cell line, M2VeroA. The mechanism of attenuation (deletion of the M2 
gene) is not affected. The Sing2016 M2SR also provides the HA and NA components from 
A/Singapore/INFIMH-16-0019/2016 that were recommended for the 2018-2019 influenza 
season. The current study is the FTIH study for Sing2016 M2SR. 
1.3. 
Non-Clinical Studies of M2SR 
In addition to the features described above, and as further summarized in the Investigator’s 
Brochure (IB) accompanying this protocol, data obtained in animal models provide a strong 
basis for proceeding with clinical testing of the Bris 10 M2SR prototype vaccine in humans 
based on the following features: 
1.3.1. 
Non-Clinical Safety 
The safety of Bris10 M2SR monovalent vaccine was evaluated in a Good Laboratory Practice 
(GLP)-compliant, repeat-dose toxicity study in ferrets. In that study (Battelle Study Number 
37234E), male and female ferrets were intranasally administered Bris10 M2SR once on Days 
1 and 28 at dosages of 1.1 x 107 or 1.1 x 108 50% tissue culture infective dose (TCID50) using 
the clinical spray device (Teleflex VaxINator). Overall, there were no observed toxicities 
from the two administrations of vaccine. The M2SR H3N2 vaccine was considered well 
tolerated, with only a transient reduction in physical activity being observed after the initial 
administration of 1.1 x 108 TCID50. No redness or swelling of the nares and no gross or 
microscopic lesions of tissues surrounding the administration site were notable after 
intranasal administration of Bris10 M2SR with either dose level. No vaccine-related effects 
were observed in either dose group in the physical examinations or on body weights, body 
temperature, food consumption, eye exams, clinical chemistry, hematology, urinalysis, or 
coagulation parameters, organ weights or gross pathology. The only vaccine-related finding 
was mild to moderate inflammation of the distal bronchioles and adjacent alveoli and the 
perivascular tissue, observed 2 days after the first and second administration of Bris10 M2SR 
(on Days 3 and 30), particularly in the high dose group. The inflammation was not associated 
with any adverse clinical signs, clinical pathology, gross pathology or organ weight changes 
and was transient in nature, completely resolving by the end of the 21-day recovery period.  
In multiple non-GLP studies of M2SR-based constructs (including H1N1, H3N2, and H5N1), 
there was (a) no evidence of weight loss or clinical symptoms in ferrets after intranasal 
administration; (b) no adverse histopathologic findings in any of the respiratory organs or 
brains of ferrets; and (c) no transmission of vaccine virus in any ferrets (3 donors and 6 
contacts). 
There is no evidence of M2SR vaccine virus replication when organs and nasal washes were 
analyzed for presence of virus. Moreover, the M2SR construct deletion prevents reversion, 
as confirmed by >10 serial passages in permissive cells and blind passage in non-permissive 
cells and in mice. 
1.3.2. 
Non-Clinical Efficacy 
Non-clinical studies of the M2SR platform confirm: 

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• M2SR-based constructs (including H1N1, H3N2, and H5N1) stimulate potent 
systemic and mucosal immune responses and confer protective immunity to animals 
against lethal homo-, hetero-, and intra-subtypic influenza virus challenge; 
• Protection following vaccination is superior to that conferred by inactivated (split) or 
live attenuated vaccines (FluMist); and 
• Robust immune responses are elicited in vaccinated animals, even in the presence of 
pre-existing anti-influenza antibody. 
These characteristics illustrate the potential for the M2SR platform to become a potentially 
safe and effective alternative to existing influenza vaccines.  
Please see the IB for a more complete description of the product and additional details of the 
pre-clinical studies. 
1.4. 
Clinical Studies  
Previous clinical experience with the M2SR vaccine platform includes a FTIH Phase 1 dose 
escalation study in healthy adults, an on-going Phase 1 safety and immunogenicity study in 
adolescents, and a Phase 2a challenge study in healthy adults using the H3N2 vaccine Bris10 
M2SR. Sing2016 M2SR has not been previously studied in humans. 
1.4.1. 
Phase 1 Dose Escalation Study 
For the FTIH Phase 1 study, 96 healthy adult male and non-pregnant female subjects ages 
18-49 years, were stratified by baseline hemagglutination-inhibition (HAI) antibody titers 
(<10 to 80) against influenza A/Brisbane/10/2007 (Bris10) and enrolled under US IND 
016968 (also see ClinicalTrials.gov identifier NCT02822105). First subject first visit 
occurred in July 2016 and last subject last visit (Day 180) was in April 2017. Subjects were 
randomly assigned to receive either a single administration of Bris10 M2SR at dose levels of 
106, 107 or 108 TCID50 (24 subjects per dose level) or saline placebo (N=24; 8 for each Bris10 
M2SR dose group). Each subject received ~ 0.1 mL of vaccine or placebo intranasally (IN) 
in each nostril ‒ except for the 108 group, who received 0.15 mL per nostril ‒ using a mucosal 
atomization device (MAD) from the Teleflex VaxINator kit including a MAD301 sprayer. 
The vaccine was safe and well tolerated at all dose levels, generated a dose-response effect 
for humoral (hemagglutination-inhibition antibody) and mucosal antibodies against both 
homologous and heterologous influenza variants, and elicited robust T-cell responses. No 
infectious virus was detected in nasal swabs collected on Days 1, 2, 3 and 7 post-dose in any 
vaccinated subject. One subject in the 107 dose cohort and one subject in the placebo cohort 
self-reported fevers as high as 38.2°C (day 7 post-dose) and 38.4°C (day 3 post-dose), 
respectively. Subjects were followed through Day 180 post-dose. There were no severe local 
or systemic reactions recorded on subject 7-day diaries, no reported serious adverse events 
(SAEs) or adverse events (AEs) of significance (attributed to the treatment) and none of the 
pre-specified halting rules (including laryngospasm, bronchospasm or anaphylaxis) were 
met.  

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1.4.2. 
Phase 1 Study in Adolescents 
In a Phase 1 study in adolescents (BB-IND 18170; sponsored by DMID and NIAID) 50 males 
and non-pregnant females ages 9 to 17 years old, inclusive are being enrolled. Subjects are 
randomized 1:1 to receive one 108 TCID50 dose of Bris10 M2SR vaccine or placebo 
administered intranasally (IN) followed by one dose of licensed quadrivalent influenza 
vaccine (QIV) administered intramuscularly 3 months later. As of February 2019, 19 subjects 
have been enrolled (first subject first visit was in August 2018) and have received both dose 
treatments. These subjects have been followed through at least the Day 113 visit (21 days 
after administration of the QIV) with no reported SAEs, AEs of significance or halting rules 
met. 
1.4.3. 
Phase 2a Challenge Study 
The Phase 2a challenge study included 108 healthy male and non-pregnant female subjects 
ages 18-55 years old who had microneutralization titers (MNT) of ≤ 20 to H3N2 
A/Belgium/4217/2015. Subjects were randomized 1:1 into two cohorts (Bris10 M2SR or 
Placebo) each receiving investigational product (IP) of either a 108 TCID50 dose of Bris10 
M2SR vaccine (N=48) or a saline control (N=51) under EudraCT 2017-004971-30. 
Approximately 28 days later, 99 of these subjects were challenged via intranasal inoculation 
with 
approximately 
106 
TCID50 
dose 
of 
an 
antigenically 
distinct 
H3N2 
A/Belgium/4217/2015. The first subject first dose was in May 2018 and the last subject 
completed the Day 180 post-IP follow-up visit in March 2019. In the period following IP 
treatment (Day -28) until Day 1, there were no severe AEs or severe local or systemic 
complaints and there were no reported fevers (≥38°C). The active phase of this Phase 2a 
challenge study has been completed and there were no SAEs, AEs of significance or 
observations that would halt the study. All subject samples (including serum, PBMC and 
nasal swabs for humoral, cellular and mucosal immunity, respectively) have been collected 
and are undergoing analytical testing. Nasal swabs collected for detection of influenza virus 
have been analyzed. The finalization and locking of the clinical database and final analyses 
are in process. 
Preliminary results from the Phase 2a challenge study suggest that the vaccine was effective 
against challenge in subjects for whom a detectable serum immune response was measured 
after vaccination. Subjects who demonstrated any increase from baseline in serum antibody 
response (~50% of the M2SR cohort) by MNT to the intranasal M2SR vaccine had lower 
viral load and influenza-like symptoms than placebo subjects. These preliminary results 
suggest that M2SR could potentially provide higher efficacy levels if a greater proportion of 
M2SR recipients can demonstrate an appropriate serological response. In an effort to increase 
the number of sero-responders to H3N2 M2SR, the Phase 1b study described in this protocol 
is planned to further optimize the dose and schedule for M2SR vaccinations. Subjects in the 
proposed Phase 1b study must have a MNT ≤ 20 to A/Singapore/INFIMH-16-0019/2016 in 
order to be enrolled. 
Between the FTIH Phase 1 and the Phase 2a challenge studies, a total of 72 adult subjects 
have been exposed to the highest dose of Bris10 M2SR tested (108) with no SAEs or AEs of 
significance or observations that would halt these studies. In addition, in the challenge study, 
48 subjects who received the live, single-replication M2SR virus were subsequently 
challenged with a live, replicating influenza virus. A portion of those individuals experienced 

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infection and symptoms consistent with influenza (e.g., nasal congestion, runny nose, sore 
throat, cough, tiredness, headache), but at frequency less than observed among individuals in 
the same study who did not receive vaccine prior to challenge. Of the 19 adolescents enrolled 
in the ongoing second Phase 1 study, while the randomization was set at 1:1 active to placebo, 
it is not known exactly how many received active investigational vaccine (M2SR), but in 
blinded review no safety concerns related to the M2SR vaccine have been reported. 
Combined, these findings indicate that the vaccine is safe and generally well tolerated as a 
single 108 TCID50 dose.  
1.5. 
Overall Rationale for the Study 
Currently available inactivated and recombinant influenza vaccines primarily aim to induce 
neutralizing antibodies that recognize only the HA and depend on a close match between the 
vaccine and circulating viruses, rendering them much less effective against drift viruses. In 
addition, while a strong relationship has been established between pre-existing T cell 
immunity and illness severity, inactivated vaccines do not elicit cellular immune responses 
and therefore generally do not provide broadly cross-reactive (heterosubtypic) immunity 
needed to protect against divergent strains. For example, the severity of the 2014-15 influenza 
season was due, at least in part, to mismatch between the circulating epidemic strain and the 
inactivated vaccine, resulting in VE of just 13% (Paules 2018). Similarly, during the 2017 
influenza season in Australia, the inactivated vaccines displayed a preliminary VE estimate 
of only 10%, again related to mismatch between the vaccine strain and the circulating 
seasonal H3N2 virus that had accumulated antigenic changes (i.e., “drifted”) (Paules 2018). 
These recent examples indicate the need for an influenza vaccine that can protect against 
seasonal influenza drift variants. 
In contrast to currently available influenza vaccines, pre-clinical testing of M2SR vaccine has 
shown induction of broadly reactive immune responses against multiple influenza subtypes 
and heterosubtypic protection in animal models, including demonstration of robust systemic, 
cellular and mucosal immunogenicity (Sarawar 2016, Hatta 2017), even in the presence of 
pre-existing anti-influenza immunity. In a pre-clinical proof-of-concept study, Bris10 M2SR 
(one of the vaccines to be used in the current study) provided protection to ferrets against a 
drifted H3N2 challenge virus, A/Alaska/140/2015, a virus belonging to clade 3c.2a1. In 
addition, adult subjects who received Bris10 M2SR (108 TCID50 dose) in the Phase 1a FTIH 
and Phase 2a studies demonstrated broad-spectrum immune responses. In the FTIH study, 
vaccine induced serum and mucosal antibody responses were cross-reactive against multiple 
antigenically different H3N2 viruses including recent strains that belong to the same clade 
(3c.3b) as the challenge virus used in the Phase 2a study (FluGen IB). In the Phase 2a study, 
early data suggest that the vaccine was effective against challenge with an antigenically 
drifted virus in subjects for whom a serum response to the vaccine was detected (data on file). 
This Phase 2a dose escalation clinical study is designed to assess the safety, 
tolerability/reactogenicity, and immunogenicity of M2SR vaccines when delivered at higher 
dosages or in two doses to increase the proportion of subjects responding serologically to the 
vaccine. For this study, an updated vaccine, Sing2016 M2SR, has been prepared that will 
provide the HA and NA components from A/Singapore/INFIMH-16-0019/2016, the H3N2 
strain recommended for the 2018-2019 influenza season. 

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1.6. 
Risk/Benefit Analysis  
1.6.1. 
Potential Risks 
In previously conducted trials, 72 adult subjects and 19 adolescents have been treated with 
Bris10 M2SR (or placebo in adolescents as the ongoing study is still blinded). No SAEs or 
AEs of significance have been reported. In the challenge study, 48 subjects who received the 
live, single-replication M2SR virus were subsequently challenged with a live, replicating 
influenza virus. A portion of those individuals experienced infection and symptoms 
consistent with influenza (e.g., nasal congestion, runny nose, sore throat, cough, tiredness, 
headache), but at frequency less than observed among individuals in the same study who did 
not receive vaccine prior to challenge. Combined, these findings indicate that the vaccine is 
safe and generally well tolerated as a single 108 TCID50 dose.  
As outlined in greater detail in the accompanying IB, the potential risks of vaccine 
administration are expected to be similar to those associated with other live attenuated 
influenza vaccines (such as FluMist). Subjects with contraindications to live vaccines, such 
as severe allergic reactions (e.g., anaphylaxis) after a previous dose of any influenza vaccine, 
and immunocompromised persons, are excluded from study participation. Severe risks 
known to be associated with vaccine administration include anaphylaxis. As with any 
experimental product, there may be unknown risks.  
1.6.2. 
Potential Benefits 
There are no expected benefits to individual subjects participating in this study. There is a 
need for an influenza vaccine that can protect against seasonal influenza drift variants. Bris10 
M2SR administration has shown induction of broadly reactive immune responses against 
multiple influenza subtypes and heterosubtypic protection in animal models, including 
demonstration of robust systemic, cellular and mucosal immune, even in the presence of pre-
existing anti-influenza immunity. This study is expected to provide important additional 
information to guide continued development of M2SR vaccine in a quadrivalent formulation 
with the aim of improving efficacy relative to currently licensed influenza vaccines. 
 

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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objectives are: 
1. To assess the safety and tolerability of one and two administrations of the Bris10 M2SR 
influenza vaccine each at 108 TCID50 delivered intranasally to healthy adult subjects. 
2. To assess the safety and tolerability of one and two administrations of the Sing2016 
M2SR influenza vaccine each at 108, 108.5 and 109 TCID50 delivered intranasally to 
healthy adult subjects 
2.1.2. 
Secondary Objectives 
The secondary objectives are: 
1. To assess the immunogenicity (serum antibody, mucosal antibody and cellular 
immune responses) of one and two administrations of Bris10 M2SR vaccine at 108 
TCID50. 
2. To assess the immunogenicity (serum antibody, mucosal antibody and cellular 
immune responses) of one and two administrations of Sing2016 M2SR vaccine at 108, 
108.5 and 109 TCID50. 
3. To evaluate vaccine virus shedding after intranasal delivery. 
2.1.3. 
Exploratory Objectives 
The exploratory objectives are: 
1. To evaluate cell mediated immunity for up to 2 months after the last vaccination. 
2. To evaluate additional vaccine-related immune responses during the period of study 
participation.  
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints are: 
1. The number and percentage of study participants who experience any vaccine-
associated AEs or SAEs after Bris10 M2SR or placebo administration. 
2. The number and percentage of study participants who experience any vaccine-
associated AEs or SAEs after Sing2016 M2SR or placebo administration. 

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2.2.2. 
Secondary Endpoints 
The secondary endpoints are:  
1. The number and percentage of study participants who after one or two doses of Bris10 
M2SR or placebo demonstrate: 
i. Influenza-specific serum antibody responses measured at specified time 
points; 
ii. Influenza-specific mucosal immunoglobulin A (IgA) antibody responses 
measured at specified time points;  
iii. Influenza-specific cellular immune responses measured by cytokine enzyme-
linked immunospot (ELISPOT) at specified time points.  
2. The number and percentage of study participants who after one or two doses of 
Sing2016 M2SR or placebo demonstrate: 
i. Influenza-specific serum antibody responses measured at specified time 
points;  
ii. Influenza-specific mucosal IgA antibody responses measured at specified 
time points;  
iii. Influenza-specific cellular immune responses measured by ELISPOT at 
specified sampling time points.  
3. Vaccine virus shedding evaluated by influenza A-specific qPCR on day 7 post IP 
administration. 
2.2.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
1. Cell-mediated immunity (CMI) assessed by frequencies and fold increases of antigen-
specific T-lymphocytes. 
2. Additional influenza-specific immunological assays may be performed.  
 
 

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3. 
STUDY DESIGN  
3.1. 
Overview of Study Design 
This is a randomized, double-blind, placebo-controlled Phase 1 study evaluating the safety and 
immunogenicity of the Bris10 M2SR and Sing2016 M2SR H3N2 influenza vaccines delivered 
intranasally to healthy adults.  
Eligible subjects will be screened and randomized to receive two administrations 28 days apart 
of Sing2016 at three dose levels, Bris10 at one dose level, or placebo in a 1:1:1:1:1 ratio. An 
overview of the planned dose cohorts is presented in Table 1. 
Table 1: 
Dose Cohorts 
Dose Cohort 
Number of 
Subjects 
Number in 
Sentinel Group 
Number in 
Expansion Group 
1. 108   TCID50 Sing2016 M2SR 
50 
9 
41 
2. 108.5 TCID50 Sing2016 M2SR 
50 
9 
41 
3. 109   TCID50 Sing2016 M2SR 
50 
9 
41 
4. 108   TCID50 Bris10 M2SR 
50 
9 
41 
5. Placebo 
50 
9 
41 
Total 
250 
45 
205 
Abbreviations: TCID50=50% tissue culture infective dose. 
 
