A Phase II, Double-Blind, Multicenter, Randomized, Placebo-Controlled Trial to Assess the Safety, Reactogenicity and Immunogenicity of Two Doses of Multimeric-001 (M-001) Followed by Seasonal Quadrivalent Influenza Vaccine
Phase: PHASE2
Conditions: Influenza, Influenza Immunisation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 14-0112 
Version 6.0 
Multimeric-001 and IIV4 
06 Dec 2018 
1 
A Phase II, Double-Blind, Multicenter, Randomized, Placebo-
Controlled Trial to Assess the Safety, Reactogenicity and 
Immunogenicity of Two Doses of Multimeric-001 (M-001) Followed 
by Seasonal Quadrivalent Influenza Vaccine 
 
 
DMID Protocol Number: 14-0112 
 
DMID Funding Mechanism: Vaccine Treatment and Evaluation Units 
 
Pharmaceutical Support Provided by:  
BiondVax 
 
IND Sponsor: Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National Institutes of Health 
Principal Investigator: Robert L. Atmar, M.D. 
DMID Clinical Project Manager: Tena Knudsen, B.S.N. 
DMID Medical Monitor: Mohamed Elsafy, M.D. 
DMID Medical Officer: Trinka Coster, M.D. 
DMID Scientific Lead: Chris Roberts, Ph.D. 
Version Number: 6.0 
06 December 2018 
 

DMID Protocol 14-0112 
Version 6.0 
Multimeric-001 and IIV4 
06 Dec 2018 
2 
STATEMENT OF COMPLIANCE 
 
The study will be carried out in accordance with Good Clinical Practices (GCP) as required by 
the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application), 21 CFR 812 (Investigational 
Device Exemptions) 
• 
International Council for Harmonisation: Good Clinical Practice (ICH E6); 62 
Federal Register 25691 (1997); and future revisions 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, Report of the National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research 
Involving Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of 
Award, as applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 
 
 

DMID Protocol 14-0112 
Version 6.0 
Multimeric-001 and IIV4 
06 Dec 2018 
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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
 
Principal Investigator  
Name: 
Title: 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
LIST OF ABBREVIATIONS ........................................................................................................11 
PROTOCOL SUMMARY .............................................................................................................13 
1. 
KEY ROLES ..............................................................................................................20 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................22 
2.1. 
Background Information .............................................................................................22 
2.1.1. 
Seasonal and pandemic influenza ...............................................................................22 
2.1.2. 
Multimeric-001 (M-001) ............................................................................................22 
2.1.3. 
Public Readiness and Emergency Preparedness Act ..................................................24 
2.2. 
Rationale .....................................................................................................................25 
2.3. 
Potential Risks and Benefits .......................................................................................25 
2.3.1. 
Potential Risks ............................................................................................................25 
2.3.2. 
Known Potential Benefits ...........................................................................................27 
3. 
OBJECTIVES .............................................................................................................29 
3.1. 
Study Objectives .........................................................................................................29 
3.1.1. 
Primary Objectives .....................................................................................................29 
3.1.2. 
Secondary Objectives .................................................................................................29 
3.1.3. 
Exploratory Objectives ...............................................................................................29 
3.2. 
Study Outcome Measures ...........................................................................................30 
3.2.1. 
Primary Outcome Measures .......................................................................................30 
3.2.2. 
Secondary Outcome Measures ...................................................................................30 
3.2.3. 
Exploratory Outcome Measures .................................................................................31 
4. 
STUDY DESIGN .......................................................................................................32 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................33 
5.1. 
Subject Inclusion Criteria ...........................................................................................33 
5.2. 
Subject Exclusion Criteria ..........................................................................................34 
5.3. 
Eligibility Criteria for Doses 2- 3 ...............................................................................36 

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5.4. 
Treatment Assignment Procedures .............................................................................36 
5.4.1. 
Randomization Procedures .........................................................................................36 
5.4.2. 
Masking Procedures ....................................................................................................37 
5.4.3. 
Reasons for Withdrawal .............................................................................................37 
5.4.4. 
Handling of Withdrawals ............................................................................................39 
5.4.5. 
Termination of Study ..................................................................................................39 
6. 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT ...............................40 
6.1. 
Study Product Description ..........................................................................................40 
6.1.1. 
Acquisition ..................................................................................................................40 
6.1.2. 
Formulation, Storage, Packaging, and Labeling .........................................................40 
6.1.3. 
Product Storage and Stability Procedures ...................................................................41 
6.2. 
Dosage, Preparation and Administration of Study Intervention/ 
Investigational Product ...............................................................................................42 
6.3. 
Modification of Study Intervention/Investigational Product for a Participant ...........43 
6.4. 
Accountability Procedures for the Study Intervention/ Investigational 
Product(s) ....................................................................................................................43 
6.5. 
Assessment of Subject Compliance with Study Intervention/ Investigational 
Product ........................................................................................................................44 
6.6. 
Concomitant Medications/Treatments ........................................................................44 
7. 
STUDY SCHEDULE .................................................................................................46 
7.1. 
Enrollment/Baseline (Visit 01, Day 1, Dose 1, Clinic Visit) ......................................46 
7.2. 
Follow-up ....................................................................................................................47 
7.2.1. 
Visit 2, Day 9, Clinic Visit (8 days [+2 days] post first study vaccination) ...............47 
7.2.2. 
Visit 3, Day 15, Clinic Visit (14 days [+2 days] post first study vaccination) ...........48 
7.2.3. 
Visit 4, Day 22, Dose 2, Clinic Visit (21 days [+2 days] post first study 
vaccination) .................................................................................................................48 
7.2.4. 
Visit 5, Day 30, Clinic Visit (8 days [+2 days] post second study 
vaccination) .................................................................................................................49 
7.2.5. 
Visit 6, Day 36, Clinic Visit (14 days [+2 days] post second study 
vaccination) .................................................................................................................50 
7.2.6. 
Visit 7, Day 43, Clinic Visit (21 days [+7 days] post second study 
vaccination) .................................................................................................................50 
7.2.7. 
Visit 8, Day 78, Clinic Visit (56 days [+7 days] post second study 
vaccination) .................................................................................................................50 

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7.2.8. 
Visit 9, Day 172, Dose 3 (150 days [+30 days] post second study 
vaccination) .................................................................................................................51 
7.2.9. 
Visit 10, Day 186, Clinic Visit (14 days [+3 days] post third study 
vaccination) .................................................................................................................52 
7.3. 
Study Visit 11, Day 200 Clinic Visit (28 days +7 post third study 
vaccination) .................................................................................................................52 
7.3.1. 
Visit 11 activities ........................................................................................................52 
7.3.2. 
Study Visit 12, Day 200 (+14 days), Safety Follow-up Phone Call (to be 
Performed Only If Visit 11 Occurs Before Study Day 200) ......................................53 
7.4. 
Early Termination Visit ..............................................................................................53 
7.5. 
Unscheduled Visit .......................................................................................................54 
8. 
STUDY PROCEDURES/EVALUATIONS ...............................................................55 
8.1. 
Clinical Evaluations ....................................................................................................55 
8.2. 
Laboratory Evaluations ...............................................................................................56 
8.2.1. 
Clinical Laboratory Evaluations .................................................................................56 
8.2.2. 
Special Assays or Procedures .....................................................................................56 
8.2.3. 
Specimen Preparation, Handling, and Shipping .........................................................57 
8.2.3.1. 
Instructions for Specimen Preparation, Handling, and Storage ..................................57 
8.2.3.2. 
Specimen Shipment ....................................................................................................57 
9. 
ASSESSMENT OF SAFETY .....................................................................................58 
9.1. 
Specification of Safety Parameters .............................................................................58 
9.2. 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ...................................................................................................................58 
9.2.1. 
Adverse Events ...........................................................................................................58 
9.2.2. 
Reactogenicity ............................................................................................................60 
9.2.3. 
Additional Adverse Event Severity Grading ..............................................................61 
9.2.4. 
Serious Adverse Events ..............................................................................................62 
9.2.5. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings ...................................................................................63 
9.3. 
Reporting Procedures ..................................................................................................64 
9.3.1. 
Serious Adverse Events ..............................................................................................64 
9.3.2. 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND ............65 
9.3.3. 
Reporting of Pregnancy ..............................................................................................65 
9.4. 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................65 

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9.5. 
Halting Rules ..............................................................................................................66 
9.6. 
Safety Oversight (ISM plus DSMB)...........................................................................67 
9.6.1. 
Independent Safety Monitor (ISM) ............................................................................67 
9.6.2. 
Data and Safety Monitoring Board (DSMB) ..............................................................67 
10. 
CLINICAL MONITORING .......................................................................................69 
10.1. 
Site Monitoring Plan ...................................................................................................69 
11. 
STATISTICAL CONSIDERATIONS .......................................................................70 
11.1. 
Study Hypotheses .......................................................................................................70 
11.2. 
Study Outcome Measures ...........................................................................................70 
11.3. 
Sample Size Considerations .......................................................................................70 
11.3.1. 
Study Design ...............................................................................................................70 
11.3.2. 
Study Population .........................................................................................................71 
11.3.3. 
Subject Enrollment and Follow-up .............................................................................71 
11.3.4. 
Sample Size ................................................................................................................71 
11.4. 
Planned Interim Analyses ...........................................................................................72 
11.4.1. 
Interim Safety Review ................................................................................................73 
11.4.2. 
Interim Immunogenicity Review ................................................................................73 
11.5. 
Final Analysis Plan .....................................................................................................73 
11.5.1. 
Analysis Populations ..................................................................................................73 
11.5.2. 
Safety Data ..................................................................................................................74 
11.5.3. 
Humoral Immunogenicity Data ..................................................................................75 
11.5.4. 
Cell Mediated Immunity Data ....................................................................................75 
11.5.5. 
Missing Values and Outliers .......................................................................................75 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................77 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................79 
14.1. 
Ethical Standard ..........................................................................................................79 
14.2. 
Institutional Review Board .........................................................................................79 
14.3. 
Informed Consent Process ..........................................................................................79 
14.4. 
Exclusion of Women, Minorities, and Children (Special Populations) ......................80 
14.5. 
Subject Confidentiality ...............................................................................................81 
14.6. 
Study Discontinuation ................................................................................................82 

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14.7. 
Costs, Subject Compensation, and Research Related Injuries ...................................82 
14.8. 
Future Use of Stored Specimens .................................................................................83 
14.9. 
Disclosure of Individual Research Information ..........................................................83 
15. 
DATA HANDLING AND RECORD KEEPING ......................................................84 
15.1. 
Data Management Responsibilities ............................................................................84 
15.2. 
Data Capture Methods ................................................................................................84 
15.3. 
Types of Data ..............................................................................................................85 
15.4. 
Timing/Reports ...........................................................................................................85 
15.5. 
Study Records Retention ............................................................................................85 
15.6. 
Protocol Deviations ....................................................................................................86 
16. 
PUBLICATION POLICY ..........................................................................................87 
17. 
LITERATURE REFERENCES..................................................................................88 
SUPPLEMENTS/APPENDICES ..................................................................................................90 
APPENDIX A: SCHEDULE OF EVENTS ..................................................................................91 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF TABLES 
Table 1: 
Treatment Arms ..........................................................................................................18 
Table 2: 
Injection Site Reactogenicity Grading ........................................................................60 
Table 3: 
Injection Site Reactogenicity Measurements ..............................................................60 
Table 4: 
Subjective Systemic Reactogenicity Grading .............................................................61 
Table 5: 
Quantitative Systemic Reactogenicity Grading ..........................................................61 
Table 6: 
Pulse and Blood Pressure Grading .............................................................................61 
Table 7: 
Clinical Safety Laboratory Adverse Event Grading (28) ...........................................62 
Table 8: 
Power (%) to Detect Safety Events ............................................................................71 
Table 9: 
Precision of Binomial Confidence Intervals: ..............................................................72 
Table 10: Power Analysis for Primary Immunogenicity Endpoint ............................................72 
Table 11: Protocol 14-0112, “A Phase II, Double Blind, Multicenter, Randomized, 
Placebo-controlled Trial to Assess the Safety, Reactogenicity and 
Immunogenicity of Two Doses of Multimeric-001 (M-001) Followed by 
Seasonal Quadrivalent Influenza Vaccine” ................................................................92 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
AESIs 
Adverse Events of Special Interest 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GBS 
Guillain-Barre Syndrome 
GCP 
Good Clinical Practice 
HAI/HI 
Hemagglutinin Inhibition 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IIV 
Inactivated influenza vaccine 
IIV3 
Trivalent inactivated influenza vaccine 
IIV4 
Quadrivalent inactivated influenza vaccine 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
M-001 
Multimeric-001 
MedDRA  
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 

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NCI 
National Cancer Institute, NIH, DHHS 
NDA 
New Drug Application 
NEJM 
New England Journal of Medicine 
Neut 
Neutralization (refers to Neutralizing antibodies) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, 
DHHS 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PBS 
Phosphate Buffered Saline 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PREP Act 
Public Readiness and Emergency Preparedness Act 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
sub-I 
Sub-Investigator 
US 
United States 
WHO 
World Health Organization 
 

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PROTOCOL SUMMARY 
 
Title: 
A Phase II, Double-Blind, Multicenter, Randomized, Placebo-
Controlled Trial to Assess the Safety, Reactogenicity and 
Immunogenicity of Two Doses of Multimeric-001 (M-001) 
Followed by Seasonal Quadrivalent Influenza Vaccine 
Phase: 
2 
Population: 
Up to 120 healthy males and non-pregnant females, aged 18 to 
49 years (inclusive) will be enrolled. 
Number of Sites: 
Three sites: Baylor College of Medicine, the University of Iowa, 
and Cincinnati Children’s Hospital Medical Center 
Study Duration: 
Approximately 24 months 
Subject Participation 
Duration: 
Approximately 7 months  
Description of Agent or 
Intervention: 
• M-001 manufactured by BiondVax  
• Licensed seasonal quadrivalent inactivated influenza vaccine 
(IIV4) 
• Normal saline placebo 
Objectives: 
 
Primary: 
Safety 
• To assess the safety as measured by vaccine related 
adverse events, reactogenicity, and laboratory adverse 
events of two doses of M-001 vaccine, each dose 
administered approximately 21 days apart 
Immunogenicity 
• To assess the T cell responses to M-001 component 
peptides following two doses of M-001 

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Secondary: 
Safety 
• To assess all serious adverse events (SAEs) following 
receipt of each dose of M-001 vaccine or placebo, each 
dose separated by approximately 21 days, through the 
end of the study  
• To assess all unsolicited non-serious adverse events 
(AEs) following receipt of each dose of M-001 or 
placebo, each dose separated by approximately 21 days, 
through 21 days after each dose of M-001 or placebo  
Immunogenicity 
• To assess the serum hemagglutination inhibition (HAI) 
and neutralizing (Neut) antibody responses to the 2018-
2019 IIV4 vaccine viruses 
Exploratory: 
• To assess the IgG responses to the M-001 vaccine after 
receipt of placebo or two doses of M-001 vaccine and 
following receipt of IIV4 
• To assess the T cell responses to M-001 component 
peptides following one dose of M-001 or placebo 
• To assess T cell responses to M-001 component peptides 
following receipt of licensed IIV4 
• To assess the T cell cross-reactive responses to current 
seasonal influenza virus antigens and pandemic 
influenza virus antigens following each vaccination (M-
001 and IIV4) 
• To assess the longevity of T cell responses to M-001 
peptides, seasonal influenza virus antigens and pandemic 
influenza virus antigens 

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Study Outcome Measures 
 
 
Primary: 
Safety 
• Occurrence of vaccine-related SAEs from the time of the 
first study vaccination (M-001 or placebo) through 
approximately 6 months after the second M-001 study 
vaccination 
• Occurrence of solicited injection site and systemic 
reactogenicity events on the day of each study 
vaccination through approximately 7 days after each M-
001 vaccination 
• Occurrence of clinical safety laboratory AEs from the 
time of each study vaccination of M-001 through 
approximately 7 days after each M-001 vaccination 
Immunogenicity 
• Geometric Mean Percentage of T cell subsets expressing 
perforin, CD107a, interferon gamma (IFN-γ), tumor 
necrosis factor-alpha (TNF-α), and interleukin 2 (IL2), 
alone or in combination, in CD4 and CD8 cells after 
stimulation with M-001 component peptides at baseline 
(Day 1) and 14 days after the second dose of M-001 
Secondary: 
Safety 
• Occurrence of all SAEs, from the time of receiving the 
first M-001 or placebo study vaccination through the end 
of the study 
• 
Occurrence of all unsolicited non-serious AEs from the 
time of first study vaccination through 21 days after each 
M-001 vaccination  

