A Pivotal Multi-center, Randomized, Modified Double-blind, Placebo-controlled Phase 3 Trial to Assess the Safety and Clinical Efficacy of M-001 Influenza Vaccine Administered Intra-muscularly Twice in Older Adults and Elderly (≥50 Years).
Phase: PHASE3
Conditions: Influenza
Sponsor: BiondVax Pharmaceuticals ltd.

 
 
 
STUDY PROTOCOL 
 
 
 
A pivotal, multicentre, randomized, modified double-blind, placebo-
controlled phase 3 trial to assess the safety and clinical efficacy of M-001, an 
influenza vaccine administered intramuscularly twice in older adults and the 
elderly (≥50 years of age). 
 
 
  
Sponsor: 
BiondVax Pharmaceuticals Ltd. 
Jerusalem Biopark, Hadassah Ein Kerem,  
Jerusalem, Israel 
Tel No.: +972 8 9302529  Fax No.: +972 8 9302531 
EudraCT number:  
2018-000468-27 
ClinicalTrials.gov identifier: 
NCT03450915 
Version and date of the Protocol: Version 5.0 final dated 08th May2019 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document is considered privileged and confidential, and may not be 
disclosed to others except to the extent necessary to obtain Ethics Committee approval, informed 
consent and the approval of local regulatory authorities as required by local law. 

Study protocol BVX-010  
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CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
 
 
 
 
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STATEMENT OF COMPLIANCE 
This study will be performed in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments) and local legal and regulatory requirements 
SIGNATURE PAGE  
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to Good Clinical Practice (GCP), the Declaration of Helsinki (with 
amendments) and the laws and regulations of the countries in which the study takes 
place 
 
 
 
Sponsor 
 
Tamar Ben-Yedidia, PhD 
Representative 
Chief Scientific officer 
 
 
 
BiondVax Pharmaceuticals ltd 
 
 
 
Jerusalem Biopark, Hadassah Ein Kerem, Jerusalem, Israel. 
 
 
 
 
Date_____________ Signature___________________ 
 
 
May 9th, 2019

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INVESTIGATOR’S COMPLIANCE DECLARATION  
 
I have read this protocol and agree to conduct the study as outlined herein, and as implemented 
by any future protocol amendment/update, according to the terms of the clinical trial contract, 
and in accordance with supplementary study: conduct procedures and/or guidance or documents 
provided by the study sponsor, complying with the obligations and requirements of clinical 
investigators and all other requirements listed in relevant national and international regulations 
including 21 CFR part 312 and ICH GCP guidelines. 
I assume responsibility for the compliance of the site personnel reporting to me or assisting me 
with the study. 
I confirm that I am aware of my obligations towards relevant regulatory authorities as it 
concerns my participation in this trial as investigator. 
I agree to disclose and provide information to the Sponsor on any potential conflict of interest I 
may have participating in this study as investigator. 
I declare that I will co-operate with the Sponsor personnel and/or representatives, and vendors 
managing or supporting the study, including CRO, timely and adequately to ensure timely study 
conduct and compliance with study documents and relevant regulations. 
 
 
Protocol: BVX-010, version 5.0 dated May 08th 2019 EudraCT number:  2018-000468-27 
 
 
 
 
 
_______________________________________________________________ 
Investigator’s signature 
 
__________________ 
Date 
 
___________________________________________ 
 
Investigator’s Name (Please print) 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................. 2 
SIGNATURE PAGE ........................................................................................................ 2 
INVESTIGATOR’S COMPLIANCE DECLARATION ................................................. 3 
LIST OF ABBREVIATIONS ........................................................................................... 8 
PROTOCOL SYNOPSIS ................................................................................................. 9 
1. 
KEY ROLES ............................................................................................................ 19 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................ 20 
2.1. Background Information ..................................................................................... 20 
2.1.1. Influenza ................................................................................................. 20 
2.1.2. Multimeric-001 (M-001)......................................................................... 20 
2.2. Rationale ............................................................................................................. 22 
2.3. Potential Risks and Benefits ............................................................................... 22 
2.3.1. Potential Risks ........................................................................................ 22 
2.3.2. Known Potential Benefits ....................................................................... 24 
3. 
OBJECTIVES .......................................................................................................... 25 
3.1. Study Objectives ................................................................................................. 25 
3.1.1. Primary Objectives ................................................................................. 25 
3.1.2. Secondary Objectives ............................................................................. 25 
3.1.3. Exploratory Objectives ........................................................................... 25 
3.2. Study Outcome Measures ................................................................................... 26 
3.2.1. Primary Outcome Measures.................................................................... 26 
3.2.2. Secondary Outcome Measures................................................................ 26 
3.2.3. Exploratory Outcome Measures ............................................................. 27 
4. 
STUDY DESIGN .................................................................................................... 29 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ................................................. 30 
5.1. Subject Inclusion Criteria .................................................................................... 30 
5.2. Subject Exclusion Criteria................................................................................... 30 
5.3. Treatment Assignment Procedures ..................................................................... 31 
5.3.1. Randomization Procedures ..................................................................... 31 
5.3.2. Masking Procedures ................................................................................ 31 
5.3.3. Reasons for Withdrawal.......................................................................... 32 
5.3.4. Handling of Withdrawals ........................................................................ 33 
5.3.5. Termination of Study .............................................................................. 34 
6. 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT............................. 35 

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6.1. Study Product Description .................................................................................. 35 
6.1.1. Acquisition .............................................................................................. 35 
6.1.2. Product Storage and Stability Procedures ............................................... 36 
6.2. Modification of Study Intervention/Investigational Product for a Participant.... 37 
6.3. Accountability Procedures for the Study Intervention/ Investigational Product 37 
6.4. Assessment of Subject Compliance with Study Intervention/ Investigational 
Product .................................................................................................... 38 
6.5. Concomitant Medications/Treatments ................................................................ 38 
7. 
STUDY SCHEDULE .............................................................................................. 40 
7.1. Enrollment/Baseline (Visit 1, Day 0, Dose 1, Site Visit).................................... 40 
7.2. Second Vaccination ............................................................................................. 41 
7.2.1. Visit 2, Day 22, Site Visit (22 days [+9 days] post first study vaccination 
day) .................................................................................................. 41 
7.2.2. Visit 3, Day 36, Site Visit (14 days [±2 days] post second study 
vaccination day(visit 3 - in season 2019/20 only) ........................... 42 
7.3. Follow up period for safety and efficacy: ........................................................... 43 
7.4. Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ Electronic 
Communication (180 days [+/-14 days] post last study vaccination) ..... 46 
7.5. Follow Up Period for Efficacy Season 2............................................................. 46 
7.6. Follow Up Period for Efficacy Season 3............................................................. 46 
7.7. Early Termination Visit....................................................................................... 46 
7.8. Unscheduled Visit ............................................................................................... 47 
8. 
STUDY PROCEDURES/EVALUATIONS ............................................................ 48 
8.1. Clinical Evaluations ............................................................................................ 48 
8.2. Laboratory Evaluations ....................................................................................... 49 
8.2.1. Clinical Laboratory Evaluations ............................................................. 49 
8.2.2. Nasopharyngeal Samples ........................................................................ 49 
8.2.3. Special Assays or Procedures ................................................................. 49 
8.2.4. Specimen Preparation, Handling, and Shipping ..................................... 50 
9. 
ASSESSMENT OF SAFETY .................................................................................. 51 
9.1. Specification of Safety Parameters ..................................................................... 51 
9.2. Safety Assessment ............................................................................................... 51 
9.2.1. Adverse Events ....................................................................................... 51 
9.2.2. Reactogenicity ........................................................................................ 53 
9.2.3. Additional Adverse Event Severity Grading .......................................... 55 
9.2.4. Serious Adverse Events .......................................................................... 55 

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9.3. Reporting Procedures .......................................................................................... 56 
9.3.1. Serious Adverse Events .......................................................................... 57 
9.3.2. Reporting of Pregnancy .......................................................................... 57 
9.4. Type and Duration of Follow-up of Subjects after Adverse Events ................... 57 
9.5. Safety Oversight (DSMB) ................................................................................... 58 
9.6. Efficacy Assessment ........................................................................................... 59 
9.6.1. Molecular Detection and Sequencing Methodology (qRT-PCR): .......... 59 
9.6.2. Influenza Culture: ................................................................................... 59 
10. CLINICAL MONITORING .................................................................................... 60 
10.1. 
Site Monitoring ....................................................................................... 60 
11. STATISTICAL CONSIDERATIONS .................................................................... 61 
11.1. 
Study Hypotheses .................................................................................... 61 
11.2. 
Study Outcome Measures ....................................................................... 61 
11.3. 
Sample Size Considerations .................................................................... 61 
11.3.1. Study Design ........................................................................................... 61 
11.3.2. Study Population and Sample Size ......................................................... 62 
11.3.3. Subject Enrollment and Follow-up ......................................................... 62 
11.4. 
Planned Interim Analyses ....................................................................... 62 
11.4.1. Interim Safety Review ............................................................................ 62 
11.4.2. Interim Efficacy Review ......................................................................... 63 
11.5. 
Final Analysis Plan ................................................................................. 63 
11.5.1. Analysis Populations............................................................................... 63 
11.5.2. Analysis of Safety Data .......................................................................... 64 
11.5.3. Analysis of Efficacy Data ....................................................................... 64 
11.5.4. Missing Values and Outliers ................................................................... 66 
11.5.5. Statistical Software ................................................................................. 66 
12. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS . 67 
13. QUALITY CONTROL AND QUALITY ASSURANCE....................................... 68 
14. ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................... 69 
14.1. 
Ethical Standard ...................................................................................... 69 
14.2. 
Ethics Committees and Competent Authorities ...................................... 69 
14.3. 
Informed Consent Process ...................................................................... 69 
14.4. 
Exclusion of Women, Minorities, and Children (Special Populations) .. 70 
14.5. 
Subject Confidentiality ........................................................................... 70 
14.6. 
Study Discontinuation ............................................................................. 71 

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14.7. 
Costs, Subject Compensation, and Research Related Injuries ................ 71 
14.8. 
Future Use of Stored Specimens ............................................................. 72 
14.9. 
Disclosure of Individual Research Information ...................................... 72 
15. DATA HANDLING AND RECORD KEEPING ................................................... 73 
15.1. 
Data Management Responsibilities ......................................................... 73 
15.2. 
Data Capture Methods ............................................................................ 73 
15.3. 
Types of Data .......................................................................................... 74 
15.4. 
Timing/Reports ....................................................................................... 74 
15.5. 
Study Records Retention ......................................................................... 74 
15.6. 
Protocol Deviations ................................................................................. 74 
16. PUBLICATION POLICY. ...................................................................................... 76 
17. SUPPLEMENTS/APPENDICES ............................................................................ 77 
18. SUMMARY OF CHANGES ................................................................................... 78 
19. LITERATURE REFERENCES .............................................................................. 189 
 
LIST OF TABLES 
Table 1: 
Trial Design(Cohort 1flu season 2018/2019) .............................................. 14 
Table 2: 
Trial Design (Cohort 2, flu season 2019/2020)…………………………14 
Table 3: 
Schedule of Events (Season 1, 2018/2019) for Cohort 1……………….15 
Table 4: 
Schedule of Events (Season 2, 2019/2020) for Cohort 2……………….16 
Table 5: 
Injection Site Reactogenicity Grading ......................................................... 53 
Table 6: 
Injection Site Reactogenicity Measurements ............................................... 54 
Table 7: 
Subjective Systemic Reactogenicity Grading .............................................. 54 
Table 8: 
Quantitative Systemic Reactogenicity Grading , ......................................... 55 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
AESIs 
Adverse Events of Special Interest 
CFR 
Code of Federal Regulations 
CMI 
Cell-mediated immunity 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EMA 
European Medicinal Authority 
EU 
European Union 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAI/HI 
Hemagglutinin Inhibition 
ICS 
Intra Cellular Staining 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IFN-g 
Interferon gamma 
IIV 
Inactivated influenza vaccine 
IIV3 
Trivalent inactivated influenza vaccine 
ILI 
Influenza-like illness 
ITT 
Intent-to-treat 
M-001 
Multimeric-001 
MedDRA  
Medical Dictionary for Regulatory Activities 
N 
Number (typically refers to subjects) 
NOCI 
New Onset of Chronic Illness 
NP 
Nasopharyngeal 
PBMC 
Peripheral Blood Mononuclear Cell(s) 
PBS 
Phosphate Buffered Saline 
PCR 
Polymerase Chain Reaction 
Ph.Eur. 
European Pharmacopoeia (Pharmacopoeia Europaea) 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
p.r.n. 
Pro re nata (dosing as needed) 
QA 
Quality Assurance 
QC 
Quality Control 
qRT-PCR 
Quantitative Reverse Transcriptase Real Time PCR 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
SI 
Sub-Investigator 
TBD 
To be determined later 
US 
United States 
WHO 
World Health Organization 

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PROTOCOL SYNOPSIS 
Title of the study: A pivotal, multicentre, randomized, modified double-blind, placebo-
controlled phase 3 trial to assess the safety and clinical efficacy of M-001, an influenza vaccine 
administered intramuscularly twice in older adults and the elderly (≥50 years of age). 
EudraCT number: 2018-000468-27 
ClinicalTrial.gov identifier: NCT03450915 
Protocol code: BVX-010 
 
Sponsor: 
BiondVax Pharmaceuticals LTD, Jerusalem Biopark, Hadassah Ein Kerem, Jerusalem, 
 ISRAEL. 
Central Study Site:  
The trial will be conducted at approximately 85 institutions in Europe (including, but not 
limited to Bulgaria, Hungary, Poland, Ukraine, Latvia, Georgia and Croatia)  
Planned study duration: up to 2 years (2 
consecutive flu seasons). It is designed to be 
completed after 2 influenza seasons unless 
stopped earlier or extended following 
recommendation of the DSMB.  
Subject participation duration: planned - up 
to 2 years. 
Phase of Development: Phase III 
Study population: Older adults and elderly (≥50 years of age). Randomization will be 
stratified by cohort and age of <65>. For season 2, randomization will also be stratified by 
participation (or not) to the sub-study. At least half of the participants will be ≥65 years old. 
Study design: A pivotal multicentre, randomized, modified double-blind, placebo-controlled 
study. 

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Planned number of subjects:  
Adaptive design (flexible enrolment); initially assumed to be 9,630 with an increase to 12,000 
if the influenza attack rate in Season 1 is lower than expected. At least half of the participants 
will be ≥65 years of age at the time of the randomization. 
 
Year 1 - cohort 1 (flu season 2018-2019): 4,055 subjects enrolled, as follows: 
M-001: n = 2,027 (Lot #1, vials); Placebo: n = 2,028 
Year 2 - cohort 2 (flu season 2019-2020): Approximately 8,000 subjects will be enrolled, as 
follows: 
M-001: n = 4,000 (Lot#2, pre-filled syringes); Placebo: n = 4,000 
 
PBMC (CMI) sub-study: 
To assess the immune response to the vaccine, blood samples will be collected pre- and post-
vaccination from a subset of 350 participants selected at random in pre-specified sites 
participating in Season 2.  Approximately two hundred sixty three (263) will be selected from 
the M-001 group and 87 from the placebo group.  
The endpoint for assessing the immune response will be the change from baseline in the 
percentage of CD4+ lymphocytes producing Th1 cytokine (e.g. INF-γ) in response to any of the 
9 peptides in M-001 measured at 14 ± 2 days after the day of the second vaccination (Visit 3) 
(Day 36). 
 
Rationale for sample size: 
The initial study sample size of 9,630 subjects is based on the lower bound of the two-sided 
95% confidence interval for Vaccine Efficacy (VE) being above 40% with 80% probability 
when true VE is 62%. It assumes 1:1 randomization, a 3% attack rate in the study population, 
and no more than 10% of subjects lost to follow-up or excluded from the per protocol 
population. Under these assumptions, 182 first episodes of either qRT-PCR or culture-
confirmed influenza of any strain occurring at least 15 days after the second dose of study 
vaccine or control will be needed to demonstrate efficacy is at least 40%.  
In Year 1, about 4,000 subjects will be enrolled. If during the first flu season a substantially 
reduced attack rate is anticipated, the Sponsor may elect to increase the total sample size to 
12,000. If the average attack rate across Year 1 and Year 2 is at least 2.4%, the study should 
maintain power at 80%. If during the second flu season another mild season is expected, the 
Sponsor may consider extending the trial to Year 3 with a third cohort based on an amendment 
to the protocol which will be submitted for ethics/regulatory approval. 
In Year 2, an immunogenicity sub-study will be conducted at select sites. Assuming the 
percentage of CD4+ lymphocytes producing Th1 cytokine (e.g. INF-γ) in response to any of the 
9 peptides in M-001 measured at Day 36 (14 ± 2 days after the day of the second vaccination) 
has a mean (standard deviation) of 25% (12%), the sub-study should have reasonable power 
with 210 evaluable vaccinees to demonstrate the non-inferiority of the immune response in 
other populations with a non-inferiority margin of 5%. Power calculations are based on an 
equally sized trial in the population to which vaccine efficacy is being bridged. 
 
Medical condition or disease under investigation: Influenza disease 

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Inclusion criteria 
1. Male and female subjects 50 years of age (inclusive) or older, willing and able to give the 
written informed consent prior to study entry. 
2. Able to comply with the trial procedures and be available for all study visits including 
answering phone calls and coming to the site as defined by the Protocol. 
3. Medically stable (subjects may have underlying systemic chronic conditions such as 
hypertension, diabetes, ischemic heart disease, or hypothyroidism, as long as their 
symptoms/signs are controlled; if they are on systemic pharmacological treatment for such 
condition, the treatment must have been stable for at least 3 months preceding first 
vaccination). 
4. Women of childbearing potential (not surgically sterile or postmenopausal for greater than 
or equal to one year) and men must agree to practice adequate effective contraception - 
barrier or hormone-based methods or intra uterine device (IUD) for women and a condom 
for males -whose female partner has childbearing potential - throughout the study treatment 
and for at least up to day 81 (for females) and day 111 (for males) of the trial (i.e. 60 (for 
females) and 90 (for males) days after the last dose of the IMP). In addition, women of 
childbearing potential must have practiced the contraception for a minimum of 30 days prior 
to study product exposure. 
5. Female subjects of childbearing potential must have a negative urine or serum pregnancy 
test within 24 hours prior to both study vaccinations. 
 
Exclusion criteria 
1. History of neurological symptoms or signs, or anaphylactic shock following administration 
of any vaccine. 
2. Known or suspected (or have a high risk of developing) significant impairment/alteration of 
immune function (excluding that normally associated with advanced age) as judged by 
PI/SI. 
3. Receipt of: a) Current (including within 60 days before Visit 1 or planned during the study) 
daily use of immunosuppressive drugs: i) systemic glucocorticoids ≥ 10 mg prednisone per 
day ii) cytotoxic drugs b) Investigational drugs within 30 days before, or planned during, the 
study c) Blood products within 3 months before, or planned during, the study d) Influenza 
vaccine within 6 months before the study or planned during the study e) Other vaccines 
within 30 days before, or planned during, the study. 
4. Any serious disease such as: cancer, autoimmune disease, advanced arteriosclerotic disease 
or complicated diabetes mellitus, chronic obstructive pulmonary disease (COPD) that 
requires oxygen therapy, acute or progressive hepatic disease, acute or progressive renal 
disease, or congestive heart failure, as judged by the PI/SI. 
5. An acute illness, which occurred within 1 week before first vaccination, as judged by the 
PI/SI, or body temperature greater than: for participants age 50-59 37.9ºC (axillary or 
forehead) or 38.4 ºC (oral), or 38.9ºC (ear/tympanic or rectal); for participants of age 60 or 
more, greater than 37.2ºC (axillary or forehead) or 37.7 ºC (oral), or 38.2ºC (ear/tympanic or 
rectal), which occurred within 1 week before first vaccination. 
6. Anatomical deficiencies which exclude possibility of taking NP swab or throat and nasal 
swab.  
7. Women who are breastfeeding or planning pregnancy during the period of the study. 
8. Institutionalized subjects or subjects unable to come to the study site as expected by the 
Protocol. 
 

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Test product, dose and mode of administration: 
M-001 vaccine, 1.0 mg. Administered twice intramuscularly at 21 days interval (recommended 
range: 21-30 days) 
Reference product, dose and mode of administration: 
Normal Saline, Placebo. Administered twice intramuscularly at 21 days interval (recommended 
range: 21-30 days) 
Duration of treatment:  Approximately 22 (+9) days for 2 vaccination visits.Cohort 2 
participants will attend 3 site visits.  Subset of Cohort 2 participants will attend , including 
additional Visit 3 for immunogenicity testing, and remaining Cohort 2 participants will have the 
third visit as safety assessment focused site visit. The Visit 3 is planned 14±2 days after Visit 2 
day. The total duration of this trial for each subject will be up to 1 year. Shall the optional study 
extension have occurred for the purpose of follow up on efficacy (subject to future protocol 
amendment), the participants will have no obligation to continue their follow up thru Year 3. 
Criteria for evaluation: 
Primary endpoint: 
 
Safety 
To assess M-001 Safety by solicited local and systemic reactogenicity events occurring within 
8 days (day of the vaccination inclusive) following receipt of each of the two doses of M-001 or 
placebo and to assess SAEs, and new-onset of chronic medical illnesses (NOCIs) during period 
from Day 0 until end of first passive surveillance period in each group. To assess M-001 Safety 
by occurrence of unsolicited AEs from the time of first study vaccination through 22 days after 
each study vaccination (day of the vaccination inclusive). 
 
Clinical Efficacy 
Compare the occurrence of either qRT-PCR or culture confirmed influenza in the M-001 
experimental group vs. placebo (≥ 15 days after the second vaccination until epidemiological 
levels of influenza are low as defined by the medical director) caused by any influenza A or B 
virus in association with a protocol defined Influenza Like Illness (ILI is defined as symptoms 
that include one of the following respiratory symptoms (sore throat, cough, sputum production, 
nasal discharge or congestion, wheezing or difficult breathing) and at least one additional 
systemic symptom [fever (oral temperature >37.2°C for age 50-59, or >36.7°C for age 60 or 
more, or increased ≥ 1.3°C from baseline), headache, myalgia and/or arthralgia, chills, and 
fatigue (tiredness for at least 12 hours)]. NP (Nasopharyngeal) or combined nasal and throat 
swab will be collected from participants who meet the ILI definition for qRT-PCR analysis of 
influenza A and/or B virus. Influenza positive samples by PCR will be further analysed for 
culture confirmation 

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Secondary endpoints: 
1. Compare the occurrence of culture confirmed influenza in the M-001 experimental 
group vs. placebo (≥ 15 days after the second vaccination until epidemiological levels of 
influenza are low as defined by the medical director) caused by any influenza A or B 
virus in association with a protocol defined ILI. Nasopharyngeal swab will be collected 
from participants who meet the ILI definition within 24 hours from ILI being reported 
to or identified by study personnel for qRT-PCR confirmation of influenza A and/or B 
virus (a nasal and throat sample can be collected as alternative method), and the samples 
identified with qRT-PCR as positive for influenza A or B virus will be verified with 
virus culture. 
 
2. Reduced Severity of influenza illness  
Reduction of either qRT-PCR or Culture-confirmed influenza illness severity: The 
reduction due to M-001 in the average number of days with respiratory or systemic 
symptoms during the first laboratory-confirmed influenza illness episode.  
3. The percentage of subjects having ILI symptoms in the experimental and control group 
4. The change from baseline in the percentage of CD4+ lymphocytes producing Th1 
cytokine (e.g. INF-γ) in response to any of the 9 peptides in M-001.  This endpoint will 
be assessed within a randomly selected subset of participants from pre-selected sites 
participating to the substudy in Year 2.  
 
 
Exploratory endpoints: 
 
Incidence of antibiotics use due to post-influenza secondary  infections of respiratory tract 
 
Incidence of hospitalization associated with the ILI (≥15 days after dosing until 
epidemiological levels of influenza are low as defined by the medical director) 
 
Incidence of death due to influenza-like illness (≥15 days after dosing until epidemiological 
levels of influenza are low as defined by the medical director) with or without confirmation 
of presence of influenza virus by viral culture and qRT-PCR analysis 
 
To determine the specific influenza strains in flu cases in experimental and control group 
 

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Statistical methods: 
For the primary analysis of vaccine efficacy (VE), the efficacy of M-001 after a first influenza 
season in each cohort will be estimated by 
𝑉𝐸= 1 −[(𝐶𝑉/ 𝑁𝑉)/ ( 𝐶𝑃 /𝑁𝑃)] 
where CV and CP are the number of per protocol cases of influenza meeting the primary case 
definition in the vaccine and placebo group, respectively, and NV and NP are the number of per 
protocol subjects in the vaccine and placebo group, respectively. The confidence interval for 
VE will be calculated by the Clopper-Pearson exact method conditional on the total number of 
cases in the vaccine and placebo groups combined. Similarly, vaccine efficacy and its 95% 
confidence interval will be calculated for the ITT population. 
Determination of sample size for the CMI substudy:The endpoint for assessing immune 
response to the vaccine will be the change from baseline in the percentage of CD4+ 
lymphocytes producing Th1 cytokine (e.g. INF-γ) in response to any of the 9 peptides in M-
001. Based on preliminary immunogenicity data, the percentage of CD4+ lymphocytes is 
approximately normally distributed with a mean of 25% and standard deviation 12%.  A sample 
size of 210 M-001 subjects will provide an estimate of the change from baseline in percentage 
of CD4+ lymphocytes producing e.g. INF-γ with a precision (1/2 width of the 95% CI) at most 
2% .  
 
Table 1: 
Trial Design(Cohort 1flu season 2018/2019) 
  
Year 1 
Interim data analysis after Year 1 
Visit 1 Day 0  
Visit 2 Day 22 
Visit 4 Day 202 
Experimental  
1mg M-001 
1mg M-001 
Safety, 
qRT-PCR 
/Culture 
confirmation in  
ILI cases 
(through passive  
surveillance 
period) 
Control 
 
Placebo 
Placebo 
 
 
Table 2: 
Trial Design (Cohort 2, flu season 2019/2020) 
 
 
Year 2 (flu season 2019/2020) 
 
Visit 1 (Day 
0)*  
Visit 2 (Day 
22) (site) 
Visit 3 (Day 
36)* (site) 
Visit 4 (Day 202)  
(phone) 

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(site) 
Experimental  
1mg M-001 
1mg M-001 
Safety, phone 
call no 
treatment; 
procedures 
depend on study 
group 
Safety (phone 
call), qRT-PCR 
in  ILI cases 
(through passive  
surveillance 
period 
Control  
Placebo 
Placebo 
 
Flu season 2 
Interim Data 
Review 2 
Flu season 3 
 
≥ Cutoff1 
     YES 
No season 3. Study 
completed. 
      NO 
Cohort 3 initiation will be 
considered 
 
Flexible enrollment scheme according to interim data review that will be available after Year 
1 and 2. Flu season 3 (Year 3) is not planned. If decided that it is needed after Year 2, 
protocol amendment will be issued and submitted for relevant approvals. 
  the cutoff will be at most 182 and will be defined precisely in the DSMB charter 
* In subset of subjects – visits at selected sites with collection of blood for CMI assessment at 
Visit 1 and 3. Visit 3 should take place in 14 days +/-2 since date of Visit 2 
 
Table 3: Schedule of Events (Season 1, 2018/2019) for Cohort 1 
Study Visit (V) 
01 
02 
04 
Study Day 
0 
22 
202 (180 days after last 
vaccination day) 
(Phone call or email) 
Visit Windows 
 
(+9) 
(±14) 
Consent process and Signed Consent Form1 
X 
 
 
Assess eligibility 
X 
X 
 
Demographic data and Review Medical & flu 
vaccination History2 
X 
X 
 
Concomitant meds 
X 
X 
 
Vital signs 
X 
 
 
Oral temperature 
X 
X 
 
Physical examination 
X 
 
 
Randomization 
X 
 
 
Review contraception/ Counseling3 
X 
X 
 
Pregnancy Test4 
X 
X 
 
Solicited/reactogenicity events assessment 
X* 
X* 
 

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Unsolicited AEs/ Assessment 
X# 
X# 
NOCIs, AESIs, SAE  
X 
X 
X 
Vaccination5 
X 
X 
 
Evaluate vaccination site 
X 
X 
 
Postvaccination procedures6 
X 
X 
 
Provision of Memory Aid  
X 
X 
 
Review of Memory Aid Data 
 
X 
 
Interim report 
End of Season 2018/19, June 2019 
Collection of ILI symptoms through passive and 
active surveillance 
Passive Surveillance: Subjects will be instructed to contact the study site if 
they experience symptoms of a respiratory illness from Day 14 post-second 
vaccination day until 15 May the following year. 
Active Surveillance: Between November 15, 2018 and March 31, 2019, the 
dedicated study staff will contact subjects twice a week (see 7.3). 
Collection of nasopharyngeal (or nasal and 
throat) swabs for 
laboratory confirmation of influenza 
From Day 14 post second vaccination day until 30 April of the following 
year. Every effort must be made to obtain the NP or nasal and throat swab 
specimen on the same or following day after reporting of qualifying ILI 
symptoms and no later than 4 days (sample to be collected within 24 hours 
from ILI being reported to or identified by study personnel through Day 3 of 
the illness, considering that Day 0 is the day of illness onset) after onset of 
qualifying ILI symptoms (start date). NP or nasal and throat swab collection 
according to:  https://www.cdc.gov/flu/pdf/freeresources/healthcare/flu-
specimen-collection-guide.pdf. A combination of deep nasal and throat swab 
will be sampled from participant that will not allow for or cannot have NP 
swab collection, however NP swab is preferred. Swabs collection period 
starting on September 15, 2018). 
Collection of disease burden data and 
concomitant medications 
At any time during the study a disease burden and concomitant medications 
in association with respiratory disease, ILI or AE, and for up to 30 days 
following the start of a qualifying ILI symptoms. All other concomitant 
medications from 3 months before V1. 
Collection of information on AESIs, NOCIs, 
and SAEs 
At any time during the study period. 
 