As shown in Table 2, three sentinel groups will be vaccinated first, containing 15 subjects 
(9 subjects receiving escalating doses of Sing2016 M2SR, 3 subjects receiving Bris10 M2SR, and 
3 subjects receiving placebo), followed by the remainder of the subjects in an expansion group. 
Cohorts are split into two groups to alleviate PBMC processing issues of large numbers of samples. 
Dosing will be staggered to allow for review of AEs through day 3 post-administration for each 
sentinel group prior to dose escalation. A Safety Review Committee (SRC) will review available 
safety data from all sentinel subjects, after subjects have completed 7 days after vaccination, prior 
to dosing of the expansion group. A comprehensive list of safety parameters collected during the 
study are described in Table 3.  

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Table 2: 
Dosing and Safety Reviews 
 
*Dose Cohort 1 = Sing2016 M2SR 108, Dose Cohort 2 = Sing2016 M2SR 108.5, Dose Cohort 3 = Sing2016 
M2SR 109, Dose Cohort 4 = Bris10 M2SR108, Dose Cohort 5 = saline placebo 
Note: Safety indicates a review by the Lead PI and/or Medical Monitor as detailed below in Study Conduct.  
Note: SRC indicates a review by the SRC as detailed below in Study Conduct. The Expansion Group schedule 
may be extended based on speed of enrollment. 
Using one nasal sprayer per nare the IP, up to 0.5 mL of the Sing2016 M2SR vaccine or placebo 
(a total of up to 1.0 mL) and up to 0.2 mL of the Bris10 M2SR vaccine (a total of up to 0.4 mL), 
will be delivered per subject per administration. The study will administer escalating doses of 
Sing2016 M2SR vaccine, with a starting dose of 108 TCID50 increasing in half log (3-fold) 
increments to a maximum dose of 109 TCID50. Controls will be saline placebo and a 108 TCID50 
dosage of Bris10 M2SR.  
Five (5) dose cohorts of 50 subjects each will be enrolled, for a total of approximately 250 subjects 
randomized 1:1:1:1:1 to receive either Sing2016 M2SR 108, Sing2016 M2SR 108.5, Sing2016 
M2SR 109, Bris10 M2SR or saline placebo. A sentinel group of 9 subjects (~18% of each 
escalating dose cohort) will be vaccinated first, followed by the remainder of the dose cohort in an 
expansion group. Subjects in each sentinel group will be actively followed for 3 days and if the 
Medical Monitor and/or Lead PI determine that no halting rules have been met, the next sentinel 
group will be enrolled. After all sentinel subjects have completed 7 days following vaccination, a 
Safety Review Committee (SRC) will review safety data prior to enrollment and vaccination of 
the expansion groups. Note that the expansion subjects will be dosed in rolling waves in order to 
accommodate time-consuming study procedures, i.e., PBMC isolation, and not due to safety 
concerns. All dosed subjects will receive a second dose of the assigned IP approximately 28 days 
after receiving the first dose. The SRC review of sentinel data prior to enrollment of expansion 
subjects may occur concurrently with or following the administration of second doses of vaccine 
to sentinel subjects.  

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SAEs occurring at any time during the study will be recorded. Administration site and solicited 
AEs will be recorded through 7 days after each vaccination (Days 8 and 29) and unsolicited AEs 
will be recorded through 28 days after the last vaccination (Day 57). An SRC, comprised at a 
minimum of two independent physicians experienced in vaccine research and a biostatistician, will 
be available to review safety data at specified time points and as needed. 
Based on the safety reviews, an intermediate or lower dose may be chosen to replace the planned 
dose for a dose cohort. If a lower or intermediate dose is chosen that dose will be used for an entire 
dose cohort. Should dosing be delayed for safety review or enrollment issues, subjects may receive 
their second dose at a time later than defined in the proposed dosing window. 
While safety and tolerability are the primary objectives, this clinical study is also designed to assess 
the immune response to one and two doses of each of the investigational vaccines at each of the 
designated dose levels. Immunogenicity will be assessed by measuring serum antibody responses 
by HAI and/or microneutralization (MN) assay. Additional immune parameters will be assessed 
including mucosal antibody titers and cell-mediated immunity. Subjects will be pre-screened, 
under a site-specific Informed Consent Form (ICF), to avoid enrollment of individuals with high 
MN titers (> 1:20) against the target component (A/Singapore/INFIMH-16-0019/2016 [H3N2]). 
3.2. 
Study Conduct and Safety Reviews 
After subjects have signed an informed consent and have met the inclusion /exclusion criteria, 
healthy adults will receive a single administration of the IP (active M2SR or placebo) delivered 
intranasally as a liquid formulation. The Phase 1 and Phase 2a trials in adults and the ongoing 
Phase 1 trial in adolescents have demonstrated that a single dose of Bris10 M2SR at 108 TCID50 
with and without a subsequent administration of a live, replicating influenza virus is generally safe 
and well-tolerated with no shedding of infectious vaccine virus. Hence, the study will be conducted 
in an outpatient setting and with safety reviews as shown in Table 2 and summarized here: 
1. Deliver first dose to sentinel group 1 on Day 1. Lead PI reviews AEs through 3 days post-
administration of first dose (Day 4), confirms that no halting rules have been met, and 
communicates this to the Sponsor. 
2. If no safety concerns in sentinel group 1, deliver first dose to sentinel group 2. Lead PI 
reviews AEs for sentinel group 2 through Day 4, and cumulative AEs for sentinel group 1, 
confirms that no halting rules have been met, and communicates this to the Sponsor. 
3. If no safety concerns in sentinel groups 1 and 2, deliver first dose to sentinel group 3. Lead 
PI reviews AEs for sentinel group 3 through Day 4 and cumulative AEs for group 1 and 2, 
confirms that no halting rules have been met, and communicates this to the Sponsor. 
4. If no halting rules are met, second doses are administered to sentinel subjects in all groups 
at Day 29 according to the study schedule. 
5. Safety reviews through 3 days post administration of the second dose (Day 32) are 
conducted in the same manner as outlined above for second doses of sentinel groups. 
6. After sentinel subjects have completed 7 days following first vaccination (Day 8), SRC 
reviews available safety data for sentinel groups 1-3. If no safety concerns are identified, 
deliver first dose to expansion group subjects.  

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7. After all sentinel subjects have completed 7 days following second vaccination (Day 36), 
SRC reviews cumulative safety data. If no safety concerns are identified, deliver second 
dose to expansion group subjects.    
8. During enrollment of the expansion cohorts, the occurrence of events which could prompt 
a study halt will be reviewed weekly by the Medical Monitor, until all subjects have 
completed 7 days following second vaccination (Day 36).  
Each subject will undergo the following testing (also depicted in Table 3): [Note that a Pre-screen 
with blood draw to assess the subject’s microneutralization (MN) titer to Sing2016 may be 
conducted under a site-specific ICF in the period spanning 90 calendar days before enrollment in 
this study.] Subjects who meet eligibility criteria will be enrolled in the proposed Phase 1b study, have 
a baseline blood draw, be randomized to a dose cohort and administered IP of either active M2SR 
vaccine or placebo on Days 1 (Visit 01) and 29 (Visit 04). For 7 days following each dose the 
subjects will record symptoms in a Symptom Memory Aid (Appendix 5) and after 3 days (Days 4 
and 32) will be contacted via a phone call by the site staff representative to report symptoms and 
AEs. Subjects will attend the investigational site for follow-up on Days 8, 29, 36, 57 and 209 
(Visits 03, 04, 06, 07 and 08, respectively) for a limited physical exam, safety evaluation, nasal 
swabs and blood draws. Day 209 will also be the end of study visit for each subject in the study. 
Serum samples for analysis of anti-HA antibody titers for the H3N2 antigen in Sing2016 and 
Bris10 will be collected at baseline and on Days 8, 29, 36, 57 and 209. PBMC samples for analysis 
of cell-mediated immunity and/or innate transcriptome gene expression will be collected at 
baseline and on Days 4 (optional), 8, 29, 32 (optional), 36 and 57 from select sites for ~160 subjects. 
Nasal swabs will be collected on Days 1, 8, 29, 36, 57 and 209 for analysis of IgA-specific anti-
HA antibody titers. Nasal swabs will be collected at Days 1, 8, 29, and 36 to evaluate shedding of 
vaccine virus. A nasal swab collected at Day 1 may be evaluated for presence of respiratory 
pathogens. Safety clinical laboratory testing will be performed at screening, and on Days 1, 8, 29, 
and 36. During the treatment period (Day 1 – Day 57), subjects will be asked to notify the site 
immediately if symptoms of influenza (fever, chills, sore throat, rhinorrhea, cough, muscle/body 
aches) occur. When increased influenza infections are being reported in the geographic region of 
the investigational site, subjects will additionally be contacted at Days 15±2, 21±2, 43±2, and 50±2 
by phone or messaging. If influenza is suspected the subject will be asked to return to the site for 
laboratory confirmation of influenza using nasal swabs. 
A Safety Review Committee (SRC) will review blinded safety data, as needed. The SRC includes 
3 members, 2 independent infectious disease clinicians and a statistician. The SRC will be 
convened if halting rules are met (Section 7.3) or at the request of the Sponsor, Medical Monitor, 
Investigator, or any SRC member if they have cause for concern regarding subject safety in relation 
to the vaccine where no other cause could be attributed (Section 9.11). 
3.3. 
Expected Duration of a Subject’s Participation in the Entire Study 
Subjects are expected to participate in person for a duration of up to approximately 7 months. This 
includes up to 30 days for screening pre-vaccination and 209 days post-initial IP treatment. Study 
entry is defined as the moment that the subject signs consent.  

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3.4. 
Total Study Duration 
It is anticipated that the total study length will be 8 to 9 months. 
3.5. 
Discussion of Study Design 
3.5.1. 
Rationale for Use of Bris10 M2SR (H3N2) Vaccine and Route of Administration 
The Bris10 M2SR (H3N2) and Sing2016 M2SR vaccines contain live, single-replication viruses. 
Intranasal administration of the vaccines, as proposed for this trial, mimics the natural route of 
infection of a wild-type influenza virus in which the virus adsorbs onto cells in the upper 
respiratory tract, enters the cell and uses host cell processes to generate viral RNA and proteins 
and stimulate mucosal and systemic immune responses by the host.  
3.5.2. 
Rationale for Dose Selection 
FluGen has conducted 3 clinical trials with Bris10 M2SR (a FTIH Phase 1 study, an ongoing 
Phase 1 study in adolescents, and a Phase 2a challenge study). See Sections 1.4.1,  1.4.2, and 1.4.3, 
respectively, for summaries of these studies.  
Combined, the findings of these 3 clinical trials indicate that (1) the vaccine is safe and generally 
well tolerated as a single 108 TCID50 dose; and (2) did not lead to exacerbated symptoms when 
followed by administration of a live, replicating wild-type influenza virus. Thus, there are no 
signals indicating that a safety concern might exist for studies that will increase either the dose 
level or exposure to more than one consecutive administration of M2SR as proposed in the current 
protocol. 
3.5.3. 
Rationale for Placebo Control 
Placebo control will be used to establish the frequency and magnitude of changes in laboratory 
and clinical endpoints that may occur in the absence of active vaccination. 
3.5.4. 
Rationale for Randomization and Blinding 
Randomization will be used to avoid bias in the assignment of subjects to, to increase the likelihood 
that known and unknown subject attributes (e.g., demographic and baseline characteristics) are 
evenly balanced across treatment groups, and to enhance the validity of statistical comparisons 
across treatment groups. 
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints. Only the pharmacist or their designee preparing the treatment, the unblinded 
monitor and the unblinded statistician who prepares the randomization list are unblinded with 
respect to treatment. 

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4. 
SELECTION OF STUDY POPULATION 
Sites will undergo a rigorous site qualification vetting to ensure they have an existing site database 
that can support the study requirements. Once the sites are allowed to screen, they will be 
instructed to search within the site database for candidates based generally on the 
inclusion/exclusion criteria (Section 4.1 and Section 4.2, respectively). Candidates who have 
indicated an interest in future study participation will be contacted by email using an IRB 
approved “email blast”. FluGen will also provide the sites with IRB-approved advertising (emails, 
posters, flyers). Sites may request to use their own advertising (including radio, print, social 
media) and these requests will be considered on a case-by-case basis and must be IRB-approved. 
Potential candidates may also contact the site via a provided phone number in the email blast or 
advertising. As a follow-up, trained interviewers from the site will make phone calls to responsive 
candidates. 
Screening for eligible subjects, healthy male and non-pregnant/lactating female subjects ages 18 
49 years old, will be performed within approximately 4 weeks prior to randomization. Candidates 
who respond to outreach will be assessed by phone for interest in the study, have the opportunity 
to ask questions, and will be queried to confirm general eligibility (e.g. pregnancy status, age). 
Eligible and willing candidates will then be scheduled to attend the on-site screening visit. At this 
visit, the site staff will discuss study details with potential candidates. If the candidate agrees to 
be screened to determine eligibility for participation in the study, he/she will be asked to review 
and sign the informed consent prior to any study procedures. Activities conducted at the screening 
visit (e.g., collecting subject health information and biological samples, and a physical exam) are 
listed in Section 6.1.1 and further described in Section 6.2. Candidates who screen fail will be 
added to the site database if they agree to participate in future studies. Recruitment and enrollment 
metrics will be provided by each site to the Sponsor for tracking purposes. 
The study will enroll approximately 250 subjects who will receive two doses of experimental 
Bris10 or Sing2016 M2SR vaccine or placebo (physiological saline) on Study Days 1 and 29. 
Subjects will be randomized 1:1:1:1:1 (Sing2016 M2SR 108, Sing2016 M2SR 108.5, Sing2016 
M2SR 109, Bris10 M2SR or Saline placebo). 
For details on the sample size calculation, please refer to Section 8.3.1. 
Because this is a Department of Defense funded study and subjects are expected to attend all study 
related visits, active military personnel are excluded from participating in this study.  
4.1. 
Inclusion Criteria 
Subjects meeting all the following criteria are eligible to participate in this study: 
1. Give written informed consent to participate; a legally authorized representative (LAR) 
may not be used. 
2. Age 18 – 49 years old, inclusive. 
3. Judged suitable by the PI, as determined by medical history, physical examination, vital 
signs, and clinical safety laboratory examinations. 
4. Negative test for pregnancy at screening visit and on Day 1. A positive test on Patient 
Day 29 will exclude subject from a second dose. 

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5. Negative test (urine) for drugs of abuse at screening. Patients who are on stable (6 months 
or longer) medications prescribed by their physician which result in a positive screen for 
that substance are allowed at the discretion of the investigator. 
6. Female subjects should fulfill one of the following criteria: 
a. Post-menopausal status defined as no menses for 12 consecutive months without 
an alternative medical cause. 
b. Surgically sterile. 
c. Willing to use oral, implantable, transdermal or injectable contraceptives, or sexual 
abstinence as outlined in inclusion criteria 7, from screening and until 28 days after 
second vaccine dose (Patient Day 57). 
7. Female subjects of childbearing potential must agree to sexual abstinence, use a reliable 
form of contraception approved by the Investigator (e.g., oral, implantable, transdermal, or 
injectable contraception, combined oral, intrauterine device [IUD], or a sterile sexual 
partner) from screening and until 28 days after the second vaccine dose (Patient Day 57). 
Non-surgically sterile male subjects who are sexually active with a female partner(s) of 
childbearing potential (i.e. males who have not been sterilized by vasectomy for at least 
6 months prior to screening) must be willing to use condoms from screening and until 
28 days after the second vaccine dose (Patient Day 57).  
8. Willing to adhere to the requirements of the study and willing and able to communicate 
with the Investigator and understand the requirements of the study. 
9. Non-smoker (defined as no use of tobacco products and no use of inhaled non-tobacco 
products in the past 30 days prior to Study Day 1; nicotine patches and gum are allowed). 
Subject must also agree to restrict the use of these products until 7 days after last vaccine 
administration. 
10. H3N2 Sing2016 MN titers ≤1:20 (determination within 90 calendar days of study 
enrollment is acceptable and does not need to be repeated for entry to this study). 
4.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria are excluded from participation in this study: 
1. Any subject who is a family member of a) study site personnel and other personnel directly 
involved in conduct or monitoring of study, or b) the Sponsor. 
2. Any condition that would limit the subject’s ability to complete the study based on the 
opinion of the Investigator (for example, a recent surgical procedure). 
3. Clinically significant abnormal screening hematology or chemistry value, as assessed by 
the investigator. 
4. Pulse rate or blood pressure outside the reference range for this study population and 
considered as clinically significant by the Investigator.  
5. Has an acute or chronic medical condition or history of a medical condition that, in the 
opinion of the Investigator, would render the study procedures unsafe or would interfere 
with the evaluation of the responses, including but not limited to, respiratory, autoimmune, 
or immune suppression conditions, neuroinflammatory conditions, mental illness 

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(including depression), active hematological, renal, hepatic, pulmonary, central nervous, 
neurological, cardiovascular, endocrine (including diabetes mellitus) or gastrointestinal 
disorders. 
6. Has been vaccinated against influenza within the last 6 months or plans to be inoculated 
with an influenza vaccine (other than study vaccine) until one month after completion of 
follow up on Patient Day 209. 
7. Had a flu-like illness (i.e., fever, chills and myalgia), influenza treatment (i.e., commercial 
drug such as Oseltamivir, etc.), or prophylactic influenza viral drug administered in the 
previous 6 months before screening.  
8. Positive screening test or known infection with human immunodeficiency virus (HIV), 
hepatitis B virus (HBV) and hepatitis C virus (HCV). 
9. History of cancer within 5 years prior to screening (except basal cell carcinoma and cervical 
carcinoma in situ). 
10. Presence or clinically significant history of lung disease, asthma, chronic obstructive 
pulmonary disease (COPD), or otherwise poor lung function. Childhood asthma that 
resolved by age 12 years is not criteria for exclusion.  
11. Any significant abnormality altering the anatomy of the nose or nasopharynx. A test 
swabbing by mock swab may be performed at screening at the Investigator’s discretion. 
12. Any confirmed or suspected immunosuppressive or immunodeficient state including: 
asplenia, recurrent severe infections and chronic (more than 14 days) immunosuppressant 
medication (such as systemic corticosteroids at a dose of ≥ 0.5 mg/kg/day for longer than 
1 week, or immunosuppressants such as cytotoxic drugs) within the last 6 months (topical 
steroids are permitted). Use of immunosuppressive medications, such as allergy shots, 
immune globulin, interferon, or immunomodulators in the past 6 months or planned to be 
used during the course of the trial. Use of intranasal corticosteroids within the last 7 days 
before screening. 
13. Significant adulthood history of seasonal hay fever, a seasonal allergic rhinitis, perennial 
allergic rhinitis, chronic nasal or sinus condition such as sinusitis, at the discretion of the 
investigator. 
14. Received any licensed vaccine within 1 month before screening and during the course of 
the study.  
15. Received or planned administration of another investigational vaccine or drug during the 
period from 90 days prior to Day 1 to one month after completion of Day 209 follow up.  
16. History of allergy/hypersensitivity to any vaccine component (sucrose, sodium chloride, 
phosphate, glutamate), or material in nasal delivery device (polycarbonate, polypropylene, 
synthetic rubber). 
17. Experienced a life-threatening reaction(s) after a previous administration of any vaccine or 
experienced an allergic reaction after a previous administration of any influenza vaccine or 
component. 
18. A history or prior diagnosis of Guillain-Barré Syndrome.  