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Immunogenicity 
• For HAI and Neuts, the percentage of subjects achieving 
seroconversion (defined as either a pre-vaccination titer 
<10 and a post-vaccination titer ≥40 or a pre-vaccination 
titer ≥10 and a minimum four-fold rise in post-
vaccination antibody titer) to IIV4 vaccine viruses from 
Day 172 to Day 200 
• For HAI and Neuts, the percentage of subjects with an 
antibody titer of 40 or greater and geometric mean titers 
(GMTs) vs. IIV4 vaccine viruses on Days 1, 43, 172 and 
200 
Exploratory: 
• Percentage of subjects achieving seroconversion 
(defined as a minimum four-fold rise in post-vaccination 
ELISA antibody titer) and GMTs of ELISA antibody vs. 
M-001 from Day 1 to Days 22, 43, 78, 172 and 200  
• Percentage of T cell subsets expressing perforin, 
CD107a, IFN-γ, TNF-α, and IL2, alone or in 
combination,in CD4 and CD8 cells after stimulation 
with M-001 peptides at baseline (Day 1) and 
approximately 14 days after one dose of M-001, 21 and 
56 days following the second dose of M-001, and 
immediately prior to and 14 and 28 days after IIV4 
• Percentage of T cell subsets expressing perforin, 
CD107a, IFN-γ, TNF-α, and IL2, alone or in 
combination, in CD4 and CD8 cells after stimulation 
with other influenza A antigens (including seasonal and 
pandemic influenza antigens) at baseline (Day 1), 
approximately 14 days after each study vaccination, 21 
and 56 days following the second study vaccination and 
immediately prior to and approximately 14 and 28 days 
after IIV4 
• Percentage of influenza-specific T cell memory subsets 
expressing discrete memory markers (CCR7, CD45RO, 

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and CD57) at baseline (Day 1) and on study days 15, 36, 
43, 78, 172, 186 and 200 
• Percentage of influenza-specific CD4+ cell subsets 
expressing IL-4 or IL-17, T follicular helper cells 
(CD4+, CXCR5+, PD-1+, IL-21+), T follicular 
regulatory (Tfr) cells (CXCR5+, PD-1+, CD25+, 
CD1217+), and Tregs (CD25+, Foxp3+) at baseline 
(Day 1) and on study days 15, 36, 43, 78, 172, 186 and 
200 
Description of Study Design: This is a Phase II randomized, double-blind, placebo-controlled 
trial in 120 males and non-pregnant females, 18 to 49 years old, 
inclusive, who are in good health and meet all eligibility criteria.  
This clinical trial is designed to assess the safety, reactogenicity, 
and immunogenicity of two priming doses of M-001 followed by 
administration of IIV4.   
Subjects will be assigned randomly to 1 of 2 treatment arms (60 
subjects per treatment arm) to receive two doses of the M-001 
vaccine or placebo (saline) followed by a single dose of IIV4 
(2018-2019 formulation; see Table 1).  Group A will receive two 
doses of M-001, each containing 1 mg of M-001, on Days 1 and 
22, followed by a single dose of seasonal IIV4 on approximately 
Day 172 (window for this visit ranges from Day 142 to Day 
202).  Group B will receive saline placebo on Days 1 and 22, 
followed by a single dose of IIV4 on approximately Day 172. 
Reactogenicity will be measured by the occurrence of solicited 
injection site and systemic reactions from the time of each study 
vaccination with M-001 (or placebo) through 7 days after the 
vaccination (inclusive of vaccination day).  Unsolicited AEs will 
be collected from the time of each M-001 vaccination through 
approximately 21 days after each study vaccination.  SAEs will 
be collected from the time of the first study vaccination through 
approximately 6 months after the second M-001 (or placebo) 
study vaccination.  Clinical laboratory evaluations for safety will 
be performed on venous blood collected approximately 8 days 
after each M-001 (or placebo) vaccination (Days 9 and 30). 
Immunogenicity testing will include performing HAI and Neut 
antibody assays on serum obtained immediately at baseline (Day 
1) and on serum collected on Days 43, 172  and 200.  ELISA 
antibody responses to the M-001 vaccine will be assessed on 
serum collected at baseline (Day 1) and on Days 22, 43, 78, 172 
and 200.  Cell-mediated immune responses to influenza antigens, 

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including epitopes represented in the M-001 vaccine, and 
seasonal and candidate pandemic influenza viruses, will be 
assessed at baseline (Day 1), 14 days after each vaccination 
(Days 15, 36, and 186), approximately 21 days (Day 43) and 
approximately 56 days (Day 78) following receipt of the second 
M-001 (or placebo) dose, and immediately prior to and 
approximately 28 days after the IIV4 dose (Days 172 and 200).   
If visit 11 occurs before Study Day 200 (because Visit 9 
occurred prior to Day 172), then an additional study visit (Visit 
12, phone call) will occur on Day 200 to solicit SAE 
information. 
Estimated Time to Complete 
Enrollment: 
2 to 3 months 
 
Table 1: 
Treatment Arms 
Treatment Arm 
Dose 1 
Day 1 
Dose 2 
Day 22 
Dose 3 
Day 172 
A (n=60) 
1 mg M-001 
1 mg M-001 
IIV4 
B (n=60) 
Placebo 
Placebo 
IIV4 

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Schematic of Study Design: 
Figure 1: 
Schematic of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Arm 
Dose 1 
Day 1 
Dose 2 
Day 22 
Dose 3 
Day 172 
A (n=60) 
1 mg M-001 
1 mg M-001 
IIV4 
B (n=60) 
Placebo 
Placebo 
IIV4 
 
Randomize 
Planned Enrollment: Total N=up to 120 
subjects 
Males and non-pregnant females, 18-49 
years old, inclusive 
Consent 
Assess Eligibility 
Clinical, Safety, Reactogenicity 
Assessments 
Immunogenicity Assessments – 
Serological, Cellular and 
Cytokine Responses  

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1. 
KEY ROLES 
Individuals: 
Principal Investigator: 
Robert L. Atmar, M.D. 
Baylor College of Medicine 
1 Baylor Plaza, MS BCM280 
Houston, TX 77030 
  
 
DMID Scientific Lead:   
Chris Roberts, Ph.D. 
DMID, NIAID, NIH 
Respiratory Diseases Branch 
5601 Fishers Lane, Room 8E10, MSC 9825 
Rockville, MD 20852 
  
 
DMID Medical Officer:   
Trinka Coster, M.D. 
Medical Officer 
Respiratory Diseases Branch 
DMID, NIAID, NIH 
5601 Fishers Lane, Room 8E25, MSC 9825 
Rockville, MD 20852 
  
 
DMID Medical Monitor:  
Mohamed Elsafy, M.D. 
DMID, NIAID, NIH 
Office of Clinical Research Affairs 
5601 Fishers Lane 
Rockville, MD 20892-9826 
 
DMID Clinical Project Manager: 
Tena Knudsen, B.S.N. 
Respiratory Diseases Branch 

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DMID, NIAID, NIH 
5601 Fishers Lane, Room 8E36, MSC 9825 
Rockville, MD 20852-9825 
  
 
Safety and 
Pharmacovigilance 
Contractor 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
(CROMS) 
6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20814 
SAE Hot Line: 1-800-537-9979 (US) 
SAE Fax: 800-275-7619 (US) 
SAE Email: PVG@dmidcroms.com 
Statistical and Data 
Coordinating Center 
 
 
Ashley Wegel 
The Emmes Corporation 
401 N Washington Street, Suite 700 
Rockville, MD 20850 
  
Study Agent Repository 
Fisher BioServices 
c/o DMID Clinical Agents Repository Contract 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
 
Institutions: 
Baylor College of Medicine, University of Iowa, Cincinnati 
Children’s Hospital Medical Center 
HAI and Neut Antibody 
Assays Laboratory 
St Louis University 
1100 S. Grand Boulevard 
St. Louis, MO 63104 
 

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2. 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1. 
Background Information 
2.1.1. 
Seasonal and pandemic influenza 
Influenza is a common acute viral respiratory illness.  Seasonal influenza occurs annually, and in 
the United States it causes an estimated 100 to 600 thousand hospitalization annually and up to 
50,000 deaths a year (1-3).  The continued emergence of novel influenza A viruses in humans—
including subtypes H5N1, H3N2v, H7N7, H9N2, 2009 H1N1, and most recently H7N9, 
underscores the need for focused efforts to prepare for the next influenza pandemic (4-9).  Four 
pandemics occurred during the last century.  It was estimated that during the 1918 influenza 
A/H1N1 pandemic as many as 40 million deaths occurred worldwide (10).  Excess mortality, 
high morbidity, and social disruption were all noted during the 1957 influenza A/H2N2 and the 
1968 influenza A/H3N2 pandemics (11).  In April 2009, a novel influenza virus (2009 A/H1N1) 
originated in pigs and spread to humans around the world becoming the first pandemic of this 
century.  In each of these influenza pandemics, human populations lacked significant levels of 
pre-existing immunity to a highly transmissible form of the virus enabling it to spread rapidly.  
Thus, each emergence of a new subtype of influenza virus in the human population has the 
potential to result in a global public health emergency. 
Use of influenza vaccines is the primary means for preventing influenza.  Current licensed 
inactivated vaccines (IIVs) are good for preventing influenza, but are less effective than 
desirable.  
Serum IgG antibody to the influenza virus HA, the major component of inactivated subunit and 
split virus vaccines, has a major role in protective immunity to influenza virus infection (12).  
Resistance to infection with seasonal influenza virus strains correlates directly with both serum 
hemagglutination inhibition (HAI) and neutralizing (Neut) antibody levels, and measurements of 
serum HAI and Neut antibodies are used routinely to assess the immunogenicity of both seasonal 
and pandemic IIVs.  Cellular immunity also can have a role in preventing influenza-associated 
illness (13).  
Other strategies to improve immune responses to potential pandemic strains are needed.  One 
such approach includes the use of a vaccine that enhances cellular immunity against all influenza 
viruses (a universal vaccine) and that might also prime for serological responses to inactivated 
influenza antigens.   
2.1.2. 
Multimeric-001 (M-001) 
The use of epitope-based vaccines is another approach that may be used to prime for immune 
responses to influenza antigens (14).  The M-001 vaccine from BiondVax consists of  

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 The epitopes in the vaccine are 
common to a large majority of influenza virus strains, and the epitopes are recognized by both 
the humoral and cellular arms of the immune system (14). Based upon these characteristics, the 
M-001 vaccine is hypothesized to provide priming immunity against both existing as well as 
future emergent seasonal and pandemic influenza virus strains. 
The M-001 vaccine is produced as a 
. In the current study, the 
vaccine is intended to be administered in a non-adjuvanted formulation at a 1 mg/dose level that 
has been found to be safe and immunogenic in previous clinical trials performed by BiondVax. 
Preclinical studies using epitopes expressed in the vaccine in combination with adjuvant 
demonstrated both vaccine immunogenicity and protection from lethal challenge in a mouse 
model using highly pathogenic influenza A/H5N1 (15).  The safety and efficacy results of M-001 
in the preclinical studies led to its evaluation in people (16). 
The initial study of M-001 in humans (BVX-002) was conducted in 63 healthy adults as a Phase 
1 trial that evaluated the safety and immunogenicity of two doses of M-001 administered by the 
intramuscular (IM) route at 3 different dosage levels (125, 250 and 500 mcg) with or without 
Montanide ISA 51 VG adjuvant (17).  No safety concerns were identified.  Recipients of the 
adjuvanted 500 mcg dose of M-001 had 22-28% more frequent antibody-dependent, 
complement-mediated lysis of cells infected with influenza virus strains contained in seasonal 
vaccines compared to placebo recipients.  This group also had significantly higher cellular 
(PBMC proliferation) responses after exposure to vaccine compared to unprimed groups. 
The next study (BVX-003) performed in 60 older adults (55-75 years of age) evaluated the safety 
and ability of M-001 to 
 
 
 
 A greater proportion of recipients of 
 
 
.  Following this study and based upon the lack of safety concerns, 
 
 
BVX-004 evaluated the safety and immunogenicity of 
 
 
, when administered 
 
when administered 
 was found 
 
  

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The fourth study of M-001 (BVX-005) compared two priming doses of M-001 with one priming 
dose of alum-adjuvanted or non-adjuvanted M-001 administered 3 weeks prior to seasonal IIV3 
in 120 elderly individuals (18). Seroconversion rates were significantly higher in the two-dose 
M-001 regimen for the seasonal A (H1N1) and B strains compared to placebo (IIV3 alone), and 
cellular immune responses (IFN-γ expressing CD4 and CD8 lymphocytes) were also 
significantly increased from pre-immunization levels after exposure to influenza antigens. No 
safety concerns were identified. 
A fifth placebo-controlled study (BVX-006) examining two different dosage levels (0.5 mg and 
1 mg) of M-001 as a three-dose prime for seasonal IIV3 immune responses has been conducted 
in 36 adults.  No SAEs were observed and no safety concerns were identified (50). Elevated HAI 
responses were demonstrated in the experimental group receiving 1 mg M-001 before the IIV3 
and hence, this dosage was selected for future trials. 
2.1.3. 
Public Readiness and Emergency Preparedness Act 
For this protocol the study product M-001 (manufactured by BiondVax Ltd.) is covered under 
the Public Readiness and Emergency Preparedness Act (PREP Act). Under the PREP Act, 
covered persons are immune from liability actions brought from the administration or use of a 
covered countermeasure that is the subject of a declaration. The PREP Act provides immunity 
for covered persons (such as manufacturers, distributers, program planners and other qualified 
persons who prescribe, administer or dispense the M-001 study vaccine) from tort liability, 
unless the injury was caused by willful misconduct. 
The PREP Act also established the Countermeasures Injury Compensation Program (CICP) to 
provide compensation for serious injuries that occur as the result of the administration or use of 
certain countermeasures. Any requests for compensation must be filed within one year of 
administration or use of the countermeasure. Requests would go to the Health Resources and 
Services Administration (HRSA) Preparedness Countermeasures Injury Compensation Program 
(http://www.hrsa.gov/cicp/). Compensation may then be available for medical benefits, lost 
wages and death benefits to eligible individuals for specified injuries in accordance with 
regulations published by the Secretary of HRSA. Eligibility for compensation and the injuries for 
which compensation may be available are further defined by regulation. 
An individual who suffers a serious physical injury or death from administration and use of the 
M-001 study vaccine may request benefits from CICP.  A serious physical injury means an 
injury that is life threatening, results in, or requires medical or surgical intervention to prevent 
permanent impairment of a body function or permanent damage to body structure. The CICP is 
the payer of last resort. This means that it only covers expenses or provides benefits that other 
third-party payers, such as health insurance, the Department of Veterans Affairs, or Workers’ 
Compensation programs don’t have an obligation to pay. 

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If no funds have been appropriated to the compensation program, the Secretary of HRSA does 
not make a final determination on the individual’s request within 240 days, or if the individual 
decides not to accept the compensation, the injured individual or his representative may pursue a 
tort claim in the United States District Court for the District of Columbia, but only if the claim 
involves willful misconduct, is pled with particularity required under the PREP Act, verified, and 
accompanied by an affidavit by a physician who did not treat the individual and certified medical 
records. Any award is reduced by any public or private insurance or worker’s compensation 
available to the injured individual. Awards for non-economic damages, such as pain, suffering, 
physical impairment, mental anguish, and loss of consortium are also limited. If the individual 
accepts compensation, or if there is no willful misconduct, then the individual does not have a 
tort claim that can be filed in a United States Federal or a State court. 
2.2. 
Rationale 
Seasonal and pandemic influenza pose perpetual threats to human populations.  The rapid and 
constant evolution of influenza viruses likewise poses challenges to the development of vaccines 
for the prevention and control of influenza.  Recent vaccine development efforts have focused on 
the development of “universal” influenza vaccines; that is, vaccines which could offer protection 
against multiple influenza subtypes.  BiondVax has developed a novel vaccine, M-001, that has 
been shown in preclinical and clinical trials to stimulate both the humoral and cellular arms of 
the immune system.  When used as a primer ahead of a strain-specific boost, M-001 enhances 
immunity to strains contained within the boost and to drifted strains.   The goals of the study are 
to determine the safety of a M-001 prime followed by an IIV4 boost vaccine strategy, and to 
assess the effects of M-001 immunization on cellular and humoral immunity to seasonal 
influenza virus strains.  
2.3. 
Potential Risks and Benefits 
2.3.1. 
Potential Risks 
The potential risks of this study are those associated with having blood drawn, IM injection of 
the M-001 and IIV4 vaccines, possible reactions to the M-001 and quadrivalent seasonal 
influenza vaccines, and breach of confidentiality. 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down. Bruising at the blood draw site may occur, but can be 
prevented or lessened by applying pressure to the draw site for several minutes. IM injection also 
may cause transient discomfort and fainting. Drawing blood and IM injection may also cause 
infection. The use of sterile technique will make infection at the site where blood will be drawn 
or where the study vaccination is given extremely unlikely. 
Occasionally, adult recipients of seasonal non-adjuvanted, licensed IIVs may develop influenza-
like reactions such as fever, feverishness, fatigue, malaise, myalgia, arthralgia, headache, and/or 

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nausea. Some subjects may develop reactions at the injection site, including pruritus, 
ecchymosis, erythema, induration /swelling, pain, and/or tenderness. With non-adjuvanted 
licensed, IIVs most of these reactions peak in intensity in the first 24 hours after vaccination and 
usually disappear without treatment within 1 or 2 days. Analgesics (e.g., acetaminophen, or 
ibuprofen or similar non-steroidal anti-inflammatory drugs (NSAIDs)) and rest may generally 
relieve or lessen these reactions. Bruising can sometimes occur due to the vaccination procedure. 
In addition, post-marketing surveillance indicates the following autoimmune, auto-inflammatory 
and immune-mediated diseases as potential risks for the seasonal IIVs: neuritis, convulsions, 
severe allergic reactions, syncope, encephalitis, thrombocytopenia, vasculitis, and Guillain-Barré 
syndrome. Reports of these reactions were rare; therefore, exact incidence rates cannot be 
precisely calculated. 
 have been 
completed to date (16).  AEs described following receipt of 
 
 but have included 
 
 
 