Table 4: Schedule of Events (Season 2, 2019/2020) for Cohort 2 
Study Visit (V) 
1 
2 
3 
(site visit9) 
 
4 
(Phone call or email) 
Study Day 
0 
22 
36 (14 days post 
date of Visit 2)) 
202 (180 days 
after last 
vaccination 
day) 
 
Visit Windows 
 
(+9) 
(±2) 
(±14) 
Consent process and Signed Consent Form1 
X 
 
 
 
Assess eligibility 
X 
X 
 
 
Demographic data, Review Medical & flu 
vaccination History2 
X 
X 
 
 
Concomitant meds 
X 
X 
 
 
Vital signs 
X 
 
 
 

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Oral temperature 
X 
X 
 
 
Physical examination 
X 
 
 
 
Randomization 
X 
 
 
 
Review contraception/ Counseling3 
X 
X 
X 
 
Pregnancy Test4 
X 
X 
 
 
Blood sample for CMI (40 mL, Subset) 
X 
 
X 
 
Solicited/Reactogenicity Events Assessment  
X* 
X* 
 
 
Unsolicited AEs 
X# 
X# 
 
 
NOCIs, AESIs, SAE 
X 
X 
X 
X 
Vaccination5 
X 
X 
 
 
Evaluate vaccination site 
X 
X 
 
 
Postvaccination procedures6 
X 
X 
 
 
Provision of Memory Aid7  
X 
X 
 
 
Review of Memory Aid Data 
 
X 
X 
 
Interim Report/Final Report8 
End of Season 2019/20, June 2020 
Collection of ILI symptoms through passive 
and active surveillance for participants from 
season 2. 
Passive Surveillance: Subjects will be instructed to contact the study site 
if they experience symptoms of influenza-like illness from Day 14 post-
second vaccination day until 15 May the following year 
Active Surveillance: Between December 1st , 2019 and March 31st, 2020, 
the dedicated study staff will contact subjects up to twice a week (see 7.3) 
Collection of nasopharyngeal (or nasal and 
throat) swabs for laboratory confirmation of 
influenza for participants from season 2 
From Day 14 post second vaccination day, until 30 April of the following 
year. Every effort must be made to obtain the NP or nasal and throat swab 
specimen on the same or following day after qualifying ILI symptoms 
being reported to or identified by study personnel and no later than 4 days 
(sample to be collected through Day 3 of the illness, considering that Day 
0 is the day of illness onset) after onset of qualifying ILI symptoms (start 
date). NP or nasal and throat swab collection according to: 
https://www.cdc.gov/flu/pdf/freeresources/healthcare/flu-specimen-
collection-guide.pdf..  
A nasal and throat swab will be sampled from participant that will not 
allow NP swab collection.  
Collection of disease burden data and 
concomitant medications for participants from 
season 2 
At any time during the study year disease burden data and concomitant 
medications in association with respiratory disease, ILI or AE, and for up 
to 30 days following the start of a qualifying ILI symptoms. All other 
concomitant medications from 3 months before V1 
Collection of information on AESIs, NOCIs, 
and SAEs for participants from season  2. 
At any time during the study period 

1 Consent process completed and form signed before any study-related procedures are conducted.  
2 Information on past influenza vaccinations for at least 3 years prior to study entry.  
3 Counseling on avoidance of pregnancy for women of childbearing potential.  
4 Urine pregnancy test must be completed within 24 hours prior to vaccination for women of childbearing potential. If 
urine pregnancy test is positive, subject is not eligible unless local laboratory performed serum pregnancy test is 
negative.   
5 All subjects will be observed for a minimum of 20 minutes following vaccination.  
6 Post-vaccination procedures will include documentation of any reactogenicity during the observation period and any 
AEs/SAEs post-vaccination (i.e. with onset before the participant leaves the site after receipt of the study drug 
injection), as well as provision of memory aid and instructions on completion. 
7 Paper diaries will be used as memory aid 
8If study is not extended for season 3 final report will be produced after season 2 
9 In subset of subjects – visit at site with collection of blood for CMI assessment at Visit 1 and 3. For remaining 
subjects only– site visit or - if site visit not feasible - phone call. Blood sampling applicable only for on site visits in a 
subset of subjects participating in the CMI assessment. 
10 If indicated by medical interview on period between Visit 1 and 2 
* Occurence and severity of reactogenicity events will be collected through seven days after each study 
vaccination day (8 days in total)  
# Occurrence of unsolicited AEs will be analyzed from the time of first study vaccination through 22 days after 
each study vaccination (day of the vaccination inclusive).  
Note: within exploratory outcome measures, endpoints and objectives: “dosing” to be understood as 
second vaccination received (unless second dose will not be administered to given subject); “≥15 
days after” is to be understood as ≥15 days after the vaccination, including the day of the 
vaccination. 
 
 

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1. 
KEY ROLES 
Sponsor: 
 
BiondVax Pharmaceuticals Ltd. 
Jerusalem Biopark, Hadassah Ein Kerem, Jerusalem, Israel 
Tel No.: +972 8 9302529  Fax No.: +972 8 9302531 
 
 
Sponsor’s Medical 
Director 
Prof. Shai Ashkenazi, M.D. M.Sc.  
Schneider Children’s Medical Center of Israel  
Petah tiqva 49202, Israel  
Tel No.:  +972-3-9253680  Mobile No.: +972-543030685 
Email:  shaiashkenazi7@gmail.com 
 
 
Investigators 
A list of investigators is provided in the trial master file.  
 
 
Contract Research 
Organization (CRO) 
KCR S.A. 
6 Postepu str. 
02-676 Warsaw, Poland 
Tel No. +48 22 313 13 13 Fax No. +48 22 313 13 14 
 
 
 
CRO Responsible Person 
Anna Baran M.D. 
Chief Medical Officer  
Tel No.: +48 22 313 13 13  Mobile No.: +48 695 801 611 
Email: Anna.Baran@kcrcro.com  
 
 
CRO Drug Safety 
Reporting Contact 
KCR S.A. 
6 Postepu Str. 
02-676 Warsaw, Poland 
FAX:  +48 22 203 56 58 
Email: SAE@kcrcro.com   
 
 
European Legal 
Representative  
KCR s.r.o. 
8 Jégeho Str. 
821 08 Bratislava, Slovak Republic 
 
 
European Qualified 
Person 
KLIFO A/S 
Smedeland 36 
DK-2600 Glostrup 
Denmark 
Business registration no. 18 19 61 31 
Main phone:  +45 44 222 900 
Fax +45 39 20 90 45 
 
 

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2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1. 
Background Information 
2.1.1. 
Influenza 
Influenza is a common acute viral respiratory illness. Influenza is the eights leading cause of deaths 
in the western world1 resulting in worldwide death toll of 250,000-500,000 annually2.  The 
continued emergence of novel influenza A viruses in humans including pandemic subtypes 
underscores the need for focused efforts to prepare for the next influenza pandemic3 since each 
emergence of a new subtype of influenza virus in the human population has the potential to result in 
a global public health emergency.  
Increased morbidity and mortality of elderly individuals from influenza infections poses a major 
medical and public health concern. US CDC estimated the seasonal influenza vaccine effectiveness 
during the 2004–17 season to be only 40% among the general population4 and much lower among 
the elderly5. Even when most circulating flu viruses are well matched to the flu vaccine the vaccine 
can reduce the risk of flu illness by between 40-60% among the overall population during seasons6. 
Use of influenza vaccines is the primary means for preventing influenza.  Current licensed 
inactivated vaccines are good for preventing influenza but are less effective than desirable. In 
general, the older age group is more vulnerable to the disease and its complications due to 
concomitant medical conditions and a senescent immune system. People’s immune system becomes 
weaker with age, placing people 65 years and older are at high risk of serious flu-related 
complications. Accordingly, elderly individuals are also less responsive to the seasonal vaccine and 
particularly susceptible to other strains that are not incorporated in the seasonal vaccine 7 8. It is 
estimated that 70-85% of flu-related deaths in the US have occurred among this age group posing a 
more effective influenza vaccine as a very large unmet medical need. Similar findings were 
observed in Europe, where the European monitoring of excess mortality for public health action 
(EuroMOMO) network (www.euromomo.eu) monitors weekly ‘real-time’ all-cause age-specific 
excess mortality in countries in Europe through a standardized approach, allowing pooling of 
results. It is expected that a winter season with predominance of influenza A(H3N2) has higher 
mortality impact on the elderly than a season with predominant influenza A(H1N1) or a season with 
low influenza A transmission9. The reasons for that are that (1) influenza A(H1N1)pdm09 has less 
impact on the elderly and (2) since 2009 this strain is contained in the seasonal vaccine. Whereas 
current vaccines focus on enhancement of humoral immunity against the virus, it is known that 
cellular immunity also can have a role in preventing influenza-associated illness10.  
An approach to improve vaccine efficacy especially in the old adults and elderly is the use of a 
broadening vaccine that enhances cellular immunity against multiple influenza viruses (a universal 
vaccine) and that might also prime serological responses to influenza antigens.   
2.1.2. 
Multimeric-001 (M-001) 
The use of epitope-based vaccines is an approach that may be used to improve protection of elderly 
by activating cell mediated immunity and prime for immune responses to influenza antigens11.  The 
M-001 vaccine from BiondVax consists of 3 repetitions of 9 conserved linear epitopes from the 
hemagglutinin, nucleoprotein and matrix 1 (M1) protein that are prepared as a single recombinant 

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protein. 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 system12. Based 
upon these characteristics, the M-001 vaccine is hypothesized to provide immunity against both 
existing as well as future emergent virus strains13. 
The M-001 vaccine is produced as a recombinant protein in E. coli. 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 adjuvanted M-001 demonstrated both vaccine immunogenicity and 
protection from lethal challenge in a mouse model using highly pathogenic influenza A/H5N114.  
The safety and efficacy results of M-001 in the preclinical studies led to its evaluation in people as 
detailed in the Investigator Brochure 15. Additional information on the clinical trials conducted with 
M-001 is listed below and in the Investigator Brochure. 
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 adjuvant16.  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) was performed in 60 older adults (55-75 years of age) and evaluated the 
safety and ability of M-001 to improve humoral and cellular responses when used for priming prior 
to administration of a trivalent seasonal inactivated influenza vaccine [IIV3].  Participants (n=10 
per group) either received Montanide ISA 51 VG-adjuvanted or non-adjuvanted M-001 or placebo 
3 weeks prior to IIV3. A greater proportion of recipients of an adjuvanted 250 mcg M-001 dose 
(50-80%) had HAI seroresponses to the seasonal vaccine strains than did participants who only 
received IIV3 (20-30%). Following this study and based upon the lack of safety concerns, the 500 
mcg dosage of M-001 was selected for further study. 
BVX-004 evaluated the safety and immunogenicity of Montanide ISA 51 VG-adjuvanted M-001 
when it was co-administered with IIV3 or used in a priming strategy in 200 healthy adults 18-49 
years of age.  Adjuvanted M-001, when administered twice before delivery of IIV3 and when 
administered in combination with partial IIV3 (either co-administered or in a prime-boost approach) 
was found to be safe and induced immune responses that exceeded those exhibited by subjects 
immunized with placebo or IIV3 alone.  
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 (see Atsmon et al ref. #11). 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-g expressing CD4 and CD8 lymphocytes) were also 
significantly increased from pre-immunization levels after exposure to influenza antigens. No safety 
concerns were identified.  

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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 has been conducted in 36 adults.  No SAEs 
were observed and no safety concerns were identified. 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. 
The recent Phase 2b clinical trial was conducted (BVX-007) was conducted by UNISEC 
consortium in which BiondVax participated. 219 adults (18-65 years old) were divided into 3 
groups and vaccinated with either low (0.5mg) or high (1 mg) M-001 or saline twice, next, all the 
participants were immunized with a sub-optimal dose of H5N1 vaccine17. No SAEs were observed 
and no safety concerns were identified, a significant Th1 cell mediated immunity was induced in 
the group that was immunized with the M-001 at the high dose18. 
2.2. Rationale 
 
Seasonal influenza poses continuous threats to human populations and especially to elderly and 
toddlers.  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 directly the 
cellular arms of the immune system and indirectly, 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.  In 
view of these immunological outcomes and the good safety profile of the M-001 vaccine candidate, 
the purposes of the study are to determine the safety and clinical efficacy of M-001 in a large 
population of older adults and elderly.  Cell-mediated immunity expected to be induced by the M-
001 will also be evaluated based on samples from subset of participants from Cohort 2.  Blood 
samples will be collected from approximately 263 participants receiving M-001 and 87  
participants receiving the placebo (to maintain the blinding). The blood samples from all 350  
participants will be collected at baseline (visit 1) and on Visit 3 -14 ± 2 days after the day of the 
Visit 2 (second vaccination).  
2.3. Potential Risks and Benefits 
2.3.1. 
Potential Risks 
The potential risks of this study are mostly those associated with having blood drawn and receiving 
an IM injection that may result in injection site or other adverse reactions, and risk associated with 
swab collection.  
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. 

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Six previous trials in which approximately 460 participants received M-001 intramuscularly have 
been completed to date in addition to 2027 who participated in season 1 of the current trial (see 
Investigator Brochure).  AEs described following receipt of M-001 have been similar to those seen 
in placebo recipients. These included rhinitis/nasal congestion, malaise, myalgia, sore throat, 
injection site pain and erythema, cough, headache, diarrhea, neck pain, fever, back pain, arthralgia, 
nausea, vomiting, rash, flushing, dizziness and decreased blood pressure. 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. There were no treatment related SAEs. 
 
The procedure for collection of an NP, deep nasal or throat swab is associated with a slight 
discomfort, and may, in some instances, cause watering of the eyes or gag reflex. Other than that, 
there is little to no risk involved. 
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, 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 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 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. Urine pregnancy test must be completed within 24 hours prior 
to vaccination for women of childbearing potential. If urine pregnancy test is positive, subject is not 
eligible unless serum pregnancy test is negative. If a female subject becomes pregnant while 
participating in this study, she will be asked for 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 applicable laws including European Union General 
Data Protection Regulation 2016/679 (GDPR) where applicable. 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 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 sites for quality assurance and data analysis include 
groups such as EMA and local regulatory authorities. 
There may be other unknown risks, discomforts, or side effects. 

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2.3.2. 
Known Potential Benefits 
There are no known benefits attributable to the receipt of the M-001 vaccine, but there is a prospect 
of benefit. It is possible that vaccination with M-001 will prime the participant for improved 
responses to future seasonal or pandemic influenza vaccines. 
There may be influenza preparedness benefits to society in the future if the M-001 is shown to have 
a long-lasting efficacy based on the improved cellular immune responses to influenza.  

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3. 
OBJECTIVES  
3.1. Study Objectives 
3.1.1. 
Primary Objectives 
Safety 
To assess M-001 Safety by solicited local and systemic reactogenicity events occurring within 8 
days (day of the vaccination inclusive) following receipt of each of the two doses of M-001 or 
placebo and to assess SAEs and new-onset of chronic medical illnesses (NOCIs) during period from 
Day 0 until end of first passive surveillance period in each group. To assess M-001 safety by 
occurrence of unsolicited AEs from the time of first study vaccination through 22 days after each 
study vaccination (day of the vaccination inclusive). 
 
Clinical Efficacy 
To assess efficacy of M-001 in the prevention of influenza disease by comparing the occurrence of 
either qRT-PCR or culture confirmed influenza in the M-001 experimental group vs. placebo 
caused by any influenza A or B virus in association with a protocol defined Influenza Like Illness 
(ILI)  
3.1.2. 
Secondary Objectives 
Clinical efficacy 
 
Compare the occurrence of culture confirmed influenza in the M-001 experimental group 
vs. placebo caused by any influenza A or B virus in association with a protocol defined 
ILI. 
 
Assess reduction of severity of either qRT-PCR or culture -confirmed influenza illness by 
the reduction due to M-001 in the average number of days with respiratory or systemic 
symptoms during the first laboratory-confirmed influenza illness episode. 
 
To assess proportion of subjects having ILI symptoms in the experimental or control 
group. 
Immunogenicity 
 To assess in at least a subset of samples in season 2 the change from baseline in the 
percentage of CD4+ lymphocytes producing Th1 cytokine (e.g. INF-γ) in response to 
any of the 9 peptides in M-001.  This endpoint will be assessed within a randomly 
selected subset of participants from pre-selected sites participating to the substudy in 
Year 2. 
3.1.3. 
Exploratory Objectives  
 
Incidence of antibiotics use due to post-influenza secondary infections of respiratory tract  
as evidenced with medical records or declared by the participant 
 

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 
Incidence of hospitalization associated with the ILI (≥15 days after dosing until 
epidemiological levels of influenza are low as defined by the medical director). 
 
Incidence of death due to influenza-like illness (≥15 days after dosing until 
epidemiological levels of influenza are low as defined by the medical director) with or 
without confirmation by viral culture or qRT-PCR analysis. 
 
To determine the specific influenza strains in confirmed flu cases in experimental and 
control group  
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) until end of first passive surveillance period 
 
Occurrence of NOCIs from the time of the first study vaccination (M-001 or placebo) until 
end of first passive surveillance period 
 
Occurrence of solicited injection site and systemic reactogenicity events on the day of each 
study vaccination through 8 days after each study vaccination (day of the vaccination 
inclusive) 
• Occurrence of unsolicited AEs from the time of first study vaccination through 22 days after 
each study vaccination (day of the vaccination inclusive)  
• Occurrence of all SAEs, regardless of the assessment of relatedness, from the time of 
receiving the first M-001 study vaccination until end of first passive surveillance period  
Clinical Efficacy  
 
Percentage of either qRT-PCR or culture-confirmed influenza cases in the M-001 
experimental group vs. placebo (during period of ≥ 15 days after the second vaccination 
until epidemiological levels of influenza are low as defined by the medical director) caused 
by any influenza A or B virus in association with a protocol defined Influenza Like Illness 
(ILI is defined as symptoms that include one of the respiratory symptoms (sore throat, 
cough, sputum production, nasal discharge or congestion, wheezing or difficult breathing) 
and at least one additional systemic symptom [fever (oral temperature >37.2°C for age 50-
59, or >36.7°C for age 60 or more, or increased ≥ 1.3°C from baseline), headache, myalgia 
and/or arthralgia, chills, and fatigue (tiredness for at least 12 hours)]. NP or combined nasal 
and throat swab will be collected from participants who meet the ILI definition within 24 
hours from ILI being reported to or identified by study personnel for qRT-PCR analysis of 
influenza A and/or B virus. PCR confirmed samples will be further analyzed for culture 
confirmation. 
3.2.2. 
Secondary Outcome Measures 
1. Clinical efficacy 

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 Percentage of culture confirmed influenza cases in the M-001 experimental group vs. 
placebo (during period of ≥ 15 days after the second vaccination until epidemiological levels 
of influenza are low as defined by the medical director) caused by any influenza A or B 
virus in association with a protocol defined Influenza Like Illness. NP or nasal and throat 
swab will be collected from participants who meet the ILI definitions within 24 hours from 
ILI being reported to or identified by study personnel for Culture confirmation of influenza 
A and/or B virus (a nasal and throat sample will be collected if the participant object the NP 
swab collection), and the samples identified with qRT-PCR as positive for influenza A or B 
virus will be verified with virus culture 
 Average time to all symptoms alleviation/fever resolution in the experimental vs control 
group expressed as reduction (in group with M-001 vs. control group) of number of days  
with respiratory or systemic symptoms during the first laboratory-confirmed influenza 
illness episode. “Alleviation/resolution” time is defined as the first time point at which all of 
the following influenza symptoms (body aches (myalgia and/or arthralgia), cough, 
fatigue/tiredness, headache, nasal congestion/ runny nose/ sputum production, wheezing or 
difficult breathing, chills and sore throat) were absent and fever had resolved, with both 
(resolution of all symptoms and fever) maintained for at least 1 day. 
 Percentage of subjects having ILI symptoms in the experimental or control group 
 
2. 
Immunogenicity In Sub-Study  
 
 
Change from baseline in the percentage of T cell expressing e.g. interferon gamma (IFN-g) 
in CD4+ PBMCs after stimulation with M-001 16 days after the second dose of M-001 
(day of the vaccination inclusive) .  This endpoint will be evaluated in a subset of 
participants in the experimental group and will further be compared to the percentage of T 
cell expressing e.g. interferon gamma (IFN-g) in CD4+ PBMCs after stimulation in another 
study. 
3.2.3. 
Exploratory Outcome Measures 
 Reduction in the proportion of subjects taking antibiotics use due to a post-influenza 
secondary  infections of respiratory tract, due to vaccination with M-001 as compared to the 
control group. In case of lack of documented medical record subject’s provided information 
will be sufficient. 
 
 Reduction in the number of hospitalizations associated with ILI episodes, due to vaccination 
with M-001 compared to Placebo. Hospitalization associated with ILI (≥15 days after 
dosing* until epidemiological levels of influenza are low as defined by the medical director) 
in the experimental group as compared to the control group. 
 Incidence of death due to influenza-like illness (≥15 days after dosing* until 
epidemiological levels of influenza are low as defined by the medical director) in the 

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experimental group as compared to the control group, with or without confirmation by viral 
culture and qRT-PCR analysis. 
 Define influenza virus subtype in the swab samples to compare the viruses causing disease 
in the experimental vs control group 
* - within exploratory outcome measures, endpoints and objectives: “dosing” to be 
understood as second vaccination received.;  ≥15 days after” is to be understood as ≥15 days 
after the second vaccination, including the day of the vaccination. 
 

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4. 
STUDY DESIGN  
This is a pivotal, multicentre, randomized, modified double-blind, placebo-controlled phase 3 trial 
to assess the safety and clinical efficacy of M-001, an influenza vaccine administered 
intramuscularly twice in older adults and the elderly (≥50 years of age) who meet all eligibility 
criteria. 
Subjects will be assigned randomly to 1 of 2 treatment arms (6000 per study arm during the study) 
to receive two doses of the M-001 vaccine or placebo (saline).  Group A will receive two doses of 
M-001, each containing 1 mg of M-001, on Day 0 and 22.  Group B will receive saline placebo on 
the same days.  
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 8 days after the study 
vaccination (inclusive of vaccination day). Unsolicited non-serious AEs collected from the time of 
each study vaccination through approximately 22 days after each study vaccination (day of the 
vaccination inclusive) will be analyzed separately. SAEs (including AESIs)and NOCIs will be 
collected from the time of the first study vaccination through the entire trial period.   
In cohort 2, immunogenicity testing will be performed and will include performing CMI assays on 
blood samples obtained immediately at baseline (Day 0) and on samples collected on Visit 3 
(referred to as Day 36, taking place 14±2 days since day of the administration of second dose of the 
vaccine/placebo).  At sites participating in the CMI sub-study, data will be obtained from a subset 
of approximately 263 participants randomly selected from the experimental group and from a 
subset of 87 participants randomly selected from the placebo group. Cell mediated immune 
responses to influenza antigens, including epitopes represented in the M-001 vaccine, will be 
assessed at baseline (Day 0, before vaccination), and at 14±2 days since day of the administration of 
second dose of the vaccine/placebo (Day 36).   
The duration of this trial for each subject will be up to 1 year (reflecting time between vaccination 
and end of the flu season as stated in the protocol). 
For additional details on study procedures and evaluations and study schedule by study visits/days, 
see Sections 7 and 8 as well as Table 3 and Table 4 – Schedule of events.  

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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. Male and female subjects 50 years of age (inclusive) or older, willing and able to give 
and sign the written Informed consent form (ICF) prior to study entry. 
2. Able to comply with the trial procedures and be available for all study visits including 
answering phone calls and coming to the site as defined by the Protocol. 
3. Medically stable (subjects may have underlying systemic chronic conditions such as 
hypertension, diabetes, ischemic heart disease, or hypothyroidism, as long as their 
symptoms/signs are controlled;. if they are on systemic pharmacological treatmentfor 
such condition, the treatment must have been stable for at least 3 months preceding 
vaccination). 
4. Women of childbearing potential (not surgically sterile or postmenopausal for greater 
than or equal to one year) and men must agree to practice adequate effective 
contraception – barrier or hormone-based methods or intra uterine device (IUD) for 
women and a condom for males -whose female partner has childbearing potential - 
throughout the study treatment and for at least up to day 81 (for female) and day 111 
(for male) of the trial (i.e. 60 (for females) and 90 (for males) days after the last dose of 
the IMP). In addition, women of childbearing potential must have practiced the 
contraception for a minimum of 30 days prior to study product exposure. 
5. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 24 hours prior to both study vaccinations. 
 
5.2. Subject Exclusion Criteria  
Subjects eligible to participate in this study must not meet any of the following exclusion criteria: 
1. History of neurological symptoms or signs, or anaphylactic shock following 
administration of any vaccine. 
2. Known or suspected (or have a high risk of developing) significant 
impairment/alteration of immune function (excluding that normally associated with 
advanced age) as judged by PI/SI. 
3. Receipt of: a) Current (including within 60 days before Visit 1 or planned during the 
study) daily use of immunosuppressive drugs: i) systemic glucocorticoids ≥ 10 mg 
prednisone per day ii) cytotoxic drugs b) Investigational drugs within 30 days before, or 
planned during, the study c) Blood products within 3 months before, or planned during, 
the study d) Influenza vaccine within 6 months before the study or planned during the 
study e) Other vaccines within 30 days before, or planned during, the study. 
4. Any serious disease such as: cancer, autoimmune disease, advanced arteriosclerotic 
disease or complicated diabetes mellitus, chronic obstructive pulmonary disease (COPD) 
that requires oxygen therapy, acute or progressive hepatic disease, acute or progressive 
renal disease, or congestive heart failure, as judged by the PI. 
5. An acute illness, which occurred within 1 week before first vaccination, as judged by the 
PI/SI, or body temperature greater than: for participants age 50-59 37.9ºC (axillary or 

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forehead) or 38.4 ºC (oral), or 38.9ºC (ear/tympanic or rectal); for participants of age 60 
or more greater than 37.2ºC (axillary or forehead) or 37.7 ºC (oral), or 38.2ºC 
(ear/tympanic or rectal); which occurred within 1 week before first vaccination. 
6. Anatomical deficiencies which exclude possibility of taking NP swab or throat and nasal 
swab. 
7. Women who are breastfeeding or planning pregnancy during the period of the study. 
8.  Institutionalized* subjects unable to come to the study site as expected by the Protocol. 
*except for institutionalization without subsequent overnight stays  
5.3. Treatment Assignment Procedures 
5.3.1. 
Randomization Procedures 
Central randomization will be implemented in this study. Subjects will be randomized to 1 of 2 
treatment arms, based on a computer-generated randomization schedule prepared by or under the 
supervision of the sponsor before the study. The randomization will be stratified by cohort and age 
group (i.e., 50- 65, ≥ 65) and balanced by using permuted blocks. At least 50% of study participants 
will be 65 or older in each randomization cohort. The Interactive Web Response System (IWRS) will 
assign a unique treatment code, which will dictate the treatment assignment and matching study drug 
kit(s) for the subject. 
For season 2, the randomization will be further stratified by sub-study participation (i.e. Yes or No).  
For the CMI substudy, 350 subjects from sites participating to the sub-study (sub-study sites) are 
randomly chosen among 700 sub-study sites subjects with appoximately 263 subjects selected at 
random from 350 M-001 sub-study sites subjects and approximately 87 from 350 placebo sub-study 
sites subjects.  
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, the 
subject will be enrolled. A total of 12,000 subjects will be randomly assigned to one of 2 arms: 
experimental and control.  A total of 700 subjects will be randomly chosen to participate to the sub-
study, with approximately 263 subjects selected at random from 350 M-001 sub-study sites subjects 
and approximately 87 from 350 placebo sub-study sites subjects. 
The investigator will not be provided with randomization codes. The codes will be maintained within 
the IWRS, which has the functionality to allow the investigator to break the blind for an individual 
subject, if necessary. 
Per International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP), 
screening records will be kept at each participating site to document the reason why an individual 
was screened, but failed trial entry criteria.   
5.3.2. 
Masking Procedures  
 
This is a modified double-blind study. Blinding will prevent conscious or unconscious 
misclassification of study endpoints based on subjective perceptions; blinding will be accomplished 
by using a randomization scheme for the participants.  

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Subjects, investigators, and study personnel performing any study-related assessments following 
study injection, as well as collecting swab specimends or blood samples, will be blinded to study 
group and treatment assignment to both: M-001 or placebo. Laboratory personnel will be blinded to 
treatment assignment. Separate unblinded laboratory personnel will be assigned if needed. 
As the M-001 and placebo solutions differ in appearance (see section 6.1), at each study site, an 
appropriately qualified person, who will otherwise not be involved in the treatment or follow-up of 
trial patients, will not be blinded to study treatment. The person will be responsible for the 
preparation of the study treatment syringe. This will in most cases be the site nurse.  
 
The site unblinded staff member will be responsible for preparing the syringe and covering it or 
making it (the content) in other way not visible for the subject before its administration to keep the 
subject blinded. This un-blinded staff member will not participate in the assessment of respiratory 
illnesses or ILI, or in the collection of safety information. 
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 relevant Unblinding Plan for unblinding procedures. 
5.3.3. 
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 SI, 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. 
 As deemed necessary by the site PI or appropriate SI for noncompliance or other reasons. 
 Subject withdrawal of consent. 
 Subject lost to follow-up. 
 Termination of the study or the study cohort. 
 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 SI, would pose a risk to the subject or would be likely to confound interpretation 
of the results. 

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 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, the subsequent study vaccinations should be postponed/deferred until signs, 
symptoms, or acute illness have sufficiently resolved as per PI/SI judgment, and if within 
the expected protocol-specified window for that visit. If outside this window, the PI must 
first obtain approval for the second study vaccination from the study sponsor and the 
documentation of the approval should be filed in the subject’s file.  
 Any unresolved by or continuing at Visit 2 Grade 3 AE. An unresolved or continuing Grade 
1 or 2 AE (grade 2 except for temperature which at grade 2 is not acceptable for 
vaccination) is permissible unless, in the opinion of the PI or SI, it would render study 
vaccination unsafe or interfere with the evaluation of responses.  
 Solicited reactogenicity event grade 3 or AE grade 3 AE, within the 8 days following study 
vaccination (day of the vaccination inclusive), that has no alternative (to the vaccination) 
etiology.  
 Subject no longer meets eligibility criteria. 
 As deemed necessary by the site PI or appropriate SI 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. 
5.3.4. 
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 7.7. Although subjects are free to withdraw at 
any time or may be withdrawn by the site PI or appropriate SI 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 – in cohort 2 -  collection of venous blood samples for immunogenicity testing. 
Every attempt will be made to follow all AEs, including solicited injection site and systemic 
reactions, SAEs, ongoing at the time of early withdrawal to resolution. 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort (i.e., 
three documented contact attempts via e.g. phone calls, e-mails, etc., made on separate occasions 
and followed by a certified letter, as applicable per local law) 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 for alternate follow-up requirements. 

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Subjects who withdraw, or are withdrawn or terminated from the study, or are lost to follow-up 
after signing the ICF, randomization, and receipt of study vaccine will not be replaced. Subjects 
who withdraw, or are withdrawn or terminated from the study, or are lost to follow-up after signing 
the ICF and randomization but before receipt of study vaccine may be replaced.  
Subjects who do not receive second vaccination dose but have not withdrawn the consent for 
pariticpation in the study are allowed to remain in the study upon PI’s decision. 
5.3.5. 
Termination of Study  
Although the study Sponsor has every intention of completing the study, it reserves the right to 
terminate the study or the study cohort 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. 