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19. Living in the same household with any person with a non-functional or suppressed immune 
system, or with a confirmed influenza infection or febrile illness within the previous two 
weeks.  
20. History of drug or alcohol abuse in the 6 months before the study. 
21. Current use of any new prescription or new over-the-counter (OTC) medications starting 
within 1 month of vaccination, except for contraceptive pills, implants, transdermal or 
injections in female subjects, which may have been started within the previous 1 month. 
Herbal medications and supplements other than vitamins are prohibited.  
22. Receipt of blood products or immunoglobulin within 6 months before study entry or 
planned for within 180 days after the last vaccination. 
23. Donation of blood or blood products within 30 days before study entry or planned donation 
at any time during the 30 days post last vaccination. 
24. Females who are pregnant or lactating (i.e., a nursing mother). 
25. Acute febrile illness within 72 hours prior to vaccination, defined as the presence of a 
moderate or severe illness with or without fever (as determined by the Investigator through 
medical history and physical examination), or presence of a fever >38ºC orally. 
Vaccination (or administration of the second dose of vaccine) should be delayed until the 
subject has recovered. Persons with a minor illness, such as diarrhea, or mild upper 
respiratory tract infection with or without low-grade fever, may be enrolled after resolution 
of the illness.  
26. Any condition, in the opinion of the Investigator, (such as subjects who have medically 
high-risk conditions) that might interfere with the primary study objectives for safety of 
the study subject. 
27. Previous exposure to M2SR investigational vaccine. 
28. Any active military personnel/member. 
 
Exclusions at Day 29: 
Pregnancy, receipt of a prohibited medication, or new prohibited diagnosis, including laboratory 
confirmed influenza and/or treatment for influenza, or high-risk condition are exclusions for 
second vaccination. 
 
Note: At the discretion of the investigator, subjects may be rescreened; out-of-range clinical 
laboratory tests may be repeated twice, and vital signs may be repeated three times. Results of 
any retest must be available prior to enrollment. 
4.3. 
Lifestyle Guidelines 
No blood donation will be allowed until 30 days after the second vaccination. 
Information on prohibited therapies can be found in Section 5.9.2. 

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4.3.1. 
Contraception 
Female subjects are either postmenopausal (defined as without menses for at least 12 consecutive 
months without an alternative medical), are surgically sterile, or if of childbearing potential, must 
agree to sexual abstinence or the use of a reliable method of contraception as noted in Section 4.1.  
Non-surgically sterile male subjects who are sexually active with a female partner(s) of 
childbearing potential must also agree to use a reliable method of contraception as noted in 
Section 4.1.  

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5. 
TREATMENTS 
5.1. 
Study Vaccines 
Bris10 M2SR Vaccine: One IP, Bris10 M2SR, is a recombinant, monovalent influenza A virus 
that was initially generated by use of a plasmid rescue system. The virus does not express an 
essential viral protein (influenza M2), restricting it to a single replication cycle in the host. 
Therefore, for production it is grown in an M2-complementing cell line, M2VeroA. The Bris10 
M2SR also provides the HA and NA components from A/Brisbane/10/2007. 
Sing2016 M2SR Vaccine: The second IP is termed Sing2016 M2SR and is a recombinant, 
monovalent influenza A virus that was generated as described above for Bris10 M2SR. It contains 
a similar PR8 backbone but with nine amino acid changes distributed over five genes (PB1, PB2, 
PA, NP and NS1) that facilitate growth in the production cell line, M2VeroA. The mechanism of 
attenuation (deletion of the M2 gene) is not affected. The Sing2016 M2SR also provides the HA 
and NA components from A/Singapore/INFIMH-16-0019/2016 that were recommended for the 
2018-2019 influenza season. 
The Bris10 M2SR vaccine (Lot# 10250) and the Sing2016 M2SR (Lot# 19097) for this Phase 1b 
study were manufactured using master virus stocks and working cell bank at Ology Bioservices 
(Alachua, Florida, USA) under current Good Manufacturing Practice (cGMP) in a liquid 
formulation. The Bris10 M2SR vaccine will be provided frozen and in single-use cryovials. The 
Sing2016 M2SR vaccine will be provided frozen and in single-use cryovials. Details for IP titer 
and dilutions will be provided in the study-specific Pharmacy Manual. 
Copies of the certificates of analysis (CoAs) of the Bris10 M2SR and Sing2016 M2SR vaccines 
will be provided upon request. 
A pharmacist or designee will thaw the vial contents to room temperature just prior to dose 
administration. The contents will be diluted to the target dosing concentration with provided SPG 
diluent for each subject. The final diluted product will be drawn into two 1 mL disposable 
polypropylene syringes each fitted with a mucosal atomization device (MAD301; Teleflex, Salt 
Lake City, Utah, US) for intranasal delivery. 
5.2. 
Placebo Administered in the Study 
The reference product (placebo) is a physiological saline suitable for intranasal delivery. The 
placebo will be provided as a liquid and in single-use vials. The placebo will be drawn into two 
1 mL disposable syringes (~50% volume each) that are fitted with a Teleflex MAD301 sprayer for 
intranasal delivery. Administration and post-dose restrictions will be as described for the M2SR 
vaccines.  
The placebo is a clear solution whereas the M2SR vaccines are a light yellowish color. The 
unblinded pharmacy staff will prepare the vaccine and placebo doses, fill delivery devices and 
apply an opaque label to the device barrel to obscure any coloration of the contents and maintain 
the blind. 
Commercially available supplies of the placebo will be used and will be supplied by the site 
following approval from the Sponsor. 

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5.3. 
Packaging and Labeling 
5.3.1. 
Vaccines 
Manufacturing, packaging, and labeling of the M2SR vaccines is under the responsibility of the 
Sponsor. 
The Bris10 M2SR vaccine will be provided frozen and in single-use cryovials. The Sing2016 
M2SR vaccine will be provided frozen and in single-use cryovials. The viruses are suspended in 
SPG-NaCl buffer comprised of 303 mM sucrose, 5 mM glutamic acid, 136.9 mM sodium chloride, 
2.67 mM potassium chloride, 1.47 mM potassium dihydride phosphate and 8.1 mM disodium 
phosphate, at pH 7.2. Each vial will be diluted in SPG-NaCl buffer based on the intended dose and 
is considered to be a single-use vial.  
The primary package for both the vaccine products and for the SPG-NaCl buffer is a 2 mL cryovial 
with a threaded cap closure. The vaccine and buffer will be labeled according to local law and 
regulatory requirements. Each vial label will include the following information: product name, 
item and lot numbers, date of manufacture, storage condition, volume, vial number, manufacturer, 
and “Caution: New Drug – Limited by Federal law to Investigational Use.” The vial label for the 
vaccine is a light-blue label with black text and for the SPG-NaCl buffer is a white label with black 
text. Sample vial labels are shown in Figure 1. 
The vaccine and buffer vials will be packed into separate multi-vial boxes. Each box will be labeled 
with the following information: product name, item and lot numbers, storage condition, vial 
number range and volume, manufacturer and “Caution: New Drug – Limited by Federal law to 
Investigational Use.” The box label for the vaccine will be a light-blue label with black text and 
for the buffer will be a white label with black text.  

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Figure 1: 
Sample labels for drug product and SPG-NaCl buffer. 
 
5.3.2. 
Placebo 
The placebo is a commercially available physiological saline that will be supplied in single-use 
containers. The 0.9% sodium chloride for injection, USP, is a sterile, nonpyrogenic, isotonic 
solution of sodium chloride and water for injection. It is preservative-free and supplied in a 
single-dose container. The pharmacist or designee will aseptically fill placebo into the delivery 
devices on an as needed basis. A CoA will be provided for the placebo. 
5.4. 
Storage and Drug Accountability 
The Investigator (or designee) is responsible for the safe storage of all study drugs assigned to the 
clinical site, in a locked, secure storage facility with access limited to those individuals authorized 
to dispense the study drugs and maintained within the appropriate ranges of temperature. All study 
drugs must be stored as specified at delivery and in the original packaging. Instructions for the 
storage and handling of the study drugs will also be provided to the clinical site. 
5.4.1. 
Vaccines 
The M2SR vaccine products and the SPG-NaCl buffer will be delivered frozen and must be 
stored frozen at < -65°C in the provided multi-vial boxes. Each vaccine vial is a single-use vial. 
Once the vial contents have been thawed, the vial must be stored at 2-8°C prior to use in vaccine 
administration. The thawed vial contents will remain stable in the Sponsor-identified cryovials, 
neat or diluted with SPG-NaCl buffer, for up to 8 hours. Any vaccine product that has been 
Bris10 M2SR Drug Product 
Item #.: 10-0002305 Lot #.: XXXXXXX 
DOM: DDMMMYYYY Store at ≤ -65°C 
Volume: 0.5 mL Vial # XYZ 
Manufactured by Ology Bioservices, Inc. 
Caution: New Drug-Limited by Federal 
Law to Investigational Use 
 
Sing2016 M2SR Drug Product 
Item #.: 10-0004082 Lot #.: XXXXXXX 
DOM: DDMMMYYYY Store at ≤ -65°C 
Volume: 0.5 mL Vial # XYZ 
Manufactured by Ology Bioservices, Inc. 
Caution: New Drug-Limited by Federal 
Law to Investigational Use 
 
SPG-NaCl Diluent 
I/N: 10-0001613 L/N: XXXXXXX 
DOM: DDMMMYYY Store at ≤ -65°C 
Vial# XYZ Volume: 0.5 mL 
Manufactured by Ology Bioservices, Inc. 
Caution: New Drug- Limited by Federal 
Law to Investigational Use 

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thawed and held at 2-8°C for longer than 8 hours is no longer suitable for use in the study and 
must be accounted for. Such product will be labeled as damaged and will be quarantined at room 
temperature until the study monitor conducts on-site drug accountability. After that, this product 
should be destroyed per clinic Standard Operating Procedures (SOPs) and a certificate of 
destruction, or equivalent should be filed on site and provided to the Sponsor for internal filing.  
Each SPG-NaCl buffer vial is a single-use vial. Once the vial contents have been thawed, the 
vial must be stored at 2-8°C prior to use in treatment administration. The thawed vial contents 
will remain stable in the Sponsor-identified cryovials for up to 8 hours. Any buffer product that 
has been thawed and held at 2-8°C for longer than 8 hours is no longer suitable for use in the 
study and must be accounted for and then destroyed per clinic SOPs. 
Investigational product must be stored under temperature-controlled and monitored conditions. 
The site will also maintain a temperature log record of the relevant equipment for IP storage. 
Should an excursion in storage conditions occur, the clinical site must not further dispense the 
affected study vaccine until after notification and consultation with the Sponsor. 
The Investigator is responsible throughout the study for ensuring inventory and account record of 
all study drugs received at the clinical site. All drug accountability records must be stored in the 
site file and must be readily available for inspection by the study monitor and/or auditor, and open 
to regulatory inspections at any time. 
As misallocations of study drugs may have a detrimental effect on subjects’ safety and/or the study 
drugs’ efficacy and are a potential source of bias, utmost care should be taken to correctly dispense 
the study drugs as assigned by the randomization code. 
The vaccine and placebo should be dispensed under the supervision of the Investigator, a qualified 
member of the clinical staff, or by a hospital/clinic pharmacist or designee. The pharmacist or 
designee must maintain accurate records demonstrating date and amount of vaccine and the 
placebo supplied to whom and by who. The investigational vaccine and placebo will be supplied 
only to subjects participating in the study. 
The Sponsor’s designated study monitor will periodically check the supplies of vaccine and the 
placebo held by the Investigator or pharmacist/designee to ensure accountability and appropriate 
storage conditions of all vaccine and placebo used. 
Unused vaccine and placebo must be available for verification by the study monitor during on-site 
monitoring visits. Any discrepancies between returned and expected returned vaccine and placebo 
should be explained and documented. 
After the database has been locked and all on-site drug accountability has been completed by the 
monitor, any unused vaccine (including neat and diluted remnants) may be returned to the Sponsor 
or destroyed at the clinical site with the Sponsor’s written permission (in this case a certificate of 
destruction or equivalent will be provided and filed in the electronic Trial Master File [eTMF]). 
Hazardous materials such as used ampoules, needles, syringes and vials containing hazardous 
liquids, should be disposed of immediately in a safe manner and therefore will not be retained for 
drug accountability purposes. 

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5.4.2. 
Placebo  
Each placebo cartridge is a single-use container. The solution will be stored at USP controlled 
room temperature (20 – 25°C) prior to use in treatment administration. The contents may be used 
up to the date of expiry as stated by the manufacturer.  
Procedures for handling and storage of the commercially available placebo are detailed on the 
product-specific labels. 
5.5. 
Randomization 
Subjects will be assigned to IP (M2SR vaccines or saline) using a permuted block design. The 
randomization list will be prepared prior to study start by Sponsor’s statistician and shared with 
the unblinded pharmacist or designee. This treatment assignment list is to be treated as a 
controlled document and is not to be shared with other blinded personnel. Eligible subjects will 
be randomized to receive two administrations 28 days apart of Sing2016 at three dose levels, 
Bris10 at one dose level, or placebo in a 1:1:1:1:1 ratio. Approximately 15 subjects will be 
vaccinated at a time in up to 3 sentinel groups, and approximately 41 subjects will be vaccinated 
in  expansion groups. 
5.6. 
Blinding 
The blind will be maintained during this trial, including use of the following measures: 
(1) All subjects, whether receiving a M2SR vaccine or placebo, will undergo the same 
procedures, i.e., administration, AE assessment, blood collections, nasal swabs, etc. 
(2) The unblinded pharmacist or designee will prepare doses (active and placebo), fill 
delivery devices and apply an opaque label to the device barrel to obscure any 
coloration of the contents.  
(3) The unblinded site staff and unblinded study monitor will agree to maintain the blind 
by not providing details of the dose (active or placebo) to any blinded clinic staff 
including the Investigator and to study subjects. Furthermore, the unblinded individuals 
will be restricted from participating in other study procedures the interpretation of 
which could be impacted by their unblinded status, such as evaluation of AEs. 
(4) If any blinded investigational site staff learn of treatment assignments, a record of the 
event will be maintained, and the investigator will be informed. The investigator will 
consult with FluGen on how to preserve the blind.  
With the exception of the unblinded statistician who generates the randomization list, the 
unblinded pharmacist(s) or their designee(s) who prepare the study product for administration and 
the unblinded study monitor who may observe the study product preparation and performs IP 
accountability, all subjects, the Investigator, statistical programmers and all clinical site staff will 
be blinded to IP treatment (vaccine or placebo). All clinic staff who may be involved in making 
assessments of safety (including local reactions) will be blinded to treatment. Should a blinded 
monitor observe study product preparation, precautions must be taken to maintain the blind. 
Masking of the IP (vaccine or placebo) will be described in the Pharmacy Manual.  