Acute and potentially life-threatening allergic reactions are also possible. Very rarely, occurring 
in about 1 in 4 million people given a licensed IIV, there can be a serious allergic reaction to a 
vaccine. These reactions can manifest as skin rash (hives), swelling around the mouth, throat or 
eyes, difficulty breathing, a fast pulse, or loss of blood pressure. If these reactions occur, they 
can usually be stopped by the administration of emergency medications by the study personnel. 
As with any vaccine or medication, there is a very small chance of a fatal reaction, although 
researchers do not expect this to occur.  
During the swine influenza (H1N1) vaccine campaign of 1976, some recipients developed a 
paralytic illness called Guillain-Barré syndrome (GBS). GBS is an acute inflammatory 
neuropathy characterized by weakness, hyporeflexia or areflexia, and elevated protein 
concentrations in cerebrospinal fluid. The rate of GBS was significantly increased in individuals 
receiving the 1976 swine influenza (H1N1) vaccine at about 1 per 100,000 vaccine recipients. 
This syndrome has not been seen consistently with other influenza vaccines. Most persons who 
develop GBS recover completely, although the recovery period may be as little as a few weeks 
or as long as a few years. About 30% of those with GBS still have residual weakness after 3 
years and about 3% may suffer a relapse of muscle weakness and tingling sensations many years 
after the initial attack. Intensive surveillance of GBS after administration of IIVs since 1976 has 
shown a slight increase in risk over background cases (more than one additional case of GBS per 
million persons) following vaccination, typically with onset within 6 weeks after vaccination 
(19). Interestingly, although vaccination rates have increased in the last 10 years the numbers of 
reported cases of vaccine-associated GBS have declined (20). A recent study in Canada showed 
that the 2009 H1N1 vaccine was associated with a small but significant risk of GBS in persons 

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50 years and older (21). An active, population-based surveillance study conducted during the 
2009-2010 influenza season found less than 1 excess GBS case per million doses of 2009 H1N1 
vaccine administered – a rate similar to that associated with some previously administered 
annual influenza vaccines (22-25). Another study using the Medicare system showed an elevated 
risk of GBS with 2009 monovalent H1N1 vaccination (incidence rate ratio = 2.41, 95% 
confidence interval: 1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% 
confidence interval: 0.21, 5.48) (26). An international collaboration study also supported a 
conclusion of an association between 2009 H1N1 vaccination and GBS (27).  
It is unknown if the M-001 vaccine poses any risks to an unborn child. Female subjects of 
childbearing potential who are not surgically sterile via tubal sterilization, bilateral 
oophorectomy, hysterectomy, or successful Essure® placement with documented radiological 
confirmation at least 90 days after the procedure, or who are not postmenopausal for ≥ 1 year, 
must agree to practice highly effective contraception that may include, but is not limited to, 
abstinence from intercourse with a male partner, monogamous relationship with a vasectomized 
partner, male condoms with the use of applied spermicide, intrauterine devices, and licensed 
hormonal methods, for a minimum of 30 days prior to study product through 2 months (defined 
as 60 days) after the last dose of M-001 or placebo. A highly effective method of contraception is 
defined as one which results in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly. In addition to contraceptive use, all female subjects of childbearing 
potential will be required to have a negative serum or urine pregnancy test within 24 hours prior 
to receiving each dose of study vaccine. If a female subject becomes pregnant while participating 
in this study, we will ask her permission to follow-up with her about her health and the health of 
her baby through pregnancy outcome. 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subjects’ PHI. All records will be kept in a locked file cabinet 
or maintained in a locked room at the participating VTEU sites. Electronic files will be password 
protected. Only people who are involved in the conduct, oversight, monitoring, or auditing of 
this study will be allowed access to the PHI that is collected. Any publications from this study 
will not use information that will identify subjects by name. Organizations that may inspect 
and/or copy research records maintained at the participating VTEU sites for quality assurance 
and data analysis include groups such as NIAID and FDA. 
There may be other unknown risks, discomforts, or side effects. 
2.3.2. 
Known Potential Benefits 
There are no known benefits attributable to the receipt of the M-001 vaccine, but there is the 
prospect of benefit. It is possible that vaccination with M-001 will prime the participant for 

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improved responses to future seasonal or pandemic influenza vaccines.  Vaccination with IIV4 
likely will lead to protection against seasonal influenza viruses. 
There may be pandemic preparedness benefits to society in the future if the M-001 is shown to 
have a significant priming effect that leads to improved cellular immune responses to influenza 
and proves to be sufficiently safe so that it can be employed if a need for widespread vaccination 
against pandemic influenza virus strains occurs. 

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3. 
OBJECTIVES 
3.1. 
Study Objectives 
3.1.1. 
Primary Objectives 
Safety 
• To assess the safety as measured by vaccine related adverse events, reactogenicity, 
and laboratory adverse events of two doses of M-001 vaccine, each dose 
administered approximately 21 days apart  
Immunogenicity 
• To assess the T cell responses to M-001 component peptides following two doses 
of M-001 
3.1.2. 
Secondary Objectives 
Safety 
•  To assess all serious adverse events (SAEs) following receipt of each dose of M-
001 vaccine or placebo, each dose separated by approximately 21 days, through 
the end of the study 
•  To assess all unsolicited non-serious AEs following receipt of each dose of M-001 
or placebo, each dose separated by approximately 21 days, through 21 days after 
each dose of M-001 or placebo  
Immunogenicity 
• 
To assess the serum HAI and Neut antibody responses to the 2018-2019 IIV4 
vaccine viruses 
3.1.3. 
Exploratory Objectives 
• 
To assess the IgG responses to the M-001 vaccine after receipt of placebo or two 
doses of M-001 vaccine and following receipt of licensed IIV4  
• 
To assess the T cell responses to M-001 component peptides following one dose 
of M-001 or placebo 
• 
To assess T cell responses to M-001 component peptides following receipt of 
licensed IIV4 

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• 
To assess the T cell cross-reactive responses to current seasonal influenza virus 
antigens and pandemic influenza virus antigens following each vaccination (M-
001 and IIV4)  
• 
To assess the longevity of T cell responses to M-001 peptides, seasonal influenza 
virus antigens and pandemic influenza virus antigens 
3.2. 
Study Outcome Measures 
3.2.1. 
Primary Outcome Measures 
Safety 
• Occurrence of vaccine-related SAEs from the time of the first study vaccination 
(M-001 or placebo) through approximately 6 months after the second M-001 
study vaccination  
• Occurrence of solicited injection site and systemic reactogenicity events on the 
day of each study vaccination through approximately 7 days after each M-001 
vaccination 
• Occurrence of clinical safety laboratory adverse events from the time of each 
study vaccination of M-001 through approximately 7 days after each M-001 
vaccination 
Immunogenicity 
• Geometric Mean Percentage of T cell subsets expressing perforin, CD107a, IFN-
γ, TNF-α, and IL2, alone or in combination, in CD4 and CD8 cells after 
stimulation with M-001 component peptides at baseline (Day 1) and 14 days after 
the second dose of M-001  
3.2.2. 
Secondary Outcome Measures 
Safety 
• Occurrence of all SAEs, from the time of receiving the first M-001 or placebo 
study vaccination through the end of the study 
• Occurrence of all unsolicited non-serious AEs from the time of first study 
vaccination through 21 days after each M-001 vaccination  
Immunogenicity 

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• For HAI and Neuts, the percentage of subjects achieving seroconversion (defined 
as either a pre-vaccination titer <10 and a post-vaccination titer ≥40 or a pre-
vaccination titer ≥10 and a minimum four-fold rise in post-vaccination antibody 
titer) to IIV4 vaccine viruses from Day 172 to Day 200 
• For HAI and Neuts, the percentage of subjects with an antibody titer of 40 or 
greater and GMTs vs. IIV4 vaccine viruses on Days 1, 43, 172 and 200 
3.2.3. 
Exploratory Outcome Measures 
• Percentage of subjects achieving seroconversion (defined as a minimum four-fold 
rise in post-vaccination ELISA antibody titer) and GMTs of ELISA antibody vs. 
M-001 from Day 1 to Days 22, 43, 78, 172 and 200  
• Geometric Mean Percentage of T cell subsets expressing perforin, CD107a, IFN-
γ, TNF-α, and IL2, alone or in combination,in CD4 and CD8 cells after 
stimulation with M-001 peptides at baseline (Day 1) and approximately 14 days 
after one dose of M-001, 21 and 56 days following the second dose of M-001, and 
immediately prior to and 14 and 28 days after IIV4 
• Percentage of T cell subsets expressing perforin, CD107a, IFN-γ, TNF-α, and 
IL2, alone or in combination, in CD4 and CD8 cells after stimulation with other 
influenza A antigens (including seasonal and pandemic influenza antigens) at 
baseline (Day 1), approximately 14 days after each study vaccination, 21 and 56 
days following the second study vaccination and immediately prior to and 
approximately 14 and 28 days after IIV4 
• Percentage of influenza-specific T cell memory subsets expressing discrete 
memory markers (CCR7, CD45RO, and CD57) at baseline (Day 1) and on study 
days 15, 36, 43, 78, 172, 186 and 200 
• Percentage of influenza-specific CD4+ cell subsets expressing IL-4 or IL-17, T 
follicular helper cells (CD4+, CXCR5+, PD-1+, IL-21+), T follicular regulatory 
(Tfr) cells (CXCR5+, PD-1+, CD25+, CD1217+), and Tregs (CD25+, Foxp3+) at 
baseline (Day 1) and on study days 15, 36, 43, 78, 172, 186 and 200  

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4. 
STUDY DESIGN 
This is a Phase II randomized, double-blind, placebo-controlled trial in 120 males and non-
pregnant females, 18 to 49 years old, inclusive, who are in good health and meet all eligibility 
criteria.  This clinical trial is designed to assess the safety, reactogenicity, and immunogenicity of 
two priming doses of M-001 followed by administration of IIV4.   
Subjects will be assigned randomly to 1 of 2 treatment arms (60 subjects per treatment arm) to 
receive two doses of the M-001 vaccine or placebo (saline) followed by a single dose of IIV4 
(see Table 1).  Group A will receive two doses of M-001, each containing 1 mg of M-001, on 
Days 1 and 22 followed by a single dose of IIV4 on approximately Day 172 (window for this 
visit ranges from Day 142 to Day 202).  Group B will receive saline placebo on both Days 1 and 
22, followed by a single dose of IIV4 approximately on Day 172.  
Reactogenicity will be measured by the occurrence of solicited injection site and systemic 
reactions from the time of each study vaccination with M-001 (or placebo) through 7 days after 
the vaccination (inclusive of vaccination day).  Unsolicited AEs will be collected from the time 
of each M-001 (or placebo) vaccination through approximately 21 days after each study 
vaccination. SAEs will be collected from the time of the first study vaccination through 
approximately 6 months after the second M-001 (or placebo) study vaccination.  Clinical 
laboratory evaluations for safety will be performed on venous blood collected approximately 8 
days after each M-001 (or placebo) vaccination (Days 9 and 30). 
Immunogenicity testing will include performing HAI and Neut antibody assays on serum 
obtained immediately at baseline (Day 1) and on serum collected on Days 43, 172 and 200.  
ELISA antibody responses to the M-001 vaccine will be assessed on serum collected at baseline 
(Day 1) and on Days 22, 43, 78, 172 and 200.  Cell-mediated immune responses to influenza 
antigens, including epitopes represented in the  M-001 vaccine, and seasonal and candidate 
pandemic influenza viruses, will be assessed at baseline (Day 1), 14 days after each vaccination 
(Days 15, 36, and 186), approximately 21 days (Day 43) and approximately 56 days (Day 78) 
following receipt of the second M-001 (or placebo) dose, and immediately prior to and 
approximately 28 days after the IIV4 dose (Days 172 and 200).   
The duration of this trial for each subject will be approximately 7 months.  If visit 11 occurs 
before Study Day 200 (because Visit 9 occurred prior to Day 172 and moved visits 10 and 11 to 
earlier times after study start), then an additional study visit (Visit 12, phone call) will occur on 
Day 200 to solicit SAE information. 
For additional details on study procedures and evaluations and study schedule by study 
visits/days, see Sections 7 and 8 and Appendix A:  Schedule of Study Procedures and 
Evaluations. 

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5. 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1. 
Subject Inclusion Criteria 
Subjects eligible to participate in this study must meet all of the following inclusion criteria: 
1.  Provide written informed consent prior to initiation of any study procedures. 
2.  Are able to understand and comply with planned study procedures and be available for all 
study visits. 
3.  Are males or non-pregnant females, 18 to 49 years old, inclusive. 
4.  Are in good health*. 
*As determined by medical history and targeted physical examination to evaluate acute or currently ongoing chronic 
medical diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the 
assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions 
should be stable for the last 60 days prior to investigational vaccine study product administration. This includes no 
change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical 
diagnosis or condition in the 60 days prior to enrollment and investigational vaccine study product administration . Any 
prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial 
reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any 
change in prescription medication due to improvement of a disease outcome, as determined by the site principal 
investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may 
be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-
investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do 
not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and 
investigational study product vaccination are acceptable provided there was no deterioration in the subject’s chronic 
medical condition that necessitated a medication change. All chronic medical condtions should pose no additional risk 
to the subject or interference with the evaluation of responses to study vaccination. Note: Topical, nasal, and inhaled 
medications (with the exception of inhaled corticosteroids as outlined in the Subject Exclusion Criteria (see Section 5.2), 
herbals,  vitamins, and supplements are permitted. 
5.  Oral temperature is less than 100.0°F. 
6.  Pulse† is 50 to 100 bpm, inclusive. 
†Acceptable pulse range prior to IIV4 dose is 45 to 115 bpm, inclusive and no symptoms. 
7.  Systolic blood pressure¶ is 85 to 150 mm Hg, inclusive. 
¶Acceptable systolic blood pressure range prior to IIV4 dose is 80 to 155 mm Hg, inclusive and no symptoms. 
8.  Diastolic blood pressure** is 55 to 95 mmHg, inclusive. 
**Acceptable diastolic blood pressure range prior to IIV4 dose is 50 to 100 mm Hg, inclusive and no symptoms. 
9.  Women of childbearing potential‡ must use an acceptable method of contraception§ from 
30 days prior to vaccination until 60 days after the second of dose of M-001 or placebo. 
10. Women of childbearing potential‡ must use an acceptable method of contraception§ from 
30 days prior to receipt of IIV vaccination, and must plan to use until 28 days after the 
IIV. 
‡Not sterilized via tubal ligation, bilateral oophorectomy, hysterectomy, or successful Essure® placement (permanent, 
non-surgical, non-hormonal sterilization with history of documented radiological confirmation test achieved or with 

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use of another approved birth control method if confirmation test not confirmed)  and still menstruating or < 1 year of 
the last menses if menopausal). 
§Includes, but is not limited to, non-male sexual relationships, abstinence from sexual intercourse with a male partner, 
monogamous relationship with a vasectomized partner, male condoms with the use of applied spermicide, intrauterine 
devices, NuvaRing®, and licensed hormonal methods such as implants, injectables, contraceptive patches or oral 
contraceptives (“the pill”). Method of contraception will be captured on the appropriate data collection form. 
11.  Female subjects of childbearing potential must have a negative urine or serum pregnancy 
test within 24 hours prior to study vaccination. 
5.2. 
Subject Exclusion Criteria 
Subjects eligible to participate in this study must not meet any of the following exclusion 
criteria: 
1.  Have an acute illness1, as determined by the site PI or appropriate sub-investigator, 
within 72 hours prior to study vaccination. 
1An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion 
of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety 
parameters as required by the protocol. 
2.  Have any medical disease or condition that, in the opinion of the site PI or appropriate 
sub-investigator, is a contraindication to study participation2.  
2Including acute or chronic medical disease or condition, defined as persisting for at least 90 days, that would place 
the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or 
may interfere with the evaluation of responses or the subject’s successful completion of this study. 
3.  Have immunosuppression as a result of an underlying illness or treatment, or use of 
anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to study 
vaccination. 
4.  Have known active neoplastic disease or a history of any hematologic malignancy. Non-
melanoma skin cancers that are not active are permitted.  
5.  Have known HIV, hepatitis B, or hepatitis C infection. 
6.  Have known hypersensitivity or allergy to eggs, egg or chicken protein, or other 
components of the study vaccine. 
7.  Have a history of severe reactions following previous immunization with licensed or 
unlicensed influenza vaccines. 
8.  Have a history of Guillain-Barré Syndrome. 
9.  Have a history of alcohol or drug abuse within 5 years prior to study vaccination. 
10. Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric 
diagnosis that may interfere with subject compliance or safety evaluations. 
11. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement 
for danger to self or others within 10 years prior to study vaccination. 