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6. 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1. Study Product Description 
M-001 
Multimeric-001 (M-001) vaccine developed by BiondVax is a multimeric peptide-based vaccine, a 
single chain recombinant protein containing 9 B and T cell epitopes derived from HA, Nucleoprotein 
and M1 sequences 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 
BiondVax. 
Placebo 
Sterile normal saline will be used as the placebo.  
6.1.1. 
Acquisition 
M-001 will be provided by BiondVax. Packaging, labeling and distribution will be performed by 
Klifo A/S. 
Placebo (normal saline) will be provided by BiondVax. Packaging, labeling and distribution will be 
performed by Klifo A/S.  
M-001 
In Season 1, M-001 is supplied as a sterile, cloudy-white suspension in single-dose vials of volume 
sufficient to dose 1 mg of M-001 (1mg is a single dose). 
Each vial contains a fill volume (less than 1 mL) of concentration provided in the study manual for 
respective product batch that should be transferred to a 1mL syringe for injection according to the 
study manual. It contains no preservative (i.e. non-thimerosal). 
Volume of the product containing 1mg of M-001 (1 mg of M-001 is the dose to be administered per 
each vaccination) will be provided in the study manual for respective product batch. 
 
In Season 2, M-001 is supplied in single-dose pre-filled syringes containing 1mg of M-001. Each 
syringe contains a fill volume (0.6 mL) of concentration provided in the study manual for respective 
product batch that should injected according to the study manual. It contains no preservative (i.e. 
non-thimerosal). 
 
Study product must be stored at 2°C to 8°C. Do not freeze.  
Placebo (Normal Saline) 
0.9% Sodium Chloride, USP, Ph.Eur. 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 in single-dose ready to use syringes, containing 

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0.6 mL.  The solution may contain hydrochloric acid and/or sodium hydroxide for pH adjustment 
(pH 5.3, range 4.5-7.0). The normal saline will be stored according to storage conditions defined in 
product-specific Summary of Product Characteristics.  
 
The packaging and labelling of study treatment will be performed according to GMP (Good 
Manufacturing Practice) and GCP (Good Clinical Practice). In addition, the content of the labels to 
be affixed on the study treatment packs will be in accordance with local regulations for clinical 
trials. A sticker on the outer study treatment pack will indicate that the study treatment pack must 
only be opened by unblinded study personnel. 
 
Each treatment pack will be identified by a treatment number. Once allocated to a patient, the study 
treatment packs should not be used for any other patient. The patient’s identification number (i.e. 
PatID number) must be written on the label by hand by the person who prepares the study 
treatment. 
 
6.1.2. 
Product Storage and Stability Procedures 
The temperature of the storage unit must be recorded daily (excluding non-business days and 
holidays as applicable), monitored during the duration of this trial per the participating 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), or if there are any concerns regarding its integrity, do NOT use the affected study 
product(s). The pharmacist or dedicated nurse 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 Sponsor for further instructions before any additional study vaccinations 
are administered. Based on the information collected, the Sponsor 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 Sponsor or destroy it on site. Dosage, 
Preparation and Administration of Study Intervention/ Investigational Product  
See the protocol-specific manuals for detailed information on the preparation, labeling, storage, and 
administration of study vaccine.  Study vaccine preparation will be performed by the participating 
site’s research pharmacist or nurse on the same day of study vaccine administration. Each dose of 
study vaccine must be administered within 120 minutes from removing the IMP from the 
refrigerator, the prepared syringe must be stored at room temperature until administered 
M-001 investigational influenza vaccine product: 
The 1 mg of M-001 dose will be administered as a single intramuscular injection according to the 
study manual. The M-001 will be provided in vials (Season 1) or syringes (in Season 2) as described 
in paragraph 6.1.1 of the protocol. 
 
Visually inspect M-001 vaccine vial (Season 1)/ ready to use syringe  (Season 2) upon receipt and 
prior to use. After shaking, the suspension will be cloudy white in appearance.  For season 2, if 
the M-001 vaccine precipitated, it should be re-suspended by tapping on the pre-filled syringe 

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strongly with the finger or by intensive shaking 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).   
Normal Saline (Placebo): 
The saline placebo dose will be administered as a single intramuscular injection. Exact volume to 
be injected will be defined in the study manual and will be equal to the volume of the M-001 
defined for the active treatment (M-001) study arm. 
The saline will be provided in ready to use syringes as described in paragraph 6.1.1 of the protocol. 
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).  
 
Study vaccine preparation will be performed by an unblinded study personnel member. Details on 
administration of the IMP will be described in relevant study manual. Briefly, vaccination will be 
performed by a person credentialed to administer medications/vaccines. The syringe containing the 
dose of study vaccine (or placebo) will be inverted a few times, and the air bubble removed before 
administered via a single IM injection given in the deltoid muscle of the subjects’ non dominant 
arm. Subject will be maintained blinded to the contents of the syringe. The site of injection (right or 
left arm) will be recorded on the appropriate data collection form. Aseptic technique will be used 
for the preparation and administration of each dose of study vaccine/placebo using a disposable 
sterile needle appropriate in length and size for each subject.  
Each dose of study vaccine must be administered within 120 minutes from removing the IMP from 
the refrigerator, the prepared syringe must be stored at room temperature until administered.  
6.2. 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 dose 2. There will be no dose modifications.  If a subject’s second study 
vaccination (study dose 2) cannot occur on Day 22, vaccination should be rescheduled to occur 
within the expected protocol-specified window for that visit (Day 22 + 9 days), if possible.   
6.3. Accountability Procedures for the Study Intervention/ Investigational 
Product 
After receipt of the M-001 and placebo vials or syringes, 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 another study site team member(s) the responsibility for study product 
accountability. Such person(s) will be responsible for maintaining complete records and 
documentation of product receipt, accountability, dispensation, temperature and 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. 

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Accountability and study product handling must follow blinded/unblinded personnel assignment at 
the site level. 
 
Used and unused vials or syringes of M-001 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 and empty vials or syringes will be 
determined by the Sponsor. For details regarding final disposition of study products see the relevant 
manual.  
6.4. Assessment of Subject Compliance with Study Intervention/ 
Investigational Product  
Study product will be administered to subjects by an unblinded vaccine administrator via IM 
injection at all dosing times according to subject treatment assignment and as described in sections 
5.3 and 6 of the protocol. Thus, subject compliance with appropriate administration is not 
anticipated to be an issue. Deviations from the dose schedule may only occur as described in 
Section 6.2.  
6.5. Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate data 
collection form. Records of concomitant medications will include at least all current medications 
and medications taken within 3 months prior to Day 0 through 21 days after last vaccination day. 
After this period, only concomitant medications relevant for background chronic respiratory illness 
as per PI judgment, or related to AE or ILI, will be recorded. Subjects who do not receive both M-
001/placebo study vaccinations will have all concomitant medications collected through 
approximately 22 days after the first study vaccination, day of the vaccination inclusive, or early 
termination, whichever occurs first. Prescription and over-the-counter drugs will be included as 
well as herbals, vitamins and supplements. In addition, information on receipt of other influenza or 
non-influenza study vaccines will be solicited at each subject’s visit at the site or phone call by 
PI/SI or delegated study site personnel, and, if confirmed, such vaccination will be reported in the 
eCRF. Past use of influenza vaccinations should be recorded for at least 3 years prior to study entry. 
Identified 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. However, as the study concerns elderly population use of such 
medications cannot be excluded. Medications in this category include the prohibited medications 
per the Subject Exclusion Criteria (see Section 5.2). In addition, the site PI or appropriate SI may 
identify other mediations that should not be used due to a risk to subject safety or assessment of 
reactogenicity and immunogenicity. 
Subjects may be on chronic or as needed (p.r.n.) medications if, in the opinion of the site principal 
investigator or appropriate SI, they pose no additional risk to subject safety or assessment of 
reactogenicity and immunogenicity. Note: Topical, nasal, and inhaled medications, vitamins, and 
contraceptives are permitted. 

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Medications which require relatively frequent dose adjustments, like insulin, hormones, anti-
inflammatory or pain relieve medications, are considered as stable treatment for a chronic condition 
for the purpose of Inclusion Criterion number 3 compliance assessment as long as the treatment 
(regular or p.r.n.) has been continued for at least 3 months prior to first vaccination. Switch within 
the same therapeutic class or type of treatment is not automatically considered as an unstable 
treatment but is subject to PI’s assessment and decision. 

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7. 
STUDY SCHEDULE  
7.1. Enrollment/Baseline (Visit 1, Day 0, Dose 1, Site Visit)  
 Subjects will be provided with a description of the study (purpose and study procedures) and 
asked to read and sign the ICF. The ICF will be signed prior to performing any study 
procedures, including administration of the first study vaccination. 
 Eligibility criteria will be reviewed with subjects prior to the first study vaccination. 
 History of receipt of licensed seasonal influenza vaccine(s) from at least last 3 years, 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. 
 All concomitant medications taken before signing the ICF (at minimum those taken within 3 
months prior to it, if applicable) will be recorded on the appropriate data collection form 
prior to the first study vaccination. 
 Vital signs, including oral temperature and pulse, will be obtained prior to the first study 
vaccination. Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes 
prior to taking oral temperature. 
 Height and weight will be collected on Day 0 prior to the first study vaccination for the 
calculation of Body Mass Index (BMI). 
 Standard physical examination (PE) will be performed on day 0 prior to the first study 
vaccination. If subject’s medical history is known based on medical records (but not if there 
are no medical records available at all), a limited, targeted physical examination may be 
performed instead of standard scope PE prior to the first study vaccination by a study 
clinician, however in any case neurologic component of PE and physical examination of 
head/upper respiratory tract must be performed. Except for neurologic, head and upper 
respiratory tract physical examination, for other body systems only findings relevant from 
the study perspective and not obvious from medical history need to recorded in the eCRF 
 Counsel women of childbearing potential on contraception and avoidance of pregnancy. 
 A urine 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 40 mL of venous blood will be collected prior to the first study vaccination 
for isolation of PBMCs from a subset from Cohort 2 intended for CMI testing (applicable 
only for selected study sites). 
 Subjects entered into EDC system will be randomly assigned to a treatment arm prior to the 
first study vaccination. 
 In study sites participating in CMI assessment, additional, nested randomization is planned 
to assign certain number of subjects to one of the subset substudy groups. 

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 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 non-dominant 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 observed reactions, AEs, 
SAEs (as applicable) 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 (paper diaries) and other study-related 
materials to record daily oral temperature (e.g. thermometers), solicited injection site and 
systemic reactions, any unsolicited AEs, and concomitant medications. Subjects will be 
encouraged to take their temperature on the vaccination day in the evening and then at 
selected approximately the same time each day for next 7 days after the vaccination day. 
Subjects will be instructed on how to use the provided materials, prior to discharge from the 
clinic. Subjects will be instructed to notify the study center if they develop any reactions 
after the first study vaccination. PI or appropriate SI will assess the reaction and will give 
the subject further instructions on the proper course of action, including request for return to 
the clinic for immediate evaluation. The participants will be instructed to return the 
completed diary, covering period between Visit 1 and Visit 2 to the site for Visit 2, and to 
bring their study thermometer with them to the Visit 2. 
7.2. Second Vaccination  
7.2.1. 
Visit 2, Day 22, Site Visit (22 days [+9 days] post first study vaccination day) 
 Study personnel will review the memory aid information with subjects and assess and record 
all solicited, reported reactions, AEs, SAEs (as applicable) 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 or recent medical history, obtain vital signs 
 A targeted physical examination should be performed by a study physician if assessed as 
needed based on medical interview concerning period between Visit 1 and Visit 2 . 
 Examine the vaccination site for Dose 1. 
 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. 
 Oral temperature 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. 

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 All unsolicited AEs/ SAEs will be assessed and recorded on the appropriate data collection 
form prior to the second study vaccination. 
 A urine 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.  
 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 reactions, AEs 
or SAEs (as applicable) 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 (paper diaries) in a stamped envelope 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 on the 
vaccination day in the evening and then at selected approximately the same time each day 
for next 7 days after the vaccination day. Subjects will be instructed on how to use the 
memory aid and how to measure and record solicited events and / or unsolicited AEs prior to 
discharge from the clinic. Subjects will be instructed to notify the study center if they 
develop any significant reactions after the second study vaccination. If the site PI or 
appropriate SI 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. The participants will be instructed to return the diary to the site after completion 
of the diary. The participants that are  coming for visit 3 to the site will be requested to bring 
the diary to that visit. 
7.2.2. 
Visit 3, Day 36, Site Visit (14 days [±2 days] post second study vaccination day(visit 
3 - in season 2019/20 only)  
 This is a visit in study site for the subset of subjects selected for immunogenicity evaluation 
and site visit or a phone call (if site visit is not feasible) for the rest of the participants. The 
following #4 and #6 points refer to those actually visiting the clinic: 
 Study personnel will review the memory aid information with subjects and assess and record 
all solicited events / unsolicited reactions, AEs, SAEs and concomitant medications on the 
appropriate data collection form.  
 Counsel women of childbearing potential on contraception and avoidance of pregnancy. 
 [site visits only] A targeted physical examination and/or vital signs collection may be 
performed by a study clinician if assessed as needed based on review of recent medical 
history. 

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 Study personnel will review interim medical history (other than reactogenicity events) with 
subjects and assess and record all unsolicited AE/SAEs and concomitant medications on the 
appropriate data collection form. 
 [site visits only] Approximately 40 mL of venous blood will be collected for isolation of 
PBMCs from a subset of subjects from Cohort 2. 
7.3. Follow up period for safety and efficacy:  
Safety surveillance: 
All serious adverse events (SAEs) and new onset of chronic medical illness (NOCIs) will be 
collected from Day 0 until the end of the participation in the trial by the subject. 
Adverse events of special interest (AESIs) will be captured as SAEs. These include new 
onset of Guillain-Barré Syndrome (GBS), Bell’s Palsy, encephalitis / myelitis, optic neuritis, 
Stevens-Johnson Syndrome, and toxic epidermal necrolysis. 
Passive efficacy surveillance: Following randomization and vaccinations, subjects will be 
instructed to contact the site if they experience symptoms of a respiratory illness or 
influenza-like illness during the annual surveillance periods defined as from Day 14 after 
second vaccination day until 15 May of the following year. 
Active efficacy surveillance will be performed from November 15th (in Season 1) or from 
December 1st (in Season 2) until the week of 30 March the following year, the most likely 
period of influenza virus circulation in the Northern Hemisphere.  
The participants will be contacted by a dedicated study staff up to twice a week between 
approximately November 15th through March 31st .  
Participants will be contacted as described above by non-site study staff to monitor for 
influenza-like illness (ILI).; participants identified this way as potentially having ILI will be 
followed up by relevant study site personnel to confirm if the participant’s symptoms and 
signs meet study ILI definition. 
ILI is NOT to be understood as condition caused specifically by influenza virus. The 
etiology of ILI may be very different, and only after analysis of swabs taken from subjects , 
the presence or absence of influenza virus in swab sample can be determined. Hence, even if 
it is suspected that ILI is caused by e.g. a bacteria, or by some other virus than influenza 
virus, such ILI remains valid reason for swab collection, also because in some cases there 
may be a superinfection or parallel infection with influenza virus. 
However, if an Investigator is sure that an ILI-qualifying symptom/sign comes purely from 
underlying chronic condition (e.g. arthritis, COPD, asthma), including also the severity of 
the symptoms/signs, or belongs to clinical presentation of another, known, completely non-
infectious condition (e.g. toxicity, injury, cancer), then it is understood that the investigator 
may decide to NOT recognize the case as meeting ILI criteria, and to NOT qualify the 
subject for swab collection. The rationale behind disqualifying such cases from ILI is 
preference for avoidance of exposing subjects to swab collection procedure in case when it 
is absolutely sure a priori that infectious etiology of the symptoms/signs is highly unlikely. 
During the period from Day 14 after second vaccination day until 30 April of the following 
year (or longer if decided by the medical director based on actual influenza season duration), 
the site will arrange for an NP/nasal and throat swab to be collected if the subject 

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experiences a new onset of the above mentioned symptoms of ILI (that persist for or reoccur 
after a period of at least 12 hours). 
During the passive and active efficacy surveillance period participants suffering from ILI 
will be asked to provide information on the symptoms that they developed using also 
standardized sets of questions.  
 
NP/nasal and throat swab collection: 
NP swab (or nasal and throat swab) specimens will be collected during the period from Day 
14 after second vaccination day until 30 April of the following year (or longer if decided by 
the medical director based on actual influenza season duration), within 24 hours from ILI 
being reported to or identified by study personnel and up to 4 days of the onset of ILI 
qualifying symptom(s) for confirmation of influenza virus A or B via qRT-PCR followed by 
culture (Rhesus Monkey Kidney or Madin–Darby Canine Kidney tissue cultures) 
confirmation for qRT-PCR positive samples as described in Vesikari et al 19. Every effort 
must be made to obtain the NP(or nasal and throat) swab specimen within 24 hours from ILI 
being reported to or identified by study personnel according to the qualifying ILI symptoms, 
and no later than 4 days (sample to be collected through Day 3 of the illness, considering 
that Day 0 is the day of the illness onset) following the onset of the ILI. 
 
 
The end of influenza season will be defined for each participating country by the Medical 
director based on national surveillance and study data. 
The Sponsor's Responsible Medical Director will base the decision on the following criteria: 
1) The influenza activity level for the region/zone where the research site is located has to be 
evident by increased ILI and laboratory confirmed influenza detection together with e.g. 
outbreaks in schools, hospitals, residential institutions and/or other types of facilities 
occurring in less than 50% of the influenza surveillance region), based on the most updated 
report. 
2) The percentage of specimens tested that are positive for influenza has to be at least 10% 
for the country where the site is located, based on data present in the most updated report.  
 
If the 2 criteria are met for the region/zone where the research site is located, the site will be 
instructed to continue obtaining NP/nasal and throat swabs if a subject has a new influenza-
like illness. 
 
On 15 May (unless other instructions are given by the medical director), all surveillance and 
the swab collection procedures will end. 
 
Any influenza A or B strain will be included in the vaccine efficacy analysis. Culture 
confirmation of influenza will be performed only for qRT-PCR highly positive samples. 
 
After 30th of April, passive surveillance will continue, with subjects expected to call the 
research site to report the occurrence of any new respiratory illness or influenza-like illness 
symptoms. However, the research site will schedule the collection of the NP/ nasal and 
throat swab only if the Sponsor has categorized the site as requiring continued testing based 

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on DSMB recommendation which will be based on influenza epidemiologic data. The 
Sponsor's Responsible Medical Director will perform weekly assessments of the applicable 
influenza surveillance system to determine whether a particular research site needs to 
continue collecting the swabs. 
 
ILI follow-up calls:  
Any ILI must be followed up for up to 30 days following the start date or until resolved. Site 
personnel will follow up the participant with ILI at 10±3 days after ILI start date. Follow up 
information on symptoms associated with the ILI will be collected by study staff through a 
telephone call performed at 10±3 days (and up to 30 days) (unless collected at unscheduled 
site visit at relevant time point) following the illness start date.  
Protocol defined ILI end date is the date when for at least 24 hours ILI symptoms are no 
longer present. Of note, some symptoms may persist after ILI for a long time, but the 
duration of ILI is to be determined by presence of symptoms of ILI understood as active 
disease, or “influenza symptom”, contrary to symptoms being part of an underlying chronic 
condition (e.g. COPD, arthritis), and contrary to chronic complications and/or sequelae of 
the ILI. When no clear end of ILI can be observed, the PI is requested to make rational 
judgment and determine the ILI end date based on available data and his/her experience. It is 
expected, that normally, ILI should not last longer than 2-3 weeks, and in case of suspected  
overlapping new infection, the two infection episodes should be recognized by PI as 
separate ILI cases.  
 
Laboratory testing for the confirmation of influenza:  
All NP/nasal and throat swab specimens will be submitted for analysis by polymerase chain 
reaction (qRT-PCR), and when the result is found positive, and if there is a sufficient 
content of viruses (as determined by Ct value ≤35)” [Ct= cycle threshold] another aliquot 
from such specimen will be also examined by culture confirmation test. Typing and 
subtyping of the influenza virus will be performed with PCR based method. 
Optional test: Positive cultures samples will be stored and may undergo additional testing 
in the future (subtyping or strain identification, utilizing genetic sequencing and antigenic 
analysis using hemagglutination inhibition [HAI] against a panel of known standard ferret 
reference antisera to different viral strains) to further determine the breadth of protection 
provided by M-001. 
Out of study influenza infection confirmation: in cases when no swab collection was 
performed within study framework, but valid, relevant external medical documentation 
exists confirming recent or ongoing influenza infection (laboratory confirmation – PCR, 
culture or serology - IgM antibodies), such medical documentation will be subject to 
sponsor’s approval as surrogate proofs of influenza infection, and if approved as valid, may 
be taken into account for exploratory analyzes. Details of exploratory analyzes will be 
defined in statistical analysis plan. 
 
 

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7.4. Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ Electronic 
Communication (180 days [+/-14 days] post last study vaccination day)  
Subjects will be contacted by phone or electronic communication (e.g., email, text message) 
to query for safety events.  In case follow-up contact is needed based on the responses, 
subjects will be asked to provide further details to the follow-up by phone. AEs limited to 
NOCIs and SAEs that have occurred since the previous visit will be solicited.  Based on the 
information, subjects may be asked to return to the clinic for evaluation. 
7.5. Follow Up Period for Efficacy Season 2  
Passive surveillance will take place starting 14 days after the second injection and until May 
15, 2020. 
Active surveillance for cohort 2 will take place between December 1st , 2019 and March 31, 
2020. During this period, the dedicated study staff will contact the participants up to twice a 
week to monitor for ILI symptoms as detailed above in 7.3. (Follow up calls in season 
2019/20 will be for participants in cohort 2 only).  
As of the end of the season 1, the follow up for Cohort 1 subjects in season 2019/2020 is not 
planned and participation of all Cohort 1 subjects will be assumed as completed with the end 
of Season 1, i.e. the latest on May 15th except for cases defined elsewhere (e.g. ongoing ILI, 
SAE follow-up). 
7.6. Follow Up Period for Efficacy Season 3  
Season 3 is not planned and is not encompassed by this study protocol. 
7.7. 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 22 days after the last 
study vaccination, day of the vaccination inclusive). 
 If indicated by medical history, perform physical examination and/or obtain vital signs 
including oral temperature. 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 within 22 days after the last study 
vaccination, day of the vaccination inclusive). 
 Information regarding reactions recorded in diary/-ies, AEs and SAEs will be recorded on 
the appropriate data collection form. Recording of AEs in the EDC will be limited to SAEs 
if after 21 days following the last study vaccination day. 

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 Examine study vaccination site, and perform post- administration reactogenicity assessment 
(if within 8  days after the last study vaccination, day of the vaccination inclusive ). 
7.8. 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 22 days after the last study vaccination day, inclusive of the 
vaccination day). 
 Review and record all concomitant medications (if within 22 days after the last study 
vaccination day, inclusive of the vaccination day). 
 All reactions recorded in diary/-ies, AEs, SAEs will be recorded on the appropriate data 
collection form.  Recording of AEs in the EDC will be limited to SAEs if after 21 days after 
the last study vaccination day. 
 Obtain interim medical history by interview of subjects and note any changes since the 
previous visit (if indicated). 
 If deemed as relevant and/or needed, perform physical examination and/or obtain vital signs 
including oral temperature. Subjects must not eat or drink anything hot or cold, or smoke 
within 10 minutes prior to taking oral temperature. 
 Examine study vaccination site and perform post- administration reactogenicity assessment 
(if within 8 days after the last study vaccination, inclusive of vaccination day). 

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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 – clinically or from the study protocol perspective - 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. All Past influenza 
vaccinations should be recorded (up to 3 years). Other vaccines history should include at least 30 
days before the study and any other study-relevant vaccination received in the past. 
Concomitant Medications: All current medications and medications taken within 3 months before 
Study Day 0 (prescription and over-the-counter drugs) will be included, as well as vitamins and 
supplements, through 21 days after the last study injection day, unless relevant for chronic 
background respiratory illness, as per PI judgment, or related to AE or ILI. 
Vital signs: blood pressure, oral temperature and pulse will be collected at study visit 1, and as 
needed at any other study visits Only oral temperature is required to be measured on visit 2. 
Measurement of oral temperature should be performed with thermometers provided by the study 
Sponsor. Oral temperature should be measured by keeping the tip of the thermometer under the 
tongue for sufficient amount of time until the temperature reading stabilizes. In cases when level of 
oral temperature seems too low the measurement should be repeated and care should be taken to 
correctly place the tip of the thermometer and to keep it under the tongue for sufficient amount of 
time (until the temperature stops growing). 
Height, weight: These parameters will be measured at Day 0 (Visit 1). 
Physical Examination: On Visit 1 standard physical examination should be performed prior to the 
first study vaccination, but if subject’s medical history is known based on medical records, a 
limited, targeted physical examination may be performed instead of standard scope PE prior to the 
first study vaccination by a study clinician,  however in any case neurologic component of PE and 
physical examination of head/upper respiratory tract must be performed. On visits other than 1 
limited, targeted physical examination may be performed if assessed by investigator as needed.  
Reactogenicity Assessments: This will include an assessment of solicited events occurring from the 
time of each M-001 study vaccination [Day 0 (Visit 1), Day 22 (Visit 2] through 8  days after the 
study vaccination (inclusive of vaccination day), which includes an assessment of systemic 
reactions (Fever; Decreased blood pressure and/or dizziness; Chills and/or sweating; Joint and/or 
muscle pain; Headache; Nasal congestion, runny nose, phlegm production, rhinitis; Problems with 
breathing (difficulty breathing, wheezing); General malaise, fatigue, loss of appetite; Itching on 
body/ pruritus; Swelling/tender lymph nodes; Irritability; Rash; Cough; Sore throat; Stomach 
problems (abdominal pain, diarrhea, nausea, vomiting)) and local – injection site reactions (Blue 
spot/ bruising; Induration / Swelling; Redness / Warmth; Itching),Pain/ tenderness 
Memory Aids: All subjects will complete a subject memory aid (paper diary) from the time of each 
study vaccination [Day 0 (Visit 1), Day 22 (Visit 2)] through 8 days after the study vaccination 
(study vaccination day inclusive).  Subject memory aids will be reviewed with the subject for AEs 
at the site visit following the first study injection, and over the phone after the second study 

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injection (unless the subject comes to the site for Visit 3). If a subject noted ongoing injection site 
or systemic reactogenicity on the 7th day following the study injection day, the memory aid will 
continue to be completed and reviewed until resolved. Subjects will be requested to deliver memory 
aids filled in after the second vaccination when completed – to the site. 
Questionnaires: information on ILI clinical presentation, duration etc. will be collected in the study 
by study personnel.  
8.2. Laboratory Evaluations 
Schedules and volumes of clinical laboratory tests and immunogenicity assays are specified in 
Schedule of events (Table in the Synopsis).  
8.2.1. 
Clinical Laboratory Evaluations  
Urine pregnancy tests will be performed by the local or site laboratory within 24 hours prior to each 
study vaccination (Day 0 (Visit 1) and approximately Day 22 (Visit 2) on all female subjects of 
childbearing potential. Result must be negative and known prior to randomization on Day 0 (Visit 
1) and administration of each study vaccination to be eligible for participation in the study and 
receipt of each dose of study vaccine. 
8.2.2. 
Nasopharyngeal Samples  
For assessment of influenza virus through culture and qRT-PCR, an NP/nasal and throat swab 
sample will be collected from both nasal passages using two different swab applicators; both swabs 
are then placed in the same tube of universal transport medium (UTM). Optionally, if NP swab 
cannot be collected, combined swabs collection from deep nasal (both nostrils) and throat - can be 
collected instead of NP with three separate applicators, and all three swabs are then placed into the 
same tube of UTM. Immediately prior to taking the sample, the person performing the procedure 
will verify the subject’s identity and will confirm that the subject number and any other required 
information on the laboratory request form are those of the subject. Each tube of UTM will be 
clearly labeled with the self-adhesive bar-coded label provided on the Swab Requisition form that 
will be applied to the tube immediately before collection of the NP/nasal and throat swab. The 
subject’s identification number and any other required information, the date of sampling, and the 
date and time of preparation will be clearly documented. 
Detailed instructions for the preparation of NP (or combination of nasal and throat swabs) samples 
are contained in the relevant study manual provided to the sites and relevant study personnel. 
8.2.3. 
Special Assays or Procedures  
Cellular (CMI) Studies  
Assays to measure T cell responses will be performed by a qualified laboratory.  Venous blood 
samples for isolation of PBMCs will be collected from a subset of cohort 2, immediately prior to 
the first study vaccination (Day 0, visit 1 in season 2), and approximately 15 days (day of the 
vaccination inclusive) after the second study vaccination (Day 36, visit 3, season 2). 

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8.2.4. 
Specimen Preparation, Handling, and Shipping  
8.2.4.1. 
Instructions for Specimen Preparation, Handling, and Storage 
Instructions for specimen preparation, handling, and storage are included in the relevant study 
manual, as appropriate. 
8.2.4.2. 
Specimen Shipment 
Swab samples will be shipped and stored according to applicable regulations and according to the 
technical requirements aiming at preserving good quality of the material before it is processed for 
qRT-PCR and (where applicable) for culture confirmation. Swab samples will be analyzed in a 
qualified laboratory. Details will be contained in the relevant laboratory and study manuals. 
Swab samples will be shipped in batches regularly during the course of this study. 
Samples for PBMC will be shipped from the sites to the qualified laboratory in a blinded fashion 
for PBMC isolation and storage before the planned cellular assays take place. Details on shipment 
and PBMC isolation will be contained in the relevant laboratory and study manuals. 
Samples for PBMC will be shipped from sites on ongoing basis aiming at same day or next day 
delivery, as possible. 

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9. 
ASSESSMENT OF SAFETY  
9.1. Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
1. SAEs and NOCIs occurring from the time of the first study vaccination through subjects’ 
participation in the trial. 
2. Solicited events – reactogenicity events occurring on the day of each study vaccination 
through 8 days* after each study vaccination: 
*Vaccination day is considered Day 0, with 7 days following (8 days in total) 
a)  Injection site reactions including pruritus, ecchymosis, erythema,warmth, induration, 
swelling, pain and tenderness. 
b)  Systemic reactions including fever, feverishness, general malaise, fatigue, loss of 
appetite, myalgia or arthralgia, decreased blood pressure or dizziness, chills and/or 
sweating, nasal congestion, runny nose, phlegm production, rhinitis, problems with 
breathing (difficulty breathing, wheezing), itching on body/ pruritus, swelling/tender 
lymph nodes, irritability, rash, cough, sore throat, headache and stomach problems 
(abdominal pain, diarrhea, nausea, vomiting). 
3.  Unsolicited AEs/SAEs – unsolicited AEs/SAEs occurring from the time of the study 
vaccination through approximately 22 days after each study vaccination (day of the 
vaccination inclusive) . 
9.2. Safety Assessment  
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, 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, will be captured on the appropriate data collection form and electronic case report form 
(eCRF) as described below in terms of reporting periods. Information to be collected for AEs 
includes event description, date of onset, licensed study physician’s assessment of severity and 
relationship to study product and considered etiology (if case not related or unlikely related to study 
product) 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. 