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The randomization schedule will be inaccessible to the Investigator or to the blinded study team 
(monitors and/or FluGen team) during the study. After the Day 209 is complete for all subjects, 
after database lock, and after reconciliation with pharmacy and site records, the randomization 
code will be provided to the Study Statistician to enable data analysis by the Sponsor. Data 
collected at the Day 209 visit will be maintained in a separate follow-up database, and will be 
unblinded after cleaning and reconciliation, as for the primary database.  
The unblinded Statistician provides the randomization list to the unblinded pharmacist or their 
designee. This list will be used to prepare study product dosages and in the event of an emergency 
code break (see below).  
In the event of a medical emergency wherein knowledge of the IP treatment assignment will 
influence the subject's care, the Principal Investigator (PI) may be provided with the IP treatment 
assignment for that subject, at the discretion of the PI. The unblinded pharmacist or their designee 
will use the IP treatment assignment code to break the blind for the PI only in case of emergency. 
The PI will contact the FluGen Medical Monitor and document the event with the information 
regarding the reasons for unblinding as soon as possible, and no later than 24 hours after such 
unblinding. In the event the IP treatment code is broken, it will be broken ONLY for the subject 
in question. The reason for unblinding will be documented in the subject’s paper source. Subjects 
who are unblinded for any reason during their participation in the study will not be replaced and 
will be withdrawn immediately from the study; however, all attempts will be made to collect safety 
data through 28 days post-dose of the vaccine/placebo. In the event of a request to break a 
treatment code, the study monitor will be notified within 24 hours and the rationale for breaking 
the code will be documented. 
5.7. 
Dose and Administration 
5.7.1. 
Vaccine 
A rationale for the doses of vaccine selected in this study is provided in Section 3.5.2. 
Subjects will be randomly and sequentially assigned, according to the randomization schedule and 
in a blinded fashion, to one of 3 IP treatments: i.e., vaccine or placebo.  
Each vaccine and placebo dose will be filled into a sterile 1 mL polypropylene syringe that is 
fitted with a Teleflex MAD301 sprayer for intranasal delivery (Figure 2) by the unblinded 
pharmacist or designee.  
Figure 2: 
Image of the MAD301 Sprayer Device Fitted to a Syringe 
 
 
To fill the syringe, the contents are drawn into the syringe barrel via an 18-gauge needle. The 
needle is removed and replaced with the MAD301 sprayer via a Luer lock fitting. The spray device 

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is then primed. Further details for filling and actuating the spray device are provided in the 
Pharmacy Manual. The pharmacist or designee 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 on the label. The clinical staff credentialed to administer 
vaccines will then use the masked, filled spray device to administer the dose (active or placebo) 
intranasally to the subject.  
For delivery, on each of Days 1 and 29, subjects will receive a single intranasal dose of vaccine 
(or placebo) via a MAD301 spray device. Subjects will be in a semi-recumbent position and 
receive approximately two administrations of ~50% volume per nasal cavity by employing 2 spray 
devices. Devices will be weighed pre- and post-dose to allow calculation of dose eliminated from 
the devices. Subjects will remain semi-recumbent and under observation for thirty (30) minutes 
and will not be allowed to blow their noses, eat, or drink during this time; any deviations are 
captured in the source documents and reported to the study monitor/Clinical Project Manager. 
Any deviation from the dose defined in the protocol must be documented on source and in the 
eCRF system. 
5.8. 
Treatment Compliance 
Monitoring treatment compliance is not applicable because treatment will be administered per 
protocol in the clinic by study personnel. 
5.9. 
PRIOR AND CONCOMITANT THERAPY 
The use of concomitant therapies should be kept to a minimum throughout the study. All therapies 
administered (prescriptions and over-the-counter medications), other than the vaccine, from 
informed consent until the day 57 study visit, must be recorded in the source documents and in the 
concomitant therapy section of the Electronic Case Report Form (eCRF) (name of the drug, dosage, 
route and dates of administration). 
In the event that medical conditions after study treatment dictate use of medications, subjects are 
encouraged to obtain adequate care, comply with the course of therapy as prescribed by their 
physician, and inform the Investigator as soon as practical.  
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered to a study subject. 
Female subjects of childbearing potential and non-vasectomized male subjects having a female 
partner of childbearing potential must agree to the use of an effective method of contraception 
throughout the study, as outlined in Section 4.1. The use of oral, injectable, and implantable 
hormonal contraceptives is to be recorded in the source documents and in the concomitant therapy 
section of the eCRF. 
5.9.1. 
Permitted Concomitant Therapies 
The following medications and treatment are permitted in this study after Day 1: 
• Non-steroidal 
anti-inflammatory 
drugs 
(NSAIDs), 
acetaminophen, 
or 
antihistamines may be used after dosing if the subject has a fever ≥ 38.0C (100.4F) 

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or if the subject has significant nasal pain, myalgia, or headache. NSAIDs or 
acetaminophen should only be taken after documentation of symptoms or fevers on 
the Symptom Memory Aid and should not be taken prophylactically. 
• Low-dose aspirin 
5.9.2. 
Prohibited Concomitant Therapies  
The following medications are not permitted in the study 7 days prior to each vaccination and 
continuing until 7 days after each vaccination: 
• Concomitant use of any new prescription or over-the-counter (OTC) medications 
(except for contraceptive pills, implants, transdermal or injections) 
Any medication that is not covered by the permitted and non-permitted medication sections can be 
allowed at the discretion of the Investigator and documented on eCRF. 

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6. 
ASSESSMENTS 
6.1. 
Timing of Assessments 
An overview of the timing of treatment(s) and assessments is given in the Schedule of Events 
(Table 3). Details of safety and efficacy assessments are provided in Section 6.2.1 through 
Section 6.2.3, and Section 6.2.4, respectively. 
When visit assessments are planned at the same time point in the study, the order of assessments 
should be in order of less invasive to more invasive. For example, during the randomization visit, 
vitals, medical history, pregnancy testing and drug testing should be conducted before blood work 
and subsequent nasal swab. 

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Table 3: 
Schedule of Events 
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
Early 
Term7 
Study Day  
Post-First Dose 
Days -30 
to -1 
Day 1 
Day 4 
±1 
Day 8 
±1 
Day 29 
+/- 7 
Day 32 
Day 36 
Day 57  
20Day 
209 
Study Day 
Post-Second Dose 
 
 
 
 
D1 
Day 4 
±1 
Day 8 
-1/+7 
Day 29 
+/-7 
D181 
+/-14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X2 
 
 
X2 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X1 
 
 
 
 
 
 
 
 
X8 
Limited physical exam10 
 
X2,4 
 
X 
X2,4 
 
X 
X 
X 
X9 
Medical/medication history 
X 
X2 
 
 
X2 
 
 
 
 
 
Vital signs (height, weight, BP, HR, temp)16 
X 
X2, 4 
 
X 
X2, 4 
 
X 
X 
X 
X8 
Pregnancy testing (urine) 
X 
X3 
 
 
X3 
 
 
 
 
 
Hematology6 
X 
X2,5 
 
X 
X 
 
X 
 
 
X13 
Chemistry6 
X 
X2,5 
 
X 
X 
 
X 
 
 
X13 
Urinalysis (dipstick) 
X 
X2, 5 
 
X 
 
 
X 
 
 
X13 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
Serology for HIV, Hep B & C 
X 
 
 
 
 
 
 
 
 
 
Symptom Memory Aid 11 
 
X 
 
X 
X 
 
X 
 
 
X 
Scripted phone call with site to report 
symptoms 
 
 
X 
 
 
X 
 
 
 
 
Assessment for influenza19 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum collection (HAI, MN, NAI and 
ELISA) 
X 
X2 
 
X 
X2 
 
X 
X 
X 
X 
PBMC collection (CMI) & plasma18 
 
X2, 15 
X17 
X15 
X2, 15 
X17 
X15 
X 
 
X 
Nasal swab for secretory IgA immune 
response and/or vaccine virus detection 
X12 
X2, 9, 
12,14 
 
X9, 12 
X2, 9, 12 
 
X9, 12 
X12 
X12 
X9, 12 
Dose administration 
 
X 
 
 
X 
 
 
 
 
 
Device Weights 
 
X 
 
 
X 
 
 
 
 
 
AEs 
 
X4 
X 
X 
X2,4 
X 
X 
X 
 
X 
Conmeds 
X 
X2 
X 
X 
X2 
X 
X 
X 
 
X 
SAEs and medically attended AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1Complete Physical is required; neurological, rectal and gynecological exams do not need to be performed unless clinically indicated 

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2Prior to dosing  
3 Pregnancy test by urine dipstick on days 1 and 29 must be negative and reviewed prior to dosing 
4At 5 (+/- 1) and 30 (+/- 3) min after dosing 
5 Lab values at Day 1 are considered baseline 
6Laboratory tests as indicated in Appendix 2. 
7Early Term visit is only applicable if a subject does not complete the study within 28 days after dose administration 
8Limited physical exam and vital sign evaluations will be completed if early termination occurs within 28 days after dose administration 
9Sample aliquoted for vaccine virus detection (qPCR & infectivity) 
10 Specifically includes the nares (including edema), throat, and lungs (including evaluation for wheezing). A targeted physical examination may be performed on other 
body systems if indicated based on review of interim medical history or subject symptoms as observed by site or by PI. 
11 Dispense/Review/Collect for 7 days following each dose administration including day of dosing 
12 Sample aliquoted for secretory IgA immune response 
13 Sample collected if subject presents with AE 
14 Sample may be tested for respiratory pathogens 
15 Collected from PBMC processed blood 
16 Blood pressure will be measured from the subject’s arm after the subject has been at rest (seated or semi-recumbent) for approximately 5 minutes with the arm 
supported at the level of the heart. Blood pressure will be recorded to the nearest mmHg. Height and weight will be measured only at the screening visit. 
17 Optional PBMC collection (Days 4 and 32) at select sites based on subject consenting on Day 4 and/or Day 32 
18 PBMC and plasma collected at select sites for ~160 subjects 
19 During the treatment period (Day 1 – Day 57), subjects will be asked to notify the site immediately if symptoms of influenza (fever, chills, sore throat, rhinorrhea, 
cough, muscle/body aches) occur. Subjects will be reminded at every scheduled visit and phone call, and in addition to visits and calls scheduled above (when increased 
influenza infections are being reported in the geographic region of the investigational site) will be contacted at Days 15±2, 21±2, 43±2, and 50±2 by phone or 
messaging.  If influenza is suspected the subject will be asked to return to the site for laboratory confirmation of influenza using nasal swabs. 
20 Due to the COVID-19 pandemic, local governments may issue stay-at-home orders which prevent centers from conducting on-site Day 209 visits. This protocol allows 
for Day 209 visit to be a safety follow-up phone call. 
 

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6.1.1. 
Screening Period 1 (Days -30 to Dosing) 
In a private, individual setting, subjects will be given a full explanation of the nature of the study 
and written informed consent (IRB approval will be obtained before any study-related assessment) 
will be carried out. Group consenting will not be permitted and subjects requiring a Legally 
Authorized Representative may not participate in this study.  
Screening for eligible and consenting subjects will be performed within approximately 30 days 
prior to randomization/IP administration.  
Subjects may be consented and screened for serosusceptibility under a site-specific IRB-approved 
ICF.  
At screening, subjects will be asked to attend the clinical site to have assessments performed as 
indicated in the Schedule of Events (Table 3). 
All results from the screening procedure needed to evaluate eligibility, including the clinical 
laboratory results, must be available prior to study vaccination on Day 1. Any abnormal assessment 
at the screening visit will be assessed according to its clinical relevance, and if found clinically 
significant, the subject will not be included in the study. 
During the screening period, the following procedures and assessments will be carried out for each 
subject to determine their eligibility for participation in the study: 
• 
Obtain informed consent prior to any procedures being performed 
• 
Record demographics 
• 
Confirm eligibility criteria for enrollment and vaccination 
• 
Obtain medical history  
• 
Record concomitant medications 
• 
Perform complete physical examination (neurological, rectal and gynecological exams do 
not need to be performed unless clinically indicated) 
• 
Vital signs (height, weight, blood pressure, heart rate, and temperature) 
• 
Collect urine for drug screen 
• 
Collect urine for pregnancy test (applicable females only)  
• 
Collect blood for serology for HIV, Hepatitis B & HCV 
• 
Collect blood for serum chemistry and hematology  
• 
Collect blood for immunogenicity assays 
• 
Urinalysis (dipstick)  
• 
Perform nasal swab 
• 
Record any concomitant therapy/medically attended AEs/SAEs after signing of consent 
Unscheduled visits may be planned to assess, confirm, and follow-up on out-of-range clinical 
laboratory test, or vital sign values that determine a subject’s eligibility, or in case of a positive 

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urine drug screen. The result of the retest will be considered for subject eligibility. Findings made 
during unscheduled visits should be reported in the eCRF system. 
A record of the number of screening failures and the reasons for screening failure will be captured 
in eCRF, but subjects who fail screening and are not enrolled will not otherwise be included in the 
database. The failure details will be documented in the subjects’ study file. 
6.1.2. 
Treatment Period (Day 1 to Day 57) 
Assessments will be performed as indicated in the Schedule of Events (Table 3). 
6.1.2.1. 
Day 1  
• 
Update medical history 
• 
Vital signs (blood pressure, heart rate, and temperature) 
• 
Collect urine for pregnancy test (applicable females only) 
• 
Collect blood for serum chemistry and hematology 
• 
Urinalysis (dipstick) 
• 
Review of inclusion and exclusion criteria  
• 
Collect pre-dose blood sample for humoral immunogenicity assays (baseline MNT and 
other serum assays) 
• 
Collect pre-dose blood sample (PBMC) for cellular immunogenicity assays (ELISpot) 
and/or innate transcriptome gene expression – select sites only 
• 
Collect pre-dose blood sample (plasma) for cytokine expression – only if PBMC collected 
by site 
• 
Perform limited physical examination 
• 
Nasal swab into buffer for mucosal IgA and virus shedding 
• 
Symptom Memory Aid (distribute and provide instructions, fill out form pre-dose to train 
subject on execution) 
• 
Randomization 
• 
Device weights (pre- and post-IP administration) 
• 
IP administration 
• 
Record concomitant therapy prior to dosing 
• 
Record AEs/SAEs at 5 (+/- 1) and 30 (+/- 3) min after dosing 
6.1.2.2. 
Day 4 ± 1 day 
• 
Optional on-site visit for collection of blood sample (PBMC and plasma) for innate 
transcriptome gene expression – select sites only 
• 
If subject does not attend on-site visit, scripted phone call with site to report symptoms (if 
unable to reach subject then email or SMS is acceptable) 

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• 
Record concomitant therapy/AEs/SAEs 
6.1.2.3. 
Day 8 ± 1 day 
• 
Perform limited physical examination  
• 
Vital signs (blood pressure, heart rate, and temperature) 
• 
Collect blood for serum chemistry and hematology  
• 
Urinalysis (dipstick)  
• 
Symptom Memory Aid reviewed 
• 
Nasal swab into buffer for mucosal IgA and virus shedding 
• 
Collect blood sample for humoral immunogenicity assays (MNT and other serum assays) 
• 
Collect blood sample (PBMC) for cellular immunogenicity assays (ELISpot) and/or innate 
transcriptome gene expression – select sites only 
• 
Collect blood sample (plasma) for cytokine expression – only if PBMC collected by site 
• 
Record concomitant therapy/AEs/SAEs 
6.1.2.4. 
Day 29 ± 7 days  
• 
Confirm eligibility for second vaccination  
• 
Update medical history 
• 
Vital signs (blood pressure, heart rate, and temperature) 
• 
Collect urine pre-dose for pregnancy test (applicable females only) 
• 
Collect blood for serum chemistry and hematology 
• 
Perform limited physical examination 
• 
Nasal swab into buffer for mucosal IgA and virus shedding 
• 
Collect pre-dose blood sample for humoral immunogenicity assays (MNT and other serum 
assays) 
• 
Collect pre-dose blood sample (PBMC) for cellular immunogenicity assays (ELISpot) – 
only by select sites 
• 
Collect pre-dose blood sample (plasma) for cytokine expression – only if PBMC collected 
by site 
• 
Symptom Memory Aid (distribute and provide instructions) 
• 
IP administration 
• 
Device weights (pre- and post-IP administration) 
• 
Record concomitant therapy/AEs/SAEs prior to dosing and at 5 (+/- 1) and 30 (+/- 3) 
min after dosing 

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6.1.2.5. 
Day 32 (3 days ± 1 day after second dose) 
• 
Optional on-site visit for collection of blood sample (PBMC and plasma) for innate 
transcriptome gene expression – select sites only 
• 
If subject does not attend on-site visit, scripted phone call with site to report symptoms (if 
unable to reach subject then email or SMS is acceptable) 
• 
Record concomitant therapy/AEs/SAEs 
6.1.2.6. 
Day 36 (7 days -1/+7 day after second dose) 
• 
Perform limited physical examination  
• 
Vital signs (blood pressure, heart rate, and temperature) 
• 
Collect blood for serum chemistry and hematology 
• 
Urinalysis (dipstick)  
• 
Symptom Memory Aid reviewed 
• 
Nasal swab into buffer for mucosal IgA and virus shedding  
• 
Collect blood sample for humoral immunogenicity assays (MNT and other serum assays) 
• 
Collect blood sample (PBMC) for cellular immunogenicity assays (ELISpot) – only by 
select sites 
• 
Collect blood sample (plasma) for cytokine expression – only if PBMC collected by site 
• 
Record concomitant therapy/AEs/SAEs 
6.1.2.7. 
Day 57 (28 days ± 7 days after second dose) 
• 
Perform limited physical examination  
• 
Vital signs (blood pressure, heart rate, and temperature) 
• 
Nasal swab into buffer for mucosal IgA and virus shedding 
• 
Collect blood sample for humoral immunogenicity assays (MNT and other serum assays) 
• 
Collect blood sample (PBMC) for cellular immunogenicity assays (ELISpot) – only by 
select sites 
• 
Record concomitant therapy/AEs/SAEs 
6.1.2.8. 
Day 209 (180 days ± 14 days after second dose)- on-site visit 
• 
Perform limited physical examination  
• 
Vital signs (blood pressure, heart rate, and temperature) 
• 
Nasal swab into buffer for mucosal IgA and virus shedding  
• 
Collect blood sample for humoral immunogenicity assays (MNT and other serum assays) 
• 
Record SAEs 

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Due to the COVID-19 pandemic, local governments may issue stay-at-home orders which prevent 
centers from conducting on-site Day 209 visits. This protocol allows for the Day 209 visit to be a 
follow-up phone call focusing on the following safety points: 
• 
Has the subject received any licensed vaccines since Day 1 of the trial? 
• Has the subject received any investigational product (other than study IMP/placebo) since 
Day 1? 
• Has the subject had any SAEs or medically attended AEs since the last contact with the 
site? 
6.1.3. 
Testing for Influenza  
During the treatment period (Day 1 – Day 57), when increased influenza infections are being 
reported in the geographic region of the investigational site, subjects will be asked to notify the 
site immediately if they experience symptoms of influenza (fever, chills, sore throat, rhinorrhea, 
cough, muscle/body aches). If influenza is suspected the subject will be asked to return to the site 
and will have nasal swabs collected for laboratory confirmation of influenza. Subjects will be 
reminded at every scheduled visit and phone call, and in addition to visits and calls scheduled 
above, will be contacted at Days 15±2, 21±2, 43±2, and 50±2 by phone or messaging. Subjects 
may also have a rapid diagnostic test performed and may be treated for influenza at the 
investigator’s discretion.   
6.1.4. 
Early Termination Visit 
Subjects who withdraw consent will be asked to attend the clinic for safety evaluation as described 
in Early Termination assessments. 
Early Termination assessments should be completed within 7 (± 3) days of discontinuation for 
subjects who discontinue from the study. The following assessments are to be performed: 
• 
Complete physical examination (neurological, rectal and gynecological exams do not need 
to be performed unless clinically indicated); a limited physical exam will be completed if 
early termination occurs within 28 days after dose administration 
• 
Vital signs (height, weight, blood pressure, heart rate, and temperature) 
• 
Collect blood for serum chemistry and hematology  
• 
Urinalysis (dipstick)  
• 
Symptom Memory Aid 
• 
Nasal swab into buffer for mucosal IgA and virus shedding  
• 
Collect blood sample for humoral immunogenicity assays (MNT and other serum assays) 
• 
Collect blood sample for cellular immunogenicity assays (PBMC, ELISpot) – only for 
select sites 
• 
Collect blood for gene expression (PBMC, plasma) – only for select sites 
• 
Record concomitant therapy/AEs/SAEs 