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12. Have taken oral or parenteral (including intraarticular) corticosteroids of any dose within 
30 days prior to study vaccination. 
13. Have taken high-dose3 dose inhaled corticosteroids within 30 days prior to study 
vaccination4.   
3High-dose defined as per age as using inhaled high dose per reference chart https://www.nhlbi.nih.gov/health-
pro/guidelines/current/asthma-guidelines/quick-reference-html#estimated-comparative-daily-doses. 
4Topical and nasal steroids are permissible. 
14. Received any licensed live vaccine or plan to receive a licensed live vaccine within 30 
days prior or 21 days after each M-001 study vaccination.  
15. Received a licensed inactivated vaccine within 14 days prior to or 21 days after each M-
001 study vaccination. 
16. Plans to or received the current 2018-2019 influenza vaccine (inactivated or live prior to 
orduring the study (the 2018-2019 influenza vaccine will be given during the trial.) 
17. Received immunoglobulin or other blood products (with exception of Rho D 
immunoglobulin) within 90 days prior to study vaccination. 
18. Received an experimental agent5 within 30 days prior to the first study vaccination, or 
expects to receive an experimental agent6 during the 7-month trial-reporting period. 
5Including vaccine, drug, biologic, device, blood product, or medication. 
6Other than from participation in this study. 
19. Are participating or plan to participate in another clinical trial with an interventional 
agent7 that will be received during the 7-month trial-reporting period. 
7Including agent (licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication) during the 9-
month study period. 
20. Plan to travel outside the U.S. (continental U.S., Hawaii and Alaska) in the time between 
the first study vaccination and 21 days after the last study vaccination8. 
8Study vaccination refers to investigiational study product vaccination 
21. Female subjects who are breastfeeding or plan to breastfeed at any given time from the 
first study vaccination until 30 days after the last study vaccination. 
22. Blood donation or planned blood donation within 30 days prior to the study vaccination 
through 30 days after the last blood drawn for this study. 
23. Have signs or symptoms that could confound or confuse assessment of study vaccine 
reactogenicity9.  
 

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9The study vaccination should be postponed/deferred until signs or symptoms have resolved and if within the 
acceptable protocol-specified window for that visit.  
24. Have a history of convulsions or encephalomyelitis within 90 days prior to study 
vaccination. 
5.3. 
Eligibility Criteria for Doses 2- 3 
Subjects must meet all inclusion and none of the exclusion criteria as outlined in sections 5.1 and 
5.2 for all subsequent vaccination visits (note that inclusion criteria for IIV4 administration are 
different than those for investigational study product administration).  Subjects must not have 
received the 2018-2019 influenza vaccine prior to Dose #3. In addition, the presence of any 
unresolved or continuing solicited or unsolicited Grade 2 or 3 AE (Doses #2 to #3) or the 
presence of any Grade 2 or 3 clinical laboratory value (prior to Doses #2 or #3 administered on 
Days 22 and 172, respectively), will be exclusions to subsequent doses of vaccine.  An 
unresolved or continuing Grade 1 AE is permissible unless, in the opinion of the site PI or sub-
investigator (sub-I), it would render study vaccination unsafe or interfere with the evaluation of 
responses. 
5.4. 
Treatment Assignment Procedures 
5.4.1. 
Randomization Procedures 
Per International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practice 
(GCP), screening records will be kept at each participating VTEU site to document the reason 
why an individual was screened, but failed trial entry criteria.  The reasons why individuals 
failed screening will be recorded in the Statistical and Data Coordinating Center’s (SDCC) 
AdvantageEDCSM (Electronic Data Capture System). 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled.  One hundred twenty subjects will be randomly assigned to one of 2 
treatment arms, as shown in Table 1.  Randomization will be stratified based upon prior receipt 
of the 2017-2018 influenza vaccine. The list of randomized treatment assignments will be 
prepared by statisticians at the SDCC and included in the enrollment module for this trial. 
AdvantageEDC will assign each volunteer a treatment code from the list after demographic and 
eligibility data have been entered into the system.  A designated individual at each site will be 
provided with a treatment key, which links the treatment code to the actual treatment assignment, 
which will be kept in a secure place. 
Instructions for use of the enrollment module are included in the AdvantageEDC User’s Guide.  
Manual back-up randomization procedures are provided in the MOP for use in the event that the 
site temporarily loses access to the Internet or the online enrollment system is unavailable. 

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The randomization scheme for this study is presented in Table 1Table 1. 
5.4.2. 
Masking Procedures 
This is a double-blind study.  
Subjects, investigators, and study personnel performing any study-related assessments following 
study injection will be blinded to treatment assignment to the two M-001 dosing regimen or 
placebo.  Laboratory personnel performing immunology assays will be blinded to treatment 
assignment. 
The randomization scheme will be generated by the SDCC and provided to unblinded study 
personnel (i.e., pharmacists performing study product preparations and unblinded study product 
administrators). 
The unblinded study product administrator is a study personnel licensed, registered, or certified 
to administer medications/vaccines, but will not be involved in study-related assessments or have 
subject contact for data collection following study injection. Following administration of the first 
two doses of either M-001 or placebo, the licensed seasonal influenza vaccine will be given to all 
subjects at Visit 09, but does not require administration by an unblinded study product 
administrator. The site PI may instead elect to assign administration of the licensed seasonal 
influenza vaccine at Visit 09 to the study personnel licensed, registered, or certified to administer 
medications/vaccines who may be otherwise blinded. 
The Data and Safety Monitoring Board (DSMB) may receive data in aggregate and by treatment 
arm, or may be unblinded to individual subject treatment assignments, as needed, to adequately 
assess safety issues. 
Refer to the MOP for unblinding procedures. 
5.4.3. 
Reasons for Withdrawal 
Subjects may voluntarily withdraw their consent for study participation at any time and for any 
reason, without penalty. 
A subject may withdraw or be withdrawn from the study for any of the following reasons: 
• Medical disease or condition, or any new clinical findings for which continued 
participation, in the opinion of the site PI or appropriate sub-I, would compromise the 
safety of the subject, or would interfere with the subject's successful completion of the 
study, or would interfere with the evaluation of responses. 
• Subject no longer meets eligibility criteria. 

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• As deemed necessary by the site PI or appropriate sub-investigator for noncompliance or 
other reasons. 
• Subject withdrawal of consent. 
• Subject lost to follow-up. 
• Termination of the study. 
• New information becomes available that makes further participation unsafe. 
Subsequent study vaccinations will not be administered to a subject if any of the following 
criteria are met: 
• Medical condition for which continued participation, in the opinion of the site PI or 
appropriate sub-investigator, would pose a risk to the subject or would be likely to 
confound interpretation of the results. 
• Presence of signs or symptoms that could confound or confuse assessment of study 
vaccine reactogenicity. For subjects with injection site or systemic signs or symptoms, or 
with an acute illness, including an oral temperature greater than or equal to 100.0°F, the 
subsequent study vaccinations should be postponed/deferred until signs, symptoms, or 
acute illness have resolved and if within the acceptable protocol-specified window for 
that visit. No exceptions to the protocol-specified window will be made.  
• Any unresolved or continuing solicited or unsolicited Grade 2 or 3 AE. An unresolved or 
continuing Grade 1 AE is permissible unless, in the opinion of the site PI or sub-I, it 
would render study vaccination unsafe or interfere with the evaluation of responses.  
• Subject no longer meets eligibility criteria. 
• As deemed necessary by the site PI or appropriate sub-I for noncompliance or other 
reasons. 
• Subject refusal of further study vaccination. 
• Subject withdrawal of consent. 
• Subject lost to follow-up. 
• Termination of the study. 
• New information becomes available that makes further participation unsafe. 

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Subsequent investigational study vaccinations will not be administered to a subject if any of the 
following criteria are met: 
• Grade 2 or 3 clinical safety laboratory value (according to the toxicity table, Section 
9.2.3) that does not decrease to Grade 1 or less prior to any subsequent study vaccination. 
Any clinical safety laboratory parameter may be re-evaluated for eligibility only once at 
the central (clinical) laboratory prior to any subsequent study vaccination. If the clinical 
safety laboratory value decreases to Grade 1 or less, the subject may receive the 
subsequent study vaccination. Subsequent study vaccinations should be scheduled to 
occur within the acceptable protocol-specified window for that visit. 
• Grade 3 AE in the 8 days following a study vaccination that has no alternative etiology.  
5.4.4. 
Handling of Withdrawals 
The primary reason for withdrawal from the study will be recorded on the Study Status data 
collection form. Subjects will be encouraged to complete the Early Termination Visit. The Early 
Termination Visit procedures are listed in Section 7.4. Although subjects are free to withdraw at 
any time or may be withdrawn by the site PI or appropriate sub-I at any time, subjects who 
receive at least one dose of study vaccine will be encouraged to remain in the study for follow-up 
safety assessments and collection of venous blood samples for immunogenicity testing. Every 
attempt will be made to follow to resolution all AEs, including solicited injection site and 
systemic reactions, and/or SAEs that are ongoing at the time of early withdrawal. 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort (i.e., 
three documented contact attempts via phone calls, e-mails, etc., made on separate occasions and 
followed by a certified letter) will be made to locate or recall them, or at least to determine their 
health status. These efforts will be documented in the subjects’ records. See the protocol-specific 
Manual of Procedures (MOP) for alternate follow-up requirements. 
Subjects who withdraw, or are withdrawn or terminated from the study, or are lost to follow-up 
after signing the informed consent form, randomization, and receipt of study vaccine will not be 
replaced. If subjects who withdraw, or are withdrawn or terminated from the study, or are lost to 
follow-up after signing the informed consent form and randomization but before receipt of study 
vaccine, additional subjects may be enrolled and randomized for replacement. 
5.4.5. 
Termination of Study  
Although the study Sponsor has every intention of completing the study, it reserves the right to 
terminate the study at any time for clinical or administrative reasons. Reasons for termination 
include, but are not limited to, study closure due to DSMB review and recommendation and at 
the discretion of DMID. 

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6. 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
6.1. 
Study Product Description 
Seasonal Quadrivalent Inactivated Influenza Vaccine (IIV4) 
Quadrivalent Inactivated Influenza Vaccine (IIV4) for intramuscular injection is indicated for 
active immunization against influenza disease caused by influenza virus subtypes A and type B 
present in the vaccine.  IIV4 is manufactured using virus grown in eggs. 
M-001 
Multimeric-001 (M-001) vaccine developed by BiondVax is a 
 
 
 that are conservatively expressed among influenza A and B viruses.  
It has been produced under aseptic conditions and according to the rules of current Good 
Manufacturing Practice and guidelines applicable to investigational medicinal products (IMPs). 
The vaccine lots used in this trial have been tested and released by the quality control department 
of the BiondVax. 
Placebo (Normal Saline) 
Sterile normal saline will be used as the placebo.   
6.1.1. 
Acquisition 
IIV4 will be purchased by DHHS. 
M-001 will be provided by BiondVax under contract to DHHS.  
Placebo (normal saline) will be provided by the DMID Clinical Agents Repository (CMS, Fisher 
BioServices). 
IIV4, M-001 and normal saline will be provided through the DMID CMS to the participating 
VTEU site research pharmacies after all applicable regulatory and site approvals have been 
obtained. Should the site PI require additional study product during this trial, further instructions 
are provided in the protocol-specific MOP. 
6.1.2. 
Formulation, Storage, Packaging, and Labeling 
Seasonal Quadrivalent Inactivated Influenza Vaccine (IIV4) 

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The IIV4 is supplied as a sterile, clear, and colorless to slightly opalescent suspension in a single-
dose, 0.5ml prefilled syringe.  It is formulated to contain 60 mcg hemagglutinin (HA) per 0.5ml 
dose in the recommended ratio of 15 mcg HA for each of the four vaccine strains.  
It contains no preservative (i.e., thimerosal-free). 
The vaccine must be stored at 2°C to 8°C (36°F to 46°F). Do not freeze. 
M-001 
M-001 is supplied as a sterile, cloudy-white suspension in single-dose vials containing: 
• 1 mg M-001 per 0.4 mL (dose for injection) 
Each vial contains a fill volume of 0.6 mL at a concentration of 2.5mg/mL. It contains 
 
 
The vials containing study product must be stored at 2°C to 8°C (35.6°F to 46.4°F). Do not 
freeze.  
Placebo (Normal Saline) 
0.9% Sodium Chloride, USP or normal saline is a sterile, nonpyrogenic, isotonic solution; each 
mL contains sodium chloride 9 mg.  It contains no bacteriostatic agent, antimicrobial agent, 
preservatives, or added buffer and is supplied only in single-dose containers.  The solution may 
contain hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 5.3, range 4.5-7.0). 
The normal saline vials are to be stored at 20-25°C (68°F to 77ºF) [See USP Controlled Room 
Temperature; excursions between 15°C and 30°C (59°C and 86°F) are permitted].  
 
Each study product will be labeled according to manufacturer specifications and include the 
statement “Caution: New Drug – Limited by Federal (or United States) Law to Investigational 
Use.” 
 
Further details are included in the Investigator’s Brochures for the M-001 vaccine and the IIV4 
Package Insert, as well as in the protocol-specific MOP.  
6.1.3. 
Product Storage and Stability Procedures 
The temperature of the storage unit must be manually recorded daily (excluding non-business 
days and holidays as applicable), monitored during the duration of this trial per the participating 
VTEU sites’ standard operating procedures, and documentation will be maintained. If the 
temperature fluctuates outside of the required range, the affected study product(s) must be 
quarantined at the correct storage temperature and labeled as ‘Do Not Use’ (until further notice). 
If any study product appears to have been damaged, contaminated or discolored, contains visible 
particulate matter (for normal saline and IIV4 vaccine), or if there are any concerns regarding its 
integrity, do NOT use the affected study product(s). The pharmacist must alert the site PI and 
study coordinator, if the temperature fluctuates outside of the required range. The site PI or 
responsible person should immediately contact the DMID Product Support Team at 

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DMIDProductSupportTeam@niaid.nih.gov for further instructions before any additional study 
vaccinations are administered. Based on the information collected, DMID and/or the 
manufacturer will determine whether the affected study product(s) can be used. If it cannot be 
used, the site will receive specific instructions on how to return the affected study product(s) to 
the DMID CMS or destroy it on site. Additional instructions for quarantine are provided in the 
protocol-specific MOP. 
6.2. 
Dosage, Preparation and Administration of Study Intervention/ 
Investigational Product  
See the protocol-specific MOP for detailed information on the preparation, labeling, storage, and 
administration of study vaccine.  Study vaccine preparation will be performed by the 
participating VTEU site’s research pharmacist on the same day of study vaccine administration. 
M-001 investigational influenza vaccine product: 
The 
 of M-001 dose will be administered as a single 
 intramuscular injection.  
 
Visually inspect M-001 vaccine upon receipt and prior to use. After shaking well, the 
suspension will be cloudy white in appearance.  If the M-001 vaccine precipitated, it should be 
re-suspended by tapping on the vial with the finger or mixing by vortex until the suspension 
looks homogeneous. If the M-001 vaccine appears to have been damaged, contaminated or 
discolored, or if there are any concerns regarding its integrity, do NOT use the affected study 
product(s).   
Additional instructions for quarantine and DMID contact information are provided in the 
protocol-specific MOP.   
 
Seasonal quadrivalent inactivated influenza vaccine product: 
The IIV4 will be administered as an intramuscular injection using a single-dose 
 prefilled 
syringe.  
Shake thoroughly and inspect visually before use.  The vaccine product should be free of 
particulate matter and discoloration prior to administration.  If either of these conditions exists, 
the vaccine should not be administered.  Administer the vaccine immediately after the thorough 
shaking and inspection. 
Normal Saline (Placebo): 
The saline placebo dose will be administered as a single 0.4 mL intramuscular injection.  
Visually inspect the placebo (normal saline) upon receipt and prior to use. The solution will be 
clear to colorless in appearance.  If the placebo appears to have been damaged, contaminated or 
discolored, contain visible particulate matter, or if there are any concerns regarding its integrity, 
do NOT use the affected study product(s).  Additional instructions for quarantine and DMID 
contact information are provided in the protocol-specific MOP.   
 