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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 may be recorded as an AE or SAE. 
AEs must be graded for severity and assessed for relationship to study product (see definitions 
below). AEs characterized as intermittent require documentation in the subject’s file of onset and 
duration of each episode. It is up to PI’s decision whether the episodes are recorded in the eCRF as 
separate events or under one event with comment added on the intermittent (or similar) nature of 
the event. The start and stop date of each reported AE will be recorded on the appropriate data 
collection form and eCRF within study periods as described below. 
•Unsolicited AEs – which do not meet SAE criteria, nor ILI, AESI or NOCI definition should be 
reported only until ~22 days post each study vaccination, thus - per protocol – such AEs, if they 
occurred later then 22 days post study vaccination day, should not be recorded in the AE section of 
the eCRF. They still need to be documented in the subject’s study file at the site. 
Adverse events of special interest (AESIs) will be captured as SAEs and within the same timelines 
throughout the subject’s participation in the trial. These include new onset of Guillain-Barré 
Syndrome (GBS), Bell’s Palsy, encephalitis / myelitis, optic neuritis, Stevens-Johnson Syndrome, 
and toxic epidermal necrolysis.  
NOCIs should be collected from the time of the first study vaccination throughout the subject’s 
participation in the trial. NOCI is defined as diagnosis of a chronic medical condition where the 
symptoms commenced or worsened following exposure to the study vaccine. NOCIs meeting 
criteria of SAE will be recorded as SAE. 
Events classified as ILI will not be recorded as AEs/SAEs unless they occur during period from 
first or second vaccination within 8 days (the vaccination day inclusive) post the respective 
vaccination or if they meet seriousness criteria - then they are also (in addition to being reported as 
ILI) reported as SAEs, because ILI cases are to be recorded separately and analyzed for efficacy 
assessment. 
Severity of Event: AEs will be assessed by a licensed study physician 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 by PI/SI to quantify severity, taking into account subject’s 
medical history, concomitant medications, and baseline values:  
 Mild (Grade 1): Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
 Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures. Moderate events may cause some interference with functioning and 
daily activities. 
 Severe (Grade 3): Events interrupt the subject’s usual daily activities and may require 
systemic drug therapy or other treatment. 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 

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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: 
none, unlikely, possible, probable, certain. In a clinical trial, the study product should be considered 
as potential suspect. To help assess, the following guidelines are used: 
 
 NONE no evidence of any causal relationship is present 
 
 UNLIKELY There is only little evidence to suggest there may be a causal relationship.  
Another reasonable explanation for the event exists (medical history, treatment) 
 
 POSSIBLE 
There is some evidence to suggest a causal relationship but the influence of 
other factors has been reasonably possible 
 
 PROBABLE There is a reasonable evidence to suspect a causal relationship, and the 
relevant influence of other factors is less likely. 
 
 CERTAIN - There is clear evidence for the causal relationship, and other reason is very 
unlikely 
9.2.2. 
Reactogenicity 
Reactogenicity events are solicited events which are common and considered as possible to occur 
following administration of this type of vaccine. Reactogenicity (solicited) events are recorded only 
for 8 days post vaccination (day of the vaccination inclusive). Solicited events (reactogenicity 
events) which match at least one of the below criteria must be also recorded as AE/SAE or 
unsolicited AE/SAE: 
 
- symptom/event continues/occurs beyond 7 days post vaccination day (unsolicited AE/SAE) 
- reactogenicity symptom/event(s) required medical (i.e. physician’s) assistance (AE/SAE) 
- reactogenicity symptom/event has been graded by subject or by investigator as severe (AE/SAE) 
- oral body temperature of severe grade as per section 9.2.2 Table 8 (AE/SAE) 
 
Per PI/SI’s judgment, also cases of symptoms/events occurring within 8 days post vaccination (day 
of the vaccination inclusive) not meeting the above criteria can be recorded as SAE. 
 
The following Toxicity Grading Scales will be used by PI/SI to grade solicited injection site and 
systemic (subjective and quantitative) reactions in order to assess whether they qualify as AE/SAE, 
and if they are severe enough to delay administration of second dose: 
Table 5: 
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-
Subject is aware of pain, 
and it prevents daily activity 
or requires any use of a 
narcotic pain reliever 

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Injection Site Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
narcotic pain reliever for 
>24 hours 
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 (Itching) 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis (Bruising)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema (Redness)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration 
(Hardness)/Swelling* 
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 criterion for stopping the trial 
Ecchymosis, erythema, and induration /swelling as analyzed by measurement will be graded as 
follows: 
Table 6: 
Injection Site Reactogenicity Measurements 
Injection Site Reaction 
Small 
Medium 
Large 
Ecchymosis * 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration /Swelling* 
<20 mm 
20 mm – 50 mm 
>50 mm 
* Will not be used as criterion for stopping the trial. 
 
Table 7: 
Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness 
(Chills/Shivering/Sweating) 
No interference with 
daily activity 
Nonsignificant 
interference with daily 
activity 
Significant interference, 
prevents daily activity 
Fatigue (Tiredness) 
No interference with 
daily activity 
Nonsignificant 
interference with daily 
activity 
Significant interference, 
prevents daily activity 
Malaise (General Unwell 
Feeling) 
No interference with 
daily activity 
Nonsignificant 
interference with daily 
activity 
Significant interference, 
prevents daily activity 

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Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Myalgia (Body Aches/Muscular 
Pain)* 
No interference with 
daily activity 
Nonsignificant 
interference with daily 
activity 
Significant interference, 
prevents daily activity 
Arthralgia (Joint Pain)* 
No interference with 
daily activity 
Nonsignificant 
interference with daily 
activity 
Significant interference, 
prevents daily activity 
Headache 
No interference with 
daily activity 
Nonsignificant 
interference with daily 
activity 
Significant interference, 
prevents daily activity 
Nausea 
No interference with 
daily activity 
Nonsignificant 
interference with daily 
activity 
Significant interference, 
prevents daily activity 
* Not at injection site. 
Oral temperature# will be graded as follows:  
Table 8: 
Quantitative Systemic Reactogenicity Grading 20,21 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
(Age <60) Fever* - oral† 
38.0°C – 38.4°C 
38.5°C – 38.9°C 
>38.9°C 
(Age 60+) Fever* - oral† 
37.3°C – 37.7°C 
37.8°C – 38.2°C 
>38.2°C 
# Oral temperature assessed on Day 0 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 changes will be graded according to the PI/SI judgment taking into 
consideration subject’s medical history, concomitant medications, and baseline values. 
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/meets any of the following:  
 death, 
 a life-threatening AE*, 
 inpatient hospitalization or prolongation of existing hospitalization (excluding pre-planned 
elective surgeries or other pre-planned hospitalizations; for this option it is not required that 
they were pre-planned solely before Visit 1, they might be pre-planned also after Visit 1), 
 a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
 a congenital anomaly/birth defect 

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 an 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. 
 Note: all AESIs will also be considered SAEs as within the confines of this protocol are 
deemed as important medical events  
 Note: cases of NOCIs which meet criteria of SAE will be recorded as SAE with annotation 
that they are also considered NOCIs. 
 Note: ILI cases meeting seriousness criterion/criteria should be recorded as SAE in parallel 
with recording them as ILI cases, except for periods of 8 days post vaccination day (day of 
the vaccination inclusive) for both vaccine doses when such cases will only be recorded as 
SAE. 
* 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. 
 Recorded on the appropriate paper SAE form and in eCRF. 
 Followed through resolution by a licensed study physician. 
 Reviewed and evaluated by the DSMB (periodic review unless related) 
9.3. Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be documented from the time of each 
study vaccination (Day 0 (Visit 1) and approximately Day 22 (Visit 2) through 8 days after each 
study vaccination (day of the vaccination inclusive). 
Unsolicited non-serious AEs (excluding NOCIs) will be documented from the time of the study 
vaccination until 22 days after the study vaccination (day of the vaccination inclusive). 
ILI will be documented as AE if occurs within 8 days post vaccination (day of the vaccination 
inclusive). 
SAEs and NOCIs will be documented from the time of the first study vaccination (Day 0 (Visit 1)) 
through subject’s participation in the trial. 

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SAEs occurring after the participant completes the study or after early termination need not 
be reported unless the Investigator believes that the event may have been caused by the study 
product or a protocol procedure. 
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 CRO representative at the following: 
KCR S.A. 
Email: SAE@kcrcro.com 
 
FAX: +48 22 203 56 58 
In addition to the SAE form, selected SAE data fields must also be entered into EDC,  
Other supporting documentation of the event may be requested by the DSMB and should be 
provided as soon as possible. 
All SAE report(s) will be reviewed and assessed for regulatory reporting purposes and potential 
impact on study subject safety and protocol whithin 1 business day from receipt. SAE reports will 
beshared with DSMB. 
At any time after completion of the study, if the site PI or appropriate SI becomes aware of an SAE 
that is suspected to be related to study product, the site PI or appropriate SI will report the event to 
the study Sponsor directly. 
9.3.2. 
Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported via Pregnancy Report Form (paper) and 
recorded in the EDC under SAE category. 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 
AE will be followed until it reaches a satisfactory resolution, or becomes stable, or clinical 
judgment indicates that further evaluation is not warranted. 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. Safety Oversight (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises the sponsor. 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.   
 Data review for safety at study specific time frames; at least annually (shortly after each 
influenza season). 
 After all 8-day post second study vaccination safety data are available for all study 
participants. 
 Interim review meeting: Review the blinded safety data for the interim report 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 the sponsor. 
 Final review meeting: After clinical database lock to review the cumulative unblinded safety 
and efficacy 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 
the sponsor. 
 Ad hoc, for evaluation of immediate concerns regarding observations during this trial, or as 
needed. 
The DSMB will operate under the Medical director that will forward information and organize 
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 a charter prepared by the 
Medical director. The DSMB will review applicable data to include, but not limited to, study 
progress and participant, clinical (total number of influenza confirmed cases), safety, and 
reactogenicity data.  Reports may include enrollment and demographic information, medical 
history, concomitant medications, physical assessments, clinical laboratory values, dosing 
compliance, and solicited/reactogenicity events and AE/SAEs.  Additional data may be requested 
by the DSMB, and interim statistical reports may be generated as deemed necessary and appropriate 
by the sponsor.  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. 

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Upon completion of this review and receipt of the advice of the DSMB, the sponsor will determine 
if study entry or study dosing should be interrupted or if study entry and study dosing may continue 
according to the protocol. 
9.6. Efficacy Assessment  
9.6.1. 
Molecular Detection and Sequencing Methodology (qRT-PCR): 
Clinical samples collected during the study period will undergo an extraction procedure to isolate 
the viral RNA from the NP/nasal and throat swab prior to testing. 
The initial test will be a qRT-PCR-based assay to determine if Influenza strains are present in the 
clinical sample. A multiplex qRT-PCR will be performed to define Influenza A/H1 or A/H3 or B in 
a single test, Influenza B samples will be re-tested by qRT-PCR to define the Victoria/Yamagate 
lineage specification. 
For samples that are found positive for influenza in the qRT-PCR assay, further testing 
by culture confirmation will be performed if there is a sufficient content of viruses (as determined 
by Ct value <35)” [Ct= cycle threshold].  
 
If swab specimen was not collected but infection with influenza virus has been confirmed outside of 
the study framework and valid medical documentation exists confirming such virus identification 
(e.g. hospital discharge), such cases may be recognized by study sponsor as valid confirmed 
influenza cases. Extent to which such results will be included in the statistical analyses will be 
defined in statistical analysis plan. 
9.6.2. 
Influenza Virus Culture: 
Swab samples from subjects with ILI that were found positive in qRT-PCR, will be used to 
inoculate and infect influenza virus susceptible tissue culture cell lines (e.g. MDCK). Optionally, 
Influenza positive cultures will be confirmed by using direct immunofluoresence techniques with 
influenza type–specific (i.e., for influenza A and influenza B) antibodies.  

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10. 
CLINICAL MONITORING  
10.1. Site Monitoring  
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study center visit log that will be kept at the site.  The first post-
initiation visit will be made as soon as possible after enrollment has begun.  At these visits, the 
monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF are known to the sponsor and investigational 
staff and are accessible for verification by the sponsor site contact.  If electronic records are 
maintained at the investigational site, the method of verification must be discussed with the 
investigational staff.  
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data.  Findings 
from this review of eCRF and source documents will be discussed with the investigational staff.  
The sponsor expects that, during monitoring visits, the relevant investigational staff will be 
available, the source documentation will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct. 
Please refer to Monitoring Plan for further details. 

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11. 
STATISTICAL CONSIDERATIONS 
This section provides an overview of the statistical considerations for the design, conduct, and 
analysis of the phase 3 trial of Multimeric-001 influenza vaccine. A formal statistical analysis plan 
will be  developed and finalized prior to first DSMB meeting for Year 1 cohort and will be 
amended to reflect changes made to previous version of the protocol. 
11.1. Study Hypotheses  
The null hypothesis of vaccine efficacy (VE) equals 40% against the alternative hypothesis VE > 
40% will be tested using the two-sided, 95% Clopper-Pearson confidence interval for VE. If the 
lower bound of the 95% confidence interval is above 40%, adequate efficacy will have been 
established. 
11.2. Study Outcome Measures 
Please refer to Section 3.2. 
11.3. Sample Size Considerations 
11.3.1. 
Study Design  
This is a pivotal, multicentre, randomized, modified double-blind, placebo-controlled phase 3 trial 
to assess the safety and clinical efficacy of M-001, an influenza vaccine administered 
intramuscularly twice in older adults and the elderly (≥50 years of age). Subjects will be 
randomized 1:1 to vaccine or placebo with randomization stratified by cohort and age group. For 
season 2, stratification will also be performed for participation to the sub-study. All doses will be 
administered IM approximately 21 days apart (recommended window is 21-30 days). All subjects 
from cohort 1 will be followed for up to two consecutive influenza seasons with no obligation to 
continue in season 3 if the study is extended to third season with protocol amendment. It is not 
planned to extend the participation of the cohort 1 subjects beyond season 1. Subjects from cohort 2 
will be followed up for one season. If the study is extended to third season with protocol 
amendment, it will be determined by the amendment if they are offered possibility to continue their 
participation in the next season and new, relevant consent will be then collected.  
A total of up to 10 sites will be selected to participate to the CMI substudy. Blood samples will be 
collected prior to the first study vaccination (Day 0) and approximately 15 days (day of the 
vaccination inclusive) after the second vaccination (Day 36, 14±2 days since day of the second 
vaccination) in 350 randomly chosen subset of subjects from these sites.  M-001 subjects will be 3 
times more likely to be selected in the subset than placebo subjects and T cell responses will be 
measured only in subjects who receive M-001. 
 
 

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11.3.2. 
Study Population and Sample Size 
The study population for this clinical trial includes 12,000 males and non-pregnant females, ≥50 
years old, inclusive, who meet all eligibility criteria.  The participants will be recruited from the 
general population. At least half of the participants will be ≥65 years old. 
The study sample size of 12,000 subjects is based on the lower bound of the two-sided 95% 
confidence interval for vaccine efficacy (VE) being above 40% with 80% probability when true VE 
is 62%. It assumes 1:1 randomization, a 2.41% attack rate in the study population, and no more than 
10% of subjects lost to follow-up or excluded from the per protocol population. Under these 
assumptions, 182 first episodes of qRT-PCR -confirmed influenza of any strain occurring at least 
15 days after the second dose of study vaccine or control and prior to the end of the first influenza 
season will be needed to demonstrate efficacy is at least 40%.  
A total of up to 10 sites will be selected to participate to the CMI substudy. A total of 350 subjects 
will be randomly chosen among 700 subjects from the selected sites: approximately 263 subjects 
selected at random from 350 M-001 subjects and approximately 87 from 350 placebo subjects; 
placebo subjects being selected to maintain the study blind. Assuming that among the 263 M-001 
selected subjects, 210 will have valid measurement for the change from baseline in percentage of 
CD4+ lymphocytes producing Th1 cytokine (e.g. INF-γ) in response to any of the 9 peptides in M-
001, then this endpoint can be estimated with a precision of at most 2% (1/2 width of the 95% CI).  
 
11.3.3. 
Subject Enrollment and Follow-up 
Based on the accrual rate for similar studies, it seems reasonable to expect that the participating 
sites will be able to enroll this trial in a timely fashion.  Prior experience suggests up to 10% of 
subjects may be excluded from the per protocol analysis for the primary outcome either because 
they were lost-to-follow-up or otherwise do not have data available following the study vaccination 
or because they had a protocol deviation requiring their exclusion from the per protocol analysis.   
11.4. Planned Interim Analyses 
Interim unblinded analyses would be used to terminate this trial in the event that unanticipated 
safety events deemed to be of sufficient concern require such action by the sponsor. Sample size re-
estimation at the end of Year 1 and possibly at the end of Year 2 will be based on the pooled 
number of influenza cases in the PP population and not on any interim estimate of efficacy or the 
observed attack rate in the control group. Details of the sample size re-estimation will be provided 
in the DSMB charter. 
11.4.1. 
Interim Safety Review  
A DSMB will be convened by the sponsor to review study progress and participant, clinical, safety, 
reactogenicity, and efficacy data as described in section 9.5. Once the last subject in Year 1 
completes the visit that occurs approximately at Day 202, the clinical database will be cleaned, 
monitored and analyzed in blinded manner. The first partly unblinded report will be issued to the 
DSMB at the end of the first influenza season of the trial approximately in June 2019, though some 

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data may be requested by DSMB to be provided to them earlier. Based on the interim review of 
safety data, the DSMB may recommend continuing the study as planned, stopping the study for 
safety concerns, or modifying the study to ensure study objectives are followed.  
11.4.2. 
Interim Efficacy Review 
There are no plans to stop the trial for futility or for efficacy at the end of Year 1. However if after 
the first flu season the total number of per protocol cases of confirmed influenza infection is 
substantially fewer than  there may be a decision made by the Sponsor about increasing the sample 
size for Year 2.  
11.5. Final Analysis Plan 
At the end of Year 2 a clinical study report (CSR) will be prepared (unless the study is decided to 
be continued for Year 3) summarizing the efficacy, safety, reactogenicity, and immunogenicity 
data. The clinical database will be cleaned, monitored, and locked prior to analysis.   
A formal statistical analysis plan for the efficacy and immunogenicity data will be developed and 
finalized prior to start of the study. Any changes to the plan including post hoc analyses will be 
documented and clearly indicated in the CSR. 
11.5.1. 
Analysis Populations 
The Safety Analysis population includes all subjects who received at least one dose of study 
vaccine. Subjects in the safety population will be analyzed according to the treatment actually 
received. 
The intent-to-treat (ITT) population includes all subjects who received at least one dose of study 
vaccine. Subjects in the ITT population will be analyzed according to their randomization. 
The per protocol (PP) population includes all subjects in the ITT subset satisfying the following 
criteria: 
 Subject met all protocol-specified inclusion criteria and met no exclusion criterion, 
 Subject received both doses of M-001/placebo as randomized, in the protocol-specified 
time frame, and at the intended dose level, 
 Subject did not receive M-001/placebo that was not properly handled or was otherwise 
not acceptable for administration, 
 Subject had at least one successful surveillance contact 15 days or more after the second 
dose of M-001/placebo, or attended at least one ILI visit due to ILI symptoms 
 Subject did not receive a seasonal influenza vaccine between randomization and end of 
the surveillance period for Season 1, 
 Subject did not receive a licensed live vaccine within 30 days of any dose of M-
001/placebo, and 
 Subject did not receive a licensed non-live vaccine within 21 days of any dose of M-
001/placebo. 

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11.5.2. 
Analysis of Safety Data 
Summaries and analysis of safety data will be presented for the Safety Analysis Population. 
Solicited events will be summarized by severity for each day after each study vaccination (Days 0-7 
post each study vaccination, 8 days in total) and as the maximum severity over all 8 days (day of 
the vaccination inclusive).  Additionally, solicited events will be analyzed by taking the most severe 
response over the follow-up period 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 events 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) 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 number of SAEs is expected to be small in this 
trial and SAEs 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. 
Graphical presentations may include box plots and shift plots. 
11.5.3. 
Analysis of Efficacy Data  
Primary Efficacy Assessment 
For the primary analysis of vaccine efficacy (VE), the efficacy of M-001 after a first influenza 
season in each cohort will be estimated by 
𝑉𝐸= 1 −[(𝐶𝑉/ 𝑁𝑉)/ ( 𝐶𝑃 /𝑁𝑃)] 
where CV and CP are the number of per protocol cases of influenza meeting the primary case 
definition in the vaccine and placebo group, respectively, and NV and NP are the number of per 
protocol subjects in the vaccine and placebo group, respectively. The confidence interval for VE 
will be calculated by the Clopper-Pearson exact method conditional on the total number of cases in 
the vaccine and placebo groups combined. Similarly, vaccine efficacy and its 95% confidence 
interval will be calculated for the ITT population. 
VE and its 95% confidence interval will be estimated by age group (i.e., < 65 years, ≥ 65 years) for 
both the PP and ITT analysis populations. Given VE for a specific age group can be approximated 

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by 1 minus the age group specific odds ratio, the Breslow-Day test for the homogeneity of the odds 
ratios will be used to test for a common VE across age groups.  In addition, given that circulating 
strains of flu may vary over the course of the trial, VE and its 95% confidence interval will be 
estimated by flu season as well for both the PP and ITT analysis populations; Breslow-Day test for 
the homogeneity of the odds ratios will be used to test for a common VE across cohort (flu season). 
If the study discontinuation or loss to follow-up rate varies by vaccine group, a Cox proportional 
hazards model will be used to estimate vaccine efficacy. For this analysis, time from 15 days after  
the second dose of study vaccine or placebo to the first episode of culture or PCR confirmed 
influenza caused by any influenza A or B virus in association with a protocol-defined influenza like 
illness (ILI) will be the endpoint. All subjects will be censored at the earliest of their date of study 
withdrawal, date of lost to follow-up, or end of their first influenza season defined as April 30th for 
countries in the northern hemisphere. The model will have a single covariate for vaccine group and 
will be stratified by age group. Vaccine efficacy will be estimated by 1 minus the estimated hazard 
ratio from this model. If the lower limit of the 95% confidence interval for vaccine efficacy based 
on the PP population is above 40%, the vaccine will have demonstrated sufficient efficacy.  
Kaplan-Meier plots of time to first episode by vaccine group will be generated. 
Secondary Efficacy Assessments 
The first secondary efficacy assessment will be analyzed using the same methodology than the one 
used for the primary endpoint (including the supportive and sensitivity analyses). Notice that samples 
with Ct ≤35 only will be grown for culture. 
The second secondary efficacy assessment consisting in the between-group difference in average 
number of days with respiratory or systemic symptoms among subjects with laboratory-confirmed 
influenza illness will be tested in an ANOVA model with vaccine group, age category, and 
season/cohort as main factors.   
The risk ratio for the total number of ILI events during the flu season will be compared between the 
vaccine groups using an overdispersed Poisson model with offset being the duration of follow-up in 
days and factors for vaccine group, age category and season/cohort.   
 
All secondary efficacy assessments will be performed on the ITT and PP sets. 
Exploratory efficacy assessments: 
For both vaccine groups, the following proportions will be estimated with an exact 95% CI within 
the PP set  
 
Proportions of subjects taking antibiotics due to a post-influenza (laboratory confirmed) 
respiratory tract infection 
 
Proportions of subjects who died due to influenza-like illness with or without 
confirmation by viral culture and qRT-PCR analysis due to vaccination with M-001 
Between-groups comparisons will be performed using Fisher’s exact test. 
For both vaccine groups, the following rates will be estimated on the PP set using a 95% CI based on 

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a Poisson model on the number of events with duration of follow-up (in days) as offset  
 
 Rate of hospitalizations associated with ILI episodes over the flu season  
 
Comparisons between the 2 groups will be performed on the basis of an overdispersed Poisson model 
with group as factor and duration of follow-up (in days) as offset. Incidence rate ratios between the 2 
groups will be estimated and their 95% CI provided.  Because it is expected that very few 
hospitalizations cases will occur, no additional factor will be included in the Poisson model. 
Descriptive statistics for the specific influenza strains in confirmed flu cases in experimental and 
control groups will also be provided. 
In addition, the following descriptive statistics will be provided to describe the ILI episodes: 
 For the PP set, the distribution of influenza confirmed episodes  
 For the PP set, the distribution of influenza confirmed episodes by severity. 
 
 
 
Exploratory CMI assessment in substudy: 
A subset of patients will be be enrolled in Season 2 to assess immunogenicity:  the average percentage 
of CD4+ lymphocytes producing Th1 cytokine (e.g. INF-γ) in response to any of the 9 peptides in 
M-001 measured at Day 36 (14±2 days since day of the second vaccination) and its two-sided 95% 
confidence interval will be calculated. Additional exploratory  analyses to be performed on the 
immunogenicity data from these subjects will be detailed in a separate SAP for immunogenicity. 
 
11.5.4. 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol.  As missing data are expected to be 
minimal, no imputation will be performed for missing values.  Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier.  If 
data points are identified as outliers, sensitivity analyses will be performed to examine the impact of 
including or excluding the outliers.  Any substantive differences in these analyses will be reported.  
11.5.5. 
Statistical Software 
Statistical analyses will be performed using SAS® version 9.4 or later under a Windows operating 
system. 

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12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating 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 site will permit authorized 
representatives of the sponsor, 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 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigator and 
associated personnel before the study, and periodic monitoring visits by the sponsor.  Written 
instructions will be provided for collection, preparation, and shipment of blood samples and 
NP/nasal and throat swabs.  
Guidelines for eCRF completion will be provided and reviewed with study personnel before the 
start of the study.  
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits and 
after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate.  After entry of the data into the clinical study database they will be 
verified for accuracy.  
 

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14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1. Ethical Standard 
The investigator is responsible for ensuring that the clinical study is performed in accordance with 
the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory 
and country-specific requirements.  
14.2. Ethics Committees and Competent Authorities 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
and ethics committees in each respective country, as applicable.  The study may not be initiated 
until all local regulatory requirements are met. 
At the end of the study, the investigator (or sponsor where required) will notify the relevant ethics 
committee about the study completion. 
14.3. Informed Consent Process  
Each subject must give written consent according to local requirements after the nature of the study 
has been fully explained.  The consent form must be signed before performance of any study-
related activity. The consent form that is used must be approved by both the sponsor and by the 
reviewing ethics committee.  The informed consent should be in accordance with principles that 
originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor’s policy. 
Before enrollment in the study, the investigator or an authorized member of the investigational staff 
must explain to potential subjects (or their legal representatives) the aims, methods, reasonably 
anticipated benefits, and potential hazards of the study, and any discomfort participation in the 
study may entail.  Subjects will be informed that their participation is voluntary and that they may 
withdraw consent to participate at any time.  They will be informed that choosing not to participate 
will not affect the care the subject can expect.  Subjects will be told that alternative vaccines are 
available if they refuse to take part and that such refusal will not prejudice future access to an 
influenza vaccination as normally available country-specific.  Finally, they will be told that the 
investigator will maintain a subject identification register for the purposes of long-term follow-up if 
needed and that their records may be accessed by health authorities and authorized sponsor staff 
without violating their confidentiality, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the subject (or legal representative) is authorizing such access, and 
agrees to allow his or her study physician to re-contact the subject for the purpose of obtaining 
consent for additional safety evaluations, if needed, or to obtain information about his or her 
survival status. 
The subject will be given sufficient time to read the ICF and the opportunity to ask questions.  After 
this explanation and before entry into the study, consent should be appropriately recorded by means 
of the subject’s personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject. 

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Depending on local regulations, if the subject is unable to read or write, an impartial witness should 
be present for the entire informed consent process (which includes reading and explaining all 
written information) and should personally date and sign the ICF after the oral consent of the 
subject is obtained. 
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,  
hysterectomy, or successful Essure® placement, 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 study 
product exposure, including 2 months (defined as 60 days) after the last study vaccination (at least 
up to day 81 of the trial). A highly effective method of contraception is defined as one which results 
in a low failure rate 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. 
In selected, individual cases, PI, where justified, may accept complete abstinence from sexual 
activity in women not having male partner as basis for considering such female subject as of no 
childbearing potential. Rationale for such decision must be available and documented. 
Males whose female partner has childbearing potential, if not after vasectomy, must use condoms  
throughout the study treatment and for at least up to day 111 of the trial 90 days after the last dose 
of the IMP. 
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 according to the applicable laws including European Union General Data Protection 
Regulation 2016/679 (GDPR) where applicable. This confidentiality is extended to cover testing of 
biological samples, in addition to the clinical information relating to participating subjects. 

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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 
sites 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 ethics and/regulatory bodies 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 EMA, 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 sites will permit 
access to such records. 
14.6. Study Discontinuation 
If the trial is discontinued, subjects who have signed the ICF, 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 requirements and procedures, and subject to Ethics Committee approval. 
If it is determined by the participating 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 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 site 
for any injury suffered due to participation in this trial beyond that provided by clinical trial 
insurance. 

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14.8. Future Use of Stored Specimens  
Subjects will be asked for permission to keep any remaining 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 sites and with other 
investigators at other institutions. 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. 
Any unused part of the NP/nasal and throat swab samples (including retention vials of universal 
transport media, tissue culture amplified isolates, and any repeat amplification harvests) will be 
securely stored at the CRO’s site (including initial sample receiving laboratories and different 
testing laboratories) at least until publication of the final clinical study report (CSR). At any time 
during the 3 to 6 months before expiration of the CRO contract, the Sponsor may request that the 
CRO store these samples for a longer period, based on needs or requests. At any time during 
storage, the samples may be transferred to another Sponsor-approved laboratory. 
14.9. Disclosure of Individual Research Information 
In this protocol, it is not planned to provide each participant with a summary of overall study results 
as these will be generally published by the sponsor. The sponsor will register and/or disclose the 
existence of and the results of clinical studies as required by international and local regulations. 
Disclosure of assignment to study arms for individual subjects can be provided during the study 
only based on justified urgent medical need as assessed by the sponsor, and after the study has been 
completed, as per local regulations and based on sponsor’s decision. 
 

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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 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 site clinical team, who 
will ensure that they are accurate and complete. AEs must be recorded and assessed for severity and 
relationship, and reviewed by the site PI or appropriate SI. 
Data collection is the responsibility of the study personnel at the participating sites under the 
supervision of the respective site PI. During the study, the site PI must maintain complete and 
accurate documentation for the study. 
15.2. Data Capture Methods 
All clinical trial information collected by the study personnel will be recorded electronically by the 
authorized persons using a web-based CRF (i.e., using an eCRF within the EDC system). The eCRF 
has been designed specifically for this trial under the responsibility of the Sponsor, using a 
validated Electronic Records/Electronic Signature-compliant platform (21 CFR Part 11). To ensure 
the correct and consistent completion of the eCRFs, the Sponsor will provide all necessary 
instructions, and training to all staff involved in data entry prior to granting them access to the 
EDC. Additional instructional documents such as training manuals and completion guidelines will 
be provided to assist with data entry during the course of the trial. Upon completion of training, 
each user requiring access to the EDC system will be issued individual username and password. In 
the event of a change in trial personnel, each newly assigned individual will receive individual, 
dedicated username and password. In case a user is no longer authorized to access the EDC, e.g. in 
case of departure from the study team, the Investigator or appropriate manager is responsible for 
informing the Sponsor immediately so that their access is deactivated. An audit trail will be 
available in the EDC system at the time of the first data entry in order to track all modifications and 
to ensure database integrity. 