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6.1.5. 
Unscheduled Visits 
Unscheduled visits can be planned: 
− To obtain additional information to ensure safety to the subject. Additional blood and urine 
samples may be taken at the discretion of the Investigator. 
− To obtain a nasal swab for assessment of potential influenza infection. 
−  To assess, confirm, and follow-up on out-of-range clinical laboratory test, or vital sign 
values that will determine a subject’s eligibility, or in case of a positive drug screen. 
− The result of the retest will be considered for subject eligibility. 
Findings made during unscheduled visits should be reported in the eCRF. 
6.2. 
Study Assessments 
6.2.1. 
Clinical Evaluations 
6.2.1.1. 
Medical History 
A complete medical history will include a review of all major body systems. Significant past and 
present medical history will be obtained by interview during the screening visit.  
6.2.1.2. 
Concomitant Medications 
Details of prescription and over-the-counter medications (including vitamins) currently used will 
be recorded during the screening visit. Concomitant medications will be reviewed at each visit and 
any new medications will be documented on the eCRF.  
6.2.1.3. 
Demographics 
Demographics will be obtained during screening only. Demographics will include the age and race 
as described by the subject.  
6.2.1.4. 
Physical Examination 
6.2.1.4.1. Complete Physical Examination 
A complete physical examination will be performed for each subject at the time points specified 
in the Schedule of Events (Table 3). The examination will consist of assessment of the following 
organs/systems: 
• Head 
• Eyes 
• Ears, nose, throat 
• Neck 
• Cardiovascular 
• Chest 

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• Respiratory 
• Abdomen 
• Genitourinary – only if clinically indicated 
• Extremities 
• Musculoskeletal 
• Nervous system – only if clinically indicated 
• Dermatological 
• Other conditions of note 
6.2.1.4.2. Limited Physical Examination 
A limited physical exam will be performed for each subject at the time points specified in the 
Schedule of Events (Table 3). The examination will include the nares (including edema), throat, 
and lungs (including evaluation for wheezing). A targeted physical examination may be performed 
on other body systems if indicated based on review of interim medical history or subject symptoms 
as observed by site or by PI.  
6.2.1.5. 
Vital Signs 
Vital signs include height, weight, oral temperature (°C), blood pressure (mmHg), pulse rate (beats 
per minute). Vital signs will be obtained at the time points specified in the Schedule of Events 
(Table 3). Subjects should have weight and height measured while wearing light street clothing 
and with shoes off. Blood pressure will be measured from the subject’s arm after the subject has 
been seated or semi-recumbent for approximately 5 minutes with the arm supported at the level of 
the heart. Blood pressure will be recorded to the nearest mmHg.  
6.2.1.6. 
Symptom Memory Aids 
Subjects will be asked to record post-treatment symptoms in a Symptom Memory Aid 
(Appendix 5) at the time points specified in the Schedule of Events (Table 3) for reactogenicity. 
At time of first dose, the first entries will be in concert with study staff as a training session at pre-
dose, the second entry will be the evening of vaccination and subsequent 6 entries will be made 
each evening following the IP delivery. Since visit Day 36 may occur ±1 day, the subject may not 
complete all days listed on the memory aid prior to the first post-dose visit. For subjects who attend 
the clinic at Day 35, a stamped and pre-addressed envelope will be provided so that the diary may 
be completed and mailed to the Site. Symptoms recorded on diaries returned by mail will be 
reviewed with the subject by telephone, if needed. Subject diaries will be retained as source 
documents.  
Events that are reported in the Symptom Memory Aid will be reviewed by the study staff and 
assessed and recorded as AEs according to the appropriate toxicity scale (Appendix 1 for vital 
signs and systemic AEs and Appendix 3 for reactogenicity assessments). During this time, subjects 
are asked to take their oral temperature (at approximately the same time each evening using the 
thermometer provided to them by the site) and record it in the Symptom Memory Aid. Any 
medications taken by the subjects will also be recorded in the Symptom Memory Aid. In addition, 

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subjects will be asked to record symptoms they may be experiencing during this time period, 
including: 
• Feverish 
• Nasal irritation 
• Nasal bleeding 
• Runny nose 
• Stuffy nose/Congestion 
• Sore/scratchy/itchy or painful throat 
• Body/muscle aches 
• Joint pain 
• Headache 
• Cough 
• Body rash 
• Tiredness 
• Nausea 
• Vomiting 
• Other symptoms 
 
6.2.1.7. 
Urine Samples 
Urine samples for the determination of pregnancy for women of childbearing potential, drug 
screening, and urinalysis will be collected at the time points specified in the Schedule of Events 
(Table 3). 
A midstream urine sample will be collected for urinalysis by dipstick for specific gravity, pH, 
glucose, protein, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, and occult blood. If 
dipstick urinalysis is abnormal, microscopic examination for WBC, RBC, and epithelial cells will 
be performed. Crystals, casts, and bacteria will only be reported if present. 
A urine drug of abuse screen will be performed. 
6.2.2. 
Bioanalysis 
Blood and urine samples for determination of the concentration of analytes specified in 
Appendix 2 will be analyzed by a qualified vendor under the responsibility of the Sponsor, using 
validated analytical methods. 
The Investigator must review the laboratory report, document this review, and record any change 
occurring during the study he considers to be clinically relevant in the AE section in the EDC 
system. Laboratory values outside the normal range will be flagged and their clinical relevance as 

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an AE will be assessed by the Investigator. Laboratory values which are Grade 3 or higher based 
on the grading scales in Appendix 2 will be reported to the Sponsor within 24 hours of 
investigator awareness, and assessment of clinical relevance will be reviewed by the Medical 
Monitor.  
The laboratory analysis will be carried out following the principles of Good Laboratory Practice 
(GLP) regulations.  
6.2.3. 
Adverse Events 
Adverse events will be monitored continuously from first administration of IP treatment until study 
Day 57. At regular intervals during the study, subjects will be asked non-leading questions to 
determine the occurrence of any AEs. All AEs reported spontaneously during the course of the 
study will be recorded as well. Solicited and unsolicited signs and symptoms will be reported as 
AEs after review by the Investigator or designee, either separately using the corresponding 
Medical Dictionary for Regulatory Activities (MedDRA) terminology of the sign or symptom or 
combined using the appropriate term. For example, a subject who experiences dysuria with blood, 
WBCs, and bacteria in the urine would be recorded as having a urinary tract infection. 
For detailed definitions and reporting procedures of AEs, see Section 9. 
6.2.4. 
Efficacy Evaluations 
6.2.4.1. 
Nasal Swabs 
Nasal swabs will be collected from subjects for the following purposes: 
1. 
To determine mucosal immunity 
2. 
To test for the presence of shedding influenza virus 
3. 
To test for the presence of respiratory viruses and bacteria (Optional) 
Nasal swabs will be collected at the time points specified in the Schedule of Events (Table 3) from 
all subjects. Individual swabs will be collected from each nostril and combined into a single vial 
of media. Samples will be aliquoted to use in various tests.  
To evaluate mucosal immunity, an ELISA-based test will be used to measure 1) mucosal IgA 
antibody titer to HA and 2) total IgA concentration  
To detect shedding influenza virus, a quantitative H3N2 RT-PCR assay will be used. Only swabs 
that have a positive qRT-PCR test result will be subjected to quantitative infectious culture assay.  
Possible infection with respiratory viruses and bacteria may be evaluated by use of a qualitative 
PCR test. This multiplexed assay will be performed by use of a commercial, qualitative viral and 
bacterial upper respiratory tract infection panel PCR device (adventitious agent screening). 
If a subject presents within 7 days of vaccination with symptoms of fever, upper respiratory illness, 
nephritis/cystitis, conjunctivitis or diarrhea, regardless of the severity of the symptoms, an 
additional nasal swab(s) should be collected and/or analyzed outside of the defined time points.  

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6.2.4.2. 
Delivery Device Weights 
The weight of each IP-filled device will be collected prior to dose administration and the weight 
recorded in the eCRF at the time point specified in the Schedule of Events (Table 3). Following 
administration of the dose (active and placebo) the actuated device will again be weighed, and the 
weight recorded in the eCRF. A calculation of the filled device weight minus the emptied device 
weight will indicate the weight of dose that was delivered from the device and will be used to 
determine volume dispensed.  
6.2.4.3. 
Blood Collection for Influenza Antibody Testing 
Blood samples will be collected and used for serum antibody titers against influenza using 
microneutralization (MN) and research assays. Samples will be collected as indicated in the 
Schedule of Events (Table 3). 
The MNT will measure all serum antibodies that neutralize the virus and prevent infection of cells 
and will be analyzed as directed in the Laboratory Manual.  
Research testing will be performed by the Sponsor or a vendor under supervision of the Sponsor. 
The research assays include enzyme-linked immunosorbent assays (ELISAs) or similar methods 
that may be used to detect anti-influenza immunoglobulin G (IgG) and/or IgA antibodies against 
influenza HA, HA stalk or NA. Additional assays may be conducted for detection of antibody 
response to influenza or other respiratory virus, for example neuraminidase inhibition assays 
(NAI). 
Further details regarding sample collection, processing and shipping can be found in the 
Laboratory Manual.  
6.2.4.4. 
PBMCs for Cell-mediated Immunity Testing 
Blood samples will be collected from all subjects at select sites and peripheral blood mononuclear 
cells (PBMCs) will be isolated and cryopreserved to be tested for CMI. Samples are taken as 
indicated in the Schedule of Events (Table 3) for ~160 subjects. 
PBMCs will be used to evaluate T cell responses by ELISPOT assays measuring cytokine secretion 
upon stimulation with influenza specific peptides. PBMCs may also be evaluated using flow 
cytometric (FACS) methods and intracellular cytokine staining (ICS) to characterize the duration 
of the responses, and whether memory phenotypes are generated. PBMCs may also be used in a 
direct ex-vivo ELISPOT assay for evaluation of plasma B cell responses or for detection of 
memory B cell responses after stimulation. 
Further details regarding sample collection, processing and shipping can be found in the 
Laboratory Manual. PBMC preparation will be the responsibility of each site.  
6.2.4.5. 
Plasma for Gene Expression and Cytokine Testing 
The plasma fraction will be collected from all subjects at select sites from blood samples processed 
for PBMC isolation. The plasma will be isolated, at select sites, and cryopreserved for later use for 
innate transcriptome gene expression and cytokine profile analysis. Samples are taken as indicated 
in the Schedule of Events (Table 3). These exploratory samples are being collected for research 
purposes only. 

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Further details regarding sample collection, processing and shipping can be found in the 
Laboratory Manual.  
Serum, plasma, PBMC and nasal swab samples that remain after protocol-specific assessments 
have been performed may be used for further exploratory work on pharmacokinetics, metabolites, 
plasma protein binding, protein analysis, and biochemistry. No human deoxyribonucleic acid 
(DNA) or ribonucleic acid (RNA) analysis will be performed, except cytokine expression as 
specified in the protocol or study manual. 
 

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7. 
STUDY TERMINATION/COMPLETION 
7.1. 
Study Completion and End of Study Definition 
A subject will be considered to have completed the study if he or she received the last study 
vaccination and attended the last protocol-defined follow-up visit. 
End of study will be defined as the point when all patients have completed follow up. The Sponsor 
will notify all applicable regulatory agencies in accordance with local requirements when the study 
has ended.  
7.2. 
Termination of the Study by the Sponsor 
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons, or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to all Investigators and 
regulatory authorities and will specify the reason(s) for early termination. The Lead PI must inform 
the IRB promptly and provide the reason(s) for the termination. 
7.3. 
Study Halting Rules 
Vaccination of subjects will be suspended until after review of safety data by the SRC if any of 
the following halting rules are met:  
1. One or more subjects experience a Grade 4 AE, vital sign or laboratory AE that cannot be 
clearly attributed to another cause. 
2. Three or more subjects within a single sentinel group or ten or more subjects within the 
expansion group experience the same Grade 3 AE, vital sign or laboratory AE that cannot 
be clearly attributed to another cause.  
3. One or more subjects experiences a SAE assessed as related to IP.  
4. One or more subjects has laryngospasm, bronchospasm, or anaphylaxis associated with the 
study product within 72 hours of product administration. 
Any AE or SAE that falls into the above criteria for suspending or terminating the study (including 
the occurrence of any Grade 3 AE, vital sign or laboratory AE that cannot be clearly attributed to 
another cause) must be reported by the investigator to the Sponsor immediately (within 24 hours). 
In the case of halting rules being met, the SRC will be convened as quickly as possible. After 
review of the safety data the SRC will make a recommendation to the Sponsor whether to resume, 
suspend or terminate the study. The Sponsor will communicate a decision to suspend or terminate 
the study to the Investigators. 
Subsequent review of serious, unexpected, and related AEs by the Medical Monitor, SRC, IRB, 
the Sponsor(s), or the FDA or relevant local regulatory authorities may also result in suspension 
of further trial interventions/administration of study product at a site. The FDA and study 
Sponsor(s) 
retain 
the 
authority 
to 
suspend 
additional 
enrollment 
and 
study 
interventions/administration of study product for the entire study, as applicable. 

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7.4. 
Removal of Subjects from the Study 
Subjects have the right to withdraw from the study at any time for any reason, including personal 
reasons. A subject can withdraw without giving a reason. The Investigator should however try to 
determine why a subject withdraws from the study and document the reason for withdrawal in the 
source documents and in the EDC system. 
Subjects may be withdrawn from the study in the event of: 
 
- 
Meeting any of the halting rules in Section 7.3 
 
- 
A severe AE or serious AE (SAE); 
 
- 
Difficulties in obtaining blood or other samples; 
 
- 
Failure of the subject to comply with the protocol requirements or to cooperate with 
the Investigator. 
 
Subjects must be withdrawn from the study in the event of: 
 
− Withdrawal of consent 
− Lost to follow-up 
− Death 
− Termination of the study by the Sponsor (described in Section 7.2) 
− For safety reasons, it being in the best interest of the subject that he/she be withdrawn, in 
the Investigator’s opinion; 
− A positive pregnancy test (the subject or, if reported by a male subject, his female partner), 
or if the subject/partner is non-compliant with the contraception requirements (see 
Section 4.1); 
− Development of a medical condition that requires concomitant treatment with a prohibited 
therapy (see Section 5.9.2); 
− Breaking of the randomization code during administration of the study drugs. If the code 
is broken for safety reporting purposes, the subject may remain in the study; however, in 
such case subject and site staff will remain blinded to IP treatment. 
The monitor and Sponsor will be informed in the event of a subject being withdrawn from the 
study. In case of withdrawal due to an SAE (for details on AE reporting see Section 9.7), the 
Sponsor should be notified within 24 hours; in case of withdrawal for other reasons; the Sponsor 
should be notified within 2 days from the event.  
Subjects who are withdrawn from the study prior to completion of the scheduled study procedures 
for any reason (AE, withdrawal of consent, etc.) should be invited to complete the assessments as 
much as possible: as long as the subject consents, all relevant assessments of the day on which the 
subject withdrew from the study should be completed, at least those related to safety, and the 
subject should come for a safety follow-up visit 4 weeks after vaccination. In case of an AE, the 
appropriate follow-up will be done. 
Subjects who are withdrawn from the study will not be replaced. 

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8. 
STATISTICAL METHODS AND CONSIDERATIONS 
8.1. 
General Considerations 
Prior to the analysis of the study data, statistical methods and table shells will be detailed in a 
Statistical Analysis Plan (SAP) and finalized before database lock.  
The final analysis will be done after the last subject has had the day 57 visit and the data base has 
been locked. The day 209 data will be included as a supplemental analysis.  
Statistical analysis will be the responsibility of Northrim Consulting, Inc, using SAS® (SAS 
Institute Inc., Cary, NC, USA; version 9.4 or higher). 
There are primary, secondary and exploratory objectives, endpoints and analyses. Depending upon 
the result of the primary and secondary analyses, not all exploratory analyses may be done. 
Safety and subject disposition analyses will be conducted on the safety analysis set. 
Summarization of primary and secondary efficacy endpoints will be done using FAS. These 
summaries may be repeated using the PP analysis set. 
There are no formal tests of hypotheses in this study. Efficacy outcomes are descriptive only. 
The data will be summarized in tables listing the number, mean, standard deviation, median, 
minimum, maximum, standard error (SE) and a 95% CI of subjects for continuous data, or in tables 
listing count and percentage for categorical data where appropriate. Tables will be presented by IP 
treatment and overall. Data listing by subject will be provided. 
8.2. 
Analysis Sets 
The following populations are defined for this study: 
- 
Safety Set (SS) – consists of any subject who receives at least one administration of IP; 
- 
Full Analysis Set (FAS) – consists of all subjects randomized, received IP and had at least 
one post baseline assessment. 
- 
(If necessary) Per-protocol Set (PP) - consists of all subjects in FAS with no major protocol 
violations or deviations. 
Unless otherwise specified the FAS population will be used for analysis.  
8.3. 
Subject Disposition and Baseline Comparability 
Subject disposition will be tabulated; the number of enrolled, randomized, prematurely terminated 
and completed subjects will be summarized by IP treatment group and overall. A list of dropouts 
will be prepared including reason and (study) time of discontinuation. 
Subject IP treatment groups will be characterized using tables, figures and descriptive statistics for 
demographic and baseline variables. Observed differences between the groups, should there be 
any, will be interpreted for clinical significance and their potential use as covariates in the analysis 
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8.3.1. 
Sample Size 
The sample size of 50 subjects per group was chosen based on reports of studies of other vaccines 
in early stage development. This study is not powered for any formal comparisons. 
8.3.2. 
Subject Characteristics Data Set 
Demographics will include by-treatment summaries of age, height, weight, BMI, race, and gender.  
BMI will be calculated in metric units using the formula provided below: 
 
 
 
BMI = weight (kg)/height (m)2 
Other baseline characteristics may be summarized. 
8.3.3. 
Safety Analyses 
Safety and tolerability of the Bris10 M2SR and Sing2016 M2SR influenza vaccines as assessed 
by subject diaries, solicited and unsolicited AEs, vaccine -associated AEs, SAEs, safety labs, vital 
signs, and physical examinations.  
Exposure  
Vaccine exposure will be summarized by actual dose, % of expected dose, and % of subjects 
receiving the expected dose. 
Adverse Events 
Treatment-emergent AEs (local and systemic) will be summarized as N (%) with AEs, with 
related-AEs, and by worst severity. 
Incidence of TEAEs will be reported by MedDRA-coded SOC, PT and maximum severity. 
Incidence of most frequent TEAEs and most frequent treatment-related TEAEs will be reported 
by SOC and PT  
Listings of subjects who died, discontinued the study due to an AE, or experienced an SAE will 
be provided. 
Dose-site reactions will be presented by reaction and severity. 
Post-administration of symptoms (memory aid) will be summarized by time point, worst 
occurrence, and days with symptoms.  
Clinical Laboratory Tests 
Biochemistry and hematology laboratory results and change from baseline results will be 
summarized by timepoint using descriptive statistics.  
Shift tables of maximum grade compared to baseline tabulated according to the FDA guidance: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, or in accordance with the normal ranges of the clinical laboratory (below, 
within, or above normal range) for parameters for which no toxicity grades are defined. 
A listing of clinical laboratory test results outside the reference ranges will be provided.  