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The first two doses of study vaccine administration will be performed by an unblinded study 
personnel member who is credentialed to administer medications/vaccines and may also 
participate in dose preparation. The licensed seasonal influenza vaccine to be given to all 
subjects at Visit 09 does not require administration by an unblinded study product administrator. 
The site PI may instead elect to assign administration of the licensed seasonal influenza vaccine 
at Visit 09 to the study personnel licensed, registered, or certified to administer 
medications/vaccines who may be otherwise blinded.  
Each dose of study vaccine will be administered via a single IM injection given in the deltoid 
muscle of the subjects’ preferred arm. The site of injection (right or left arm) will be recorded on 
the appropriate data collection form. Aseptic technique will be used for the withdrawal and 
administration of each dose of study vaccine using a disposable sterile needle appropriate in 
length for each subject and a disposable sterile 1-mL syringe. See the protocol-specific MOP for 
information on how to administer IM injections. Each dose of study vaccine must be 
administered within 30 minutes of drawing into the syringe, and the prepared syringe must be 
stored at room temperature until administered.  
6.3. 
Modification of Study Intervention/Investigational Product for a 
Participant 
Individuals must meet the appropriate inclusion and exclusion criteria prior to receiving the 
subsequently scheduled study injections.  There will be no replacement of individuals who do not 
qualify to receive study doses 2 or 3. There will be no dose schedule modifications, other than 
within the protocol-specified windows.  If a subject’s study vaccination (study doses 2 or 3)  is 
deferred, vaccination should be rescheduled to occur within the acceptable protocol-specified 
window for that visit.  No exceptions to the protocol-specified window will be made.  
Subjects who do not receive Dose 2 or Dose 3 will continue with follow-up safety assessments 
(may be conducted by phone call rather than in person) continuing through approximately 6 
months after their last dose of M-001 or placebo. These subjects will also be asked to provide a 
venous blood sample for anti-viral antibody assays at approximately 21 days after their last dose 
of M-001. See Sections 5.4.3 and 5.4.4 for reasons for and handling of withdrawals and 
discontinuation of treatment. See the protocol-specific MOP for alternate follow-up 
requirements. 
6.4. 
Accountability Procedures for the Study Intervention/ 
Investigational Product(s) 
After receipt of the IIV4, M-001, and placebo vials, the site PI is responsible for study product 
distribution and disposition, and has ultimate responsibility for study product accountability.  The 
Site PI may delegate to the site Research Pharmacist the responsibility for study product 
accountability.  The site Research Pharmacist will be responsible for maintaining complete 
records and documentation of product receipt, accountability, dispensation, temperature and 

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storage conditions, and final disposition of study product.  All study product, whether 
administered or not, must be documented on the appropriate study product accountability record 
or dispensing log. 
Used and unused vials of M-001 and placebo and IIV4 will be retained until monitored and 
released for disposition as applicable.  Upon completion or termination of the study and after the 
final monitoring visit, final disposition of unused study products will be determined by DMID 
and communicated to the participating VTEU sites by the DMID Clinical Project Manager. For 
details regarding final disposition of study products see the Manual of Procedures (MOP). 
6.5. 
Assessment of Subject Compliance with Study Intervention/ 
Investigational Product  
The first two doses of study product will be administered to subjects by an unblinded vaccine 
administrator via IM injection according to subject treatment assignment and as described in 
Section 6.2. Thus, subject compliance is not anticipated to be an issue.  Deviations from the dose 
schedule may only occur as described in Section 6.3. The licensed seasonal influenza vaccine to 
be given to all subjects at Visit 09 does not require administration by an unblinded study product 
administrator. The site PI may instead elect to assign administration of the licensed seasonal 
influenza vaccine at Visit 09 to the study personnel licensed, registered, or certified to administer 
medications/vaccines who may be otherwise blinded.  
6.6. 
Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
data collection form. Concomitant medications will include all current medications, vaccinations 
and medications taken in the 60 days prior to Day 1 through approximately Day 43. Subjects 
who do not receive both M-001 study vaccinations will have concomitant medications collected 
through approximately 21 days after the first study vaccination, or early termination, whichever 
occurs first. Medications reported in the electronic case report form (eCRF) are limited to those 
taken within 30 days prior to the first study vaccination through approximately 21 days after the 
second M-001 study vaccination. Concomitant medications (vaccines only) will be recorded on 
the appropriate data collection form after Visit 7 through the end of the study. Prescription and 
over-the-counter drugs will be included as well as herbals, vitamins and supplements. In 
addition, receipt of  any non-study vaccines will be solicited at each clinic visit or phone call, 
and reported in the eCRF.  
Use of new medication should prompt evaluation for the presence of a new diagnosis of chronic 
medical disease or condition. 
Medications that might interfere with the evaluation of the investigational product should not be 
used unless absolutely necessary. Medications in this category include the prohibited 

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medications per the Subject Exclusion Criteria (see Section 5.2). In addition, the site PI or 
appropriate sub-I may identify other mediations that should not be used due to a risk to subject 
safety or assessment of reactogenicity and immunogenicity. 

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7. 
STUDY SCHEDULE 
7.1. 
Enrollment/Baseline (Visit 01, Day 1, Dose 1, Clinic Visit) 
• Subjects will be provided with a description of the study (purpose and study procedures) 
and asked to read and sign the informed consent form (ICF). The ICF will be signed prior 
to performing any study procedures, including administration of the first study 
vaccination. 
• Eligibility criteria will be reviewed with subjects prior to the first study vaccination.  
Subject receipt of licensed 2016-2017 and 2017-2018 seasonal influenza vaccine, what 
type (LAIV or inactivated), and approximate date of vaccination will be recorded on the 
appropriate data collection form, if known.  
• Complete medical history will be obtained by interview of subjects prior to the first study 
vaccination to assure eligibility. 
• Demographic information will be obtained by interview of subjects. 
• All concomitant medications and vaccinations taken within 60 days prior to signing the 
ICF will be recorded on the appropriate data collection form prior to the first study 
vaccination and those taken within 30 days prior to signing the ICF will be recorded on 
the eCRF. 
• Vital signs, including oral temperature, pulse, and blood pressure, will be obtained prior 
to the first study vaccination. Vital signs assessed on Day 1 (Visit 01) prior to the first 
study vaccination will be considered as baseline. Subjects must not eat or drink anything 
hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
• Height and weight will be collected on Day 1 prior to the first study vaccination for the 
calculation of Body Mass Index (BMI). 
• A targeted physical examination may be performed prior to the first study vaccination by 
a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-I, if indicated based on review of complete medical history. 
• Counsel women of childbearing potential on contraception and avoidance of pregnancy. 
• A urine or serum pregnancy test will be performed within 24 hours prior to the first study 
vaccination on all female subjects of childbearing potential. Results must be negative and 
known prior to randomization and first study vaccination. 
• Approximately 10 mL of venous blood will be collected prior to the first study 
vaccination for safety labs. 
• Approximately 10 mL of venous blood will be collected prior to the first study 
vaccination for baseline antibody assays. 

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• Approximately 60 mL of venous blood will be collected prior to the first study 
vaccination for isolation of PBMCs. 
• Subjects will be enrolled in AdvantageEDC and randomly assigned to a treatment arm 
prior to the first study vaccination. 
• Pre-administration reactogenicity assessments will be performed prior to the first study 
vaccination to establish baseline. Subjects will then receive a single dose of study vaccine 
via IM injection in the deltoid muscle of the preferred arm. The site of injection (right or 
left arm) and time of administration will be recorded on the appropriate data collection 
form. Subjects will be observed in the clinic for at least 20 minutes after the first study 
vaccination. The study vaccination site will be examined, and any AE/SAEs will be 
assessed and recorded on the appropriate data collection form prior to discharge from the 
clinic. 
• Subjects will be provided with a Memory Aid and other study-related materials to record 
daily oral temperature, solicited injection site and systemic reactions, any unsolicited 
AEs, and concomitant medications/vaccinations. Subjects will be encouraged to take their 
temperature around the same time each day for 8 days post vaccination. Subjects will be 
instructed on how to use the Memory Aid and how to measure and record AEs prior to 
discharge from the clinic. Subjects will be instructed to notify the study center if they 
develop any severe reactions after the first study vaccination. If the site PI or appropriate 
sub-I deems the reaction severe enough, s/he will give further instructions on the proper 
course of action, including a return to the clinic for immediate evaluation if appropriate. 
7.2. 
Follow-up  
7.2.1. 
Visit 2, Day 9, Clinic Visit (8 days [+2 days] post first study vaccination) 
• Study personnel will review the Memory Aid information with subjects and 
assess and record all AE/SAEs and concomitant medications on the appropriate 
data collection form. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• If indicated by review of Memory Aid, obtain vital signs. 
• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history. 
• Examine the vaccination site for Dose 1. 
• Approximately 10 mL of venous blood will be collected for safety labs. 

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7.2.2. 
Visit 3, Day 15, Clinic Visit (14 days [+2 days] post first study vaccination) 
• Study personnel will review interim medical history with subjects and assess and 
record all AE/SAEs and concomitant medications on the appropriate data 
collection form. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• If indicated, obtain vital signs. 
• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history. 
• 
Approximately 40 mL of venous blood will be collected for isolation of PBMCs. 
7.2.3. 
Visit 4, Day 22, Dose 2, Clinic Visit (21 days [+2 days] post first study 
vaccination) 
• Eligibility criteria will be reviewed with subjects prior to the second study 
vaccination to assure continued eligibility. 
• Obtain interim medical history by interview of subjects prior to the second study 
vaccination and note any changes since the previous visit. 
• All concomitant medications will be recorded on the appropriate data collection 
form prior to the second study vaccination. 
• All AE/SAEs will be assessed and recorded on the appropriate data collection 
form prior to the second study vaccination. 
• Vital signs, including oral temperature, pulse, and blood pressure, will be 
obtained prior to the second study vaccination. Subjects must not eat or drink 
anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
• A targeted physical examination may be performed prior to the second study 
vaccination by a study clinician licensed to make medical diagnoses and listed on 
the Form FDA 1572 as the site PI or sub-I, if indicated based on review of interim 
medical history. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• A urine or serum pregnancy test will be performed within 24 hours prior to the 
second study vaccination on all female subjects of childbearing potential. Results 
must be negative and known prior to the second study vaccination. 

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• Approximately 10 mL of venous blood will be collected prior to the study 
vaccination for antibody assays. 
• Pre-administration reactogenicity assessments will be performed prior to the 
second study vaccination to establish baseline. Subjects will then receive a single 
dose of study vaccine via IM injection into the deltoid muscle of the same arm 
that received Dose 1 as long as there is no interference with the reactogenicity 
assessment. The site of injection (right or left arm) and time of administration will 
be recorded on the appropriate data collection form. Subjects will be observed in 
the clinic for at least 20 minutes after the second study vaccination. The study 
vaccination site for Dose 2 will be examined, and any AE/SAEs will be assessed 
and recorded on the appropriate data collection form prior to discharge from the 
clinic. 
• Subjects will be provided with a Memory Aid and other study-related materials to 
record daily oral temperature, solicited injection site and systemic reactions, any 
unsolicited AEs, and concomitant medications. Subjects will be encouraged to 
take their temperature around the same time each day. Subjects will be instructed 
on how to use the Memory Aid and how to measure and record AEs prior to 
discharge from the clinic. Subjects will be instructed to notify the study center if 
they develop any severe reactions after the second study vaccination. If the site PI 
or appropriate sub-I deems the reaction severe enough, s/he will give further 
instructions on the proper course of action, including a return to the clinic for 
immediate evaluation if appropriate. 
7.2.4. 
Visit 5, Day 30, Clinic Visit (8 days [+2 days] post second study vaccination) 
• Study personnel will review the Memory Aid information with subjects and 
assess and record all AEs/SAEs and concomitant medications on the appropriate 
data collection form.  
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• If indicated, obtain vital signs. 
• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history. 
• Examine the vaccination site for Dose 2. 
• Approximately 10 mL of venous blood will be collected for safety labs. 

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7.2.5. 
Visit 6, Day 36, Clinic Visit (14 days [+2 days] post second study vaccination) 
• Study personnel will review interim medical history with subjects and assess and 
record all AE/SAEs and concomitant medications on the appropriate data 
collection form. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• If indicated, obtain vital signs. 
• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history. 
• Approximately 40 mL of venous blood will be collected for isolation of PBMCs. 
7.2.6. 
Visit 7, Day 43, Clinic Visit (21 days [+7 days] post second study vaccination) 
• Study personnel will review interim medical history with subjects and assess and 
record all AE/SAEs and concomitant medications on the appropriate data 
collection form. 
• If indicated, obtain vital signs. 
• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• Approximately 10 mL of venous blood will be collected for influenza antibody 
assays. 
• Approximately 60 mL of venous blood will be collected for isolation of PBMCs. 
7.2.7. 
Visit 8, Day 78, Clinic Visit (56 days [+7 days] post second study vaccination) 
• Study personnel will review interim medical history with subjects and assess and 
record all SAEs on the appropriate data collection form. 
• Concomitant medications (vaccines only) will be recorded on the appropriate data 
collection form. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy through study day 82 (60 days after second vaccination). 
• If indicated, obtain vital signs. 

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• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history.   
• Approximately 10 mL of venous blood will be collected for influenza antibody 
assays. 
•  Approximately 40 mL of venous blood will be collected for isolation of PBMCs.  
7.2.8. 
Visit 9, Day 172, Dose 3 (150 days [+30 days] post second study vaccination) 
• Eligibility criteria will be reviewed with subjects prior to the third study 
vaccination IIV4) to assure continued eligibility. 
• Obtain interim medical history by interview of subjects. 
• Concomitant medications (vaccines only) will be recorded on the appropriate data 
collection form. 
• All SAEs will be assessed and recorded on the appropriate data collection form. 
• Vital signs, including oral temperature, pulse, and blood pressure, will be 
obtained prior to the third study vaccination. Subjects must not eat or drink 
anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
• A targeted physical examination may be performed prior to the third study 
vaccination by a study clinician licensed to make medical diagnoses and listed on 
the Form FDA 1572 as the site PI or sub-I, if indicated based on review of interim 
medical history. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• A urine or serum pregnancy test will be performed within 24 hours prior to the 
third study vaccination on all female subjects of childbearing potential. Results 
must be negative and known prior to the third study vaccination. 
• Approximately 20 mL of venous blood will be collected prior to the third study 
vaccination for influenza antibody assays. 
• Approximately 40 mL of venous blood will be collected prior to the study 
vaccination for isolation of PBMCs. 
• Subjects will then receive a single dose of IIV4 study vaccine via IM injection 
into the deltoid muscle of the same arm that received Dose 1.  The site of 
injection (right or left arm) and time of administration will be recorded on the 
appropriate data collection form.  

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• Subjects will be instructed to notify the study center if they develop any 
worrisome adverse events or experienced an SAE. 
7.2.9. 
Visit 10, Day 186, Clinic Visit (14 days [+3 days] post third study vaccination) 
• Study personnel will review interim medical history and assess and record all 
SAEs. 
• Concomitant medications (vaccines only) will be recorded on the appropriate data 
collection form. 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• If indicated, obtain vital signs. 
• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history. 
• Approximately 40 mL of venous blood will be collected for isolation of PBMCs. 
7.3. 
Study Visit 11, Day 200 Clinic Visit (28 days +7 post third study 
vaccination) 
7.3.1. 
Visit 11 activities 
• Study personnel will review interim medical history with subjects and assess and 
record all SAEs on the appropriate data collection form.   
• Concomitant medications (vaccines only) will be recorded on the appropriate data 
collection form.  
• If indicated, obtain vital signs. 
• A targeted physical examination may be performed by a study clinician licensed 
to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
I, if indicated based on review of interim medical history. 
• Approximately 20 mL of venous blood will be collected for influenza antibody 
assays. 
• Approximately 40 mL of venous blood will be collected for isolation of PBMCs. 

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7.3.2. 
Study Visit 12, Day 200 (+14 days), Safety Follow-up Phone Call (to be 
Performed Only If Visit 11 Occurs Before Study Day 200) 
• Study personnel will review interim medical history with subjects and assess and 
record all SAEs on the appropriate data collection form.  
• Concomitant medications (vaccines only) will be recorded on the appropriate data 
collection form. 
7.4. 
Early Termination Visit 
The following activities will be performed at the early termination visit for subjects who 
withdraw, 
or are withdrawn or terminated from the study: 
• Obtain interim medical history by interview of subjects and note any changes since 
the previous visit. 
• Memory Aid information will be reviewed with subjects (if within 8 days after a M-
001 study vaccination). 
• If indicated by medical history, obtain vital signs. Subjects must not eat or drink 
anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
• Review and record all concomitant medications (if prior to 21 days after the last study 
vaccination). 
• Information regarding AEs/SAEs will be recorded on the appropriate data collection 
form. AEs will be limited to SAEs if after 21 days following the second M-001 study 
vaccination. 
• A targeted physical examinationmay be performed by a study clinician licensed to 
make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-I, if 
indicated based on review of interim medical history. 
• Examine study vaccination site, and perform post-administration reactogenicity 
assessment (if within 8 days after a M-001 study vaccination). 
• Approximately 10 mL of venous blood will be collected for clinical labs, and 
performed by the central (clinical) laboratory (if within 7 (+2) days after a M-001 
study vaccination), or if indicated based on review of interim medical history, or to 
follow-up on any grade 2 or higher laboratory abnormalities. 
• Approximately 10 mL of venous blood will be collected for influenza antibody 
assays. 
• Approximately 40 mL of venous blood will be collected for isolation of PBMCs. 

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7.5. 
Unscheduled Visit  
Unscheduled visits may occur at any time during the study. Any of the following activities may 
be performed: 
• Review Memory Aid (if within 8 days after the previous study vaccination, inclusive 
of vaccination day). 
• Review and record all concomitant medications (if prior to 21 days after the last study 
vaccination). 
• Counsel women of childbearing potential on contraception and avoidance of 
pregnancy. 
• All AEs/SAEs will be recorded on the appropriate data collection form.  AEs will be 
limited to SAEs if after 21 days after the last study vaccination. 
• Obtain interim medical history by interview of subjects and note any changes since 
the previous visit (if indicated). 
• If indicated, obtain vital signs. Subjects must not eat or drink anything hot or cold, or 
smoke within 10 minutes prior to taking oral temperature. 
• A targeted physical examination may be performed by a study clinician licensed to 
make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-I, if 
indicated based on review of interim medical history. 
• Examine study vaccination site and perform post- administration reactogenicity 
assessment (if within 8 days after the last study vaccination, inclusive of vaccination 
day). 
• Approximately 10 mL of venous blood will be collected for clinical labs, and 
performed by the central (clinical) laboratory (if within 9 days after a M-001 study 
vaccination), or if indicated based on review of interim medical history, or to follow-
up on any laboratory abnormalities determined to be AEs. 