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The study personnel performing data entry are responsible for the timeliness, completeness, and 
accuracy of the information in the eCRFs and must provide explanations for all missing information 
as requested by Sponsor or its designees. 
15.3. Types of Data 
Data for this study will include clinical, safety, and outcome measures (e.g., reactogenicity, efficacy 
(influenza confirmation) and possibly, immunogenicity data). 
15.4. Timing/Reports 
The primary clinical study report (CSR) will include clinical, safety, reactogenicity, efficacy and 
possibly, cellular immunogenicity data through the end of the last follow up period. At this time, 
the clinical database will be cleaned, monitored and locked. Unblinded analyses of safety, 
reactogenicity, and available PBMCs, including all primary and secondary endpoint data will be 
performed after the clinical database is locked. The CSR will be completed when all efficacy data 
are available. 
Given the higher complexity of the data generation and analysis and increased time frame for 
completion of the exploratory studies, compared to the primary and secondary safety and efficacy 
assessments and analyses, the exploratory endpoint analysis will be optionally summarized in one 
or more addenda to the primary CSR. Of note, several of the exploratory studies are contingent 
upon the study team’s approval for moving forward based on the results from the interim 
immunogenicity report.  
After full analysis and final reporting is complete, and upon request and upon sponsor approval, the 
PIs from participating sites may be provided with a summary of results by treatment arm and/or 
subject treatment assignments. In this regard, the participating sites requesting such information to 
share with study subjects must do so in compliance with their respective legal regulations. 
15.5. Study Records Retention 
Study records and reports, including, but not limited to, eCRFs, source documents, ICFs, and study 
drug disposition records, shall be maintained for 2 years (or as required per applicable local 
regulations) 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 (or as required per applicable local regulations) after the investigation is 
discontinued and EMA has been so notified. The participating site must contact the sponsor for 
authorization prior to the destruction of any study records. Informed consent forms for future use 
will be maintained as long as the sample exists. 
15.6. Protocol Deviations 
As protocol deviation will be considered any noncompliance with the clinical trial protocol, Good 
Clinical Practice (GCP), or study manuals 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.  

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Sites are expected to maintain vigilance to identify deviations from the Protocol and address them 
as soon as possible including reporting of suspected major protocol deviations within 5 working 
days of its identification, or for deviations related to study schedule - within 5 working days of the 
scheduled protocol-required activity.  Suspected major protocol  deviations must be reported to the 
sponsor directly or to the sponsor’s contracted representative (e.g. clinical research monitor or 
medical monitor). All deviations from the protocol must be addressed in study subject source 
documents.  Protocol deviations must be sent to the local ethics committees per their requirements. 
The site PI/study staff is responsible for knowing and adhering to their ethics committees’ 
requirements. 

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16. 
PUBLICATION POLICY. 
Following completion or during the trial, the sponsor will be responsible for any publication. This 
clinical trial will be registered in a public trials registry.  
 
 

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17. 
SUPPLEMENTS/APPENDICES 
None 

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18. 
SUMMARY OF CHANGES 
List of changes vs. study protocol version 1.0 dated 21st February 2018 
Description 
Wording 
Title page 
 
ClinicalTrials.gov 
identifier 
 
Original wording 
TBD 
New wording 
NCT03450915 
Version and date of the 
Protocol 
 
Original wording 
Version 1.0 dated 21st February 2018 
New wording 
Version 2.0 dated 28th March 2018 
INVESTIGATOR’S 
COMPLIANCE 
DECLARATION 
 
Change description 
Whole paragraph and page removed from the protocol 
New wording 
 
Protocol Synopsis 
 
ClinicalTrials.gov 
identifier 
 
Original wording 
TBD 
New wording 
NCT03450915 
Planned study duration 
 
Original wording 
up to 3 years (3 consecutive flu seasons 
New wording 
up to 2 years (2 consecutive flu seasons) 
Rationale for sample 
size 
 
Original wording 
If after the first flu season the relative number of cases is not met 
(i.e., less than 82 cases), the DSMB may, following issuance of 
interim report #1, recommend increasing the sample size for Year 2. 
Otherwise, the sample size for Year 2 will remain at 5,296 subjects. 
 
The same methodology will be used after the second flu season by 
issuing interim report #2 and optionally extending the trial to year 3 
with a third cohort. 
New wording 
If after the first flu season the total number of per protocol cases of 
confirmed influenza infection is substantially fewer than 82 cases, the 
DSMB may, following issuance of interim report #1, recommend 
increasing the sample size for Year 2. Otherwise, the sample size for 
Year 2 will remain at 5,296 subjects. Details for sample size re-
estimation will be defined in the DSMB charter. 
 
The same methodology will be used after the second flu season by 
issuing interim report #2 and optionally extending the trial to year 3 
with a third cohort based on amendment to the protocol which will be 

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submitted in such case for ethics/regulatory approval. 
 
Inclusion criteria 
 
#4 
 
Original wording 
Women of childbearing potential (not surgically sterile or 
postmenopausal for greater than or equal to one year) and men must 
agree to practice adequate contraception 
New wording 
Women of childbearing potential (not surgically sterile or 
postmenopausal for greater than or equal to one year) and men must 
agree to practice adequate effective contraception 
Exclusion criteria 
 
#5 
 
Original wording 
An acute illness, including an axillary temperature greater than 38ºC, 
occurred within 1 week before first vaccination 
New wording 
An acute illness, including body temperature greater than 37.5ºC 
(axillary or forehead) or greater than 38.0 ºC (oral), or greater than 
38.5ºC (ear/tympanic or rectal), occurred within 1 week before first 
vaccination 
Criteria for evaluation 
 
Primary endpoint 
 
Original wording 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring between 0 and 7 days following 
receipt of each of the two doses of M-001 or placebo and to assess 
SAEs, Medically Attended AEs (MAAEs) and new-onset of chronic 
medical illnesses (NOCIs) during period from Day 0 until end of first 
passive surveillance period in each group. 
New wording 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring between 0 and 7 days following 
receipt of each of the two doses of M-001 or placebo and to assess 
SAEs, and new-onset of chronic medical illnesses (NOCIs) during 
period from Day 0 until end of first passive surveillance period in 
each group. To assess M-001 Safety by occurrence of unsolicited 
AEs from the time of first study vaccination through 21 days after 
each M-001 vaccination 
Original wording 
protocol defined Influenza Like Illness (ILI is defined as symptoms 
that interfere with normal daily activities and that include one of the 
following respiratory symptoms (sore throat, cough, sputum 
production, nasal discharge, wheezing or difficult breathing) and at 
least one additional systemic symptom [fever (oral temperature 
>37.2°C), headache, myalgia and/or arthralgia, chills, and fatigue 
(tiredness for at least 12 hours) 
New wording 
protocol defined Influenza Like Illness (ILI is defined as symptoms 
that include one of the following respiratory symptoms (sore throat, 
cough, sputum production, nasal discharge or congestion, wheezing 
or difficult breathing) and at least one additional systemic symptom 
[fever (oral temperature >37.2°C for age 50-59, or >36.7°C for age 

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60 or more, or increased ≥ 1.3°C from baseline), headache, myalgia 
and/or arthralgia, chills, and fatigue (tiredness for at least 12 hours) 
Secondary endpoints 
 
Original wording 
4. Compare the occurrence of qualitative PCR confirmed 
influenza in the M-001 experimental group vs. placebo (≥ 15 
days after the second vaccination until epidemiological levels 
of influenza are low as defined by the medical director) 
caused by any influenza A or B virus in association with a 
protocol defined ILI (ILI is defined as symptoms that interfere 
with normal daily activities and that include one of the 
following respiratory symptoms (sore throat, cough, sputum 
production, wheezing or difficult breathing) and at least one 
additional systemic symptom [fever (oral temperature 
>37.2°C), headache, myalgia and/or arthralgia, chills, and 
fatigue (tiredness)].  Nasopharyngeal swab will be collected 
from participants who meet the ILI definitions for PCR 
analysis of influenza A and/or B virus. 
 
5. Reduced Severity of influenza illness (“breakthrough illness”) 
Reduction of illness severity: The time to symptom 
alleviation/fever resolution (“alleviation/resolution”), which 
can be defined as the first time point at which all of the six 
influenza symptoms (body aches and pains, cough, fatigue, 
headache, nasal congestion, and sore throat) were either 
absent or mild and fever had resolved, with both (resolution 
of all 6 symptoms and fever) maintained for at least 21.5 
hours (i.e., 24 hours minus 10%, i.e., lower limit of detection 
of an [approximately] 1 day improvement in resolution of 
illness).  
 
6. To assess in at least a subset of samples the consistency of 
manufacturing between 3 batches of M-001 according to their 
T cell responses by ICS and FACS analysis for IFN-g 
production in PBMCs. 
 
New wording 
1. Compare the occurrence of qualitative PCR confirmed 
influenza in the M-001 experimental group vs. placebo (≥ 15 
days after the second vaccination until epidemiological levels 
of influenza are low as defined by the medical director) 
caused by any influenza A or B virus in association with a 
protocol defined ILI. Nasopharyngeal swab will be collected 
from participants who meet the ILI definition within 24 hours 
from ILI being reported to or identified by study personnel for 
PCR analysis of influenza A and/or B virus. (a nasal and 
throat sample will be collected if the participant object NP 

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swab collection). 
 
2. Percentage of subjects having ILI symptoms in the 
experimental and control group. 
 
3. Reduced Severity of influenza illness  
Reduction of PCR confirmed influenza illness severity: The 
time to symptoms alleviation/fever resolution 
(“alleviation/resolution”), which can be defined as the first 
time point at which all of the following influenza symptoms 
(body aches (myalgia and/or arthralgia), cough, 
fatigue/tiredness, headache, nasal congestion/ runny nose/ 
sputum production, wheezing or difficult breathing, chills and 
sore throat) were absent and fever had resolved, with both 
(resolution of the symptoms and fever) maintained for at least 
one day.  
 
4. To assess in at least a subset of samples the consistency of 
manufacturing between 3 batches of M-001 according to their 
T cell responses by ICS and FACS analysis for IFN-g 
production in PBMCs. 
 
5.  To assess the durability of vaccine efficacy over a second 
influenza season. 
 
Exploratory endpoints 
 
Original wording 
 
Time to alleviation of each influenza symptom and time to 
resolution of fever 
 
Incidence of physician-diagnosed secondary respiratory tract 
infections leading to a prescription for antibiotic therapy 
 
Time to return to normal activity, as assessed on an 11-point 
visual analogue scale (VAS) 
 
Incidence of clinic visits associated with the ILI episode (≥15 
days after dosing until epidemiological influenza levels are low as 
defined by the medical director); A possibility of multiple visits 
per subject; each visit will be counted once in the analysis. 
 
Incidence of hospitalization (≥15 days after dosing until 
epidemiological levels of influenza are low as defined by the 
medical director) 
 
Incidence of confirmed pneumonia (by clinical diagnosis ≥15 
days after dosing until epidemiological levels of influenza are low 
as defined by the medical director)  
 
Validated tool-based evaluation of change in severity of 
influenza-like illness 
 
Incidence of death due to influenza-like illness (≥15 days after 

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dosing until epidemiological levels of influenza are low as 
defined by the medical director) with or without confirmation by 
viral culture or PCR analysis 
 
Define influenza virus subtype in the swab samples 
New wording 
 
Incidence of secondary respiratory tractinfectionsleading to a 
prescription for antibiotic therapy  
 
Incidence of clinic visits associated with the ILI episode (≥15 
days after dosing until epidemiological influenza levels are low as 
defined by the medical director); A possibility of multiple visits 
per subject; each visit will be counted once in the analysis. 
 
Incidence of hospitalization associated with the ILI (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director) 
 
Incidence of death due to influenza-like illness (≥15 days after 
dosing until epidemiological levels of influenza are low as 
defined by the medical director) with or without confirmation of 
presence of influenza virus by viral culture or PCR analysis 
 
To determine the specific influenza strains in flu cases in 
experimental and control group 
Table 1 
 
Change description 
Removed last column (titled “Season 3 (optional)”) 
Graph embedded 
within Table 1 
 
Original wording 
≥82 cases observed 
New wording 
≥Cutoff1 
Graph embedded 
within Table 1 
 
Change description 
Removed last column from the graph (titled “Flu season 3?”) 
Table 1 (text) 
 
Original wording 
Flexible enrollment scheme according to interim reports that will be 
issued after seasons 1 and 2. 
New wording 
Flexible enrollment scheme according to interim reports that will be 
issued after seasons 1 and 2. Flu season 3 is not planned. If decided 
that it is needed, protocol amendment will be issued and submitted 
for relevant approvals. 
Table 2 (list of 
procedures in column 1) 
 
Original wording 
Sign Consent Form1 
Assess eligibility 
Review Medical & flu vaccination History2 
Concomitant meds 
Vital signs, oral temp and pulse 
Physical examination 
Randomization 
Review contraception/ Counseling3 
Pregnancy Test4 

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AE/SAE Assessment 
Vaccination5 
Evaluate vaccination site 
Postvaccination procedures6 
Provision of Memory Aid  
Review of Memory Aid Data 
Collection of reportable medications 
Interim report 
Collection of ILI symptoms through passive and active surveillance 
Collection of nasopharyngeal swabs for 
laboratory confirmation of influenza 
Collection of disease burden and health 
care information 
Collection of information on SAEs 
New wording 
Consent process and Signed Consent Form1 
Assess eligibility 
Demographic data and Review Medical & flu vaccination History2 
Concomitant meds 
Vital signs 
Oral temperature 
Physical examination 
Randomization 
Review contraception/ Counseling3 
Pregnancy Test4 
AE/SAE Assessment 
Vaccination5 
Evaluate vaccination site 
Postvaccination procedures6 
Provision of Memory Aid  
Review of Memory Aid Data 
Interim report 
Collection of ILI symptoms through passive and active surveillance 
Collection of nasopharyngeal swabs for 
laboratory confirmation of influenza 
Collection of disease burden data and concomitant medications  
Collection of information on AEs, NOCIs, and SAEs 
Table 2 (plan of 
procedures) 
 
Description of change 
Procedure Vital signs, oral temp and pulse split to two procedures 
Vital signs and Oral temperature. Vital signs marked as to be done 
at Visit 1, Oral temperature marked as to be done at Visit 1 and 2 
Table 2 
 
Collection of ILI 
symptoms through 
passive and active 
surveillance 
 

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Original wording 
Active Surveillance: Between November 15, 2018 and April 30, 
2019, the dedicated study staff will contact subjects twice a week 
(see 7.3). 
Both passive and active surveillance will be replicated during second 
season (passive one starting on September 15, 2019). 
New wording 
Active Surveillance: Between November 15, 2018 and March 31, 
2019, the dedicated study staff will contact subjects twice a week 
(see 7.3). 
Both passive and active surveillance for cohort 1 subjects will be 
replicated during second season (passive one starting on September 
15, 2019). 
Table 2 
 
Collection of 
nasopharyngeal swabs 
for 
laboratory 
confirmation of 
influenza 
 
Original wording 
From Day 14 post vaccination until 30 April of the following year. 
Every effort must be made to obtain the NP specimen on the same or 
following day after reporting of qualifying symptoms and no later 
than 4 days (sample to be collected through Day 3 of the illness, 
considering that Day 0 is the day of illness onset) after onset of 
qualifying respiratory illness symptoms (start 
date). 
New wording 
From Day 14 post vaccination until 30 April of the following year. 
Every effort must be made to obtain the NP specimen on the same or 
following day after reporting of qualifying ILI symptoms and no later 
than 4 days (sample to be collected within 24 hours from ILI being 
reported to or identified by study personnel through Day 3 of the 
illness, considering that Day 0 is the day of illness onset) after onset 
of qualifying ILI symptoms (start date). 
Table 2 
 
Collection of disease 
burden and health 
care information 
 
Original wording 
At any time during the study year in association with a respiratory 
illness, and for up to 30 days following the start of a qualifying 
symptom. 
New wording 
At any time during the study a disease burdenand concomitant 
medications in association with ILI, and for up to 30 days following 
the start of a qualifying ILI symptoms. All other concomitant 
medications from 3 months before V1. 
Table 3 (list of 
procedures in column 1) 
 
Original wording 
Sign Consent Form1 

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Assess eligibility 
Review Medical & flu vaccination History2 
Concomitant meds 
Vital signs, oral temp and pulse 
Physical examination 
Randomization 
Review contraception/ Counseling3 
Pregnancy Test4 
Blood sample for CMI (40 mL, Subset) 
AE/SAE Assessment 
Vaccination5 
Evaluate vaccination site 
Postvaccination procedures6 
Provision of Memory Aid7  
Review of Memory Aid Data 
Collection of reportable medications 
Interim Report8 
Collection of ILI symptoms through passive and active surveillance 
for a total of 9,630 participants from seasons 1 and 2. 
Collection of nasopharyngeal swabs for 
laboratory confirmation of influenza for a total of 9,630 participants 
from seasons 1 and 2. 
Collection of disease burden and health 
care information for a total of 9,630 participants from seasons 1 and 
2. 
Collection of information on SAEs for a total of 9,630 participants 
from seasons 1 and 2. 
New wording 
Consent process and Signed Consent Form1 
Assess eligibility 
Demographic data, Review Medical & flu vaccination History2 
Concomitant meds 
Vital signs 
Oral temperature 
Physical examination 
Randomization 
Review contraception/ Counseling3 
Pregnancy Test4 
Blood sample for CMI (40 mL, Subset) 
AE/SAE Assessment 
Vaccination5 
Evaluate vaccination site 
Postvaccination procedures6 
Provision of Memory Aid7  
Review of Memory Aid Data 
Interim Report/Final Report8 

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Collection of ILI symptoms through passive and active surveillance 
for all participants from seasons 1 and 2. 
Collection of nasopharyngeal swabs for 
laboratory confirmation of influenza for all participants from seasons 
1 and 2. 
Collection of disease burden data and concomitant medications for all 
participants from seasons 1 and 2. 
Collection of information on AEs, NOCIs, and SAEs for all 
participants from seasons 1 and 2. 
Table 3 (plan of 
procedures) 
 
Description of change 
Procedure Vital signs, oral temp and pulse split to two procedures 
Vital signs and Oral temperature. Vital signs marked as to be done 
at Visit 1, Oral temperature marked as to be done at Visit 1 and 2 
Table 3 
 
Collection of ILI 
symptoms through 
passive and active 
surveillance 
 
Original wording 
Active Surveillance: Between November 15, 2019 and April 30, 
2020, the dedicated study staff will contact subjects twice a week 
(see 7.3). 
New wording 
Active Surveillance: Between November 15, 2018 and March 31, 
2019, the dedicated study staff will contact subjects twice a week 
(see 7.3). 
Table 3 
 
Collection of 
nasopharyngeal swabs 
for 
laboratory 
confirmation of 
influenza 
 
Original wording 
From Day 14 post vaccination until 30 April of the following year. 
Every effort must be made to obtain the NP specimen on the same or 
following day after reporting of qualifying symptoms and no later 
than 4 days (sample to be collected through Day 3 of the illness, 
considering that Day 0 is the day of illness onset) after onset of 
qualifying respiratory illness symptoms (start 
date). 
New wording 
From Day 14 post vaccination until 30 April of the following year. 
Every effort must be made to obtain the NP specimen on the same or 
following day after qualifying ILI symptoms being reported to or 
identified by study personnel and no later than 4 days (sample to be 
collected through Day 3 of the illness, considering that Day 0 is the 
day of illness onset) after onset of qualifying ILI symptoms (start 
date). 

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Table 3 
 
Collection of disease 
burden and health 
care information 
 
Original wording 
At any time during the study year in association with a respiratory 
illness, and for up to 30 days following the start of a qualifying 
symptom. 
New wording 
At any time during the study a disease burdenand concomitant 
medications in association with ILI, and for up to 30 days following 
the start of a qualifying ILI symptoms. All other concomitant 
medications from 3 months before V1. 
Denotes for Table 2 and 
3 
 
Original wording 
6 Post-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. 
(…) 
#AEs will be limited to SAEs if after 21 days after the last study 
vaccination. 
 
New wording 
6 Post-vaccination procedures will include documentation of any 
reactogenicity during the observation period and any AEs/SAEs 
post-vaccination (i.e. with onset before the participant leaves the 
site after receipt of the study drug injection), as well as provision 
of memory aid and instructions on completion. 
(…) 
#From seven days after the study vaccination AEs related to 
vaccination will no longer be collected as solicited AEs 
Occurrence of unsolicited AEs will be analyzed from the time 
of first study vaccination through 21 days after each M-001 
vaccination. 
BACKGROUND 
INFORMATION AND 
SCIENTIFIC 
RATIONALE 
 
Potential Risks 
 
Original wording 
The procedure for collection of an NP, nasal or throat swab is 
associated with a slight discomfort, and may, in some instances, 
cause watering of the eyes or gag reflex. Other than that, there is little 
to no risk involved. 
(…) 

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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. 
New wording 
The procedure for collection of an NP, deep nasal or throat swab is 
associated with a slight discomfort, and may, in some instances, 
cause watering of the eyes or gag reflex. Other than that, there is little 
to no risk involved. 
(…) 
A highly effective method of contraception is defined as one which 
results in a low failure rate when used consistently and correctly. 
OBJECTIVES 
 
Primary Objectives 
 
Original wording 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring between 0 and 7 days following 
receipt of each of the two doses of M-001 or placebo and to assess 
SAEs, Medically Attended AEs (MAAEs) and new-onset of chronic 
medical illnesses (NOCIs) during period from Day 0 until end of first 
passive surveillance period in each group. 
New wording 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring between 0 and 7 days following 
receipt of each of the two doses of M-001 or placebo and to assess 
SAEs and new-onset of chronic medical illnesses (NOCIs) during 
period from Day 0 until end of first passive surveillance period in 
each group. 
Secondary Objectives 
 
Original wording 
2. 
Reduced Severity of influenza illness (“breakthrough illness”) 
by the time to symptom alleviation/fever resolution 
(“alleviation/resolution”). 
(…) 
5. 
To assess influenza strain specific vaccine efficacy. 
New wording 
2. 
Reduced Severity of PCR-confirmed influenza illness by the 
time to symptom alleviation/fever resolution 
(“alleviation/resolution”). 
(…) 
5. 
To assess proportion of subjects having ILI symptoms in the 
experimental or control group. 
Exploratory Objectives 
 
Original wording 
 
Time to alleviation of each influenza symptom and time to 
resolution of fever 
 
Incidence of physician-diagnosed secondary respiratory tract 
infections leading to a prescription for antibiotic therapy 
 
Time to return to normal activity, as assessed on an 11-point 
visual analogue scale (VAS) 
 
Incidence of clinic visits associated with the ILI episode 
(≥15 days after dosing until epidemiological influenza levels 
are low as defined by the medical director); A possibility of 

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multiple visits per subject; each visit will be counted once in 
the analysis. 
 
Incidence of hospitalization (≥15 days after dosing until 
epidemiological levels of influenza are low as defined by the 
medical director) 
 
Incidence of confirmed pneumonia (by clinical diagnosis 
≥15 days after dosing until epidemiological levels of 
influenza are low as defined by the medical director)  
 
Change in severity of influenza-like illness (using validated 
tool) 
 
Incidence of death due to influenza-like illness (≥15 days 
after dosing until epidemiological levels of influenza are low 
as defined by the medical director) with or without 
confirmation by viral culture or PCR analysis 
 
Define influenza virus subtype in the swab samples 
New wording 
• 
Incidence of secondary respiratory tract infections leading to 
a prescription for antibiotic therapy 
• 
declared by the participant 
• 
Incidence of clinic visits associated with the ILI episode (≥15 
days after dosing until epidemiological influenza levels are low as 
defined by the medical director); A possibility of multiple visits per 
subject; each visit will be counted once in the analysis. 
• 
Incidence of hospitalization associated with the ILI (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director) 
• 
Incidence of death due to influenza-like illness (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director) with or without confirmation by 
viral culture or PCR analysis 
• 
To determine the specific influenza strains in flu cases in 
experimental and control group 
Study Outcome 
Measures 
 
Primary Outcome 
Measures 
 
Clinical efficacy 
 
Original wording 
protocol defined Influenza Like Illness (ILI is defined as symptoms 
that interfere with normal daily activities and that include one of the 
respiratory symptoms (sore throat, cough, sputum production, nasal 
discharge, wheezing or difficult breathing) and at least one additional 
systemic symptom [fever (oral temperature >37.2°C), headache, 
myalgia and/or arthralgia, chills, and fatigue (tiredness for at least 12 
hours)]. NP swab will be collected from participants who meet the 
ILI definitions for qualitative PCR analysis of influenza A and/or B 
virus. PCR confirmed samples will be further analyzed by culture 
confirmed influenza testing. 

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New wording 
protocol defined Influenza Like Illness (ILI is defined as symptoms 
that include one of the respiratory symptoms (sore throat, cough, 
sputum production, nasal discharge or congestion, wheezing or 
difficult breathing) and at least one additional systemic symptom 
[fever (oral temperature >37.2°C for age 50-59, or >36.7°C for age 
60 or more, or increased ≥ 1.3°C from baseline), headache, myalgia 
and/or arthralgia, chills, and fatigue (tiredness for at least 12 hours)]. 
NP swab will be collected from participants who meet the ILI 
definitions within 24 hours from ILI being reported to or identified 
by study personnel for qualitative PCR analysis of influenza A and/or 
B virus. PCR confirmed samples will be further analyzed by culture 
confirmed influenza testing. 
Secondary Outcome 
Measures 
 
Clinical efficacy 
 
Original wording 
protocol defined Influenza Like Illness (ILI is defined as symptoms 
that interfere with normal daily activities and that include one of the 
respiratory symptoms (sore throat, cough, sputum production, nasal 
discharge, wheezing or difficult breathing) and at least one additional 
systemic symptom [fever (oral temperature >37.2°C), headache, 
myalgia and/or arthralgia, chills, and fatigue (tiredness for at least 12 
hours)]. NP swab will be collected from participants who meet the 
ILI definitions for qualitative PCR analysis of influenza A and/or B 
virus. 
(…) 
• 
Average time to symptom alleviation/fever resolution in the 
experimental vs control group. “alleviation/resolution” time is 
defined as the first time point at which all of the six influenza 
symptoms (body aches and pains, cough, fatigue, headache, nasal 
congestion, and sore throat) were either absent or mild and fever had 
resolved, with both (resolution of all 6 symptoms and fever) 
maintained for at least 21.5 hours (i.e., 24 hours minus 10%, i.e., 
lower limit of detection of an [approximately] 1 day improvement in 
resolution of illness). 
New wording 
protocol defined Influenza Like Illness. NP swab will be collected 
from participants who meet the ILI definitions within 24 hours from 
ILI being reported to or identified by study personnel for qualitative 
PCR analysis of influenza A and/or B virus. 
(…) 
• 
Average time to symptom alleviation/fever resolution in the 
experimental vs control group. “alleviation/resolution” time is 
defined as the first time point at which all of the following influenza 
symptoms (body aches (myalgia and/or arthralgia), cough, 
fatigue/tiredness, headache, nasal congestion/ runny nose/ sputum 
production, wheezing or difficult breathing, chills and sore throat) 

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were absent and fever had resolved, with both (resolution of all 
symptoms and fever) maintained for at least 1 day. 
• 
To assess the durability of vaccine efficacy over a second 
influenza season 
Exploratory Outcome 
Measures 
 
Original wording 
• 
Average time to alleviation of each influenza symptom and 
time to resolution of fever 
• 
Reduced incidence of physician-diagnosed secondary 
respiratory tract infections leading to a prescription for antibiotic 
therapy in the experimental group as compared to the control group. 
• 
Shorter time to return to normal activity, as assessed on an 
11-point visual analog scale (VAS) in the experimental group as 
compared to the control group. 
• 
Lower incidence of clinic visits (≥15 days after dosing until 
epidemiological influenza levels are low as defined by the medical 
director) in the experimental group as compared to the control group; 
A possibility of multiple visits per subject; each visit will be counted 
once in the analysis. 
• 
Lower incidence of hospitalization (≥15 days after dosing 
until epidemiological levels of influenza are low as defined by the 
medical director) in the experimental group as compared to the 
control group. 
• 
Lower incidence of confirmed pneumonia as defined by a 
physician (≥15 days after dosing until epidemiological levels of 
influenza are low as defined by the medical director) in the 
experimental group as compared to the control group. 
• 
Lower severity of influenza-like illness according to a 
validated tool-based evaluation of change in severity in the 
experimental group as compared to the control group, with or without 
confirmation by viral culture or PCR analysis. 
• 
Lower incidence of death due to influenza-like illness (≥15 
days after dosing until epidemiological levels of influenza are low as 
defined by the medical director) in the experimental group as 
compared to the control group, with or without confirmation by viral 
culture or PCR analysis. 
• 
Define influenza virus subtype in the swab samples to 
compare the viruses causing disease in the experimental vs control 
group 
New wording 
• 
Incidence of secondary respiratory tract infections leading to 
a prescription for antibiotic therapy in the experimental group as 
compared to the control group. In case of lack of documented 
medical record subject’s provided information will be sufficient. 
• 
Incidence of clinic visits (≥15 days after dosing until 
epidemiological influenza levels are low as defined by the medical 
director) in the experimental group as compared to the control group; 

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A possibility of multiple visits per subject; each visit will be counted 
once in the analysis. 
• 
Incidence of hospitalization associated with ILI (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director) in the experimental group as 
compared to the control group. 
• 
Incidence of death due to influenza-like illness (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director) in the experimental group as 
compared to the control group, with or without confirmation by viral 
culture or PCR analysis. 
• 
Define influenza virus subtype in the swab samples to 
compare the viruses causing disease in the experimental vs control 
group 
STUDY DESIGN 
 
Original wording 
Unsolicited non-serious 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 last study 
vaccination.   
Immunogenicity testing will include performing CMI assays on 
blood samples obtained immediately at baseline (Day 1) and on 
samples collected on Days 37 from a subset of 275 participants 
randomly selected from experimental group receiving each of the 3 
batches used in the trial (total of 825). Cell mediated immune 
responses to influenza antigens, including epitopes represented in the 
M-001 vaccine, will be assessed at baseline (Day 1), at 16 days after 
the second M-001 vaccination (Days 37).   
New wording 
Unsolicited non-serious AEs collected from the time of each M-001 
vaccination through approximately 21 days after each study 
vaccination will be analyzed separately. SAEs will be collected from 
the time of the first study vaccination through the entire trial period.   
In cohort 2, immunogenicity testing will be performed and will 
include performing CMI assays on blood samples obtained 
immediately at baseline (Day 1) and on samples collected on Days 37 
from a subset of 275 participants randomly selected from 
experimental group receiving each of the 3 batches used in the trial 
(total of 825). Cell mediated immune responses to influenza antigens, 
including epitopes represented in the M-001 vaccine, will be assessed 
at baseline (Day 1), at 16 days after the second M-001 vaccination 
(Days 37).   
STUDY 
ENROLLMENT AND 
WITHDRAWAL 
 

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Subject Inclusion 
Criteria 
 
#4 
 
Original wording 
Women of childbearing potential (not surgically sterile or 
postmenopausal for greater than or equal to one year) and men must 
agree to practice adequate contraception 
New wording 
Women of childbearing potential (not surgically sterile or 
postmenopausal for greater than or equal to one year) and men must 
agree to practice adequate effective contraception 
Subject Exclusion 
Criteria 
 
#5 
 
Original wording 
5. 
An acute illness, including an axillary temperature greater 
than 38ºC, occurred within 1 week before first vaccination 
New wording 
5. 
An acute illness, including body temperature greater than 
37.5ºC (axillary or forehead) or greater than 38.0 ºC (oral), or greater 
than 38.5ºC (ear/tympanic or rectal), occurred within 1 week before 
first vaccination. 
STUDY 
INTERVENTION/INV
ESTIGATIONAL 
PRODUCT 
 
Concomitant 
Medications/Treatment
s 
 
Original wording 
Used and unused vials of M-001 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 and sterile empty vials will be 
determined by the CRO. 
(…) 
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 last M-001 
study vaccination.  
(…) 
Use of new medication should prompt evaluation for the presence of 
a new diagnosis of chronic medical disease or condition. 
New wording 
Used and unused vials of M-001 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 and sterile empty vials will be 
determined by the Sponsor. 