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Vital Signs 
Vital sign results and change from baseline results will be summarized by timepoint using 
descriptive statistics.  
Limited Physical Examination 
Abnormal findings in physical examination will be listed. 
Pregnancy 
A listing of pregnant subjects will be displayed. 
8.3.4. 
Additional Analyses 
Additional analyses will be descriptive only; p-values are descriptive and not corrected for multiple 
testing. 
Immunogenicity 
Serum antibody, mucosal antibody and cellular immune response will be summarized using 
descriptive statistics by sampling timepoint for all subjects and by baseline values. 
Seroconversion rates will be presented by timepoint and by baseline starting values. 
Viral shedding will be summarized using descriptive statistics. 
Additional (exploratory) endpoints may be analyzed. 
8.4. 
Appropriateness of Measurements 
The assessments which will be made in this study are standard, and are generally recognized as 
reliable, accurate, and relevant. 

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9. 
ADVERSE EVENT REPORTING 
9.1. 
Definitions  
Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product. 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal result of diagnostic procedures, including clinical laboratory test 
abnormalities. 
AEs will be monitored continuously from the first administration of IP treatment until Day 57. 
SAEs or medically attended events will be documented until Day 209. Events recorded at the 
follow-up phone call will be assessed and followed up as appropriate. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that meets any of the following conditions: 
− results in death; 
− is life-threatening, i.e., the subject was at risk of death at the time of the event (e.g., 
ventricular fibrillation and anaphylaxis). The term does not refer to an event which 
hypothetically might have caused death if it were more severe. 
− requires inpatient hospitalization or prolongation of existing inpatient hospitalization: 
o Hospitalization refers to an overnight admission into hospital for the purpose of 
investigating and/or treating the AE. Hospitalization for an elective procedure, or 
routinely scheduled treatment for a pre-existing condition that has not worsened, is 
not an SAE. 
− results in persistent or significant disability/incapacity, i.e., causing substantial disruption 
of the subject’s ability to conduct normal life; 
− is a congenital anomaly/birth defect; 
− is medically significant, i.e., may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject’s health or may require intervention to 
prevent one of the above outcomes. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization or development of drug dependency or drug abuse. 
Unlisted (Unexpected) Adverse Event 
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information (FluGen IB). 

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Suspected Unexpected Serious Adverse Reactions (SUSARs) 
A SUSAR is an unexpected serious adverse reaction to the IP.  
The Sponsor is to determine if the event is unexpected or not and if unexpected and to report the 
SUSAR to the Lead PI and FDA. The Lead PI will report any SUSAR(s) to the central IRB. For 
death and life-threatening cases, reporting should be done within 7 days and follow-up information 
with details provided within an additional 8 days. All other SUSARs have to be reported within 
15 days. 
9.2. 
Intensity of Adverse Events 
All AEs will be assessed by the clinician using the grading system from FDA vaccine toxicity 
criteria (Appendix 1 for vital signs and systemic AE assessment; Appendix 2 for laboratory AE 
assessment, and as described in Section 6.2.2 ). For assessment of reactogenicity in this study, see 
Appendix 3. For events not included in the protocol-defined grading system, then the following 
guidelines will be used to quantify intensity.  
Mild: events require minimal or no treatment and do not interfere with the patient’s daily activities. 
Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
Severe: events interrupt a patient’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually incapacitating. 
Life threatening: any adverse drug experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a 
reaction that had it occurred in a more severe form, might have caused death. 
Changes in the severity of an AE should be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed. Adverse events characterized as intermittent 
require documentation of onset and duration of each episode. 
9.3. 
Causality Assessment 
The clinician’s assessment of an AE's relationship to test article (vaccine or placebo) is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study product assessed 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 – The AE is not related to the study product if there is evidence that clearly indicates 
an alternative explanation. If the subject has not received the study product, the timing of the 
exposure to the study product and the onset of the AE are not reasonably related in time, or other 
facts, evidence or arguments exist that strongly suggest an alternative explanation, then the AE is 
not related.  

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9.4. 
Reactogenicity 
Reactogenicity events may be common and are known to occur for the vaccine being studied and 
will be collected as solicited AEs in a standard, systematic format using a grading scale based on 
functional assessment or magnitude of reaction. In this study, the following reactogenicity events 
will be collected for the first 7 days after each dose of IP: 
• Feverish 
• Nasal irritation 
• Nasal bleeding 
• Runny nose 
• Stuffy nose/Congestion 
• Sore/scratchy/itchy or painful throat 
• Body/muscle aches 
• Joint pain 
• Headache 
• Cough 
• Body rash 
• Tiredness 
• Nausea 
• Vomiting 
• Other symptoms 
These will be evaluated and graded daily based on the functional scale specified within the 
Symptom Memory Aid (Appendix 5). 
Should a subject experience a severe reaction (graded as a 3) and/or measure a body temperature 
equal to or greater than 39°C, he/she should immediately contact the site. 
9.5. 
Outcome 
The outcome of each AE must be rated as follows: 
− Recovered/resolved; 
− Recovering/resolving; 
− Not recovered/not resolved; 
− Recovered with sequelae/resolved with sequelae; 
− Fatal; 
− Unknown. 

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9.6. 
Recording of Adverse Events 
All (S)AEs occurring during the clinical investigation must be documented in the source 
documents and eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
“upper respiratory infection”). Investigators must record their opinion concerning the relationship 
of the (S)AE to the study drugs in the EDC System. All measures required for (S)AE management 
must be recorded in the source documents and reported according to Sponsor’s instructions. 
All AEs occurring at any time during the study (including the in-person follow-up period) will be 
followed by the Investigator until satisfactory resolution (e.g., value back to baseline value) or 
stabilization or until final database lock. If necessary, in order to obtain additional information to 
ensure safety of the subject, additional blood and urine samples may be taken at the discretion of 
the Investigator. Certain long-term AEs related to therapy cannot be followed until resolution 
within the setting of this study. In these cases, follow-up will be the responsibility of the treating 
physician. 
9.7. 
Reporting of Serious Adverse Events to the Sponsor for 
Pharmacovigilance 
All SAEs, independent of the circumstances or suspected cause, must be recorded on a Serious 
Adverse Event Form by the Investigator and reported to the Sponsor within 24 hours of knowledge 
of the event. The SAE may be initially reported by phone (Dr Ruth Ellis; 703-401-8189), with the 
completed SAE Form sent to FluGen by email (Safety@flugen.com) or fax (608-260-7704) within 
24 hours of knowledge of the event.  
The Sponsor will immediately notify the Medical Monitor, who will evaluate the SAE report(s) 
within 1 working day of receipt to determine the regulatory reporting priority or, if necessary, 
request additional information from the site to make an evaluation. 
The SAE form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in 
order to allow a complete medical assessment of the case and independent determination of the 
possible causality. 
Follow-up and outcomes should be reported for all subjects who experience an SAE. 
It is critical that the information provided on the Serious Adverse Event Form matches the 
information recorded in the source documents and in the EDC system for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and applicable. 
Follow-up reports relative to the subject’s subsequent course must be submitted to FluGen and 
IRB (as applicable) until the event has subsided or, in case of permanent impairment, until the 
condition stabilizes. 

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9.8. 
Pregnancy 
All initial reports of pregnancy in subjects or in partners of male subjects must be reported to the 
Sponsor by the Investigator within 24 hours of his/her knowledge of the event. This is done by  
contacting FluGen via email (Safety@flugen.com) or fax (608-260-7704). Any subject who 
becomes pregnant during the study must be promptly withdrawn from the study (Code of Federal 
Regulations [CFR] Section 8). 
The Investigator will contact the subject at the expected time of delivery for follow-up and will 
provide the pregnancy outcome to the Sponsor. Abnormal pregnancy outcomes (e.g., spontaneous 
or induced abortion, stillbirth, neonatal death, congenital abnormality, birth defect) are considered 
SAEs and must be reported using the Serious Adverse Event Form. 
9.9. 
Reporting of Serious Adverse Events to Competent 
Authorities/Ethics Committees 
Adverse events reporting, including suspected unexpected serious adverse reactions (SUSARs), 
will be carried out in accordance with applicable local regulations. 
All SUSARs will be the subject of expedited reporting. The Sponsor and Investigator shall ensure 
that all relevant information about a SUSAR that is fatal or life-threatening is reported to the 
relevant competent authorities and IEC/IRB within 7 days after knowledge by the Sponsor of such 
a case, and that relevant follow-up information is communicated within an additional 8 days, or 
according to the IEC/IRB’s required time frame. All other SUSARs will be reported to the relevant 
competent authorities and IEC/IRB within 15 days after knowledge by the Sponsor of such a case. 
FluGen will provide investigators with all details of all SAEs reported to regulatory authorities. 
9.10. 
Medical Monitor 
The Medical Monitor is an independent clinician (i.e. not directly employed by the Sponsor or the 
site) responsible for safety oversight of the study.  He/she should have no apparent conflict of 
interest and cannot be under the supervision of the PI or other investigators or research staff. The 
Medical Monitor will oversee interventions, interactions, data matching, data collection and data 
analysis, review the clinical monitoring plan, review SAE and SUSAR reports (Section 9.7), 
review AEs which may prompt a study halt (Section 7.3), participate in the Safety Review 
Committee (Section 9.11), participate in decisions regarding emergency unblinding (Section 5.6), 
participate in review of Grade 3 laboratory abnormalities, and review summary AE data prior to 
final database lock. The Medical Monitor is responsible to promptly report his/her observations to 
the IRB or other designated official and to the HRPO. The Medical Monitor has the authority to 
stop the study, remove individual human subjects from a research protocol if needed and take any 
steps necessary to protect the safety and well-being of the subjects until the IRB can assess the 
monitor’s report. The Medical Monitor will also participate via phone in site training and will be 
available to answer questions related to study eligibility and safety for the duration of the study 
and may discuss the research protocol with investigators. 
 

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9.11. 
Safety Review Committee  
Safety oversight will be under the direction of an SRC which is composed of an independent group 
of experts including two clinicians and a statistician who will be available to review blinded safety 
data, as needed. The SRC will monitor subject safety and advise the Sponsor. SRC members will 
be separate and independent of study personnel participating in this study and should not have 
scientific, financial or other conflict of interest related to the study.   
The SRC will operate under the rules and procedures of a Sponsor-approved charter. The SRC will 
review applicable data including, but not limited to, enrollment, demographic, dosing, laboratory 
and safety data if study halting rules are met, as defined in the protocol and the SRC charter. The 
SRC may receive data in aggregate and presented by treatment group, but without the treatment 
group identified. The SRC may review aggregate safety data for increased rate of occurrence of 
serious suspected adverse reactions. The SRC may be unblinded to study treatment, as needed, to 
assess safety issues. As an outcome of each review/meeting, the SRC will advise the Sponsor of 
its findings and make recommendations with respect to continuation of the study. 
Throughout the study, the SRC will be convened if halting rules are met. The SRC also may be 
convened at the request of the Investigator, Medical Monitor, Sponsor or any SRC member, if they 
have cause for concern regarding subject safety. The SRC can recommend study enrollment and 
vaccinations be stopped if AEs that meet the halting criteria are reported or for any overriding 
safety concern. Further details regarding composition and operation of the SRC are provided in 
the SRC Charter. 

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10. 
ETHICAL ASPECTS 
10.1. 
Study-Specific Design Considerations 
Potential subjects will be fully informed of the nature of the study and of the risks and requirements 
of the study before any study-related assessment will be carried out. During the study, subjects will 
be given any new information that may affect their decision to continue participation. They will 
be informed that their participation in the study is voluntary and that they may withdraw from the 
study at any time with no reason given and without penalty or loss of benefits to which they would 
otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and who provide their consent voluntarily will be enrolled in the study. 
10.2. 
Regulatory Ethics Compliance 
10.2.1. 
Investigator Responsibilities 
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications specified by 
the applicable regulatory requirements, and should provide evidence of such qualifications through 
up-to-date curriculum vitae or other relevant documentation requested by the Sponsor, the 
IRB/IEC, or the regulatory authorities. 
The Investigator is responsible for ensuring that the clinical study is performed in accordance with 
the protocol, current International Council for Harmonisation (ICH) guidelines on GCP, and 
applicable regulatory and country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles originating from the Declaration of 
Helsinki (1964 and revisions), and that the clinical study data are credible. 
10.2.2. 
Independent Ethics Committee or Institutional Review Board (IEC/IRB) 
An IRB/IEC should safeguard the rights, safety, and well-being of all study subjects. Special 
attention should be paid to studies that may include vulnerable subjects. 
Before the start of the study, the Sponsor (or Investigator where required) will provide the IEC/IRB 
with current and complete copies of the following documents: 
− final protocol and, if applicable, amendments; 
− Sponsor-approved ICF (and any updates or any other written materials to be provided to 
the subjects); 
− Subject recruiting materials; 
− IB (or equivalent information) and addenda; 
− available safety information; 
− information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable; 

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− Investigator’s current curriculum vitae or other documentation evidencing qualifications 
(unless not required, as documented by the IEC/IRB); 
− Clinical trial agreement; 
− any other documents that the IEC/IRB may require to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full written approval of the final 
protocol and amendments (if any), the ICF(s) and updates (if any), applicable recruiting materials, 
and any other written information to be provided to the subjects, and the Sponsor has received a 
copy of this approval. This approval letter must be dated and must clearly identify the IEC/IRB 
and the documents being approved. 
During the study, the Sponsor (or Investigator where required) will send the following documents 
and updates to the IEC/IRB for its review and approval, where appropriate: 
− protocol amendments; 
− revision(s) to the ICF and any other written materials to be provided to the subjects; 
− new or revised subject recruiting materials approved by the Sponsor; 
− revisions to compensation for study-related injuries or payment to subjects for 
participation in the study; 
− IB addenda or new edition(s); 
− summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB 
(at least annually); 
− reports of AEs that are serious, unlisted, and associated with the IMP; 
− new information that may adversely affect the safety of the subjects or the conduct of 
the study; 
− deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects; 
− report of death of any subjects under the Investigator’s care; 
− notification if a new Investigator is responsible for the study at the clinical site; 
− any other requirements of the IEC/IRB. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s), except when necessary to eliminate immediate hazard to the study subjects. If a 
deviation from or a change to the protocol was implemented to eliminate an immediate hazard to 
study subjects, then the implemented deviation or change, the reasons for it, and, if appropriate, 
the protocol amendment should be submitted to the IEC/IRB as soon as possible. 
The Sponsor (or Investigator will notify the IEC/IRB about the study completion within 90 days 
after the end of the study (defined as LPLV). 

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10.2.3. 
Informed Consent 
Each subject must give written consent according to local requirements after the nature of the study 
has been fully explained. The consent form must be signed before performance of any study-related 
activity. The consent form that is used must be approved by both the Sponsor and the reviewing 
IEC/IRB. The informed consent should be in accordance with the principles that originated in the 
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and 
Sponsor policy. 
Before enrollment in the study, the Investigator or an authorized member of the clinical staff must 
explain to potential subjects the aims, methods, reasonably anticipated benefits, and potential 
hazards of the study, and any discomfort participation in the study may entail. Subjects will be 
informed that their participation is voluntary and that they may refuse to participate or withdraw 
consent to participate at any time, without penalty or loss of benefits to which the subject was 
entitled. Finally, they will be told that the Investigator will maintain a subject identification register 
for the purposes of long-term follow-up if needed and that their records may be accessed by health 
authorities, US DoD representative as part of its human subject protection oversight activities and 
authorized Sponsor staff without violating the confidentiality of the subject, to the extent permitted 
by the applicable law(s) or regulations. By signing the ICF the subject is authorizing such access 
and agrees to allow his or her study physician to recontact the subject for the purpose of obtaining 
consent for additional safety evaluations, if needed. 
The language about the study used in the oral and written information, including the ICF, should 
be non-technical and practical and should be understandable to the subject. The subject will be 
given sufficient time to read the ICF and the opportunity to ask questions. After this explanation 
and before entry into the study, consent should be appropriately recorded by means of the subject's 
personally dated signature. After having obtained consent, a copy of the ICF must be given to the 
subject. 
The collection and processing of personal data from subjects enrolled in the study will be limited 
to those data that are necessary to investigate the safety, quality, and utility of the IMP used in the 
study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data need to agree to keep the 
identity of the study subjects confidential. 
The informed consent obtained from the subjects includes explicit consent for the processing of 
personal data and for the Investigator to allow direct access to subjects’ original medical records 
for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries. 