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8. 
STUDY PROCEDURES/EVALUATIONS 
8.1. 
Clinical Evaluations 
Medical History:  Will be obtained by interview of the subjects.  Subjects will be queried 
regarding a history of significant medical disorders of the head, eyes, ears, nose, throat, mouth, 
cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, kidney, nervous system, 
blood, lymph glands, endocrine system, musculoskeletal system, skin, and genital/reproductive 
tract.  A history of any allergies, cancer, immunodeficiency, psychiatric illness, and substance 
abuse will be solicited. The collection of medical history information will include a review of 
vaccine history and plans for vaccinations.  
Concomitant Medications:  All current medications and medications taken in the 30 days before 
Study Day 1 (prescription and over-the-counter drugs) will be recorded in the eCRF, as well as 
vaccinations, vitamins and supplements, through 21 days after the second M-001 study injection. 
All concomitant medications and vaccinations taken within 60 days prior to signing the ICF will 
be recorded on the appropriate data collection form prior to the first study vaccination. 
Concomitant medications (vaccines only) will be recorded on the appropriate data collection 
form after Visit 7 through the end of the study. Assessment of eligibility also will include a 
review of prohibited medications (per the exclusion criteria). 
Vitals signs: Blood pressure, oral temperature, and pulse will be collected at each of the study 
visits when a study vaccination is scheduled [Day 1 (Visit 01), Day 22 (Visit 04), Day 172 (Visit 
09), and as needed at the other study visits. 
Height, weight: These parameters will be measured at Day 1 (Visit 01). 
Targeted Physical Examination: This may be conducted at any study visit based on indicated 
symptoms. 
Reactogenicity Assessments:  This will include an assessment of solicited AEs occurring from 
the time of each study vaccination [Day 1 (Visit 01), Day 22 (Visit 04), through 7 days after M-
001study vaccinations (inclusive of vaccination day), which includes an assessment of 
erythema/redness, induration/swelling, pain, tenderness, ecchymosis and pruritus at the injection 
site; fever, chills, fatigue, malaise, body aches (exclusive of injection site), arthralgia (exclusive 
of injection site), headache, and nausea. 
Memory Aids:  All subjects will complete a subject Memory Aid from the time of each study 
vaccination [Day 1 (Visit 01) and Day 22 (Visit 04) through 7 days after the M-001 study 
vaccination.  Subject Memory Aids will be reviewed with the subject for AEs at the clinic visit 
following each study injection.  If a subject noted ongoing injection site or systemic 

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reactogenicity on the 7th day following the study injection, the Memory Aid will continue to be 
reviewed until resolved. The Memory Aids will be discarded after review. 
8.2. 
Laboratory Evaluations 
Schedules and volumes of clinical laboratory tests and immunogenicity assays are specified in 
Appendix A. 
8.2.1. 
Clinical Laboratory Evaluations 
Urine or serum pregnancy tests will be performed by the local or site laboratory within 24 hours 
prior to each study vaccination (Day 1 (Visit 01) and approximately Day 22 (Visit 04), and Day 
172 (Visit 09)) on all female subjects of childbearing potential. Results must be negative and 
known prior to randomization on Day 1 (Visit 01) and administration of each study vaccination 
to be eligible for participation in the study and receipt of each dose of study vaccine, 
respectively. 
Clinical safety laboratory parameters to be evaluated after receipt of the first two doses of study 
vaccine will include: WBC, hemoglobin, platelets, ALT, total bilirubin, and creatinine. These 
evaluations will be performed by the central (clinical) laboratory. Venous blood samples 
(approximately 10 mL) will be collected from each subject prior to vaccination at baseline (Visit 
01) and approximately 8 days after Dose 1 and Dose 2 of study vaccination (Visits 02 and 05, 
respectively). 
8.2.2. 
Special Assays or Procedures 
HAI and Neut Antibody 
Assays to determine serum levels of HAI and Neut antibodies will be performed at St Louis 
University. Subjects who withdraw early will have HAI and Neut antibody assays run on 
available sera. 
M-001 Antibody 
Assays to determine serum levels of antibodies to M-001 will be performed by BiondVax.  
Subjects who withdraw early will have M-001 antibody assays run on available sera. 
Cellular Studies  
Assays to measure T cell responses will be performed at Baylor College of Medicine.   

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8.2.3. 
Specimen Preparation, Handling, and Shipping 
8.2.3.1. 
Instructions for Specimen Preparation, Handling, and Storage 
Instructions for specimen preparation, handling, and storage are included in the protocol-specific 
MOP, as appropriate. 
8.2.3.2. 
Specimen Shipment 
Specimen shipment will occur at intervals during the course of this study following all applicable 
International Air Transport Association (IATA) requirements and according to the specifics for 
storage temperature and documentation as detailed in the central (clinical) laboratory manual and 
protocol-specific MOP as appropriate. 
Sera and PBMCs will be shipped from the participating VTEU sites to the DMID CMS.  Sera for 
HAI and neut assays will then be provided by the DMID CMS to St Louis University in a 
blinded manner once they become available to the DMID CMS. Serum samples for detection of 
antibody responses to M-001 will be provided to BiondVax by the DMID CMS in a blinded 
fashion once they become available.  PBMC samples will be provided by the DMID CMS to 
Baylor College of Medicine for the planned cellular assays. 
Further instructions for specimen shipment are included in the central clinical laboratory manual 
and the protocol-specific MOP, as appropriate. 
 

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9. 
ASSESSMENT OF SAFETY 
9.1. 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
1. All SAEs occuring from the time of the first study vaccination through the end of the 
study 
2. Solicited AEs – reactogenicity events occurring on the day of each study vaccination 
through 7 days* after each M-001 study vaccination: 
a)  Injection site reactions including pruritus, ecchymosis, erythema, 
induration/swelling, pain, and tenderness. 
b)  Systemic reactions including fever, feverishness, fatigue, malaise, myalgia, 
arthralgia, headache, and nausea. 
3.  Unsolicited AEs – non-serious AEs occurring from the time of the first M-001 study 
vaccination through approximately 21 days after the second M-001 study vaccination. 
4.  Safety laboratory abnormalities occurring from the time of the first study vaccination 
through 8 days after the last dose of M-001. 
a) Clinical safety laboratory parameters measured: WBC, hemoglobin, platelets, 
ALT, total bilirubin, and creatinine 
9.2. 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1. 
Adverse Events 
Adverse Event (AE): International Conference on Harmonisation (ICH) E6 defines an AE as 
any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product regardless of its causal relationship to the study treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product. 
The occurrence of an AE may come to the attention of study personnel during study visits and 
interviews of a study recipient presenting for medical care, or upon review by a study monitor. 
AEs, including solicited injection site and systemic (subjective and quantitative) reactions, not 
meeting the protocol-defined criteria for SAEs will be captured on the appropriate data collection 
form and electronic case report form (eCRF). Information to be collected for unsolicited AEs 
includes event description, date of onset, licensed study physician’s assessment of severity and 

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relationship to study product and alternate etiology (if not related to study product) (assessed 
only by those with the training and authority to make a diagnosis and listed on the Form FDA 
1572 as the site PI or sub-I), date of resolution of the event, seriousness and outcome. AEs while 
on study will be documented appropriately regardless of relationship. AEs will be followed to 
resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it will be recorded as an AE. 
AEs must be graded for severity and assessed for relationship to study product (see definitions 
below). AEs characterized as intermittent require documentation of onset and duration of each 
episode. The start and stop date of each reported AE will be recorded on the appropriate data 
collection form and eCRF. 
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Severity of Event: AEs will be assessed by a licensed study physician listed on the Form FDA 
1572 as the site PI or appropriate sub-I using a protocol-defined grading system (see Section 
9.2.2). For events not included in the protocol-defined grading system, the following guidelines 
will be used to quantify severity: 
• Mild (Grade 1): Events require minimal or no therapeutic measure(s) and do not interfere 
with the subject’s usual daily activities. 
• Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures. Moderate events cause some interference with functioning and 
usual daily activities. 
• Severe (Grade 3): Events interrupt the subject’s usual daily activities and therapeutic 
measure(s) indicated. Severe events are usually incapacitating. 
Relationship to Study Product: The study physician’s assessment of an AE's relationship to 
study product is part of the documentation process, but it is not a factor in determining what is or 
is not reported in the study. If there is any doubt as to whether a clinical observation is an AE, 
the event should be reported. The relationship to study product must be assessed for AEs using 
the terms: related or not related. In a clinical trial, the study product must always be suspect. To 
help assess, the following guidelines are used: 
• Related – There is a reasonable possibility that the study product caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the AE. 

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• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2. 
Reactogenicity 
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine.  The following Toxicity Grading Scales will be used to grade solicited 
injection site and systemic (subjective and quantitative) reactions: 
Table 2: 
Injection Site Reactogenicity Grading 
Injection Site Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous discomfort) 
Subject is aware of pain, 
but it does not interfere 
with daily activity, and 
no pain medication is 
taken 
Subject is aware of pain; 
there is interference with 
daily activity or it 
requires repeated use of a 
non-narcotic pain reliever 
for >24 hours 
Subject is aware of pain, 
and it prevents daily 
activity or requires any use 
of a narcotic pain reliever 
Tenderness – hurts only 
when injection site is 
touched or the arm is 
moved 
The area immediately 
surrounding the injection 
site hurts only when 
touched or with arm 
motion, and it does not 
interfere with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
interferes with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
prevents daily activity 
Pruritus  
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration/Edema* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
* Will be also measured in mm but size will not be used as halting criteria. 
Ecchymosis, erythema, and induration /edema as analyzed by measurement will be graded as 
follows: 
Table 3: 
Injection Site Reactogenicity Measurements 
Injection Site Reaction 
Small 
Medium 
Large 
Ecchymosis * 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration /Edema* 
<20 mm 
20 mm – 50 mm 
>50 mm 
* Will not be used as halting criteria. 

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Table 4: 
Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness 
(Chills/Shivering/Sweating) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Fatigue  
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise  
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Headache 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Nausea 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
* Not at injection site. 
Oral temperature# will be graded as follows: 
Table 5: 
Quantitative Systemic Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* - oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# Oral temperature assessed on Day 1 prior to the first primary series study vaccination will be considered as baseline. 
* A fever can be considered not related to the study product if an alternative etiology can be documented. 
† Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
9.2.3. 
Additional Adverse Event Severity Grading 
Pulse and blood pressure# will be graded as follows: 
Table 6: 
Pulse and Blood Pressure Grading 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia - beats per minute 
45 – 49 
40 – 44 
<40 
Tachycardia - beats per minute 
116 – 130 
131 – 155 
>155 
Hypotension (systolic) mm Hg 
80 – 84 
75 – 79 
<75 

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Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Hypotension (diastolic) mm Hg 
50 – 54 
45 – 49 
<45 
Hypertension (systolic) mm Hg 
151 – 155 
156 – 160 
>160 
Hypertension (diastolic) mm Hg 
96 – 100 
101 – 105 
>105 
# Pulse and blood pressure assessed on Day 1 prior to the first study vaccination will be considered as baseline.  
Clinical safety laboratory results# will be graded as follows: 
Table 7: 
Clinical Safety Laboratory Adverse Event Grading (28) 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/µL (Decrease) 
2.5 – 3.9 
1.5 – 2.4 
<1.5 
WBC 103/µL (Increase) 
10.6 – 15.0 
15.1 – 20.0 
>20.0 
Hgb g/dL (Decrease) (Female) 
10.1 – 11.4 
8.5 – 10 
<8.5 
Hgb g/dL (Decrease) (Male) 
11.0 – 12.4 
9.5 – 10.9 
<9.5 
Platelets 103/µL (Decrease) 
125 – 139 
100 – 124 
<100 
Platelets 103/µL (Increase) 
416 – 550 
551– 750 
>750 
Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
ALT IU/L (Increase) (Female) 
44 – 100 
101 – 200 
>200 
ALT IU/L (Increase) (Male) 
61 – 138 
139 – 275 
>275 
Total Bilirubin mg/dL (Increase) – when accompanied by 
any increase in ALT 
1.30 – 1.59 
1.60 – 1.80 
>1.80 
Total Bilirubin mg/dL (Increase) – when ALT is normal 
1.30 – 1.89 
1.90 – 2.40 
>2.40 
Creatinine mg/dL (Increase) (Female) 
1.1 – 1.7 
1.8 – 2.0 
>2.0 
Creatinine mg/dL (Increase) (Male) 
1.4 – 1.7 
1.8 – 2.0 
>2.0 
# Clinical laboratory evaluations assessed at the enrollment visit (Visit 01) will be considered as baseline. 
9.2.4. 
Serious Adverse Events 
An AE or suspected AE is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
• death, 
• a life-threatening AE*, 

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• inpatient hospitalization or prolongation of existing hospitalization, 
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• a congenital anomaly/birth defect. 
• important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
• all events described as Guillain-Barré syndrome will also be considered SAEs 
* Life-threatening AE. An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.  
It does not include an AE that, had it occurred in a more severe form, might have caused death. 
All SAEs will be: 
• Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 such 
as the site PI or sub-I. 
• Recorded on the appropriate SAE CRF. 
• Followed through resolution by a licensed study physician listed on the Form FDA 1572. 
• Reviewed and evaluated by an Independent Safety Monitor (ISM), the DSMB (periodic 
review unless related), DMID, and the IRB. 
9.2.5. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
The site PI or appropriate sub-I is responsible for reporting all AE/SAEs that are observed or 
reported during the study, regardless of the relationship to study product. AE/SAEs, abnormal 
clinical laboratory test values, or abnormal clinical findings will be documented, reported, and 
followed appropriately. 

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9.3. 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be documented from the time of 
each study vaccination (Day 1 (Visit 01) and approximately Day 22 (Visit 04)) through 7 days 
after each study vaccination. 
Unsolicited AEs will be documented from the time of the first study vaccination (Day 1 (Visit 
01)) through approximately 21 days after the second M-001 study vaccination (approximately 
Day 43 (Visit 07). 
SAEs will be documented from the time of the first study vaccination (Day 1 (Visit 01)) through 
the end of the study. 
9.3.1. 
Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group at the 
following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, selected SAE data fields must also be entered into AdvantageEDC. 
Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. 
The site will send a copy of the SAE report(s) to the ISM when they are provided to the DMID 
Pharmacovigilance Group. The DMID Medical Monitor and DMID Clinical Project Manager 
will be notified of the SAE by the DMID Pharmacovigilance Group. The DMID Medical 
Monitor will review and assess the SAE for regulatory reporting and potential impact on study 
subject safety and protocol conduct. 
At any time after completion of the study, if the site PI or appropriate sub-I becomes aware of an 
SAE that is suspected to be related to study product, the site PI or appropriate sub-I will report 
the event to the DMID Pharmacovigilance Group. 

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9.3.2. 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site PI or appropriate sub-I, DMID, the Investigational New 
Drug (IND) sponsor, will report any suspected adverse reaction that is both serious and 
unexpected. DMID will report an AE as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the AE. DMID will notify FDA and all 
participating site PIs (i.e., all PIs to whom the sponsor is providing drug under its IND(s) or 
under any PI’s IND(s)) in an IND safety report of potential serious risks from clinical trials or 
any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32. DMID 
will also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as 
soon as possible, but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information. Relevant follow up information to an IND safety report will be submitted as soon as 
the information is available. Upon request from FDA, DMID will submit to FDA any additional 
data or information that the agency deems necessary, as soon as possible, but in no case later 
than 15 calendar days after receiving the request. 
All serious events designated as “not related” to study product(s), will be reported to the FDA at 
least annually in a summary format. 
9.3.3. 
Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported via AdvantageEDC on the Pregnancy 
Case Report form. No further study vaccinations will be administered to pregnant subjects, but, 
with the subject’s permission, all study mandated blood samples will be obtained and the subject 
will continue in follow-up for safety events. Efforts will be made to follow all pregnancies 
reported during the course of the study to pregnancy outcome pending the subject’s permission. 
9.4. 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be followed from the time of the first study vaccination (Day 1 (Visit 01)) through 
approximately 21 days after the second M-001 study vaccination (approximately Day 43 (Visit 
07)  
SAEs will be followed from the time of the first study vaccination (Day 1 (Visit 01)) through 
resolution even if this extends beyond the study-reporting period (end of study)). Resolution of 
an AE/SAE is defined as the return to pretreatment status or stabilization of the condition with 
the expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate data 
collection form. 

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9.5. 
Halting Rules 
Further enrollment and study vaccinations will be halted for DSMB review/recommendation if 
any of the following are reported: 
• Any subject experiences ulceration, abscess, or necrosis at the injection site related to 
study product administration. 
• Any subject experiences laryngospasm, bronchospasm, or anaphylaxis within 1 day after 
administration of study product that is considered related to study product. 
• Two or more subjects experience generalized urticaria within 3 days after administration 
of study product that is considered related to study product. 
• Any subject experiences a study vaccine-related SAE from the time of the first study 
vaccination through the subject’s last study visit. 
• Any subject experiences acute weakness of limbs and/or cranial nerve innervated muscles 
(description of potential signal of GBS) after administration of study product. 
This study will also be halted for DSMB review/recommendation if, within 8 days after 
administration of either of the first 2 vaccine doses of M-001 or placebo, any of the following 
occurs: 
• 5% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date experience the same severe (Grade 3) study vaccine-related 
injection site reaction. Ecchymosis (bruising), erythema (redness), and induration 
(hardness)/edema(swelling) will also be measured in mm but size will not be used as 
halting criteria. 
• 5% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date experience the same severe (Grade 3) study vaccine-related 
subjective systemic reaction, for which the severity (grade) is corroborated by study 
personnel. 
• 5% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date experience the same severe (Grade 3) study vaccine-related 
quantitative systemic reaction. 
• 5% or more of subjects (with a minimum of 3 subjects) who received at least one dose of 
study vaccine to date experience the same severe (Grade 3) study vaccine-related clinical 
safety laboratory AE. 