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(…) 
After Day 43 only concomitant medications relevant for respiratory 
illness as per PI judgment, or related to AE or ILI will be recorded. 
Subjects who do not receive both M-001 study vaccinations will have 
all concomitant medications collected through approximately 21 days 
after the first study vaccination, or early termination, whichever 
occurs first. 
(…) 
Identified use of new medication should prompt evaluation for the 
presence of a new diagnosis of chronic medical disease or condition. 
STUDY SCHEDULE 
 
Enrollment/Baseline 
 
Original wording 
All concomitant medications taken within 30 days prior to signing 
the ICF will be recorded on the appropriate data collection form prior 
to the first study vaccination 
New wording 
All concomitant medications taken within 3 months prior to signing 
the ICF will be recorded on the appropriate data collection form prior 
to the first study vaccination 
Second Vaccination 
 
Original wording 
• 
If indicated by review of memory aid, obtain vital signs and 
temperature. 
New wording 
• 
If indicated by review of memory aid, obtain vital signs 
• 
Measure oral temperature. 
Follow up period for 
safety and efficacy 
 
Original wording 
Active efficacy surveillance will be performed from November 15th 
until the week of 30 April the following year 
(…) 
During the passive and active efficacy surveillance period 
participants suffering from ILI will be asked to provide information 
on the symptoms as they develop using standardized sets of questions 
(…) 
NP swab specimens will be collected within 4 days of the onset of 
ILI symptoms 
(…) 
following the onset of the respiratory illness. 
(…) 
The influenza peak season will be defined for each participating 
country by the Medical director based on national surveillance 
and study data 
(…) 
Respiratory Illness follow-up calls: 
Any ILI must be followed up for 30 days following the start date or 
until resolved. Information on symptom type and duration, 
occurrence of pneumonia and new onset or exacerbations of cardio-
respiratory conditions, healthcare utilization, and medication use 

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temporally associated with the respiratory illness will be collected by 
study staff through a telephone call performed up to 30 days 
following the illness start date. 
(…) 
All NP specimens will be submitted for analysis by polymerase chain 
reaction (RT-PCR), and when the result is found positive, the second 
aliquot from such specimen will be also examined by culture 
confirmation test 
New wording 
Active efficacy surveillance will be performed from November 15th 
until the week of 30 March the following year 
(…) 
During the passive and active efficacy surveillance period 
participants suffering from ILI will be asked to provide information 
on the symptoms as they develop using also standardized sets of 
questions 
(…) 
NP swab specimens will be collected within 24 hours from ILI being 
reported to or identified by study personnel and up to 4 days of the 
onset of ILI symptoms 
(…) 
following the onset of the ILI 
(…) 
The end of influenza season will be defined for each participating 
country by the Medical director based on national surveillance 
and study data 
(…) 
ILI follow-up calls: 
Any ILI must be followed up for up to 30 days following the start 
date or until resolved. Sites will follow up the participant with ILI at 
10±3 days after ILI start date. Follow up information on symptoms 
associated with the ILI will be collected by study staff through a 
telephone call performed at 10±3 days (and up to 30 days) (unless 
collected at unscheduled clinic visit at relevant time point) following 
the illness start date. 
(…) 
All NP specimens will be submitted for analysis by polymerase chain 
reaction (RT-PCR), and when the result is found positive, another 
aliquot from such specimen will be also examined by culture 
confirmation test. 
Follow Up Period for 
Efficacy Season 2 
 
Original wording 
Active surveillance will take place between November 15, 2019 and 
April 30, 2020. 
New wording 
Active surveillance will take place between November 15, 2019 and 
March 30, 2020. 

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Follow Up Period for 
Efficacy Season 3 
 
Original wording 
This 3rd season follow up period will take place according to the 
sponsor decision based on the outcomes of interim report #2. If the 
ILI attack rate in the study population is too low in season 1 and 
season 2, the sponsor will advise if and how to proceed.  
If the primary endpoints are achieved, this follow-up period will take 
place to complete the 2nd year follow up for cohort 2 to define the 2 
years duration of the protection. Passive and active surveillance will 
take place as detailed for season 1 (see 7.3).  
Passive surveillance will take place between September 15, 2020 till 
May 15, 2021. 
Active surveillance will take place between November 15 2020 until 
the week of 30 April 2021. During this period, the dedicated study 
staff will contact the participants twice a week to remind and record 
ILI and respiratory symptoms as detailed above. 
New wording 
Season 3 is not planned and is not encompassed by this study 
protocol. 
Unscheduled Visit 
 
Original wording 
Review memory aid (if within 8 days after the previous study 
vaccination, inclusive of vaccination day). 
(…) 
• 
If indicated by medical history, obtain vital signs and oral 
temperature. 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, if indicated based on review of interim medical history. 
New wording 
Review memory aid (if within 21 days after the previous study 
vaccination, inclusive of vaccination day). 
(…) 
• 
If deemed as relevant and/or needed, perform physical 
examination and obtain vital signs including oral temperature. 
Subjects must not eat or drink anything hot or cold, or smoke within 
10 minutes prior to taking oral temperature. 
STUDY 
PROCEDURES/EVAL
UATIONS 
 
Original wording 
Concomitant Medications: All current medications and medications 
taken in the 30 days before Study Day 1 (prescription and over-the-
counter drugs) will be included, as well as vitamins and supplements, 
through 21 days after the last study injection.  Assessment of 
eligibility also will include a review of prohibited medications (per 
the exclusion criteria). 

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Vital signs: oral temperature and pulse will be collected at each of the 
study visits when a study vaccination is scheduled [Day 1 (Visit 1)] 
and as needed at the other study visits. 
(…) 
Reactogenicity Assessments: This will include an assessment of 
solicited AEs occurring from the time of each M-001 study 
vaccination [Day 1 (Visit 1), Day 22 (Visit 2] through 8 days after the 
study vaccination (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. 
(…) 
Questionnaires: questionnaire(s) for collection of information on ILI 
clinical presentation, impact on subject, duration etc. will be used in 
the study. 
New wording 
Concomitant Medications: All current medications and medications 
taken within 3 months before Study Day 1 (prescription and over-the-
counter drugs) will be included, as well as vitamins and supplements, 
through 21 days after the last study injection 
Vital signs: blood pressure, oral temperature and pulse will be 
collected at study visit 1,on early termination visit and as needed at 
the other study visits. Only oral temperature will be measured on visit 
2. 
(…) 
Reactogenicity Assessments: This will include an assessment of 
solicited AEs occurring from the time of each M-001 study 
vaccination [Day 1 (Visit 1), Day 22 (Visit 2] through 8 days after the 
study vaccination (inclusive of vaccination day), which includes an 
assessment of systemic reactions (Fever; Decreased blood pressure 
and/or dizziness; Chills and/or sweating; Joint and/or muscle pain; 
Headache; Nasal congestion, runny nose, phlegm production, rhinitis; 
Problems with breathing (difficulty breathing, wheezing); General 
malaise, fatigue, loss of appetite; Itching on body/ pruritus; 
Swelling/tender lymph nodes; Irritability; Rash; Cough; Sore throat; 
Stomach problems (abdominal pain, diarrhea, nausea, vomiting)) and 
local – injection site reactions (Blue spot/ bruising; Induration / 
Swelling; Redness / Warmth; Itching),Pain/ tenderness 
(…) 
Questionnaires: information on ILI clinical presentation, duration etc. 
will be collected in the study by study personnel. 

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ASSESSMENT OF 
SAFETY 
 
Specification of Safety 
Parameters 
 
Original wording 
1. 
SAEs, MAAEs, and NOCIs occurring from the time of the 
first study vaccination through subjects’ participation in the trial. 
2. 
Solicited AEs – reactogenicity events occurring on the day of 
each study vaccination through 7 days* after each study vaccination: 
*Vaccination day is considered Day 1, with 7 days following (8 total 
days) 
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. 
New wording 
1. 
SAEs and NOCIs occurring from the time of the first study 
vaccination through subjects’ participation in the trial. 
2. 
Solicited AEs – reactogenicity events occurring on the day of 
each study vaccination through 7 days* after each study vaccination: 
*Vaccination day is considered Day 1, with 7 days following (8 total 
days) 
a)  
Injection site reactions including pruritus, ecchymosis, 
erythema,warmth, induration, swelling, pain and tenderness. 
b)  
Systemic reactions including fever, feverishness, general 
malaise, fatigue, loss of appetite, myalgia or arthralgia, decreased 
blood pressure or dizziness, chills and/or sweating, nasal congestion, 
runny nose, phlegm production, rhinitis, problems with breathing 
(difficulty breathing, wheezing), itching on body/ pruritus, 
swelling/tender lymph nodes, irritability, rash, cough, sore throat, 
headache and stomach problems (abdominal pain, diarrhea, nausea, 
vomiting). 
Safety Assessment 
 
Original wording 
Information to be collected for unsolicited AEs includes event 
description, date of onset, licensed study physician’s assessment of 
severity and relationship to study product and alternate etiology 
(…) 
The relationship to study product must be assessed for AEs using the 
terms: related or not related. In a clinical trial, the study product 
should be considered as potential suspect. To help assess, the 
following guidelines are used: 
• 
Related – There is a reasonable possibility that the study 
product caused the AE. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study product 
and the AE. 
• 
Not Related – There is not a reasonable possibility that the 
administration of the study product caused the event. 
(…) 

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9.2.3. Additional Adverse Event Severity Grading 
Pulse will be graded according to the PI/SI judgment taking into 
consideration subject’s medical history, concomitant medications, 
and baseline values 
New wording 
Information to be collected for AEs includes event description, date 
of onset, licensed study physician’s assessment of severity and 
relationship to study product and alternate etiology 
(…) 
. The relationship to study product must be assessed for AEs using 
the terms: none, unlikely, possible, probable, certain. In a clinical 
trial, the study product should be considered as potential suspect. To 
help assess, the following guidelines are used: 
 
• 
NONE no evidence of any causal relationship is present. 
 
• 
UNLIKELY There is only little evidence to suggest there 
may be a causal relationship.  Another reasonable explanation for the 
event exists (medical history, treatment) 
 
• 
POSSIBLE 
There is some evidence to suggest a causal 
relationship but the influence of other factors has been reasonably 
possible 
 
• 
PROBABLE There is a reasonable evidence to suspect a 
causal relationship, and the relevant influence of other factors is less 
likely. 
 
• 
CERTAIN - There is clear evidence for the causal 
relationship, and other reason is very unlikely 
(…) 
9.2.3. Additional Adverse Event Severity Grading 
Pulse and Blood pressure changes will be graded according to the 
PI/SI judgment taking into consideration subject’s medical history, 
concomitant medications, and baseline values. 
Table 7 
 
Description of change 
One row added to the table. Two references added to the title of the 
table (20 and 21) 
Table 7 
 
Original wording 
Fever* - oral† 38.0°C – 38.4°C 
38.5°C – 38.9°C 
>38.9°C 
New wording 
(Age <60) Fever* - oral† 
38.0°C – 38.4°C 
38.5°C – 38.9°C
 
>38.9°C 
(Age 60+) Fever* - oral† 
37.3.0°C – 37.7°C 
37.8°C – 38.2°C
 
>38.2°C 
Reporting Procedures 
 

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Original wording 
Unsolicited non-serious AEs will be documented from the time of the 
first study vaccination (Day 0 (Visit 1)) through approximately 8 
days after the last study vaccination (approximately Day 30. 
New wording 
Unsolicited non-serious AEs will be documented from the time of the 
first study vaccination until study completion by the subject. 
Serious Adverse Events 
 
Original wording 
Medical Monitor will review SAE report(s) within 24 hours from 
receipt and assess the SAE for regulatory reporting and potential 
impact on study subject safety and protocol conduct together with 
Sponsor. SAE reports are shared with DSMB. 
New wording 
SAE report(s) within 24 hours from receipt will be reviewed and 
assessed for regulatory reporting and potential impact on study 
subject safety and protocol. SAE reports are shared with DSMB. 
Reporting of Pregnancy  
Original wording 
Pregnancies occurring in study subjects will be reported via 
Pregnancy Report Form (paper) and thru EDC 
New wording 
Pregnancies occurring in study subjects will be reported via 
Pregnancy Report Form (paper) and recorded in the EDC under SAE 
category 
Type and Duration of 
Follow-up of Subjects 
after Adverse Events 
 
Original wording 
AEs will be followed from the time of the first study vaccination 
(Day 1 (Visit 1)) through approximately 8 days after the last study 
vaccination (approximately Day 30).  
SAEs will be followed from the time of the first study vaccination 
(Day 1 (Visit 1)) through resolution even if this extends beyond the 
study-reporting period. 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. 
New wording 
AE will be followed until it reaches a satisfactory resolution, or 
becomes stable, or clinical judgment indicates that further evaluation 
is not warranted. 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. 
STATISTICAL 
CONSIDERATIONS 
 
Sample Size 
Considerations 
 
Study design 
 
Original wording 
All subjects from cohort 1 will be followed for up to two consecutive 
influenza seasons with no obligation to continue in season 3 if the 
study is extended to third season. Subjects from cohort 2 will be 
followed up for two consecutive influenza seasons if such decision 

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(of study extension to season 3) is made based on review of study 
data available after season 2. 
New wording 
All subjects from cohort 1 will be followed for up to two consecutive 
influenza seasons with no obligation to continue in season 3 if the 
study is extended to third season with protocol amendment. Subjects 
from cohort 2 will be followed up for one season. If the study is 
extended to third season with protocol amendment, it will be 
determined by the amendment if they are offered possibility to 
continue their participation in the next season and new, relevant 
consent will be then collected. 
Interim Efficacy 
Review 
 
Original wording 
There are no plans to stop the trial for futility or for efficacy at the 
end of Year 1. However, if fewer than 80 per protocol cases of 
influenza are observed at the end of Year 1, the DSMB may 
recommend increasing the sample size for Year 2. The sample size 
re-estimation plan will be detailed in the DSMB charter. The final 
analysis of vaccine efficacy will be carried out at the end of Year 2 
unless the number of per protocol cases by the end of Year 2 is 
remarkably less than the planned 182 events. If too few influenza 
cases are observed, the DSMB may recommend extending enrollment 
and stud conduct for a third year (season). The exact increase in 
sample size will be detailed in the charter. Subjects enrolled in Year 3 
would be vaccinated using Lot 2 (produced in Israel). 
New wording 
There are no plans to stop the trial for futility or for efficacy at the 
end of Year 1. However if after the first flu season the total number 
of per protocol cases of confirmed influenza infection is substantially 
fewer than 82 cases, the DSMB may recommend increasing the 
sample size for Year 2. The sample size re-estimation plan will be 
detailed in the DSMB charter. The final analysis of vaccine efficacy 
will be carried out at the end of Year 2 unless the number of per 
protocol cases by the end of Year 2 is remarkably less than the 
planned 182 events. If too few influenza cases are observed, the 
DSMB may recommend extending enrollment and stud conduct for a 
third year (season). The exact increase in sample size will be detailed 
in the charter. 
Final Analysis Plan 
 
Original wording 
At the end of Year 2 (or Year 3 if a third cohort is enrolled), a clinical 
study report (CSR) will be prepared summarizing the efficacy, safety, 
reactogenicity, and immunogenicity data. The clinical database will 
be cleaned, monitored, and locked prior to analysis.  
New wording 
At the end of Year 2 a clinical study report (CSR) will be prepared 
summarizing the efficacy, safety, reactogenicity, and immunogenicity 
data. The clinical database will be cleaned, monitored, and locked 
prior to analysis. 
Analysis of Safety Data 
 

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Original wording 
The numbers of SAEs and MAAEs 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.   
New wording 
The numbers of SAEs is 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. 
ETHICS/PROTECTIO
N OF HUMAN 
SUBJECTS 
 
Exclusion of Women, 
Minorities, and 
Children (Special 
Populations) 
 
Original wording 
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 study 
product exposure, including 2 months (defined as 60 days) after the 
last study vaccination. 
New wording 
Female subjects of childbearing potential who are not surgically 
sterile via tubal sterilization, bilateral oophorectomy, hysterectomy, 
or successful Essure® placement, 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 study product exposure, including 2 
months (defined as 60 days) after the last study vaccination (at least 
up to day 81 of the trial). 
Study Discontinuation 
 
Original wording 
If the trial is discontinued, subjects who sign the ICF, and are 
randomized and vaccinated will continue to be followed for safety 
assessments. 

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New wording 
If the trial is discontinued, subjects who have signed the ICF, and are 
randomized and vaccinated will continue to be followed for safety 
assessments. 
DATA HANDLING 
AND RECORD 
KEEPING 
 
Timing/Reports 
 
Original wording 
The CSR will be completed when all efficacy data for day 202 and 
for the follow up period of season 2 or season 3 are available. 
New wording 
The CSR will be completed when all efficacy data for day 202 and 
for the follow up period of season 2 are available. 
LITERATURE 
REFERENCES 
 
Description of change 
Two literature positions added: 
20 
https://www.ncbi.nlm.nih.gov/pubmed/19886869 
21 
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110927#pone.011
0927-Katz1 
 
SUMMARY OF 
CHANGES 
 
Description of change 
Summary of changes vs previous version of the protocol added. 
 
List of changes of study protocol version 3.0 vs. study protocol version 
2.0 dated 28th March 2018 
Description 
Wording 
Title page 
 
Version and date of the 
Protocol 
 
Original wording 
Version 2.0 dated 28th March 2018 
New wording 
Version 3.0 dated 02nd June 2018 
Investigator’s 
compliance declaration 
 
Original wording 
Protocol: BVX-010, 
New wording 
Protocol: BVX-010, version 3.0 dated June 02nd 2018 
TABLE OF 
CONTENTS 
 
Description of change 
Updated 
LIST OF 
ABBREVIATIONS 
 
Description of change 
Added abbreviations: CMI- Cell-mediated immunity, ICS - Intra 
Cellular Staining, IFN-g - Interferon gamma, NOCI - New Onset of 
Chronic Illness, p.r.n. - Pro re nata (dosing as needed), qRT-PCR - 

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Quantitative Reverse Transcriptase Real Time PCR, SI - Sub-
Investigator 
PROTOCOL 
SYNOPSIS 
 
Study population: 
 
Original wording 
Older adults and elderly (≥50 years of age). A stratification for age of 
<65> will be performed for each endpoint. 
New wording 
Older adults and elderly (≥50 years of age). Randomization will be 
stratified by cohort and age of <65>. 
Planned number of 
subjects 
 
Original wording 
At least half of the participants will be ≥65 years of age 
New wording 
At least half of the participants will be ≥65 years of age at the time of 
the randomization. 
Rationale for sample size 
 
Original wording 
Under these assumptions, 182 first episodes of PCR and/or culture-
confirmed influenza of any strain occurring at least 15 days after the 
second dose of study vaccine or control will be needed to 
demonstrate efficacy is at least 40%. 
New wording 
Under these assumptions, 182 first episodes of either qRT-PCR or 
culture-confirmed influenza of any strain occurring at least 15 days 
after the second dose of study vaccine or control will be needed to 
demonstrate efficacy is at least 40%. 
Inclusion criteria 
 
Original wording 
1. 
Male and female subjects 50 years of age (inclusive) or older, 
mentally competent, willing and able to give the written informed 
consent prior to study entry 
New wording 
1. 
Male and female subjects 50 years of age (inclusive) or older, 
willing and able to give the written informed consent prior to study 
entry 
Exclusion criteria 
 
Original wording 
3. Receipt of: a) Current (including within 60 days or planned during 
the study) daily use of immunosuppressive drugs: i) systemic 
glucocorticoids ≥ 10 mg prednisone per day ii) cytotoxic drugs b) 
Investigational drugs within 30 days before, or planned during, the 
study c) Blood products within 3 months before, or planned during, 
the study d) Influenza vaccine within 6 months before the study) 
Other vaccines within 30 days before, or planned during, the study. 
(…) 
5. An acute illness, including body temperature greater than 37.5ºC 
(axillary or forehead) or greater than 38.0 ºC (oral), or greater than 
38.5ºC (ear/tympanic or rectal) , occurred within 1 week before first 
vaccination. 
6. Anatomical deficiencies which exclude possibility of taking NP 
swab. 

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New wording 
3. Receipt of: a) Current (including within 60 days or planned during 
the study) daily use of immunosuppressive drugs: i) systemic 
glucocorticoids ≥ 10 mg prednisone per day ii) cytotoxic drugs b) 
Investigational drugs within 30 days before, or planned during, the 
study c) Blood products within 3 months before, or planned during, 
the study d) Influenza vaccine within 6 months before the study e) 
Other vaccines within 30 days before, or planned during, the study. 
(…) 
5. An acute illness, which occurred within 1 week before first 
vaccination, as judged by the PI/SI, or  including body temperature 
greater than: for participants age 50-59  37.95ºC (axillary or 
forehead) or greater than 38.04 ºC (oral), or greater than 38.59ºC 
(ear/tympanic or rectal); for participants of age 60 or more, greater 
than 37.2ºC (axillary or forehead) or 37.7 ºC (oral), or 38.2ºC 
(ear/tympanic or rectal), which occurred within 1 week before first 
vaccination. 
6. 
Anatomical deficiencies which exclude possibility of taking 
NP swab or throat and nasal swab. 
Duration of treatment 
 
Original wording 
Approximately 21 (+9) days for 2 vaccination visits 
New wording 
Approximately 22 (+9) days for 2 vaccination visits 
Criteria for evaluation 
 
Original wording 
Primary endpoint: 
Safety 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring between 0 and 7 days following 
receipt of each of the two doses of M-001 or placebo  
(…) 
To assess M-001 Safety by occurrence of unsolicited AEs from the 
time of first study vaccination through 21 days after each M-001 
vaccination. 
 
Clinical Efficacy 
Compare the occurrence of culture confirmed influenza  
(…) 
Secondary endpoints: 
1. Compare the occurrence of qualitative PCR confirmed influenza in 
the M-001 experimental group vs. placebo (≥ 15 days after the 
second vaccination until epidemiological levels of influenza are low 
as defined by the medical director) caused by any influenza A or B 
virus in association with a protocol defined ILI. Nasopharyngeal 
swab will be collected from participants who meet the ILI definition 
within 24 hours from ILI being reported to or identified by study 
personnel for PCR analysis of influenza A and/or B virus. (a nasal 
and throat sample will be collected if the participant object NP swab 
collection)  

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(…) 
Reduced Severity of influenza illness 
Reduction of PCR confirmed influenza illness severity: The time to 
symptoms alleviation/fever resolution (“alleviation/resolution”), 
(…) 
To assess in at least a subset of samples the consistency of 
manufacturing between 3 batches of M-001 according to their T cell 
responses by ICS and FACS analysis for IFN-g production in 
PBMCs. 
(…) 
Exploratory endpoints: 
(…) 
Incidence of death due to influenza-like illness (≥15 days after dosing 
until epidemiological levels of influenza are low as defined by the 
medical director) with or without confirmation of presence of 
influenza virus by viral culture or PCR analysis 
New wording 
Safety 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring within 8 days (day of the vaccination 
inclusive) following receipt of each of the two doses of M-001 or 
placebo  
(…) 
To assess M-001 Safety by occurrence of unsolicited AEs from the 
time of first study vaccination through 22 days after each M-001 
vaccination (day of the vaccination inclusive). 
Clinical Efficacy 
Compare the occurrence of either qRT-PCR or culture confirmed 
influenza  
(…) 
Secondary endpoints: 
1. Compare the occurrence of culture confirmed influenza in the M-
001 experimental group vs. placebo (≥ 15 days after the second 
vaccination until epidemiological levels of influenza are low as 
defined by the medical director) caused by any influenza A or B virus 
in association with a protocol defined ILI. Nasopharyngeal swab will 
be collected from participants who meet the ILI definition within 24 
hours from ILI being reported to or identified by study personnel for 
qRT-PCR confirmation of influenza A and/or B virus. (a nasal and 
throat sample will be collected if the participant object NP swab 
collection), and the samples identified with qRT-PCR as positive for 
influenza A or B virus will be verified with virus culture. 
(…) 
2. Reduced Severity of influenza illness  
Reduction of either qRT-PCR or Culture-confirmed influenza illness 
severity: The time to all symptoms alleviation/fever resolution 
(“alleviation/resolution”) 

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(…) 
To assess in at least a subset of samples in season 2 the consistency 
of manufacturing between 3 batches of M-001 according to their T 
cell responses by ICS and FACS analysis for IFN-g production in 
PBMCs 
Exploratory endpoints: 
(…) 
• 
Incidence of death due to influenza-like illness (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director) with or without confirmation of 
presence of influenza virus by viral culture and qRT-PCR analysis 
Criteria for evaluation 
 
Description of change 
In Secondary endpoints section rearranged order of the endpoints. 
Table 1 
 
Original wording 
Day 180 
 
Safety, Culture and PCR on any ILI (flu season) 
(…) 
Follow up 
Culture and PCR on any ILI (flu season) 
New wording 
Day 180 
 
Safety, qRT-PCR on any ILI (flu season) 
(…) 
Follow up 
qRT- PCR on any ILI (flu season) 
Table 2 
 
Description of change 
Added tick “X” for Demographic data and Review Medical & flu 
vaccination History and Concomitant meds at Visit 2 
Replaced/split AE/SAE Assessment line into  
Solicited/reactogenicity events assessment 
Unsolicited AEs Assessment 
NOCIs, AESIs, SAE 
[Note: for  Solicited/reactogenicity events assessment AND 
Unsolicited AEs/ Assessment – tick “X” at Visit 1 and 2, for NOCIs, 
AESIs, SAE – tick “X” at Visits 1, 2 and 4] 
[Note: for Solicited/reactogenicity events assessment denote added 
for visits 1 and 2: *  Occurence and severity of reactogenicity events 
will be collected through seven days after each study vaccination day 
(8 days in total)] 
[Note: for Unsolicited AEs Assessment denote added for visits 1 and 
2: # Occurrence of unsolicited AEs will be analyzed from the time of 
first study vaccination through 22 days after each M-001 vaccination 
(day of the vaccination inclusive).] 
 
Table 2 
 
Original wording 
Passive Surveillance:  

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Subjects will be instructed to contact the study site if they experience 
symptoms of respiratory illness from Day 14 post-vaccination  
(…) 
From Day 14 post vaccination until 30 April of the following year. 
(…) 
Collection of information on AEs, NOCIs, and SAEs 
New wording 
Passive Surveillance:  
Subjects will be instructed to contact the study site if they experience 
symptoms of a respiratory illness from Day 14 post-second 
vaccination day 
(…) 
From Day 14 post second vaccination day until 30 April of the 
following year 
(…) 
Collection of information on AESIs, NOCIs, and SAEs 
Table 3 
 
Description of change 
Added tick “X” for Demographic data and Review Medical & flu 
vaccination History and Concomitant meds at Visit 2 
Replaced/split AE/SAE Assessment line into  
Solicited/reactogenicity events assessment 
Unsolicited AEs Assessment 
NOCIs, AESIs, SAE 
[Note: for  Solicited/reactogenicity events assessment AND 
Unsolicited AEs/ Assessment – tick “X” at Visit 1 and 2, for NOCIs, 
AESIs, SAE – tick “X” at Visits 1, 2, 3 and 4] 
[Note: for Solicited/reactogenicity events assessment denote added 
for visits 1 and 2: *  Occurence and severity of reactogenicity events 
will be collected through seven days after each study vaccination day 
(8 days in total)] 
[Note: for Unsolicited AEs Assessment denote added for visits 1 and 
2: # Occurrence of unsolicited AEs will be analyzed from the time of 
first study vaccination through 22 days after each M-001 vaccination 
(day of the vaccination inclusive).] 
 
Table 3 
 
Original wording 
Sub-set of 925  
New wording 
(Sub-set of participants, only) 
Table 3 
 
Original wording 
Passive Surveillance:  
Subjects will be instructed to contact the study site if they experience 
symptoms of respiratory illness from Day 14 post-vaccination  
(…) 
From Day 14 post vaccination until 30 April of the following year. 
(…) 
Collection of information on AEs, NOCIs, and SAEs 
New wording 
Passive Surveillance:  

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Subjects will be instructed to contact the study site if they experience 
symptoms of a respiratory illness from Day 14 post-second 
vaccination day 
(…) 
From Day 14 post second vaccination day until 30 April of the 
following year 
(…) 
Collection of information on AESIs, NOCIs, and SAEs 
Table 3 [denotes under 
table] 
 
Original wording 
#From seven days after the study vaccination AEs related to 
vaccination will no longer be collected as solicited AEs Occurrence 
of unsolicited AEs will be analyzed from the time of first study 
vaccination through 21 days after each M-001 vaccination. 
New wording 
* Occurence and severity of reactogenicity events will be collected 
through seven days after each study vaccination day (8 days in total)  
# Occurrence of unsolicited AEs will be analyzed from the time of 
first study vaccination through 22 days after each M-001 vaccination 
(day of the vaccination inclusive).  
Note: within exploratory outcome measures, endpoints and 
objectives: “dosing” to be understood as second vaccination 
received.; “≥15 days after” is to be understood as ≥15 days after the 
vaccination, including the day of the vaccination. 
2. BACKGROUND 
INFORMATION AND 
SCIENTIFIC 
RATIONALE 
 
2.3.1. Potential Risks 
 
Original wording 
All attempts will be made to keep this PHI confidential within the 
limits of applicable laws. 
New wording 
All attempts will be made to keep this PHI confidential within the 
limits of applicable laws including European Union General Data 
Protection Regulation 2016/679 (GDPR) where applicable. 
3. 
OBJECTIVES 
 
3.1.1. Primary 
Objectives 
 
Original wording 
Safety 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring between 0 and 7 days following 
receipt of each of the two doses of M-001 or placebo and to assess 
SAEs and new-onset of chronic medical illnesses (NOCIs) during 
period from Day 0 until end of first passive surveillance period in 
each group. 
Clinical Efficacy 
To assess efficacy of M-001 in the prevention of influenza disease by 
comparing the occurrence of culture confirmed influenza in the M-

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001 experimental group vs. placebo caused by any influenza A or B 
virus in association with a protocol defined Influenza Like Illness 
(ILI) 
New wording 
Safety 
To assess M-001 Safety by solicited local and systemic 
reactogenicity events occurring within 8 days (day of the vaccination 
inclusive) following receipt of each of the two doses of M-001 or 
placebo and to assess SAEs and new-onset of chronic medical 
illnesses (NOCIs) during period from Day 0 until end of first passive 
surveillance period in each group. To assess M-001 safety by 
occurrence of unsolicited AEs from the time of first study 
vaccination through 22 days after each M-001 vaccination (day of the 
vaccination inclusive). 
 