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11. 
ADMINISTRATIVE REQUIREMENTS 
11.1. 
Protocol Amendments 
Neither the Investigator nor the Sponsor will modify this protocol without a formal amendment. 
All protocol amendments must be issued by the Sponsor and signed and dated by the Investigator. 
Protocol amendments must not be implemented without prior IEC/IRB approval nor when the 
relevant competent authority has raised any grounds for non-acceptance, except when necessary 
to eliminate immediate hazard to the subjects, in which case an amendment must be promptly 
submitted to the IEC/IRB and relevant competent authority. Documentation of amendment 
approval by the Investigator and IEC/IRB must be provided to the Sponsor or his designee. When 
the change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC where 
required) only needs to be notified. 
11.2. 
Subject Identification, Enrollment, and Screening Logs 
The Investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
Sponsor site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed by 
the Investigator in the study file. To ensure subject confidentiality, no copies will be made. All 
reports and communications related to the study will identify subjects by initials and/or assigned 
number only. 
The Investigator must also complete a subject screening log which reports on all subjects who were 
seen to determine eligibility for inclusion in the study. 
11.3. 
Source Documentation 
The investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated. These individuals authorized to fulfill these responsibilities should be outlined and 
included in the Delegation of Authority Form. 
Source documents are original documents, data, and records for which the study data are collected 
and verified. Example of such source documents may include, but are not limited to, subject 
hospital/medical records, laboratory reports, physicians’ and nurses’ notes, subject diaries and 
correspondence. At a minimum, source documentation must be available for the following: subject 
identification, eligibility, and study identification; date of subject consent, dates of visits, results 
of safety and efficacy parameters as required by the protocol, record of all AEs, follow-up of AEs, 
concomitant medication, drug receipt/dispensing/return records, study drug administration 
information, laboratory printouts (if not available digitally), date of study completion, and reason 
for early discontinuation of study drugs or withdrawal from the study, if applicable.  
The Investigator and study staff are responsible for maintaining a comprehensive filing system of 
all subject records that are readily available to support monitoring activities in compliance with 
ICH-GCP guidelines and regulatory and institutional requirements for the protection of 
confidentiality of subjects. The Investigator shall supply the Sponsor or designee, on request, with 
any required background data from the study documentation or clinic records. Such requests may 
occur, for example, when documents are illegible or when errors in data transcription are 

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suspected. In case of requests for audit inspections and/or queries from National 
Authorities/Regulatory Agency, it will be necessary to have access to the complete study records, 
provided that subject confidentiality is maintained.  
No study documents should be discarded without prior written agreement between the Sponsor 
and the Investigator. Should storage no longer be available to archive source documents or must 
be moved to an alternative location, the site should notify the key sponsor contact prior to the 
shipping of documents. 
11.4. 
Case Report Form Completion 
Authorized study site personnel will complete eCRFs designed specifically for this study and 
completion guidelines will be provided. An eCRF is required and must be completed for each 
subject enrolled into the study and will be available for all data required to be entered into the 
clinical database and must match the data contained in the study specific source documentation. 
The Investigator will ensure that the eCRFs are accurate, complete and legible. The Investigator 
will ensure that source documents that are required to verify the validity and completeness of data 
transcribed on the eCRFs are never obliterated or destroyed. As required by the protocol, eCRFs 
should also be completed for those subjects who fail to complete the study. If a subject withdraws 
from the study, the reason must be noted on the eCRF and thorough efforts should be made to 
clearly document outcome.  
The eCRFs will be maintained in an electronic data collection system for this study. After the 
Investigator or designees have been appropriately trained, they will be given access to the EDC 
system and will be able to enter the data required by the protocol. Any change of data will be made 
via the EDC system, with all changes tracked by the system to provide an audit trail. 
11.5. 
Study Monitoring 
The Sponsor is responsible for assuring the proper conduct of the study with regard to protocol 
adherence and validity of the data recorded on the eCRFs. Subject confidentiality will be 
maintained. 
In addition, monitors designated by the Sponsor will periodically contact the site, including 
conducting on-site and remote monitoring visits. The on-site and remote monitoring visits will be 
conducted as frequently as necessary to ensure that all aspects of the study are carefully monitored 
for compliance with applicable government regulations with respect to current GCP practice and 
the current SOPs. The visits will be conducted in accordance with the Sponsor’s SOP and Clinical 
Monitoring Plan. 
The unblinded study monitor will be limited to observation (in real-time or via review of 
documentation) of IP preparation and delivery device filling and weighing, adherence to 
randomization to treatment group, storage of IP and IP accountability and to review of consent and 
eligibility documents. They will not participate in activities related to subject assessments. 
In general, the Investigator agrees to fully cooperate with the monitor, allow the monitor direct 
access to all relevant documents, to allocate his time and the time of his staff to the monitors to 
discuss any findings and any relevant issues as needed. 

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11.6. 
Data Management 
Electronic data collection will be used to enter study data. During the data collection process, 
automated quality assurance programs will be used to identify missing data, incorrect data and 
other data discrepancies. Requests for data clarification or correction will be queried to the 
investigative study site for resolution via the EDC system.  
Quality assurance and quality control systems will be implemented and maintained to ensure that 
the data are generated, recorded and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements. Data collection and storage will provide an audit trail, security 
mechanisms and electronic signature capabilities that meet the requirements of FDA Title 21 of 
CFR Part 11 regarding electronic records and electronic signatures. 
Data security will be controlled through appropriate and specific restriction of access to only data 
and systems required by individual users to accomplish their roles in the data management process. 
Individual login and password protections will be employed. The database will exist on physically 
secured servers. Data backups will be done regularly and will be stored in a separate facility.  
11.7. 
Data Quality Assurance 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the Investigator and 
associated personnel prior to the study, and by periodic monitoring visits by the Sponsor or 
designee. 
Written instructions will be provided for the collection, preparation, and shipment of biological 
test samples.  
The Sponsor or designee will review the paper source and eCRF entries for accuracy and 
completeness during (on-site) monitoring visits and after transmission to the Sponsor; any 
discrepancies will be resolved with the Investigator or designee, as appropriate. After upload of 
the data into the clinical study database, their accuracy will be verified using appropriate validation 
programs. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, the 
Sponsor will be entitled to audit the facilities used in the clinical and laboratory parts of the study, 
as well as to access all the data files pertaining to the study. Similar procedures may also be 
conducted by agents of any regulatory body, either as part of a national GCP compliance program 
or to review the results of this study in support of a regulatory submission. The Investigator should 
immediately notify the Sponsor if they have been contacted by a regulatory agency concerning an 
upcoming inspection. 
11.8. 
On-Site Audits 
Representatives of the Sponsor’s clinical quality assurance department may visit the clinical site 
at any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRF system. 
Subject privacy must, however, be respected. The Investigator and clinical staff are to be present 

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and available for consultation during routinely scheduled site audit visits conducted by the Sponsor 
or his designee. 
Similar procedures may also be conducted by agents of any regulatory body, either as part of a 
national GCP compliance program or to review the results of this study in support of a regulatory 
submission. The Investigator should immediately notify the Sponsor if they have been contacted 
by a regulatory agency concerning an upcoming inspection. 
11.9. 
Study Termination 
The Sponsor has the right to terminate the study at any time. In case of an early termination of the 
study for safety reasons, or temporary halt by the Sponsor, the IEC/IRB should be notified within 
15 calendar days and should be provided with a detailed written explanation for the 
termination/halt. 
An end-of-study declaration will be submitted to the regulatory authorities and IEC/IRB after the 
complete study has ended. This notification will be submitted within 90 days after the end of the 
study. 
11.10. 
Record Retention 
In compliance with the ICH/GCP guidelines, the Investigator/Institution will maintain all paper 
source documents that support the data collected from each subject, as well as all study documents 
as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical Trial, and 
all study documents as specified by the applicable regulatory requirement(s). The 
Investigator/Institution will take measures to prevent accidental or premature destruction of these 
documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the IMP. These documents will be retained for a longer period if required 
according to the applicable regulatory requirements or per agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/Institution as to when these documents no 
longer need to be retained.  
If the responsible Investigator retires, relocates, or for any other reasons withdraws from his 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the Investigator relocate or dispose of any study documents 
without having obtained written approval from the Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation related to the study, the Investigator must permit access to such reports. 
11.11. 
Use of Information and Publication 
All information, including but not limited to, information regarding the Bris10 or Sing2016 M2SR 
vaccines or the Sponsor’s operations (e.g., patent application, formulas, manufacturing processes, 
basic scientific data, prior clinical data, formulation information) supplied by the Sponsor to the 

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Investigator and not previously published, and any data generated as a result of this study are 
considered confidential and remain the sole property of the Sponsor. The Investigator agrees to 
maintain this information in confidence, to use this information only to accomplish this study, and 
not to use it for other purposes without the Sponsor’s prior written consent. 
The Investigator understands that the information generated in this clinical study will be used by 
the Sponsor in connection with the continued development of the study drug, and thus may be 
disclosed as required to other clinical Investigators or regulatory agencies. To permit information 
derived from the clinical studies to be used, the Investigator is obliged to provide the Sponsor with 
all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated under the 
responsibility of the Sponsor and will contain EDC system data from all clinical sites that 
participated in the study. Recruitment performance or specific expertise related to the nature and 
the key assessment parameters of the study will be used to determine a coordinating Investigator. 
Clinical narratives may be written for the following events (for example): 
− All deaths (irrespective of drug relationship) 
− All other SAEs during treatment with the study drugs 
− All discontinuations of the study drugs due to AEs (irrespective of drug relationship) 
− Any events of special interest explicitly requested by the regulatory agencies 
− At the discretion of the team and after statistical analysis of the data, certain 
discontinuations not related to AEs or treatment failure, i.e., related to lost to follow-up or 
withdrawal of consent (irrespective of treatment group). 
The Sponsor and Medical Monitor will sign off the final version of the Clinical Study Report. A 
summary of this final version will be provided to the Investigators, the applicable regulatory 
authorities, and the IECs/IRBs, if required by the applicable regulatory requirements, within 1 year 
after the end of the study (LPLV). 
The Sponsor shall have the right to publish study data and information without approval from the 
Investigator. If an Investigator wishes to publish information from the study, the Investigator must 
first request to do so in writing to the Sponsor at least 60 days before submission or presentation 
of the study data. A copy of the manuscript or presentation must also be provided to the Sponsor 
for review at least 60 days before submission for publication or presentation. Expedited reviews 
will be arranged for abstracts, poster presentations, or other materials to the best of the Sponsor’s 
ability and only if Sponsor agrees to allow Investigator to submit such materials to an outside 
party. The Investigator will withhold such publication for up to an additional 60 days or until the 
Sponsor provides its express written consent for Investigator to move forward with publication or 
presentation of any study data. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the Sponsor will review these issues with the Investigator. The Sponsor 
will not mandate modifications to scientific content but in no case, will Investigator have the right 
to publish, present or share with any outside party study data and/or information without the 
express written consent of the Sponsor. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the Uniform Requirements 
for Manuscripts Submitted to Biomedical Journals, which state that the named authors must have 

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made a significant contribution to the design of the study or analysis and interpretation of the data, 
provided critical review of the paper, and given final approval of the final version. 
11.12. 
Results 
The Sponsor will register the existence of a clinical study and disclose its results as required by 
law. 
11.13. 
Investigator Indemnity  
The Sponsor holds and will maintain an adequate insurance policy covering damages arising out 
of Sponsor-sponsored clinical research studies. 
The Sponsor will indemnify the Investigator and hold him/her harmless for claims related to 
damages arising from the investigation, provided that the study drugs were administered under the 
Sponsor’s or deputy’s supervision and in strict accordance with accepted medical practice and the 
study protocol. 
The Investigator must notify the Sponsor immediately upon notice of any claims or lawsuits. 
11.14. 
Confidentiality 
Subject confidentiality is strictly held by the participating Investigators, their staff, and the 
Sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor 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. 
The Investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. Throughout this study, all data will be linked to the eCRF 
via a unique identification number. The data will be blinded correspondingly in all data analyses. 
The Investigator should keep a subject enrollment log showing codes, names and addresses. The 
Investigator should maintain documents that are not for submission to the Sponsor (such as written 
consent forms) in strict confidence.  
However, in compliance with the ICH Guidelines and in fulfillment of its obligations to FluGen 
to verify compliance with this protocol, FluGen Inc. or its designee requires that the Investigator 
permit FluGen designated monitors, representatives from any Regulatory Authority, FluGen 
designated auditors, or the appropriate Independent Ethics Committee, to review the subject’s 
primary medical records (source data or documents) including, but not limited to, laboratory test 
result reports, admission and discharge summaries, and SAEs occurring during the study. Should 
access to such medical records require a waiver or authorization separate from the statement of 
informed consent, the Investigator will obtain such permission in writing from the subject before 
the subject is entered into the study. 

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12. 
REFERENCES 
Ambrose CS, Wua X, Jones T, Mallory RM. The role of nasal IgA in children vaccinated with 
live attenuated influenza vaccine. Vaccine 2012; 30:6794–801. 
CDC. Prevention and control of seasonal influenza with vaccines. Recommendations of the 
Advisory Committee on Immunization Practices—United States, 2013–14. MMWR Recomm 
Rep. 2013;62 (No. RR-7):1–43. 
CDC. Prevention and control of influenza with vaccines: Recommendations of the Advisory 
Committee on Immunization Practices ‒ United States, 2015–16 Influenza Season. MMWR. 
2015;64; 818-25. 
Clements ML, Betts RF, Tierney EL, Murphy BR. Serum and nasal wash antibodies associated 
with resistance to experimental challenge with influenza A wildtype virus. J Clin Microbiol. 
1986;24:157–60. 
Eick AA, Wang Z, Hughes H, et al. Comparison of the trivalent live attenuated vs. inactivated 
influenza vaccines among U.S. military service members. Vaccine. 2009;27:3568-75. 
FluGen, Inc. M2SR Vaccine Investigator’s Brochure, edition 4.0, 10 April2019. 
Hatta Y, Boltz D, Sarawar S, et al. M2SR, a novel live influenza vaccine, protects mice and 
ferrets against highly pathogenic avian influenza. Vaccine. 2017;35:4177–83. 
He XS, Holmes TH, Zhang C, et al. Cellular immune responses in children and adults receiving 
inactivated or live attenuated influenza vaccines. J Virol. 2006;80:11756-66. 
Hoft DF, Lottenbach KR, Blazevic A, et al. Comparisons of the Humoral and Cellular Immune 
Responses Induced by Live Attenuated Influenza Vaccine (LAIV) and Inactivated Influenza 
Vaccine (IIV) in Adults. Clin Vaccine Immunol. 2017;24: e00414-16. 
Jin H and Subbarao K. Live attenuated influenza vaccine. In: Oldstone MBA, Compans RW, 
eds. Influenza pathogenesis and control, Vol II. Cham, Switzerland: Springer International 
Publishing. 2015:181–204. 
Lanthier PA, Huston GE, Moquin A, et al. Live attenuated influenza vaccine (LAIV) impacts 
innate and adaptive immune responses. Vaccine. 2011;29:7849–56. 
Monto AS, Ohmit SE, Petrie JG, et al. Comparative Efficacy of Inactivated and Live Attenuated 
Influenza Vaccines. N Eng J Med. 2009; 361:1260-7. 
Ohmit SE, Victor JC, Rotthoff JR, et al. Prevention of antigenically drifted influenza by 
inactivated and live attenuated vaccines. N Engl J Med. 2006;355:2513-22. 
Osterholm MT, Kelley NS, Sommer A, Belongia EA. Eﬃcacy and eﬀectiveness of inﬂuenza 
vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12: 36–44. 
Paules CI, Sullivan SG, Subbarao K, Fauci AS. Chasing Seasonal Influenza — The Need for a 
Universal Influenza Vaccine. N Engl J Med. 2018;378:7-9. 
Sarawar S, Hatta Y, Watanabe S, et al; M2SR, a novel live single replication influenza virus 
vaccine, provides effective heterosubtypic protection in mice. Vaccine. 2016;34:5090–8. 

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Tamura S, Tanimoto T, Kurata T. Mechanisms of broad cross-protection provided by influenza 
virus infection and their application to vaccines. Jpn J Infect Dis. 2005;58:195–207. 
Treanor JJ, Talbot HK, Ohmit SE, et al. Effectiveness of Seasonal Inﬂuenza Vaccines in the 
United States During a Season with Circulation of All Three Vaccine Strains. Clin Infect Dis. 
2012;55:951–9. 
Wang Z, Tobler S, Roayael J, et al. Live attenuated or inactivated influenza vaccines and 
medical encounters for respiratory illnesses among US military personnel. JAMA. 2009; 
301:945-53. 
Wilkinson TM, Li CKF, Chui CSC, et al. Preexisting influenza-specific CD4+ T cells correlate 
with disease protection against influenza challenge in humans. Nat Med. 2012;18:274-80. 
Zhu W, Higgs BW, Morehouse C, et al. A whole genome transcriptional analysis of the early 
immune response induced by live attenuated and inactivated influenza vaccines in young 
children. Vaccine. 2010;28:2865–76. 

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APPENDICES 
 

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APPENDIX 1: VITAL SIGN AND SYSTEMIC TOXICITY ASSESSMENTS 
 
Please see next page. 

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97 
Vital signs 
Please score items based on the following guidance (from FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials): 
Vital Signs *  
Mild (Grade 1)  
Moderate (Grade 2)  Severe (Grade 3)  
Potentially Life Threatening 
(Grade 4)  
Fever (°C) **  
          (°F) **  
38.0 – 38.4  
100.4 – 101.1  
38.5 – 38.9  
101.2 – 102.0  
39.0 – 40  
102.1 – 104  
> 40  
> 104  
Tachycardia - beats per minute  
101 – 115  
116 – 130  
> 130  
ER visit or hospitalization for 
arrhythmia  
Bradycardia - beats per minute***  
50 – 54  
45 – 49  
< 45  
ER visit or hospitalization for 
arrhythmia  
Hypertension (systolic) - mm Hg  
141 – 150  
151 – 155  
> 155  
ER visit or hospitalization for 
malignant hypertension  
Hypertension (diastolic) - mm Hg  
91 – 95  
96 – 100  
> 100  
ER visit or hospitalization for 
malignant hypertension  
Hypotension (systolic) – mm Hg  
85 – 89  
80 – 84  
< 80  
ER visit or hospitalization for 
hypotensive shock  
Respiratory Rate – breaths per minute  
17 – 20  
21 – 25  
> 25  
Intubation  
* Subject should be at rest for all vital sign measurements.  
** Oral temperature; no recent hot or cold beverages or smoking.  
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when characterizing bradycardia among some healthy subject 
populations, for example, conditioned athletes. 
 