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Grading scales for solicited injection site and systemic (subjective and quantitative) reactions are 
included in Section 9.2.2. 
If any of the halting rules are met following any subject receipt of any study vaccination, then 
this study will not continue with the remaining enrollments or study vaccinations without a 
review by and recommendation from the DSMB to proceed. 
DMID retains the authority to suspend additional enrollment and study interventions/ 
administration of study product during the entire study, as applicable. 
9.6. 
Safety Oversight (ISM plus DSMB) 
9.6.1. 
Independent Safety Monitor (ISM) 
The ISM is a physician with relevant expertise whose primary responsibility is to provide 
independent safety monitoring in a timely fashion.  The ISM will review SAEs and other AEs as 
needed and provide an independent assessment to DMID.  Each participating study site will have 
an ISM with experience in infectious diseases or internal medicine, in close proximity to the 
participating VTEU site, and have the authority to readily access study participant records. 
9.6.2. 
Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID.  The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 
or other conflict of interest related to this trial.  The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial. 
The DSMB will review study progress and participant, clinical, safety, and reactogenicity data at 
the following time points.  A review of immunogenicity data will be performed as specified 
below. 
• Data review for safety at study-specific time frames; at least annually. 
• After all 8-day post second study vaccination safety data are available for all study 
participants. 
• Final review meeting: 6 to 8 months after clinical database lock to review the cumulative 
unblinded safety and immunogenicity data for this trial.  The data will be provided in a 
standard summary format.  The DSMB may be asked to provide recommendations in 
response to questions posed by DMID. 
• Ad hoc when a halting rule is met, for immediate concerns regarding observations during 
this trial, or as needed.   

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The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB.  At this time, each data element that the DSMB needs to 
assess will be clearly defined.  Procedures for DSMB reviews/meetings will be defined in the 
charter.  The DSMB will review applicable data to include, but not limited to, study progress and 
participant, clinical, safety, and reactogenicity data.  Reports may include enrollment and 
demographic information, medical history, concomitant medications, physical assessments, 
clinical laboratory values, dosing compliance, and solicited and unsolicited AE/SAEs.  
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID.  The DSMB may receive data in aggregate and 
presented by treatment arm.  The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion, and may request the treatment arm be unblinded for 
an individual subject if required for safety assessment.  The DSMB will review grouped and 
unblinded data in the closed session only.  The DSMB will meet and review this data at 
scheduled time points or ad hoc as needed during this trial as defined in the DSMB charter.  As 
an outcome of each review/meeting, the DSMB will make a recommendation as to the 
advisability of proceeding with study vaccinations (as applicable), and to continue, modify, or 
terminate this trial. 
Additionally, SDCC web reports using data entered into AdvantageEDC will be monitored to 
determine if any of the halting rules described in Section 9.5 are met. 
If any of the halting rules are met, the study will not proceed with the remaining enrollment or 
study injections without a review by and recommendation from the DSMB to proceed. 
Upon completion of this review and receipt of the advice of the DSMB, DMID will determine if 
study entry or study dosing should be interrupted or if study entry and study dosing may continue 
according to the protocol. 

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10. 
CLINICAL MONITORING 
10.1. 
Site Monitoring Plan 
Site Monitoring will be conducted to ensure that human subject protection, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet sponsor, CGP/ICH, and regulatory guidelines, and that the study is 
conducted in accordance with the protocol and sponsor SOPs. DMID, the sponsoring agency, or 
its designee will conduct site monitoring visits as detailed in the monitoring plan or in the 
Manual of Procedures.   
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, case report forms, informed consent forms, medical and 
laboratory reports, and protocol compliance.  Study monitors will meet with investigators to 
discuss any problems and actions to be taken and document visit findings and discussions. 

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11. 
STATISTICAL CONSIDERATIONS 
11.1. 
Study Hypotheses  
The study is not designed to test a specific hypothesis for the primary safety objectives. 
Nevertheless, this trial represents an important opportunity to extend the M-001 safety base.  
The  primary immunogenicity objective is to determine whether priming with M-001 improves T 
cell responses. The hypothesis that will be tested is: 
H0: GMPM/GMPc = 1→log10(GMPM)-log(GMPc) = 0   
H1: GMPM/GMPc ≠ 1→log10 (GMPM)-log(GMPc) ≠ 0    
Where GMPM and GMPc  are the geometric mean percentage (GMP) percentage of T cell subsets 
expressing perforin, CD107a, INFg, TNF-a, and IL-2 for the M-001 and control (placebo) 
treatment arms, respectively. 
11.2. 
Study Outcome Measures 
Please refer to Section 3.2. 
11.3. 
Sample Size Considerations 
11.3.1. 
Study Design 
This is a Phase II, randomized, double-blind, controlled trial in 120 males and non-pregnant 
females, 18 to 49 years old, inclusive, who are in good health and meet all eligibility criteria. 
Subjects will be assigned randomly to 1 of 2 treatment arms (60 subjects per treatment arm) to 
receive two doses of M-001 or two placebo controls, followed by IIV4 (see Table 1).  All doses 
will be administered IM approximately 21 days apart. 
Reactogenicity will be measured by the occurrence of solicited injection site and systemic 
reactions from the time of each M-001 study vaccination through 8 days after each study 
vaccination (inclusive of vaccination day).  Unsolicited non-serious AEs will be collected from 
the time of each M-001 study vaccination through approximately 21 days after each M-001 study 
vaccination.  SAEs will be collected from the time of the first study vaccination through end of 
the study.  Clinical laboratory evaluations for safety will be performed on venous blood collected 
approximately 8 days after each M-001 study vaccination (inclusive of vaccination day). 
Immunogenicity testing will be performed as described in Section 8.2.2.  

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11.3.2. 
Study Population 
The study population for this clinical trial includes 120 males and non-pregnant females, 18 to 49 
years old, inclusive, who are in good health and meet all eligibility criteria.  The subjects will be 
recruited from the general population at the participating VTEU sites that have substantial 
experience conducting large influenza vaccine studies.  
11.3.3. 
Subject Enrollment and Follow-up 
Based on the accrual rate for similar studies, it seems reasonable to expect that the participating 
VTEUs will be able to enroll this trial in a timely fashion.  Prior experience suggests up to 5% of 
subjects may be excluded from the per protocol analysis for the primary immunogenicity 
outcome either because they were lost-to-follow-up or otherwise do not have data available 
following the second study vaccination or because they had a protocol deviation requiring their 
exclusion from the per protocol analysis.   
11.3.4. 
Sample Size 
This study is planned to enroll 120 subjects (60 per treatment arm). The following illustrates the 
precision and power that is available for select estimates and comparisons of interest. 
Table 8 indicates the probability of observing one or more safety events, such as solicited 
injection site or systemic reactogenicity events or an unsolicited non-serious AE of a particular 
type, for a single treatment arm (N=60) and all enrolled subjects (N=120).  
Table 8: 
Power (%) to Detect Safety Events 
Event 
Frequency 
Single 
Treatment 
Arm 
N=60 
Two 
Treatment 
Arms 
N=120 
≥10% 
Very Common 
99.8 
>99.9 
≥1% 
Common 
45.3 
70.1 
≥0.1% 
Uncommon 
5.8 
11.3 
≥0.01% 
Rare 
<1 
1.2 
 
Binomial confidence intervals (CI) are widest (have the least precision) when the response rate is 
50%.  Table 9 is presented to indicate the worst case scenario for precision of observed exact 
(Clopper-Pearson) binomial confidence intervals. 

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Table 9: 
Precision of Binomial Confidence Intervals: 
N 
95% CI 
Single Treatment 
Arm 
60 
(36.8,63.2) 
Two Treatment 
Arms 
120 
(40.7, 59.3) 
With N = 60 subjects per arm and assuming the standard deviation of logGMP is 0.75, the study 
will have 80% power to detect a 2.5-fold increase in the GMP of T cell subsets expressing IFN-γ.  
Table 10 illustrates a power analysis considering a range of standard deviations for log GMP and 
a range of GMP fold-change with N=60 subjects per am, and further includes the power under 
the conservative assumption of 10% drop out in each treatment arm. Power is calculated for a 
two-sided t-test with significance level (alpha) 0.05 using PROC POWER in SAS 9.4. 
While there will be multiple comparisons performed for this primary immunogenicity objective 
(for each of five parameters alone measured in CD4 and CD8 T cells plus any combinations 
measured), it is assumed that these analyses are not intended to be confirmatory and thus no 
adjustment for multiple comparisons is considered. 
Table 10: 
Power Analysis for Primary Immunogenicity Endpoint 
GMPe/GMTc 
{fold-
change} 
log10 (GMPM)-log10 (GMPc) 
{log-difference} 
Std Dev  
log10 
(GMP) 
Power (N = 
60) 
Power (N=54) 
10% drop out 
1.5 
0.18 
0.25 
97 
96 
0.50 
49 
45 
0.75 
26 
23 
2 
0.30 
0.25 
>99 
>99 
0.50 
90 
87 
0.75 
58 
54 
3 
0.48 
0.25 
>99 
>99 
0.50 
>99 
99 
0.75 
93 
90 
4 
0.60 
0.25 
>99 
>99 
0.50 
>99 
>99 
0.75 
99 
98 
11.4. 
Planned Interim Analyses 
No interim analysis is planned.  

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11.4.1. 
Interim Safety Review 
A DSMB will be convened by DMID to review study progress and participant, clinical, safety, 
reactogenicity, and immunogenicity data as described in section 9.6.2. Interim Immunogenicity 
Review 
No interim analysis of immunogenicity data is planned.  
11.5. 
Final Analysis Plan 
Once the last subject completes the final visit, the clinical database will be cleaned, monitored 
and locked.  Upon receipt of immunogenicity data (T cell responses after stimulation with M-001 
peptides and with other Influenza A antigens, and M-001 ELISA responses) through Day 200, a 
set of topline tables will be generated. These tables will include summaries of clinical safety data 
and immunogenicity data (as described above) through the end of the study, with data presented 
aggregated by study arm. This topline report will represent a final analysis of safety data 
including reactogenicity, unsolicited non-serious AEs, and SAEs. The immunogenicity analyses 
will represent the final analyses of the included immunogenicity endpoints, and as such no p-
value adjustment is required. The topline report will be made available to the study team for 
planning subsequent trials and may be used for publication. A formal Statistical Analysis Plan 
(SAP) that specifies all planned analyses will be finalized prior to generating the topline report. 
The CSR will be completed when all cellular and humoral immunogenicity data through Day 
200 are available.  
11.5.1. 
Analysis Populations 
The Safety Analysis population includes all subjects who received at least one dose of study 
vaccine. 
The modified intent-to-treat (mITT) population includes all subjects who received at least one 
dose of study vaccine and contributed both at least one post-study vaccination venous blood 
samples for immunogenicity testing for which valid results were reported. 
The per protocol (PP) population includes all subjects in the ITT subset with the following 
exclusions: 
• Data from all available visits for subjects found to be ineligible at baseline 
• Data from all visits subsequent to major protocol deviations, such as: 
• Second or third study vaccination not received 

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• Second or third study vaccination received out of window 
• Receipt of non-study licensed live vaccine within 30 days before or 21 days after 
each study vaccination 
• Receipt of non-study licensed inactivated vaccine within 14 days before or 21 
days after each study vaccination 
• Receipt of non-study seasonal influenza vaccine (live or inactivated) within 30 
days before or for the duration of the study  
• Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days 
before or after each of the first two study vaccinations (Dose 1 and Dose 2)  
• Data from any visit that occurs out of window 
In the case of mis-randomization, subjects will be analyzed according to the study product 
actually received for all analysis populations. 
11.5.2. 
Safety Data 
Summaries and analysis of safety data will be presented for the Safety Analysis Population. 
Solicited AEs will be summarized by severity for each day after each study vaccination (Days 1-
8 post each study vaccination) and as the maximum severity over all 8 days.  Additionally, 
solicited AEs will be analyzed by taking the most severe response over the follow-up period, 
dichotomizing into a binary variable (none versus mild, moderate, or severe) and using standard 
techniques, such as exact confidence intervals, to summarize the proportion of subjects reporting 
each symptom, any injection site symptom, and any systemic symptom.  Summaries of solicited 
AEs will be presented separately for each study vaccination as well as overall study vaccinations 
by treatment arm.  The proportion of subjects reporting symptoms may be compared between 
treatment arms using Chi-square or Fisher’s exact test, as appropriate.  The proportion of 
subjects reporting solicited symptoms between the different study vaccinations (e.g., dose 1 vs. 
dose 2 or dose 3 vs dose 4) will be compared using McNemar’s test. 
Unsolicited AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) for 
preferred term and system organ class (SOC).  The numbers of SAEs are expected to be small in 
this trial and will be reported by detailed listings showing the event description, MedDRA 
preferred term and SOC, relevant dates (study vaccinations and AEs), severity, relatedness, and 
outcome for each event.  Non-serious unsolicited AEs will be summarized as number and 
percentage of subjects reporting at least one event in each MedDRA preferred term and SOC, 
cross tabulated by severity and relationship to study product.  Additionally, the proportion of 
subjects and exact 95% confidence intervals of AEs in aggregate and by MedDRA categories 
will be computed. 

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Clinical laboratory data will be summarized by severity for each visit and as the maximum over 
all post-study vaccination visits.  Graphical presentations such as box plots will be used to 
illustrate the change from baseline. 
11.5.3. 
Humoral Immunogenicity Data  
Summaries and analysis of immunogenicity data will be presented for the ITT and PP 
populations; the PP population will be considered the primary analysis. 
Immune responses in terms of strain-specific (IIV4 strains) HAI and Neut antibody titers will be 
summarized by treatment arm at each time point.  Analyses at all time points will include 
proportion of subjects with titers ≥40 and geometric mean titers (GMTs). Additionally the 
proportion of subjects achieving seroconversion from Day 172 to Day 200 (defined as either a 
pre-vaccination titer <10 and a post-vaccination titer ≥40 or a pre-vaccination titer ≥10 and a 
minimum four-fold rise in post-vaccination antibody titer) will be presented. All summaries will 
include the corresponding 95% confidence intervals.   
The proportion of subjects with seroconversion from Day 172 to 200 will be compared to 
evaluate the effect of M-001 priming using a two-sided Likelihood Ratio Test.  
M-001 antibody response will be summarized by GMTs the proportion of subjects achieving 
seroconversion (defined as a minimum four-fold rise in post-vaccination ELISA antibody titer) at 
each time point, with corresponding 95% confidence intervals. 
The correlation between HAI, Neut, and M-001 antibody titers will be evaluated.  Plots such as 
reverse cumulative distributions or longitudinal presentations of GMTs will be presented for 
each assay. 
11.5.4. 
Cell Mediated Immunity Data 
Cellular immunogenicity assays will also be performed to assess if M-001 induces a cellular 
immune response, or primes for a cellular immune response to IIV4.  T cell response will be 
measured as the percentage of T cell subsets expressing perforin, CD107a, IFN-γ, TNF-α, and 
IL2, alone or in combination in CD4 or CD8 T cells. For each measure at all time points,  the 
GMP and corresponding 95% confidence interval will be presented. For the primary endpoint of 
T cell response against M-001 peptides 14 days post dose 2, a t-test will be used to compare 
GMPs between treatment arms. 
11.5.5. 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol.  As missing data are expected to be 
minimal, no imputation will be performed for missing values.  Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier.  If 
data points are identified as outliers, sensitivity analyses will be performed to examine the 

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

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

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

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14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1. 
Ethical Standard 
The site PI will ensure that this trial is conducted in full conformity with principles of the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research of the National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 50 and 56, and ICH 
E6; 62 Federal Regulations 25691 (1997), if applicable. The site PI’s Institution will hold a 
current Federal Wide Assurance (FWA) issued by the Office of Human Research Protection 
(OHRP) for federally funded research. 
14.2. 
Institutional Review Board 
Prior to enrollment of subjects into this trial, the approved protocol and informed consent form 
will be reviewed and approved by the appropriate IRB listed on its FWA. 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to 
the start of this trial and a copy will be provided to DMID. The IRB Federal Wide Assurance 
number will be provided to DMID. 
Should amendments to the protocol be required, the amendments will be written by the sponsor 
and provided to the site PI for submission to the IRB. 
14.3. 
Informed Consent Process 
The site PI will choose subjects in accordance with the eligibility criteria detailed in Section 5. 
Before any study procedures are performed, subjects must sign an informed consent form that 
complies with the requirements of 21 CFR Part 50 and 45 CFR 46 and the local IRB. 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Before any study procedures 
are performed, subjects will receive a comprehensive explanation of the proposed study 
procedures and study interventions/products, including the nature and risks of the trial, alternate 
therapies, any known AEs, the investigational status of the components, and the other elements 
that are part of obtaining proper informed consent. Subjects will also receive a detailed 
explanation of the proposed use and disclosure of their protected health information, including 
specifically their serum samples. Subjects will be allowed sufficient time to consider 
participation in the trial, after having the nature and risks of the trial explained to them, and have 
the opportunity to discuss the trial with their family, friends or legally authorized representative 
or think about it prior to agreeing to participate.  