Clinical Efficacy 
To assess efficacy of M-001 in the prevention of influenza disease by 
comparing the occurrence of either qRT-PCR or culture confirmed 
influenza in the M-001 experimental group vs. placebo caused by any 
influenza A or B virus in association with a protocol defined 
Influenza Like Illness (ILI) 
3.1.2. Secondary 
Objectives 
 
Original wording 
Clinical efficacy 
1. Compare the occurrence of qualitative PCR confirmed influenza in 
the M-001 experimental group vs. placebo caused by any influenza A 
or B virus in association with a protocol defined ILI. 
2. Reduced Severity of PCR-confirmed influenza illness by the time 
to symptom alleviation/fever resolution (“alleviation/resolution”). 
3. To assess in at least a subset of samples the consistency of 
manufacturing between 3 batches of M-001 according to their T cell 
responses by IFN-g production in PBMCs. 
4. To assess the durability of vaccine efficacy over a second 
influenza season. 
5. To assess proportion of subjects having ILI symptoms in the 
experimental or control group. 
New wording 
Clinical efficacy 
1. Compare the occurrence of culture confirmed influenza in the M-
001 experimental group vs. placebo caused by any influenza A or B 
virus in association with a protocol defined ILI. 
 
2. Reduced Severity of either qRT-PCR or culture -confirmed 
influenza illness by the time to all symptoms alleviation/fever 
resolution (“alleviation/resolution”).  
 
3. To assess the durability of vaccine efficacy over a second 
influenza season. 

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4. To assess proportion of subjects having ILI symptoms in the 
experimental or control group. 
 
Immunogenicity and lots consistency 
To assess in at least a subset of samples in season 2 the consistency 
of manufacturing between 3 batches of M-001 according to their T 
cell responses by IFN-g production in PBMCs 
3.1.3. Exploratory 
Objectives 
 
Original wording 
- Incidence of death due to influenza-like illness (≥15 days after 
dosing until epidemiological levels of influenza are low as defined by 
the medical director) with or without confirmation by viral culture or 
PCR analysis 
- To determine the specific influenza strains in flu cases in 
experimental and control group 
New wording 
• Incidence of death due to influenza-like illness (≥15 days after 
dosing until epidemiological levels of influenza are low as defined by 
the medical director) with or without confirmation by viral culture 
and qRT-PCR analysis 
• To determine the specific influenza strains in confirmed flu cases in 
experimental and control group 
3.2.1. Primary Outcome 
Measures 
 
Original wording 
Safety 
- Occurrence of vaccine-related SAEs from the time of the first study 
vaccination (M-001 or placebo) until end of first passive surveillance 
period 
- 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 unsolicited AEs from the time of first study 
vaccination through 21 days after each M-001 vaccination 
(…) 
Clinical Efficacy 
- Percentage of culture confirmed influenza cases in the M-001 
experimental group vs. placebo 
(…) 
NP swab will be collected from participants who meet the ILI 
definitions within 24 hours from ILI being reported to or identified 
by study personnel for qualitative PCR analysis of influenza A and/or 
B virus. PCR confirmed samples will be further analyzed by culture 
confirmed influenza testing. 
New wording 
Safety 

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• Occurrence of vaccine-related SAEs from the time of the first study 
vaccination (M-001 or placebo) until end of first passive surveillance 
period  
• Occurrence of NOCIs from the time of the first study vaccination 
(M-001 or placebo) until end of first passive surveillance period 
• Occurrence of solicited injection site and systemic reactogenicity 
events on the day of each study vaccination through approximately 8 
days after each M-001 vaccination (day of the vaccination inclusive) 
• Occurrence of unsolicited AEs from the time of first study 
vaccination through 22 days after each M-001 vaccination (day of the 
vaccination inclusive)  
(…) 
Clinical Efficacy  
• Percentage of either qRT-PCR or culture-confirmed influenza cases 
in the M-001 experimental group vs. placebo (during 
(…) 
NP or combined nasal and throat swab will be collected from 
participants who meet the ILI definition within 24 hours from ILI 
being reported to or identified by study personnel for qRT-PCR 
analysis of influenza A and/or B virus. PCR confirmed samples will 
be further analyzed for culture confirmation. 
3.2.2. Secondary 
Outcome Measures 
 
Original wording 
1. Clinical efficacy 
- Percentage of PCR confirmed influenza cases in the M-001 
experimental group vs. placebo (during ≥ 15 days after the second 
vaccination until epidemiological levels of influenza are low as 
defined by the medical director) caused by any influenza A or B virus 
in association with a protocol defined Influenza Like Illness. NP 
swab will be collected from participants who meet the ILI definitions 
within 24 hours from ILI being reported to or identified by study 
personnel for qualitative PCR analysis of influenza A and/or B virus. 
- Percentage of subjects having ILI symptoms in the experimental or 
control group 
- Average time to symptom alleviation/fever resolution in the 
experimental vs control group. “alleviation/resolution” time is 
defined as the first time point at which all of the following influenza 
symptoms (body aches (myalgia and/or arthralgia), cough, 
fatigue/tiredness, headache, nasal congestion/ runny nose/ sputum 
production, wheezing or difficult breathing, chills and sore throat) 
were absent and fever had resolved, with both (resolution of all 
symptoms and fever) maintained for at least 1 day. 
- To assess the durability of vaccine efficacy over a second influenza 
season 
2. Immunogenicity and lots consistency 

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Frequency of T cell subsets from participants in the experimental 
group, expressing interferon gamma (IFN-g) in CD4+ PBMCs after 
stimulation with M-001 16 days after the second dose of M-001 as 
compared to baseline. 
New wording 
1. Clinical efficacy 
• Percentage of culture confirmed influenza cases in the M-001 
experimental group vs. placebo (during ≥ 15 days after the second 
vaccination until epidemiological levels of influenza are low as 
defined by the medical director) caused by any influenza A or B virus 
in association with a protocol defined Influenza Like Illness. NP or 
nasal and throat swab will be collected from participants who meet 
the ILI definitions within 24 hours from ILI being reported to or 
identified by study personnel for culture confirmation of influenza A 
and/or B virus (a nasal and throat sample will be collected if the 
participant object the NP swab collection), and the samples identified 
with qRT-PCR as positive for influenza A or B virus will be verified 
with virus culture. 
• Average time to all symptoms alleviation/fever resolution in the 
experimental vs control group. “Alleviation/resolution” time is 
defined as the first time point at which all of the following influenza 
symptoms (body aches (myalgia and/or arthralgia), cough, 
fatigue/tiredness, headache, nasal congestion/ runny nose/ sputum 
production, wheezing or difficult breathing, chills and sore throat) 
were absent and fever had resolved, with both (resolution of all 
symptoms and fever) maintained for at least 1 day. 
• To assess the durability of vaccine efficacy over a second influenza 
season 
• Percentage of subjects having ILI symptoms in the experimental or 
control group 
 
2. Immunogenicity and lots consistency 
Frequency of T cell subsets from participants in the experimental 
group, expressing interferon gamma (IFN-g) in CD4+ PBMCs after 
stimulation with M-001 16 days after the second dose of M-001 (day 
of the vaccination inclusive) as compared to baseline. 
3.2.3. Exploratory 
Outcome Measures 
 
Original wording 
3.2.3. Exploratory Outcome Measures 
- Incidence of secondary respiratory tract infections leading to a 
prescription for antibiotic therapy in the experimental group as 
compared to the control group. In case of lack of documented 
medical record subject’s provided information will be sufficient. 
- Incidence of clinic visits (≥15 days after dosing until 
epidemiological influenza levels are low as defined by the medical 
director) in the experimental group as compared to the control group; 

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A possibility of multiple visits per subject; each visit will be counted 
once in the analysis. 
- Incidence of hospitalization associated with ILI (≥15 days after 
dosing until epidemiological levels of influenza are low as defined by 
the medical director) in the experimental group as compared to the 
control group. 
- Incidence of death due to influenza-like illness (≥15 days after 
dosing until epidemiological levels of influenza are low as defined by 
the medical director) in the experimental group as compared to the 
control group, with or without confirmation by viral culture or PCR 
analysis. 
- Define influenza virus subtype in the swab samples to compare the 
viruses causing disease in the experimental vs control group 
New wording 
3.2.3. Exploratory Outcome Measures 
• Incidence of secondary respiratory tract infections leading to a 
prescription for antibiotic therapy in the experimental group as 
compared to the control group. In case of lack of documented 
medical record subject’s provided information will be sufficient. 
• Incidence of clinic visits (≥15 days after dosing* until 
epidemiological influenza levels are low as defined by the medical 
director) in the experimental group as compared to the control group; 
A possibility of multiple visits per subject; each visit will be counted 
once in the analysis. 
• Incidence of hospitalization associated with ILI (≥15 days after 
dosing* until epidemiological levels of influenza are low as defined 
by the medical director) in the experimental group as compared to the 
control group. 
• Incidence of death due to influenza-like illness (≥15 days after 
dosing* until epidemiological levels of influenza are low as defined 
by the medical director) in the experimental group as compared to the 
control group, with or without confirmation by viral culture or and 
qRT-PCR analysis. 
• Define influenza virus subtype in the swab samples to compare the 
viruses causing disease in the experimental vs control group 
* - within exploratory outcome measures, endpoints and objectives: 
“dosing” to be understood as second vaccination received.;  ≥15 days 
after” is to be understood as ≥15 days after the second vaccination, 
including the day of the vaccination. 
4. STUDY DESIGN 
 
Original wording 
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 study 
vaccination (inclusive of vaccination day). Unsolicited non-serious 
AEs collected from the time of each M-001 vaccination through 
approximately 21 days after each study vaccination will be analyzed 

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separately. SAEs will be collected from the time of the first study 
vaccination through the entire trial period 
New wording 
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 8 days after the study 
vaccination  (inclusive of vaccination day). Unsolicited non-serious 
AEs collected from the time of each M-001 vaccination through 
approximately 22 days after each study vaccination (day of the 
vaccination inclusive) will be analyzed separately. SAEs (including 
AESIs) and NOCIs will be collected from the time of the first study 
vaccination through the entire trial period.   
5. STUDY 
ENROLLMENT AND 
WITHDRAWAL 
 
5.1 Subject Inclusion 
Criteria 
 
Original wording 
1. 
Male and female subjects 50 years of age (inclusive) or older, 
mentally competent, willing and able to give the written informed 
consent form (ICF) prior to study entry 
New wording 
1. 
Male and female subjects 50 years of age (inclusive) or older, 
willing and able to give the written informed consent prior to study 
entry 
5.2 Subject Exclusion 
criteria 
 
Original wording 
3. Receipt of: a) Current (including within 60 days or planned during 
the study) daily use of immunosuppressive drugs: i) systemic 
glucocorticoids ≥ 10 mg prednisone per day ii) cytotoxic drugs b) 
Investigational drugs within 30 days before, or planned during, the 
study c) Blood products within 3 months before, or planned during, 
the study d) Influenza vaccine within 6 months before the study) 
Other vaccines within 30 days before, or planned during, the study. 
(…) 
5. An acute illness, including body temperature greater than 37.5ºC 
(axillary or forehead) or greater than 38.0 ºC (oral), or greater than 
38.5ºC (ear/tympanic or rectal) , occurred within 1 week before first 
vaccination. 
6. Anatomical deficiencies which exclude possibility of taking NP 
swab. 
New wording 
3. Receipt of: a) Current (including within 60 days or planned during 
the study) daily use of immunosuppressive drugs: i) systemic 
glucocorticoids ≥ 10 mg prednisone per day ii) cytotoxic drugs b) 
Investigational drugs within 30 days before, or planned during, the 
study c) Blood products within 3 months before, or planned during, 
the study d) Influenza vaccine within 6 months before the study e) 
Other vaccines within 30 days before, or planned during, the study. 
(…) 

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5. An acute illness, which occurred within 1 week before first 
vaccination, as judged by the PI/SI, or  including body temperature 
greater than: for participants age 50-59  37.95ºC (axillary or 
forehead) or greater than 38.04 ºC (oral), or greater than 38.59ºC 
(ear/tympanic or rectal); for participants of age 60 or more, greater 
than 37.2ºC (axillary or forehead) or 37.7 ºC (oral), or 38.2ºC 
(ear/tympanic or rectal), which occurred within 1 week before first 
vaccination. 
6. 
Anatomical deficiencies which exclude possibility of taking 
NP swab or throat and nasal swab. 
5.3 Treatment 
Assignment Procedures 
 
Original wording 
5.3.1. Randomization Procedures 
Central randomization will be implemented in this study. Subjects 
will be randomized to 1 of 2 treatment arms, based on a computer-
generated randomization schedule prepared by or under the 
supervision of the sponsor before the study. The randomization will 
be stratified by age group (i.e., 50- 65, ≥ 65) and balanced by using 
permuted blocks 
New wording 
5.3.1. Randomization Procedures 
Central randomization will be implemented in this study. Subjects 
will be randomized to 1 of 2 treatment arms, based on a computer-
generated randomization schedule prepared by or under the 
supervision of the sponsor before the study. The randomization will 
be stratified by cohort and age group (i.e., 50- 65, ≥ 65) and balanced 
by using permuted blocks 
5.3.3. Reasons for 
Withdrawal 
 
Original wording 
• 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 37.5°C, 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. If outside this 
window, the PI must first approve the subsequent study vaccination 
and the documentation of approval should be filed in the subject’s 
chart.  
•Any unresolved by 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.  
• Grade 3 within the 8 days following a study vaccination, that has no 
alternative (to the vaccination) etiology. 
New wording 
•Presence of signs or symptoms that could confound or confuse 
assessment of study vaccine reactogenicity. For subjects with 

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injection site or systemic signs or symptoms, or with an acute illness,  
the subsequent study vaccinations should be postponed/deferred until 
signs, symptoms, or acute illness have sufficiently resolved as per 
PI/SI judgment, and if within the acceptable protocol-specified 
window for that visit. If outside this window, the PI must first obtain 
approval for the second study vaccination from the study sponsor and 
the documentation of the approval should be filed in the subject’s 
file.  
• Any unresolved or continuing at Visit 2 Grade 3 AE. An unresolved 
or continuing Grade 1 or 2 AE (grade 2 except for temperature which 
at grade 2 is not acceptable for vaccination) is permissible unless, in 
the opinion of the PI or SI, it would render study vaccination unsafe 
or interfere with the evaluation of responses.  
• Solicited reactogenicity event grade 3 or AE grade 3 AE, within the 
8 days following study vaccination (day of the vaccination inclusive), 
that has no alternative (to the vaccination) etiology. 
5.3.4. Handling of 
Withdrawals 
 
Original wording 
Subjects who withdraw, or are withdrawn or terminated from the 
study, or are lost to follow-up after signing the ICF and 
randomization but before receipt of study vaccine may be replaced. 
Subjects who withdraw after randomization will not be replaced. 
New wording 
Subjects who withdraw, or are withdrawn or terminated from the 
study, or are lost to follow-up after signing the ICF and 
randomization but before receipt of study vaccine may be replaced. 
6. STUDY 
INTERVENTION/INVE
STIGATIONAL 
PRODUCT 
 
Original wording 
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 0.7 mL at a concentration of 
2.5mg/mL that should be transferred to a 1mL syringe for injection. It 
contains no preservative (i.e., non-thimerosal). 
Study product must be stored at 2°C to 8°C. Do not freeze. 
(…) 
M-001 investigational influenza vaccine product: 
The 1 mg of M-001 dose will be administered as a single 0.4 mL 
intramuscular injection. The M-001 will be provided in a vial 
containing 0.7 mL of solution containing the exact dose for 
immunization. Visually inspect M-001 vaccine vial upon receipt and 
prior to use. After gentle shaking, the suspension will be cloudy 
white in appearance. If the M-001 vaccine precipitated, it should be 
resuspended by tapping on the vial with the finger or mixing by 
vortex until the suspension looks homogeneous, then it should be 

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transferred to a syringe. 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). 
 
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). 
(…) 
6.4. Assessment of Subject Compliance with Study Intervention/ 
Investigational Product 
Study product will be administered to subjects by a blinded vaccine 
administrator via IM injection at all dosing times according to subject 
treatment assignment and as described in section 0. Thus, subject 
compliance with appropriate administration is not anticipated to be an 
issue. Deviations from the dose schedule may only occur as described 
in Section 6.2. 
 
6.5. Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines will be 
recorded on the appropriate data collection form. Concomitant 
medications will include all current medications and medications 
taken within 30 days prior to Day 1 through approximately Day 43. 
After Day 43 only concomitant medications relevant for respiratory 
illness as per PI judgment, or related to AE or ILI will be recorded. 
Subjects who do not receive both M-001 study vaccinations will have 
all concomitant medications collected through approximately 21 days 
after the first study vaccination, or early termination, whichever 
occurs first. Prescription and over-the-counter drugs will be included 
as well as herbals, vitamins and supplements. In addition, 
information on receipt of non-study influenza vaccines will be 
solicited at each clinic visit or phone call, and reported in the eCRF. 
New wording 
M-001 
M-001 is supplied as a sterile, cloudy-white suspension in single-
dose vials of volume sufficient to dose: 1 mg of M-001 (1mg is a 
single dose). 
Each vial contains a fill volume (less than 1 mL) of concentration 
provided in the study manual for respective product batch that should 
be transferred to a 1mL syringe for injection according to the study 
manual. It contains no preservative (i.e., non-thimerosal). 

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Volume of the product containing 1mg of M-001 (1 mg of M-001 is 
the dose to be administered per each vaccination) will be provided in 
the study manual for respective product batch. 
Study product must be stored at 2°C to 8°C. Do not freeze. 
(…) 
M-001 investigational influenza vaccine product: 
The 1 mg of M-001 dose will be administered as a single 
intramuscular injection according to the study manual. The M 001 
will be provided in vials as described in paragraph 6.1.1 of the 
protocol. 
 
Visually inspect M-001 vaccine vial upon receipt and prior to use. 
After shaking, 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 until the suspension looks 
homogeneous, then it should be transferred to a syringe. 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).   
 
Normal Saline (Placebo): 
The saline placebo dose will be administered as a single 
intramuscular injection. Exact volume to be injected will be defined 
in the study manual and will be equal to the volume of the M-001 
defined for the active treatment (M-001) study arm. 
The saline will be provided in vials as described in paragraph 6.1.1 of 
the protocol. 
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). 
(…) 
6.4. Assessment of Subject Compliance with Study Intervention/ 
Investigational Product  
Study product will be administered to subjects by a blinded vaccine 
administrator via IM injection at all dosing times according to subject 
treatment assignment and as described in sections 5.3 and 6 of the 
protocol. Thus, subject compliance with appropriate administration is 
not anticipated to be an issue. Deviations from the dose schedule may 
only occur as described in Section 6.2. 
 
6.5. Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines will be 
recorded on the appropriate data collection form. Concomitant 
medications will include all current medications and medications 

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taken within 3 months days prior to Day 0 through approximately 
Day 43. After Day 43 only concomitant medications relevant for 
respiratory illness as per PI judgment, or related to AE or ILI will be 
recorded. Subjects who do not receive both M-001 study vaccinations 
will have all concomitant medications collected through 
approximately 22 days after the first study vaccination, day of the 
vaccination inclusive, or early termination, whichever occurs first. 
Prescription and over-the-counter drugs will be included as well as 
herbals, vitamins and supplements. In addition, information on 
receipt of other influenza or non-influenza study vaccines will be 
solicited at each clinic visit or phone call by PI/SI or delegated study 
site personnel, and, if confirmed, such vaccination will be reported in 
the eCRF. 
7. STUDY SCHEDULE 
 
Original wording 
• Subjects will be entered into EDC system randomly assigned to a 
treatment arm prior to the first study vaccination 
(…) 
Subjects will be encouraged to take their temperature around the 
same time each day for 8 days post vaccination. 
(…) 
7.2.1. Visit 2, Day 22, Clinic Visit (21 days [+9 days] post first 
study 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. 
(…) 
7.2.2. Visit 3, Day 37, Clinic Visit (16 days [±3 days] post second 
study vaccination for a subset, in season 2019/20) 
(…) 
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 
(…) 
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 
(…) 
Safety surveillance: 
All serious adverse events (SAEs) will be collected from Day 0 until 
the last telephone call of the study year. 
Adverse events of special interest (AESIs) will be captured as SAEs. 
These include new onset of Guillain-Barré Syndrome (GBS), Bell’s 
Palsy, encephalitis / myelitis, optic neuritis, Stevens-Johnson 
Syndrome, and toxic epidermal necrolysis. 
Passive efficacy surveillance: Following randomization and 
vaccinations, subjects will be instructed to contact the site if they 

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experience symptoms of a respiratory illness during the annual 
surveillance periods, from Day 14 after vaccination until 15 May of 
the following year. Another period of follow up will take place in the 
influenza season that follows (total of 2 years follow up). 
Active efficacy surveillance will be performed from November 15th 
until the week of 30 March the following year, the most likely period 
of influenza virus circulation in the Northern Hemisphere. Another 
period of follow up will take place in the influenza season that 
follows (total of 2 years follow up).  
The participants will be contacted by a dedicated study staff twice a 
week between approximately November 15th through March 30th; 
Another period of follow up may take place in the influenza season 
that follows (up to 2 years follow up).  
Participants will be contacted as described above to monitor for 
influenza-like illness (ILI)), and any related symptom causing 
hospitalization or urgent care visit, and serious or specified adverse 
events. ILI was defined as listed above. 
During the period from Day 14 after vaccination until 30 April of the 
following year, the site will arrange for an NP swab to be collected if 
the subject experiences a new onset  of the above mentioned 
symptoms of ILI (that persist for or reoccur after a period of at least 
12 hours). 
During the passive and active efficacy surveillance period 
participants suffering from ILI will be asked to provide information 
on the symptoms as they develop using also standardized sets of 
questions.  
 
NP swab collection: 
NP swab specimens will be collected within 24 hours from ILI being 
reported to or identified by study personnel and up to 4 days of the 
onset of ILI symptoms for confirmation of influenza virus A or B via 
reverse transcriptase polymerase chain reaction RT-PCR followed by 
culture (Rhesus Monkey Kidney or Madin–Darby Canine Kidney 
tissue cultures) confirmation for PCR positive samples as described 
in Vesikari et al  . Every effort must be made to obtain the NP swab 
specimen within 24 hours from ILI being reported to or identified by 
study personnel  according to the qualifying ILI symptoms, and no 
later than 4 days (sample to be collected through Day 3 of the illness, 
considering that Day 0 is the day of the illness onset) following the 
onset of the ILI. 
(…) 
Laboratory testing for the confirmation of influenza:  
All NP specimens will be submitted for analysis by polymerase chain 
reaction (RT-PCR), and when the result is found positive, another 
aliquot from such specimen will be also examined by culture 
confirmation test.  

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Optional test: Positive cultures samples will be stored and may 
undergo additional testing in the future (typing, subtyping or strain 
identification, utilizing genetic sequencing and antigenic analysis 
using hemagglutination inhibition [HAI] against a panel of known 
standard ferret reference antisera to different viral strains) to 
determine the breadth of protection provided by M-001 
(…) 
7.4. 
Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ 
Electronic Communication (180 days +/-14 post last study 
vaccination)  
Subjects will be contacted by phone or electronic communication 
(e.g., email, text message) to query for safety events.  Subjects will 
be asked to provide positive responses to the follow-up by phone. 
AEs limited to SAEs that have occurred since the previous visit will 
be solicited.  Based on the information, subjects may be asked to 
return to the clinic for evaluation. 
7.5. 
Follow Up Period for Efficacy Season 2  
(…) 
Active surveillance will take place between November 15, 2019 and 
March 30, 2020. During this period, the dedicated study staff will 
contact the participants twice a week to remind and record ILI and 
respiratory symptoms as detailed above (Follow up calls in season 
2019/20 will be for all 9,630 participants). 
(…) 
• Memory aid information will be reviewed with subjects (if within 
21 days after the last study vaccination). 
• If indicated by interim medical history, perform physical 
examination and obtain vital signs including oral temperature. 
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). 
(…) 
• Examine study vaccination site, and perform post- administration 
reactogenicity assessment (if within 7 days after the last study 
vaccination). 
 
7.8. 
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 21 days after the previous study 
vaccination). 
• Review and record all concomitant medications (if prior to 21 days 
after the last study vaccination). 

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• 
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. 
New wording 
Subjects entered into EDC system will be randomly assigned to a 
treatment arm prior to the first study vaccination 
(…) 
Subjects will be encouraged to take their temperature around the 
same time each day for 8 days post vaccination (day of the 
vaccination inclusive). 
(…) 
7.2.1. Visit 2, Day 22, Clinic Visit (22 days [+9 days] post first 
study vaccination day) 
(…) 
Subjects will be instructed on how to use the memory aid and how to 
measure and record solicited events and / or unsolicited AEs prior to 
discharge from the clinic. 
(…) 
Visit 3, Day 37, Clinic Visit (16 days [±3 days] post second study 
vaccination for subset of subjects from Cohort 2, in season 2019/20) 
(…) 
Study personnel will review the memory aid information with 
subjects and assess and record all solicited events / unsolicited 
AEs/SAEs and concomitant medications on the appropriate data 
collection form 
(…) 
Study personnel will review interim medical history (other than 
reactogenicity events) with subjects and assess and record all 
unsolicited AE/SAEs and concomitant medications on the 
appropriate data collection form/ 
(…) 
Safety surveillance: 
All serious adverse events (SAEs) and new onset of chronic medical 
illness (NOCIs)  will be collected from Day 0 until the end of the 
participation in the trial by the subject. 
Adverse events of special interest (AESIs) will be captured as SAEs. 
These include new onset of Guillain-Barré Syndrome (GBS), Bell’s 
Palsy, encephalitis / myelitis, optic neuritis, Stevens-Johnson 
Syndrome, and toxic epidermal necrolysis. 
Passive efficacy surveillance: Following randomization and 
vaccinations, subjects will be instructed to contact the site if they 
experience symptoms of a respiratory illness during the annual 
surveillance periods, from Day 14 after second vaccination day until 
15 May of the following year. Another period of follow up will take 
place in the influenza season that follows (total of 2 years follow up). 
Active efficacy surveillance will be performed from November 15th 
until the week of 30 March the following year, the most likely period 

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of influenza virus circulation in the Northern Hemisphere. Another 
period of follow up will take place in the influenza season that 
follows (total of 2 years follow up).  
The participants will be contacted by a dedicated study staff twice a 
week between approximately November 15th through March 30th; 
Another period of follow up may take place in the influenza season 
that follows (up to 2 years follow up).  
Participants will be contacted as described above by non-site study 
staff to monitor for influenza-like illness (ILI)); participants 
identified this way as potentially having ILI will be followed up by 
relevant study site personnel to confirm if the participant’s symptoms 
and signs meet study ILI definition. 
During the period from Day 14 after second vaccination day until 30 
April of the following year (or longer if decided by the medical 
director based on actual influenza season duration), the site will 
arrange for an NP/nasal and throat swab to be collected if the subject 
experiences a new onset  of the above mentioned symptoms of ILI 
(that persist for or reoccur after a period of at least 12 hours). 
During the passive and active efficacy surveillance period 
participants suffering from ILI will be asked to provide information 
on the symptoms as that they developed using also standardized sets 
of questions.  
 
NP swab collection: 
NP swab (or nasal and throat swab) specimens will be collected 
during the period from Day 14 after second vaccination until 30 April 
of the following year (or longer if decided by the medical director 
based on actual influenza season duration), within 24 hours from ILI 
being reported to or identified by study personnel and up to 4 days of 
the onset of ILI symptoms for confirmation of influenza virus A or B 
via qRT-PCR followed by culture (Rhesus Monkey Kidney or 
Madin–Darby Canine Kidney tissue cultures) confirmation for qRT-
PCR positive samples as described in Vesikari et al  . Every effort 
must be made to obtain the NP(or nasal and throat) swab specimen 
within 24 hours from ILI being reported to or identified by study 
personnel  according to the qualifying ILI symptoms, and no later 
than 4 days (sample to be collected through Day 3 of the illness, 
considering that Day 0 is the day of the illness onset) following the 
onset of the ILI. 
(…) 
Laboratory testing for the confirmation of influenza:  
All NP/nasal and throat swab specimens will be submitted for 
analysis by polymerase chain reaction (qRT-PCR), and when the 
result is found positive, another aliquot from such specimen will be 
also examined by culture confirmation test. Typing and subtyping of 
the influenza virus will be performed with PCR based method. 

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Optional test: Positive cultures samples will be stored and may 
undergo additional testing in the future (subtyping or strain 
identification, utilizing genetic sequencing and antigenic analysis 
using hemagglutination inhibition [HAI] against a panel of known 
standard ferret reference antisera to different viral strains) to further 
determine the breadth of protection provided by M-001 
(…) 
7.4. 
Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ 
Electronic Communication (180 days +/-14 post last study 
vaccination)  
Subjects will be contacted by phone or electronic communication 
(e.g., email, text message) to query for safety events.  Subjects will 
be asked to provide positive responses to the follow-up by phone. 
AEs limited to NOCIs and SAEs that have occurred since the 
previous visit will be solicited.  Based on the information, subjects 
may be asked to return to the clinic for evaluation. 
7.5. 
Follow Up Period for Efficacy Season 2  
(…) 
Active surveillance will take place between November 15, 2019 and 
March 30, 2020. During this period, the dedicated study staff will 
contact the participants twice a week to monitor for ILI symptoms as 
detailed above in 7.3. (Follow up calls in season 2019/20 will be for 
all 9,630 participants). 
(…) 
• Memory aid information will be reviewed with subjects (if within 
22 days after the last study vaccination, day of the vaccination 
inclusive). 
• If indicated by interim medical history, perform physical 
examination and obtain vital signs including oral temperature. 
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 within 22 days 
after the last study vaccination, day of the vaccination inclusive). 
(…) 
• Examine study vaccination site, and perform post- administration 
reactogenicity assessment (if within 8 days after the last study 
vaccination, day of the vaccination inclusive ). 
7.8. 
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 22 days after the last study 
vaccination day, inclusive of the vaccination day). 
• Review and record all concomitant medications (if within 22 days 
after the last study vaccination day, inclusive of the vaccination day). 