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98 
 
 
Systemic Symptoms 
Please score items based on the following guidance (from FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials): 
 
Systemic (General)  
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Potentially Life 
Threatening (Grade 4)  
Nausea/vomiting  
No interference with 
activity or 
1-2 episodes/24 hours  
Some interference with 
activity or 
> 2 episodes/24 hours  
Prevents daily activity, 
requires outpatient IV 
hydration  
ER visit or hospitalization 
for hypotensive shock  
Diarrhea  
2–3 loose stools or 
< 400 g/24 hours 
4–5 stools or 
400-800 g/24 hours  
6 or more watery stools 
or > 800g/24 hours or 
requires outpatient IV 
hydration  
ER visit or hospitalization  
Headache  
No interference with 
activity  
Repeated use of non- 
narcotic pain reliever 
> 24 hours or some 
interference with activity  
Significant; any use of 
narcotic pain reliever or 
prevents daily activity  
ER visit or hospitalization  
Fatigue  
No interference with 
activity  
Some interference with 
activity  
Significant; prevents 
daily activity  
ER visit or hospitalization  
Myalgia  
No interference with 
activity  
Some interference with 
activity  
Significant; prevents 
daily activity  
ER visit or hospitalization  
Illness or clinical adverse 
event (as defined 
according to applicable 
regulations)  
No interference with 
activity  
Some interference with 
activity not requiring 
medical intervention  
Prevents daily activity 
and requires medical 
intervention  
ER visit or hospitalization  
 
 
 

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APPENDIX 2: LABORATORY ASSESSMENTS 
• Urine drug screena 
 
• Serologya: 
HIV, HCV, HbsAg 
• Urinalysis: 
Dipstick: specific gravity, pH, glucose, protein, blood, ketones, 
bilirubin, urobilinogen, nitrite, leukocyte esterase 
In case of positive dipstick results, the sediment will be examined 
microscopically for red blood cells, white blood cells, and 
epithelial cells. Crystals, casts, and bacteria will only be reported if 
they are present. 
• Hematology: 
Hemoglobin, white blood cells with differential (including 
neutrophils, lymphocytes, and eosinophils), platelets 
• Biochemistry: 
Albumin, alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, bicarbonate (or carbon dioxide), 
calcium, chloride, potassium, sodium, lipid panela (total 
cholesterol, high-density lipoprotein cholesterol, low-density 
lipoprotein cholesterol, and triglycerides), total bilirubin, direct 
bilirubinb, total protein, creatinine, C-reactive protein, creatine 
kinase, blood urea nitrogen (or urea) 
• At screening, a urine pregnancy test will be performed for women of childbearing potential 
• At the indicated time points, a urine pregnancy test will be performed for women of 
childbearing potential 
a. 
At screening only. 
b. To be assessed if total bilirubin is elevated above normal range. 

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100 
 
Grading Scale for Laboratory AEs  
Please score items based on the following guidance (from FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials): 
Serum*  
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe (Grade 3)  
Potentially Life 
Threatening 
(Grade 4)**  
Sodium – Hyponatremia mEq/L 
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia mEq/L 
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hyperkalemia mEq/L 
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Potassium – Hypokalemia mEq/L 
3.5 – 3.6  
3.3 – 3.4 
3.1 – 3.2  
< 3.1 
Glucose – Hypoglycemia mg/dL  
65 – 69  
55 – 64  
45 – 54  
< 45  
Glucose – Hyperglycemia  
Fasting – mg/dL  
Random – mg/dL  
 
100 – 110  
110 – 125  
 
111 – 125  
126 – 200  
 
>125  
>200  
 
Insulin requirements or 
hyperosmolar coma  
Blood Urea Nitrogen  
BUN mg/dL 
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires dialysis  
Calcium – hypocalcemia mg/dL 
8.0 – 8.4  
7.5 – 7.9  
7.0 – 7.4  
 < 7.0  
Calcium – hypercalcemia mg/dL  
10.5 – 11.0  
11.1 – 11.5  
11.6 – 12.0 
> 12.0  
Magnesium – hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL  
1.25 – 1.5 x ULN***  
1.6 – 3.0 x ULN  
3.1 –10 x ULN  
> 10 x ULN  
Albumin – Hypoalbuminemia g/dL  2.8 – 3.4  
2.5 – 2.7  
< 2.5  
--  

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101 
 
Total Protein – Hypoproteinemia 
g/dL  
5.5 – 6.0  
5.0 – 5.4  
< 5.0  
--  
Alkaline phosphate – increase by 
factor  
1.1 – 2.0 x ULN  
2.1 – 3.0 x ULN  
3.1 – 10 x ULN  
> 10 x ULN  
Liver Function Tests –ALT, AST 
increase by factor  
1.1 – 2.5 x ULN  
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
Bilirubin – when accompanied by 
any increase in liver function test 
increase by factor  
1.1 – 1.25 x ULN  
1.26 – 1.5 x ULN  
1.51 – 1.75 x ULN  > 1.75 x ULN  
Bilirubin – when liver function test 
is normal; increase by factor  
1.1 – 1.5 x ULN  
1.6 – 2.0 x ULN  
2.0 – 3.0 x ULN  
> 3.0 x ULN  
Cholesterol  
201 – 210  
211 – 225  
> 226  
---  
Pancreatic enzymes – amylase, 
lipase  
1.1 – 1.5 x ULN  
1.6 – 2.0 x ULN  
2.1 – 5.0 x ULN  
> 5.0 x ULN  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges 
should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory abnormalities as Potentially Life 
Threatening (Grade 4). For example. a low sodium value that falls within a Grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia 
event if the subject had a new seizure associated with the low sodium value. 
***”ULN” is the upper limit of the normal range. 

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Hematology*  
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Potentially Life Threatening 
(Grade 4)  
Hemoglobin (Female) - gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female)  
change from baseline value - 
gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) - gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male)  
change from baseline value – 
gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease - cell/mm3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  
Lymphocytes Decrease - 
cell/mm3 
750 – 1,000  
500 – 749  
250 – 499  
< 250  
Neutrophils Decrease - cell/mm3 
1,500 – 2,000  
1,000 – 1,499  
500 – 999  
< 500  
Eosinophils - cell/mm3 
650 – 1500  
1501 - 5000  
> 5000  
Hypereosinophilic  
Platelets Decreased - cell/mm3 
125,000 – 140,000  
100,000 – 124,000  
25,000 – 99,000  
< 25,000  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges 
should be provided to demonstrate that they are appropriate. 
 
 
 

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103 
 
Grading Scale for Urinalysis AEs 
Please score items based on the following guidance (from FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials): 
Urine * 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Protein  
Trace  
1+  
2+  
Hospitalization or dialysis  
Glucose  
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood (microscopic) – red 
blood cells per high power 
field (rbc/hpf) 
1 - 10  
11 – 50  
> 50 and/or gross blood 
Hospitalization or packed 
red blood cells (PRBC) 
transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges 
should be provided to demonstrate that they are appropriate.

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APPENDIX 3: REACTOGENICITY ASSESSMENTS 
 
Please see next page.

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105 
Local Reactions (intranasal administration) 
Please score reactions as follows: 
Local 
reaction  
Mild  
(Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life 
Threatening  
(Grade 4)  
Nasal pain / 
irritation  
Does not interfere  
with activity 
  
Repeated use of non-
narcotic pain reliever 
> 24 hours or interferes 
with activity  
Any use of narcotic pain 
reliever or prevents daily 
activity  
Emergency room (ER) visit 
or hospitalization  
 
Nasal 
congestion/ 
rhinorrhea  
Does not interfere  
with activity 
  
Use of saline or other 
decongestant > 24 hours or 
interferes with activity  
Repeated use of 
decongestants or 
significantly interferes with 
daily activity  
Emergency room (ER) visit 
or hospitalization  
 
Bleeding/ 
Epistaxis  
Does not interfere  
with activity 
  
Requires intervention (e.g., 
squeezing of nose to 
reduce bleeding) 
> 24 hours or interferes 
with activity  
Required repeated or near 
continuous intervention or 
significantly interferes with 
daily activity  
Emergency room (ER) visit 
or hospitalization  
 
 

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APPENDIX 4: INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
Signature of Investigator 
 
 
 
                              Site Number: 
 
 
Study Title: Phase 1b clinical study to investigate the safety and immunogenicity of the 
Bris10 (A/Brisbane/10/2007) M2SR and Sing2016 (A/Singapore/INFIMH-16-0019/2016) 
M2SR H3N2 monovalent influenza vaccines 
 
 
Name:  
Affiliation:  
Address:  
 
 
 
I have read this Clinical Study Protocol and agree that it contains all information necessary 
for proper conduct of the study. I will carry out the study as outlined herein and will 
complete the study within the designated time and in accordance with the standards of Good 
Clinical Practice (as defined by the International Conference on Harmonisation) after 
approval by an Institutional Review Board. 
 
 
 
 
Signature:  
Date: 
 
 

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APPENDIX 5: SYMPTOM MEMORY AID FOR VACCINATION PERIOD 
Please see next page for sample document showing Day 1 – Day 7. A similar document will be 
provided for Day 29 – Day 35.

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Symptom Memory Aid 
Day 1 – Day 7  
FIRST DOSE 
 
Phase 1b clinical study to investigate the safety and immunogenicity of the Bris10 
(A/Brisbane/10/2007) M2SR and Sing2016 (A/Singapore/INFIMH-16-0019/2016) M2SR 
H3N2 monovalent influenza vaccines 
 
Protocol Number: 
FLUGEN-H3N2-V003 
 
 
 
 
 
Subject Number:
  
 
 
 
 
 
 
 
 
 
- 
 
 
 
In the event of a medical emergency, call 911 then call the Study Doctor as soon as 
possible at the following telephone number [Site Emergency Number]. 
 
For medical problems which are not emergencies, call the Study Doctor at the following 
telephone number [Site Emergency Number]. 

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SYMPTOM MEMORY AID INSTRUCTIONS 
1. 
PLEASE BRING THIS MEMORY AID WITH YOU TO EVERY VISIT. 
2. 
This Memory Aid is used to help you remember any symptoms you might have after each of your 
vaccinations. The first entry to the memory aid will be done before your vaccine dose. The clinic 
staff will train you on how to use this document by having you complete the “Training Entry” 
column. The second entry will be on the evening of the vaccination and the remaining 6 entries 
will be made each evening in the week following vaccination. 
3. 
Starting on the day of your vaccine dose, complete the Memory Aid at about the same time each 
day. 
4. 
You have been given a thermometer to measure your oral temperature and the site staff will teach 
you how to use this thermometer.  Take your temperature at about the same time each day with 
the provided thermometer. Record your temperature daily, in degrees Celsius (°C) (Example: 38.2 
C), as shown on the thermometer.   
5. 
If you think you may have a fever at any time, take your temperature and record it as shown on 
the thermometer.  
6. 
Refer to the intensity levels from the guidelines on page 3 if you experience any symptoms.  
7. 
Enter a 0, 1, 2 or 3 intensity level for each symptom listed on each day of your Symptom Memory 
Aid.  
8. 
Record any other symptoms that you may have experienced under each day that you experienced 
the symptom on page 5. Then record the intensity level according to the table on page 5. 
9. 
The completed Memory Aid will be collected by the study staff during your Day 8 visit, however 
if you have any visits prior to Day 8, please bring this with you to the site.  
 
PLEASE REMEMBER TO BRING THIS MEMORY AID WITH YOU TO YOUR NEXT 
VISIT. 
 
HOW TO TAKE YOUR TEMPERATURE 
• Measure your temperature at approximately the same time each day.  If 
multiple temperatures are measured in one day, record the highest 
temperature.  Do not eat, drink, or smoke for 10 minutes prior to taking 
your temperature.  
• Push the power button on the thermometer and place it under your 
tongue toward the back of your mouth.  The tip of the thermometer 
should rest in the “correct area” as shown in the diagram to the right. 
• Keep your mouth closed and the thermometer still until the thermometer 
beeps rapidly, indicating completion.  If you do not hear the beep, leave 
the thermometer in your mouth for 2 minutes. 
• Record the temperature displayed on the screen.  Press the button to turn 
the thermometer off. 
 
 √= Correct Area 
X=Incorrect areas 

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For all symptoms, record the intensity level (0, 1, 2, or 3) using the guidelines below. 
SYMPTOM 
INTENSITY 
LEVEL 
DESCRIPTION 
Feverish 
Tiredness 
Body/Muscle aches 
Joint Pain 
Body Rash 
0 
No symptoms 
1 
Mild - No interference with activity 
2 
Moderate - Some interference with activity 
3 
Severe - Significant interference, prevents daily activity 
Stuffy Nose/Nasal 
Congestion 
0 
No symptoms 
1 
Mild - Noticeable but does not interfere with daily activity 
2 
Moderate - Moderate discomfort/interferes with breathing from nose  
3 
Severe - Not being able to breath from nose, or prevents daily activity or seeks medical 
encounter 
Runny Nose 
0 
No symptoms 
1 
Mild - Noticeable but does not interfere with daily activity 
2 
Moderate - Moderate discomfort/interferes with daily activity 
3 
Severe - Significant discomfort/prevents daily activity or seeks medical encounter 
Nasal 
Pain/Irritation/Dryness 
0 
No symptoms 
1 
Mild - Noticeable but does not interfere with daily activity 
2 
Moderate - Moderate discomfort/interferes with daily activity 
3 
Severe - Significant discomfort/prevents daily activity or seeks medical encounter 
Nasal Bleeding 
0 
No symptoms 
1 
Mild - Total duration of all episodes in a 24-hour period <30 minutes 
2 
Moderate - Total duration of all episodes in a 24-hour period > 30 minutes 
3 
Severe - Any bleeding that required visit for medical encounter 
Sore/Scratchy/Itchy or 
Painful Throat  
 
0 
No symptoms 
1 
Mild - Noticeable but does not interfere with eating and/or drinking 
2 
Moderate - Moderate discomfort. Interferes with eating and/or drinking  
3 
Severe - Significant discomfort/prevents eating and/or drinking or seeks medical 
encounter 
Headache 
0 
No symptoms 
1 
Mild - No interference with daily activity 
2 
Moderate - Some interference with daily activity 
3 
Severe - Significant interference, prevents daily activity and/or seeks medical encounter 
Cough 
0 
No symptoms 
1 
Mild - Noticeable but does not interfere with daily activity or sleeping 
2 
Moderate - Moderate discomfort/interferes with daily activity or sleeping 
3 
Severe - Significant discomfort/prevents daily activity or seeks medical encounter 
Nausea 
0 
No symptoms 
1 
Mild - Transient (<24 hours) or intermittent AND No or minimal interference with oral 
intake 
2 
Moderate - Persistent nausea resulting in decreased oral intake for 24 to 48 hours 
3 
Severe - Persistent nausea resulting in minimal oral intake for > 48 hours OR 
Rehydration indicated (e.g., IV fluids) 
Vomiting 
0 
No symptoms 
1 
Mild - Transient or intermittent AND no interference with daily activity; minimal 
interference with oral intake 
2 
Moderate - Frequent episodes with no dehydration and interferes with some daily 
activity 

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3 
Severe - Persistent vomiting, resulting in orthostatic hypotension (low blood pressure 
that happens when you stand up from sitting or lying down) or requiring rapid 
rehydration (e.g., IV fluids) or prevents normal daily activity 
 

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Symptom Memory Aid                                         Protocol:  FluGen-H3N2-V003                                 Subject #: __ __ __-__ __ __ 
Date 
(dd/mmm/2019) 
Training Entry 
(Pre-Dose) 
___/_____/2019 
Day 1  
(Dosing Day) 
___/_____/2019 
Day 2 
 
___/_____/2019 
Day 3 
 
___/_____/2019 
Day 4 
 
___/_____/2019 
Day 5 
 
___/_____/2019 
Day 6 
 
___/_____/2019 
Day 7 
 
___/_____/2019 
Record Oral 
Temperature (C) 
 ___ ___.___C 
 ___ ___.___C 
 ___ ___.___C 
 ___ ___.___C 
 ___ ___.___C 
 ___ ___.___C 
 ___ ___.___C 
 ___ ___.___C 
Feverish  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiredness 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body/Muscle Aches 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Joint Pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Rash 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stuffy Nose/Nasal 
Congestion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Runny Nose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal Irritation 
(Pain or Dryness) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal Bleeding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sore/Scratchy/Itchy 
Painful Throat 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Headache 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cough 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Important: If you experience any events of concern, contact the study staff immediately. 
Other Symptoms 
Other symptoms to report following vaccination:  
 No 
 Yes (Complete chart below) 
 
INTENSITY 
LEVEL 
DESCRIPTION 
0 
No symptoms 
1 
Mild - events require minimal or no treatment and do not interfere with daily activities 
2 
Moderate - events may cause some interference with daily activities 
3 
Severe - events may require medication or other treatment.  Severe events usually prevent daily activities. 
 
 
Study Day 
 
Date 
(dd/mmm/2019) 
Day 1  
(Dosing Day) 
 
___/_____/2019 
Day 2 
 
 
___/_____/2019 
Day 3 
 
 
___/_____/2019 
Day 4 
 
 
___/_____/2019 
Day 5 
 
 
___/_____/2019 
Day 6 
 
 
___/_____/2019 
Day 7 
 
 
___/_____/2019 
Other Symptoms 
(Describe) 
 
 
 
 
 
 
 
 
 
 
 
Include Intensity 
Level (0-3)