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Informed consent forms describing in detail the study interventions/products, study procedures, 
risks and possible benefits are given to subjects. The informed consent form must not include 
any exculpatory statements. Informed consent forms will be IRB-approved and subjects will be 
asked to read and review the appropriate document. Upon reviewing the appropriate document, 
the site PI (or designee) will explain the research study to subjects and answer any questions that 
may arise. Subjects must sign the informed consent form, and written documentation of the 
informed consent process is required prior to starting any study procedures/interventions being 
done specifically for the trial, including administering study product. 
DMID will provide the site PI, in writing, any new information that significantly impacts the 
subjects' risk of receiving the investigational product. This new information will be 
communicated by the site PI to subjects who consent to participate in the trial in accordance with 
IRB requirements. The informed consent document will be updated and subjects will be re-
consented per IRB requirements, if necessary. 
Study personnel may employ IRB-approved recruitment efforts prior to obtaining the subjects 
consent; however, before any study procedures are performed to determine protocol eligibility an 
informed consent form must be signed. Subjects will be given a copy of all informed consent 
forms that they sign. 
By signing the informed consent form, subjects agree to complete all evaluations required by the 
trial, unless the subject withdraws voluntarily, or is withdrawn or terminated from the trial for 
any reason. 
The rights and welfare of subjects will be protected by emphasizing to subjects that the quality of 
their medical care will not be adversely affected if they decline to participate in or withdraw 
from this trial. 
14.4. 
Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will be inclusive of all adults who meet the Subject Inclusion/Exclusion Criteria, 
regardless of religion, sex, or ethnic background. Should the outcome of this trial be deemed 
acceptable, additional trials may be initiated in other populations. 
It is unknown if the M-001 vaccine poses any risks to an unborn child. Female subjects of 
childbearing potential who are not surgically sterile via tubal sterilization, bilateral 
oophorectomy, or hysterectomy or who are not postmenopausal for ≥ 1 year must agree to 
practice highly effective contraception that may include, but is not limited to, abstinence from 
intercourse with a male partner, monogamous relationship with a vasectomized partner, male 
condoms with the use of applied spermicide, intrauterine devices, and licensed hormonal 
methods, with use of a highly effective method of contraception for a minimum of 30 days prior 
to study product exposure and agree to practice highly effective contraception for the duration of 

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study product exposure, including 2 months (defined as 60 days) after the last study vaccination. 
A highly effective method of contraception is defined as one which results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly. In addition to contraceptive 
use, all female subjects of childbearing potential will be required to have a negative serum or 
urine pregnancy test within 24 hours prior to receiving each dose of study vaccine. If a female 
subject becomes pregnant while participating in this study, we will ask her permission to follow-
up with her about her health and the health of her baby through pregnancy outcome. 
Children will not be included in this trial as presently there are no safety or efficacy data on this 
regimen in adults.  Should the outcome of this trial be deemed acceptable, additional trials may 
be initiated in other populations. 
14.5. 
Subject Confidentiality 
Subjects will have code numbers and will not be identified by name. Subject confidentiality is 
strictly held in trust by the participating site PIs, their study personnel, the sponsor(s), and their 
agents. This confidentiality is extended to cover testing of biological samples, 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 trial or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All information provided by the Sponsor and all data and information generated by the 
participating VTEU site as part of the trial (other than a subject’s medical records) will be kept 
confidential by the site PI and other study personnel to the extent permitted by law. This 
information and data will not be used by the site PI or other study personnel for any purpose 
other than conducting the trial. These restrictions do not apply to: (1) information which 
becomes publicly available through no fault of the site PI or other study personnel; (2) 
information which is necessary to disclose in confidence to an IRB solely for the evaluation of 
the trial (3) information which is necessary to disclose in order to provide appropriate medical 
care to a study subject; or (4) study results which may be published as described in Section 16. If 
a written contract for the conduct of the trial which includes confidentiality provisions 
inconsistent with this statement is executed, that contract’s confidentiality provisions shall apply 
rather than this statement. 
The study monitor, applicable regulatory authorities, such as the FDA, or other authorized 
representatives of the sponsor may inspect all documents and records required to be maintained 
by the site PI. This includes, but is not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the subjects in this trial. The participating VTEU sites will permit access to 
such records. 

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To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the Federal 
Food and Drug Administration (FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others. 
14.6. 
Study Discontinuation 
If the trial is discontinued, subjects who sign the informed consent form, and are randomized and 
vaccinated will continue to be followed for safety assessments. No further study vaccinations 
will be administered. 
14.7. 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for taking part in this trial. 
Subjects may be compensated for their participation in this trial. Compensation will be in 
accordance with the local IRB’s policies and procedures, and subject to IRB approval. 
If it is determined by the participating VTEU site and the site PI that an injury occurred to a 
subject as a direct result of the tests or treatments that are done for this trial, then referrals to 
appropriate health care facilities will be provided to the subject. Study personnel will try to 
reduce, control, and treat any complications from this trial. Immediate medical treatment may be 
provided by the participating VTEU site, such as giving emergency medications to stop 
immediate allergic reactions to the study vaccine. No financial compensation will be provided to 
the subject by the participating VTEU site for any injury suffered due to participation in this trial 
beyond that provided by clinical trial insurance and the PREP act. 

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14.8. 
Future Use of Stored Specimens 
Residual samples/specimens are those that are left over after the study has been completed. 
Subjects will be asked for permission to keep any remaining (residual) samples (serum) derived 
from venous blood samples for possible use in future research studies, such as examining 
additional immunological assessments or testing for antibodies against other viruses or bacteria. 
Samples will be stored at a central clinical storage facility for future use and may be shared with 
investigators at the participating VTEU sites and with other investigators at other institutions 
once the clinical study report has been finalized. The samples will not be sold or used directly for 
production of any commercial product. No human genetic tests will be performed on samples. 
Each sample will be encoded (labeled) only with a barcode and a unique tracking number to 
protect subject’s confidentiality. 
There are no benefits to subjects in the collection, storage and subsequent research use of 
specimens. Reports about future research done with subject’s samples will NOT be kept in their 
health records.  
Subjects may be given the option to decide if they want their samples to be used for future 
research or have their samples destroyed at the end of this trial. The subject’s decision can be 
changed at any time by notifying the study doctors or nurses in writing. However, if the subject 
originally consents to future use and subsequently changes his/her decision, any data from a 
previously collected sample may still be used for this research. 
14.9. 
Disclosure of Individual Research Information 
In this protocol, we intend to provide each participant with a lay summary of overall study 
results.  In addition, participants may choose to receive their treatment assignment and will be 
informed about any risks and benefits of disclosure.  Offering participants the option to decline 
and explaining the clinical significance of individual treatments is intended to minimize the 
negligible risks associated with disclosure.  Interested subjects will be asked to provide contact 
information for receipt of the information.  Results will be provided in an IRB-approved written 
document after the Clinical Study Report has been finalized. 
 

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

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15.3. 
Types of Data 
Data for this study will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values, reactogenicity, and immunogenicity data). 
15.4. 
Timing/Reports 
The clinical study report (CSR) will include clinical, safety, reactogenicity, and humoral and 
cellular immunogenicity data through the final visit.  Once the last subject completes the final 
visit, the clinical database will be cleaned, monitored and locked.   
Upon receipt of immunogenicity data (T cell responses after stimulation with M-001 peptides 
and with other Influenza A antigens, and M-001 ELISA responses) through Day 200, a set of 
topline tables will be generated. These tables will include summaries of clinical safety data and 
immunogenicity data (as described above) through the end of the study, with data presented 
aggregated by study arm. This topline report will represent a final analysis of safety data 
including reactogenicity, unsolicited non-serious AEs, and SAEs. The immunogenicity analyses 
will represent the final analyses of the included immunogenicity endpoints, and as such no p-
value adjustment is required. The topline report will be made available to the study team for 
planning subsequent trials and may be used for publication. 
Unblinded analyses of safety, reactogenicity, and immunogenicity, including all primary and 
secondary endpoint data will be performed by the SDCC after the clinical database is locked.The 
CSR will be completed when all cellular and humoral immunogenicity data through day 28 
following receipt of IIV4 are available. 
After full analysis and final reporting is complete, and upon request and DMID approval, the 
SDCC will provide the participating VTEU sites with a summary of results by treatment arm 
and/or subject treatment assignments. In this regard, the participating VTEU sites requesting 
such information to share with study subjects must do so in compliance with their respective IRB 
guidelines. 
15.5. 
Study Records Retention 
Study records and reports, including, but not limited to, eCRFs, source documents, informed 
consent forms, and study drug disposition records, shall be maintained for 2 years after a 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for the drug, 
until 2 years after the investigation is discontinued and FDA has been so notified. Informed 
consent forms for future use will be maintained as long as the sample exists. 
The participating VTEU site must contact DMID for authorization prior to the destruction of any 
study records. 

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15.6. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements.  The noncompliance may be either on the part of 
the subject, the investigator, or the study site staff.  As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site principal investigator and other study personnel to use 
continuous vigilance to identify and report deviations within five working days of identification 
of the protocol deviation, or within five working days of the scheduled protocol-required 
activity. All deviations must be promptly reported to DMID, via the SDCC’s AdvantageEDCSM. 
All protocol deviations, as defined above, must be addressed in study subject DCFs. A 
completed copy of the DMID Protocol Deviation Form must be maintained in the Regulatory 
File as well as in the subject's chart. Protocol deviations must be sent to the local IRB per its 
guidelines. The site principal investigator and other study personnel are responsible for knowing 
and adhering to their IRB requirements. 
 

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

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17. 
LITERATURE REFERENCES 
1.   Centers for Disease Control and Prevention. Estimates of death associated with seasonal 
influenza--- United States, 1976-2007.  MMWR 2010; 59 (33):1057-62. 
2.  Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, et al. Influenza-
associated hospitalizations in the United States.  JAMA 2004; 292 (11):1333-40. 
3.   Reed C, Chaves SS, Daily KP, Emerson R, Aragon D, Hancock EB, et al. Estimating 
influenza disease burden from population-based surveillance data in the United States. PLoS 
One 2015; 10(2):e0118369. 
4.   Subbarao K, Klimov A, Katz J, et al.  Characterization of an avian influenza A (H5N1) virus 
isolated from a child with a fatal respiratory illness.  Science 1998; 279:393-6. 
5.   Peiris M, Yuen KY, Leung CW, et al.  Human infection with influenza H9N2.  Lancet 1999; 
354:916-7. 
6.   CDC.  Emergence of Avian influenza A/H7N9 Virus Causing Severe Human Illness — 
China, February-April 2013.  MMWR 2013 May 10; 62(18):366-71. 
7.   Fouchier RA, Schneeberger PM, Rozendaal FW, et al.  Avian influenza A virus H7N7 
associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome.  
Proc Natl Acad Sci USA 2004 Feb 3; 101 (5):1356-61. 
8.   Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, et al.  Pneumonia and respiratory 
failure from swine-origin influenza A (H1N1) in Mexico.  N Engl J Med 2009 Aug 13; 
361(7):680-9. 
9.   Lindstrom S, Garten R, Balish A, et al.  Human infections with novel reassortant influenza A 
(H3N2)v viruses, United States, 2011.  Emerg Infect Dis 2012; 187:834-7. 
10. Oxford JS.  Influenza A pandemics of the 20th century with special reference to 1918: 
virology, pathology and epidemiology.  Rev Med Virol 2000; 10:119-33. 
11. Patriarca PA, Cox NJ.  Influenza pandemic preparedness plan for the United States.  J Infect 
Dis 1997; 176:S4-7. 
12. Couch RB, Kasel JA.  Immunity to influenza in man.  Annu Rev Microbiol 1983; 37:529-
49. 
13. Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, Liebner JC, Lambkin-Williams R, 
Gilbert A, Oxford J, Nicholas B, Staples KJ, Dong T, Douek DC, McMichael AJ, Xu XN. 
Preexisting influenza-specific CD4+ T cells correlate with disease protrection against 
influenza challenge in humans.  Nat Med 2012; 18:274-80. 
14. Gottlieb T, Ben-Yedidia T. Epitope-based approaches to a universal influenza vaccine. J 
Autoimmun 2014; 54:15-20. 
15. Adar Y, Singer Y, Levi R, Tzehoval E, Perk S, Banet-Noach C, Nagar S, Arnon R, Ben-
Yedidia T.  A universal epitope-based influenza vaccine and its efficacy against H5N1. 
Vaccine 2009; 27(15):2099-17. 
16. BiondVax Pharmaceuticals Limited. Multimeric-001 Investigator’s Brochure. 
 
 

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17. Atsmon J, Kate-Ilovitz E, Shaikevich D, Singer Y, Volokhov I, Haim KY, Ben-Yedidia T. 
Safety and immunogenicity of multimeric-001 – a novel universal influenza vaccine.  J Clin 
Immunol 2012; 32(3):595-603. 
18. Atsmon J, Caraco Y, Ziv-Sefer S, Shaikevich D, Abramov E, Volokhov I, Bruzil S, Haima 
KY, Gottlieb T, Ben-Yedidia T. Priming by a novel universal influenza vaccine (Multimeric-
001) – a gateway for improving immune response in the elderly population.  Vaccine 2014; 
32(44):5816-23. 
19. Lasky T, Tarracciano GJ, Magder L, Koski CL, Ballesteros M, Nash D, Clark S, Haber P, 
Stolley PD, Schonberger LB and Chen RT. The Guillain-Barré syndrome and the 1992-1993 
and 1993-1994 influenza vaccines. N Engl J Med 1998; 339:1797-1802. 
20. Haber P, DeStefano F, Angulo FJ, Iskander J, Shadomy SV, Weintraub E and Chen RT. 
Guillain-Barré syndrome following influenza vaccination. JAMA 2004; 292:2478-2481. 
21. De Wals P, Deceuninck G, Toth E, et al. Risk of Guillain-Barré Syndrome Following H1N1 
Influenza Vaccination in Quebec. JAMA 2012; 308(2):175-181. 
22. Wise ME, Viray M, Sejvar JJ, et. al. Guillain-Barré syndrome during the 2009-2010 H1N1 
influenza vaccination campaign: population-based surveillance among 45 million Americans. 
Am J Epidemiol 2012; 175:1110-1119. 
23. Juurlink DN, Stukel TA, Kwong J, et al. Guillain-Barré syndrome after influenza vaccination 
in adults: a population-based study. Arch Intern Med 2006 Nov 13; 166(20):2217-21. 
24. Lasky T, Terracciano GJ, Mager L, et. al. The Guillain-Barré syndrome and the 1992- 1993 
and 1993-1994 influenza vaccines. N Engl J Med 1998 Dec 17; 339(25):1797-802. 
25. Salmon DA, Proschan M, Forshee R, et al. Association between Guillain-Barré syndrome 
and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. 
Lancet 2013; 318(9876):1461-1468. 
26. Polakowski LL, Sandhu, SK, Martin DB, et al. Chart-confirmed Guillain-Barré syndrome 
after 2009 H1N1 influenza vaccination among the medicare population, 2009-2010. Am J 
Epidemiol 2013;178(6):962-73. 
27. Dodd CN, Romio SA, Black S, et al. International collaboration to assess the risk of Guillain 
Barré syndrome following influenza A (H1N1) 2009 monovalent vaccines. Vaccine 
2013;31(40):4448-58. 
28. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials, September 2007. 
 
 

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SUPPLEMENTS/APPENDICES 

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APPENDIX A: SCHEDULE OF EVENTS 

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Table 11: 
Protocol 14-0112, “A Phase II, Double Blind, Multicenter, Randomized, Placebo-controlled Trial to Assess the 
Safety, Reactogenicity and Immunogenicity of Two Doses of Multimeric-001 (M-001) Followed by Seasonal 
Quadrivalent Influenza Vaccine” 
Study Visit (V) 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
Study Day 
1 
9 
15 
22 
30 
36 
43 
78 
172 
186 
200 
200+ 
Visit Windows 
 
(+2) 
(+2) 
(+2) 
(+2) 
(+2) 
(+7) 
(+7) 
142-202 
(+3) 
(+7) 
(+14) 
Sign Consent Form1 
X 
 
 
 
 
 
 
 
 
 
 
 
Assess eligibility 
X 
 
 
X 
 
 
 
 
X 
 
 
 
Collect demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
Review Medical History 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X7 
X7 
X7 
X7 
X7 
Vital signs2 
X 
{X} 
{X} 
X 
{X} 
{X} 
{X} 
{X} 
X 
{X} 
{X} 
 
Height, Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
 
Review contraception/ Counseling3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Test2,4 
X 
 
 
X 
 
 
 
 
X 
 
 
 
Blood - Safety Labs (10 mL) 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Blood – Antibody Assays (10-20 mL) 
X 
 
 
X 
 
 
X 
X 
X* 
 
X* 
 
Blood – PBMCs (40-60 mL) 
X= 
 
X 
 
 
X 
X= 
X 
X 
X 
X 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE Assessment2# 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vaccination4 
X5 
 
 
X5 
 
 
 
 
X 
 
 
 
Evaluate vaccination site 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
Postvaccination procedures6 
X 
 
 
X 
 
 
 
 
 
 
 
 
Review Memory Aid Data 
 
X 
 
 
X 
 
 
 
 
 
 
 
Blood volume (mL) 
80 
10 
40 
10 
10 
40 
70 
50 
60 
40 
60 
 
{ } required at this visit only if clinically indicated  
1Consent process completed and form signed before any study-related procedures are conducted.  

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2Vital signs include blood pressure, pulse, and oral temperature.  On vaccination visits, these items should be completed prior to vaccination.  
3Counseling on avoidance of pregnancy for women of childbearing potential.  
4Urine or serum pregnancy test must be negative and be completed within 24 hours prior to vaccination for women of childbearing potential.   
5All subjects will be observed for a minimum of 20 minutes following vaccination.  
6Post-vaccination procedures will include documentation of any reactogenicity during the observation period and any AEs/SAEs post-vaccination, as well as 
provision of Memory Aid and instructions on completion. 
 7 Concomitant medications (vaccines only) will be recorded on the appropriate data collection form after Visit 7 through the end of the study. 
+Visit 12 will occur as a phone call only if visit 11 occurs prior to Study Day 200. 
*20 mL of blood will be collected for antibody assays on these days; 10 mL will be collected on other days of collection for antibody assays 
=60 mL of blood will be collected for PBMCs on these days; 40 mL will be collected on other days of PBMC collection 
#AEs will be limited to SAEs after 21 days after M-001 study vaccinations.