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• 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 day. 
8. STUDY 
PROCEDURES/EVALU
ATIONS 
 
Original wording 
8.1. 
Clinical Evaluations 
(…) 
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 within 3 months before Study Day 1 (prescription and over-the-
counter drugs) will be included, as well as vitamins and supplements, 
through 21 days after the last study injection 
(…)  
Reactogenicity Assessments: This will include an assessment of 
solicited AEs occurring from the time of each M-001 study 
vaccination [Day 1 (Visit 1), Day 22 (Visit 2] through 7 days after 
the study vaccination (inclusive of vaccination day),  
(…) 
Memory Aids: All subjects will complete a subject memory aid 
(paper diary) from the time of each study vaccination [Day 1 (Visit 
1), Day 22 (Visit 2)] through 7 days after the study vaccination.  
Subject memory aids will be reviewed with the subject for AEs at the 
clinic visit following the first study injection.  If a subject noted 
ongoing injection site or systemic reactogenicity on the 7th day 
following the study injection, the memory aid will continue to be 
completed and reviewed until resolved. 
(…) 
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 1) and approximately Day 22 (Visit 2) on all female subjects of 
childbearing potential. Result must be negative and known prior to 
randomization on Day 1 (Visit 1) and administration of each study 
vaccination to be eligible for participation in the study and receipt of 
each dose of study vaccine. 
8.2.2. Nasopharyngeal Samples  
For assessment of influenza virus through culture and PCR, an NP 
swab sample will be collected from both nasal passages using two 
different swab applicators; that are then placed in the same tube of 
universal transport medium (UTM). Optionally, if NP swab cannot be 
collected, combined swabs collection from deep nasal and throat - 
can be collected instead of NP, however NP swab is preferred 
method of collection of material for assessment of influenza virus 
infection. Immediately prior to taking the sample, the person 

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performing the procedure will verify the subject’s identity and will 
confirm that the subject number and any other required information 
on the laboratory request form are those of the subject. Each tube of 
UTM will be clearly labeled with the self-adhesive bar-coded label 
provided on the NP Requisition form that will be applied to the tube 
immediately before collection of the NP swab. 
(…) 
8.2.3. Special Assays or Procedures  
Cellular (CMI) Studies  
Assays to measure T cell responses will be performed by a qualified 
laboratory.  Venous blood samples for isolation of PBMCs will be 
collected from a subset, immediately prior to the first study 
vaccination (Day 1, visit 1 in season 2), and 16 days after the second 
M-001 vaccination (Day 37, visit 3, season 2). 
8.2.4. Specimen Preparation, Handling, and Shipping  
(…) 
8.2.4.2. 
Specimen Shipment 
Swab samples will be shipped and stored according to applicable 
regulations and according to the technical requirements aiming at 
preserving good quality of the material before it is processed for RT-
PCR and/or culture confirmation 
New wording 
8.1. 
Clinical Evaluations 
(…) 
The collection of medical history information will include a review 
of vaccine history and plans for vaccinations. All past influenza 
vaccinations should be recorded (up to 3 years). Other vaccines 
history should include at least 30 days before the study and any other 
study-relevant vaccination received in the past. 
Concomitant Medications: All current medications and medications 
taken within 3 months before Study Day 0 (prescription and over-the-
counter drugs) will be included, as well as vitamins and supplements, 
through 21 days after the last study injection day 
(…)  
Reactogenicity Assessments: This will include an assessment of 
solicited events occurring from the time of each M-001 study 
vaccination [Day 0 (Visit 1), Day 22 (Visit 2] through 8 days after 
the study vaccination (inclusive of vaccination day),  
(…) 
Memory Aids: All subjects will complete a subject memory aid 
(paper diary) from the time of each study vaccination [Day 0 (Visit 
1), Day 22 (Visit 2)] through 8 days after the study vaccination (study 
vaccination day inclusive).  Subject memory aids will be reviewed 
with the subject for AEs at the clinic visit following the first study 
injection.  If a subject noted ongoing injection site or systemic 
reactogenicity on the 7th day following the study injection day, the 

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memory aid will continue to be completed and reviewed until 
resolved. 
(…) 
8.2.1. Clinical Laboratory Evaluations  
Urine pregnancy tests will be performed by the local or site 
laboratory within 24 hours prior to each study vaccination (Day 0 
(Visit 1) and approximately Day 22 (Visit 2) on all female subjects of 
childbearing potential. Result must be negative and known prior to 
randomization on Day 0 (Visit 1) and administration of each study 
vaccination to be eligible for participation in the study and receipt of 
each dose of study vaccine. 
8.2.2. Nasopharyngeal Samples  
For assessment of influenza virus through culture and qRT-PCR, an 
NP/nasal and throat swab sample will be collected from both nasal 
passages using two different swab applicators; both swabs are then 
placed in the same tubes of universal transport medium (UTM). 
Optionally, if NP swab cannot be collected, combined swabs 
collection from deep nasal (both nostrils) and throat - can be 
collected instead of NP with three separate applicators, and all three 
swabs are then placed into the same tube of UTM. Immediately prior 
to taking the sample, the person performing the procedure will verify 
the subject’s identity and will confirm that the subject number and 
any other required information on the laboratory request form are 
those of the subject. Each tube of UTM will be clearly labeled with 
the self-adhesive bar-coded label provided on the Swab Requisition 
form that will be applied to the tube immediately before collection of 
the NP/nasal and throat swab. 
(…) 
8.2.3. Special Assays or Procedures  
Cellular (CMI) Studies  
Assays to measure T cell responses will be performed by a qualified 
laboratory.  Venous blood samples for isolation of PBMCs will be 
collected from a subset of cohort 2, immediately prior to the first 
study vaccination (Day 0, visit 1 in season 2), and 16 days (day of the 
vaccination inclusive) after the second M-001 vaccination (Day 37, 
visit 3, season 2). 
8.2.4. Specimen Preparation, Handling, and Shipping  
(…) 
8.2.4.2. 
Specimen Shipment 
Swab samples will be shipped and stored according to applicable 
regulations and according to the technical requirements aiming at 
preserving good quality of the material before it is processed for 
qRT-PCR and (where applicable) for culture confirmation 
9. ASSESSMENT OF 
SAFETY 
 

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9.1. Specification of 
Safety Parameters 
 
Original wording 
2. Solicited AEs – reactogenicity events occurring on the day of each 
study vaccination through 7 days* after each study vaccination: 
*Vaccination day is considered Day 1, with 7 days following (8 total 
days) 
(…) 
Unsolicited AEs – non-serious AEs occurring from the time of the 
first study vaccination through approximately 21 days after the last 
study vaccination 
New wording 
2. Solicited events – reactogenicity events occurring on the day of 
each study vaccination through 8 days* after each study vaccination: 
*Vaccination day is considered Day 0, with 7 days following (8 days 
in total) 
(…) 
Unsolicited AEs/SAEs – non-serious AEs/SAEs occurring from the 
time of the study vaccination through approximately 22 days after the 
study vaccination (day of the vaccination inclusive) 
9.2. Safety Assessment 
 
Original wording 
All unsolicited 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 AEs includes event description, date of onset, 
licensed study physician’s assessment of severity and relationship to 
study product and alternate etiology (if not related to study product) 
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. 
Events classified as ILI will not be recorded as AEs unless they occur 
within 8 days  post vaccination or if they meet seriousness criteria - 
then they are reported as AEs/SAEs, because ILI cases are to be 
recorded separately and analyzed for efficacy endpoints. 
 
Severity of Event: AEs will be assessed by a licensed study physician 
using a protocol-defined grading system (see section 9.2.2). For 

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events not included in the protocol-defined grading system, the 
following guidelines will be used to quantify severity: 
(…) 
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  
(…) 
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: 
(…) 
• all events described as Guillain-Barré syndrome will also be 
considered SAEs as within the confines of this protocol are deemed 
as important medical events  
(…) 
9.3. 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be 
documented from the time of each study vaccination (Day 1 (Visit 1) 
and approximately Day 22 (Visit 2) through 7 days after each study 
vaccination. 
Unsolicited non-serious AEs will be documented from the time of the 
study vaccination until study completion by the subject. 
SAEs will be documented from the time of the first study vaccination 
(Day 1 (Visit 1)) through subject’s participation in the trial. 
SAEs occurring after the participant completes the study or after 
early termination need not 
be reported unless the Investigator believes that the event may have 
been caused by the study product or a protocol procedure. 
 
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 CRO representative at the following address: 
KCR S.A. 
6 Postepu Str. 
02-676 Warsaw, Poland 
Email: SAE@kcrcro.com 
 
FAX:  +48 22 203 56 58 
Email: SAE@kcrcro.com 
In addition to the SAE form, selected SAE data fields must also be 
entered into EDC,  

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Other supporting documentation of the event may be requested by the 
DSMB and should be provided as soon as possible. 
SAE report(s) within 24 hours from receipt will be reviewed and 
assessed for regulatory reporting and potential impact on study 
subject safety and protocol. SAE reports are shared with DSMB. 
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 study Sponsor. 
(…) 
9.5. 
Safety Oversight (DSMB) 
(…) 
Reports may include enrollment and demographic information, 
medical history, concomitant medications, physical assessments, 
clinical laboratory values, dosing compliance, and solicited and 
unsolicited AE/SAEs. 
New wording 
AEs will be captured on the appropriate data collection form and 
electronic case report form (eCRF) as described below in terms of 
reporting periods. Information to be collected for AEs includes event 
description, date of onset, licensed study physician’s assessment of 
severity and relationship to study product and considered etiology (if 
case not related or unlikely related to study product) 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 may be recorded as an AE or SAE. 
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 within study 
periods as described below. 
Unsolicited AEs will be collected occurring from the time of the 
study vaccination through approximately 22 days after the study 
vaccination (day of the study vaccination inclusive). 
Adverse events of special interest (AESIs) will be captured as SAEs 
and within the same timelines throughout the subject’s participation 
in the trial. These include new onset of Guillain-Barré Syndrome 
(GBS), Bell’s Palsy, encephalitis / myelitis, optic neuritis, Stevens-
Johnson Syndrome, and toxic epidermal necrolysis.  
NOCIs should be collected from the time of the first study 
vaccination throughout the subject’s’ participation in the trial. NOCI 
is defined as diagnosis of a chronic medical condition where the 

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symptoms commenced or worsened following exposure to the study 
vaccine. NOCIs meeting criteria of SAE will be recorded as SAE. 
Events classified as ILI will not be recorded as AEs/SAEs unless they 
occur during period from first or second vaccination within 8 days 
(the vaccination day inclusive) post the respective vaccination or if 
they meet seriousness criteria - then they are also (in addition to 
being reported as ILI) reported as SAEs, because ILI cases are to be 
recorded separately and analyzed for efficacy assessment. 
 
Severity of Event: AEs will be assessed by a licensed study physician 
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 by PI/SI to quantify severity, taking 
into account subject’s medical history, concomitant medications, and 
baseline values: 
(…) 
9.2.2. Reactogenicity 
Reactogenicity events are solicited events which are common and 
considered as possible to occur following administration of this type 
of vaccine. Reactogenicity (solicited) events are recorded only for 8 
days post vaccination (day of the vaccination inclusive). Solicited 
events (reactogenicity events) which match at least one of the below 
criteria must be also recorded as AE/SAE or unsolicited AE/SAE: 
 
- symptom/event continues/occurs beyond 7 days post vaccination 
day (unsolicited AE/SAE) 
- reactogenicity symptom/event(s) required medical (i.e. physician’s) 
assistance (AE/SAE) 
- reactogenicity symptom/event has been graded by subject or by 
investigator as severe (AE/SAE) 
- oral body temperature of severe grade as per section 9.2.2 Table 7 
(AE/SAE) 
 
Per PI/SI’s judgment, also cases of symptoms/events occurring 
within 8 days post vaccination (day of the vaccination inclusive) not 
meeting the above criteria can be recorded as SAE. 
 
The following Toxicity Grading Scales will be used by PI/SI to grade 
solicited injection site and systemic (subjective and quantitative) 
reactions in order to assess whether they qualify as AE/SAE, and if 
they are severe enough to delay administration of second dose 
(…) 
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/meets any of the following: 

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(…) 
• Note: all AESIs will also be considered SAEs as within the confines 
of this protocol are deemed as important medical events  
• Note: cases of NOCIs which meet criteria of SAE will be recorded 
as SAE with annotation that they are also considered NOCIs. 
• Note: ILI cases meeting seriousness criterion/criteria should be 
recorded as SAE in parallel with recording them as ILI cases, except 
for periods of 8 days post vaccination day (day of the vaccination 
inclusive) for both vaccine doses when such cases will only be 
recorded as SAE. 
(…) 
9.3. 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be 
documented from the time of each study vaccination (Day 0 (Visit 1) 
and approximately Day 22 (Visit 2) through 8 days after each study 
vaccination (day of the vaccination inclusive). 
Unsolicited non-serious AEs (excluding NOCIs) will be documented 
from the time of the study vaccination until 22 days after the study 
vaccination (day of the vaccination inclusive). 
ILI as AE will be documented if occur within 8 days post vaccination 
(day of the vaccination inclusive). 
SAEs and NOCIs will be documented from the time of the first study 
vaccination (Day 0 (Visit 1)) through subject’s participation in the 
trial. 
SAEs occurring after the participant completes the study or after 
early termination need not 
be reported unless the Investigator believes that the event may have 
been caused by the study product or a protocol procedure. 
 
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 CRO representative at the following: 
KCR S.A. 
Email: SAE@kcrcro.com 
 
FAX:  +48 22 203 56 58 
In addition to the SAE form, selected SAE data fields must also be 
entered into EDC,  
Other supporting documentation of the event may be requested by the 
DSMB and should be provided as soon as possible. 
All SAE report(s) will be reviewed and assessed for regulatory 
reporting purposes and potential impact on study subject safety and 
protocol whithin 1 business day from receipt. SAE reports will be 
shared with DSMB. 

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At any time after completion of the study, if the site PI or appropriate 
SI becomes aware of an SAE that is suspected to be related to study 
product, the site PI or appropriate SI will report the event to the study 
Sponsor directly. 
(…) 
9.5. 
Safety Oversight (DSMB) 
(…) 
Reports may include enrollment and demographic information, 
medical history, concomitant medications, physical assessments, 
clinical laboratory values, dosing compliance, and 
solicited/reactogenicity events and AE/SAEs. 
9.6. Efficacy Assessment 
 
Original wording 
9.6.1. Molecular Detection and Sequencing Methodology (PCR): 
Clinical samples collected during the study period will undergo an 
extraction procedure to isolate the viral RNA from the NP swab prior 
to testing. 
The initial test will be a qualitative reverse transcriptase polymerase 
chain reaction (RT-PCR-) based assay to determine if Influenza 
strains are present in the clinical sample. 
For samples that are found positive for influenza in the RT-PCR 
assay, further testing by culture confirmation will be performed, to 
avoid false positive results.  
 
9.6.2. Influenza Culture and Virus Isolation: 
Nasopharyngeal (NP) swab samples from subjects with ILI that were 
found positive in RT-PCR 
New wording 
9.6.1. Molecular Detection and Sequencing Methodology (qRT-
PCR): 
Clinical samples collected during the study period will undergo an 
extraction procedure to isolate the viral RNA from the NP/nasal and 
throat swab prior to testing. 
The initial test will be a qRT-PCR- based assay to determine if 
Influenza strains are present in the clinical sample. A multiplex qRT-
PCR will be performed to define Influenza A/H1 or A/H3 or B in a 
single test, Influenza B samples will be re-tested by qRT-PCR to 
define the Victoria/Yamagate lineage specification. 
For samples that are found positive for influenza in the qRT-PCR 
assay, further testing by culture confirmation will be performed.  
9.6.2. Influenza Culture and Virus Isolation: 
Swab samples from subjects with ILI that were found positive in 
qRT-PCR 
11. STATISTICAL 
CONSIDERATIONS 
 
Original wording 
11.3.1. Study Design  
This is a pivotal, multicentre, randomized, modified double-blind, 
placebo-controlled phase 3 trial to assess the safety and clinical 

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efficacy of M-001, an influenza vaccine administered intramuscularly 
twice in older adults and the elderly (≥50 years of age). Subjects will 
be randomized 1:1 to vaccine or placebo with randomization 
stratified by age group. 
(…) 
For these 925 subjects, blood samples will be collected prior to the 
first study vaccination (Day 1) and approximately 16 days after the 
second vaccination (Day 37). 
(…) 
Under these assumptions, 182 first episodes of PCR and/or culture-
confirmed influenza of any strain occurring at least 15 days after the 
second dose of study vaccine or control and prior to the end of the 
first influenza season will be needed to demonstrate efficacy is at 
least 40%. 
(…) 
• Receipt of non-study licensed inactivated vaccine within 21 days 
before or anytime after each study vaccination 
(…) 
11.5.2. Analysis of 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) 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 is expected to be small in this trial and 
will be reported 
(…) 
VE and its 95% confidence interval will be estimated by age group 
(i.e., < 65 years, ≥ 65 years) for both the PP and ITT analysis 
populations. Given VE for a specific age group can be approximated 
by 1 minus the age group specific odds ratio, the Breslow-Day test 

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for the homogeneity of the odds ratios will be used to test for a 
common VE across age groups. 
New wording 
11.3.1. Study Design  
This is a pivotal, multicentre, randomized, modified double-blind, 
placebo-controlled phase 3 trial to assess the safety and clinical 
efficacy of M-001, an influenza vaccine administered intramuscularly 
twice in older adults and the elderly (≥50 years of age). Subjects will 
be randomized 1:1 to vaccine or placebo with randomization 
stratified by cohort and age group. 
(…) 
For these 925 subjects, blood samples will be collected prior to the 
first study vaccination (Day 0) and approximately 16 days (day of the 
vaccination inclusive) after the second vaccination (Day 37). 
(…) 
Under these assumptions, 182 first episodes of qRT-PCR -confirmed 
influenza of any strain occurring at least 15 days after the second 
dose of study vaccine or control and prior to the end of the first 
influenza season will be needed to demonstrate efficacy is at least 
40%. 
(…) 
• Receipt of non-study licensed inactivated vaccine within 21 days 
before or anytime after each study vaccination day 
(…) 
11.5.2. Analysis of Safety Data 
Summaries and analysis of safety data will be presented for the 
Safety Analysis Population. 
Solicited events will be summarized by severity for each day after 
each study vaccination (Days 0-7 post each study vaccination, 8 days 
in total) and as the maximum severity over all 8 days (day of the 
vaccination inclusive).  Additionally, solicited events 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 events 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) 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 

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(SOC).  The numbers of SAEs is expected to be small in this trial and 
SAEs will be reported 
(…) 
VE and its 95% confidence interval will be estimated by age group 
(i.e., < 65 years, ≥ 65 years) for both the PP and ITT analysis 
populations. Given VE for a specific age group can be approximated 
by 1 minus the age group specific odds ratio, the Breslow-Day test 
for the homogeneity of the odds ratios will be used to test for a 
common VE across age groups.  In addition, given that circulating 
strains of flu may vary over the course of the trial, VE and its 95% 
confidence interval will be estimated by flu season as well for both 
the PP and ITT analysis populations; Breslow-Day test for the 
homogeneity of the odds ratios will be used to test for a common VE 
across cohort (flu season). 
14.5. Subject 
Confidentiality 
 
Original wording 
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. 
New wording 
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 according 
to the applicable laws including European Union General Data 
Protection Regulation 2016/679 (GDPR) where applicable. 
Across the protocol 
 
Original wording 
Sub-I 
New wording 
SI 
Across the protocol 
 
Original wording 
Day 21 
New wording 
Day 22 [note: change applied to increase consistency regarding 
duration of relevant period from the time/day of the first vaccination] 
Across the protocol 
 
Original wording 
Day 7 
New wording 
Day 8 [note: change applied to increase consistency regarding 
duration of relevant period from the time/day of the vaccination] 
Across the protocol 
 
Original wording 
Day 1 
New wording 
Day 0 [note: change applied to increase consistency regarding 
numbering of the day of first vaccination] 
Across the protocol 
 
Original wording 
NP swab, NP (Nasopharyngeal) 
New wording 
NP (Nasopharyngeal) or combined nasal and throat swab; NP/nasal 
and throat swab 
Across the protocol 
 
Original wording 
PCR, qualitative PCR 
New wording 
qRT-PCR 

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List of changes of study protocol version 4.0 vs. study protocol version 
3.0 dated 02nd June 2018 
Description 
Wording 
Title page 
 
Version and date of the 
Protocol 
 
Original wording 
Version 3.0 dated 02nd June 2018 
New wording 
Version 4.0 dated 27th March 2019 
Sponsor 
 
Original wording 
BiondVax Pharmaceuticals Ltd. 
Kiryat Weizmann, 14 Einstein Street  
Ness Ziona, POB 4143, 7414002, Israel 
New wording 
BiondVax Pharmaceuticals Ltd. 
Jerusalem Biopark, Hadassah Ein Kerem,  
Jerusalem, Israel 
Investigator’s 
compliance declaration 
 
Original wording 
Protocol: BVX-010, version 3.0 dated June 02nd 2018 
New wording 
Protocol: BVX-010, version 4.0 dated March 27th 2019 
TABLE OF 
CONTENTS and LIST 
OF TABLES 
 
Description of change 
Updated 
PROTOCOL 
SYNOPSIS 
 
Description of changes 
Updated Sponsor’s address. 
Updated information on planned study allocation – change from 66 to 
85 institutions, added one new country – Georgia. 
Deleted information on planned subject participation duration 
“(including 2 consecutive flu seasons for cohort 1 participants).” 
Added information in study population section: “For season 2, 
randomization will also be stratified by participation (or not) to the 
sub-study” 
PROTOCOL 
SYNOPSIS 
 
Original wording 
Adaptive design (flexible enrolment); initially assumed to be 9,630 
(including 10% dropouts). At least half of the participants will be ≥65 
years of age at the time of the randomization. 
 
Year 1 - cohort 1 (flu season 2018-2019): Approximately 4,334 
subjects will be enrolled, as follows: 
M-001: n = 2,167 (Lot #1); Placebo: n = 2,167 
Year 2 - cohort 2 (flu season 2019-2020): Approximately 5,296 
subjects will be enrolled, as follows: 

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M-001: n = 2,648 ((Lot #1, #2 & #3); Placebo: n = 2,648 
New wording 
Year 1 - cohort 1 (flu season 2018-2019): 4,055 subjects enrolled, as 
follows: 
M-001: n = 2,027 (Lot #1, vials); Placebo: n = 2,028 
Year 2 - cohort 2 (flu season 2019-2020): Approximately 8,000 
subjects will be enrolled, as follows: 
M-001: n = 4,000 (Lot#2, pre-filled syringes); Placebo: n = 4,000 
Original wording 
PBMC sub-study: 
In addition to the main trial, blood samples will be collected pre- and 
post-vaccination from a subset of 925 participants to confirm lots 
consistency: 275 participants receiving each lot (Lot #1 produced by 
Cytovance; Lots #2 & #3 produced by BiondVax, IL facility) and 
additional 100 participants from control group (to maintain the 
blinding). Lot-to-lot consistency testing will occur during Year 2 (in 
Cohort 2). 
New wording 
PBMC (CMI) sub-study: 
To assess the immune response to the vaccine, blood samples will be 
collected pre- and post-vaccination from a subset of 350 participants 
selected at random in pre-specified sites participating in Season 2.  
Approximately two hundred sixty two (263) will be selected from the 
M-001 group and 87 from the placebo group.  
The endpoint for assessing the immune response will be the change 
from baseline in the percentage of CD4+ lymphocytes producing Th1 
cytokine (e.g. INF-γ) in response to any of the 9 peptides in M-001 
measured at 14 ± 2 days after the day of the second vaccination (Visit 
3) (Day 36). 
Original wording 
Rationale for sample size: 
The study sample size of 9,630 subjects is based on the lower bound 
of the two-sided 95% confidence interval for Vaccine Efficacy (VE) 
being above 40% with 80% probability when true VE is 62%. (…).  
 
If after the first flu season the total number of per protocol cases of 
confirmed influenza infection is substantially fewer than 82 cases, the 
DSMB may, following issuance of interim report #1, recommend 
increasing the sample size for Year 2. Otherwise, the sample size for 
Year 2 will remain at 5,296 subjects. Details for sample size re-
estimation will be defined in the DSMB charter. 
 
The same methodology will be used after the second flu season by 
issuing interim report #2 and optionally extending the trial to year 3 
with a third cohort based on amendment to the protocol which will be 
submitted in such case for ethics/regulatory approval. 
 
In the event vaccine efficacy for a single influenza season is 
demonstrated, a lot consistency analysis will be performed on Year 2. 
The endpoint for assessing lot consistency will be the percentage of 

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CD4+ lymphocytes producing INF-γ in response to any of the 9 
peptides in M-001 measured at Day 37. 
New wording 
Rationale for sample size: 
The initial study sample size of 9,630 subjects is based on the lower 
bound of the two-sided 95% confidence interval for Vaccine Efficacy 
(VE) being above 40% with 80% probability when true VE is 62% 
(…).  
In Year 1, about 4,000 subjects will be enrolled. If during the first flu 
season a substantially reduced attack rate is anticipated, the Sponsor 
may elect to increase the total sample size to 12,000. If the average 
attack rate across Year 1 and Year 2 is at least 2.4%, the study should 
maintain power at 80%. If during the second flu season another mild 
season is expected, the Sponsor may consider extending the trial to 
Year 3 with a third cohort based on an amendment to the protocol 
which will be submitted for ethics/regulatory approval. 
In Year 2, an immunogenicity sub-study will be conducted at select 
sites. Assuming the percentage of CD4+ lymphocytes producing Th1 
cytokine (e.g. INF-γ) in response to any of the 9 peptides in M-001 
measured at Day 36 (14 ± 2 days after the day of the second 
vaccination) has a mean (standard deviation) of 25% (12%), the sub-
study should have reasonable power with 210 evaluable vaccinees to 
demonstrate the non-inferiority of the immune response in other 
populations with a non-inferiority margin of 5%. Power calculations 
are based on an equally sized trial in the population to which vaccine 
efficacy is being bridged. 
PROTOCOL 
SYNOPSIS 
 
Inclusion criteria 
 
Original wording 
1. Male and female subjects 50 years of age (inclusive) or older, 
willing and able to give the written informed consent prior to 
study entry. 
2. Able to comply with the trial procedures and be available for all 
study visits. 
3. Medically stable (subjects may have underlying chronic 
conditions such as hypertension, diabetes, ischemic heart disease, 
or hypothyroidism, as long as their symptoms/signs are controlled; 
if they are on medication for a condition, the medication dose 
must have been stable for at least 3 months preceding 
vaccination). 
4. Women of childbearing potential (not surgically sterile or 
postmenopausal for greater than or equal to one year) and men 
must agree to practice adequate effective contraception - barrier or 
hormone-based methods or intra uterine device (IUD) for women 
and a condom for males -whose female partner has childbearing 
potential - throughout the study treatment and for at least up to 
day 81 (for females) and day 111 (for males) of the trial (i.e. 60 

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(for females) and 90 (for males) days after the last dose of the 
IMP). In addition, women of childbearing potential must have 
practiced the contraception for a minimum of 30 days prior to 
study product exposure. 
5. 
Female subjects of childbearing potential must have a 
negative urine or serum pregnancy test within 24 hours prior to study 
vaccination. 
New wording 
1. Male and female subjects 50 years of age (inclusive) or older, 
willing and able to give the written informed consent prior to 
study entry. 
2. Able to comply with the trial procedures and be available for all 
study visits including answering phone calls and coming to the 
site as defined by the Protocol. 
3. Medically stable (subjects may have underlying systemic chronic 
conditions such as hypertension, diabetes, ischemic heart disease, 
or hypothyroidism, as long as their symptoms/signs are controlled; 
if they are on systemic pharmacological treatment for such 
condition, the treatment must have been stable for at least 3 
months preceding first vaccination). 
4. Women of childbearing potential (not surgically sterile or 
postmenopausal for greater than or equal to one year) and men 
must agree to practice adequate effective contraception - barrier or 
hormone-based methods or intra uterine device (IUD) for women 
and a condom for males -whose female partner has childbearing 
potential - throughout the study treatment and for at least up to 
day 81 (for females) and day 111 (for males) of the trial (i.e. 60 
(for females) and 90 (for males) days after the last dose of the 
IMP). In addition, women of childbearing potential must have 
practiced the contraception for a minimum of 30 days prior to 
study product exposure. 
5. Female subjects of childbearing potential must have a negative 
urine or serum pregnancy test within 24 hours prior to both study 
vaccinations. 
Exclusion criteria 
 
Original wording 
1. History of neurological symptoms or signs, or anaphylactic shock 
following administration of any vaccine. 
2. Known or suspected (or have a high risk of developing) 
impairment/alteration of immune function (excluding that 
normally associated with advanced age). 
3. Receipt of: a) Current (including within 60 days or planned during 
the study) daily use of immunosuppressive drugs: i) systemic 
glucocorticoids ≥ 10 mg prednisone per day ii) cytotoxic drugs b) 
Investigational drugs within 30 days before, or planned during, the 
study c) Blood products within 3 months before, or planned 
during, the study d) Influenza vaccine within 6 months before the 
study e) Other vaccines within 30 days before, or planned during, 

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the study. 
4. Any serious disease such as: cancer, autoimmune disease, 
advanced arteriosclerotic disease or complicated diabetes mellitus, 
chronic obstructive pulmonary disease (COPD) that requires 
oxygen therapy, acute or progressive hepatic disease, acute or 
progressive renal disease, or congestive heart failure, as judged by 
the PI/SI. 
5. An acute illness, which occurred within 1 week before first 
vaccination, as judged by the PI/SI, or body temperature greater 
than: for participants age 50-59 37.9ºC (axillary or forehead) or 
38.4 ºC (oral), or 38.9ºC (ear/tympanic or rectal); for participants 
of age 60 or more, greater than 37.2ºC (axillary or forehead) or 
37.7 ºC (oral), or 38.2ºC (ear/tympanic or rectal), which occurred 
within 1 week before first vaccination. 
6. Anatomical deficiencies which exclude possibility of taking NP 
swab or throat and nasal swab.  
7. 
Women who are breastfeeding or planning pregnancy during 
the period of the study 
New wording 
1. History of neurological symptoms or signs, or anaphylactic shock 
following administration of any vaccine. 
2. Known or suspected (or have a high risk of developing) 
significant impairment/alteration of immune function (excluding 
that normally associated with advanced age) as judged by PI/SI. 
3. Receipt of: a) Current (including within 60 days before Visit 1 or 
planned during the study) daily use of immunosuppressive drugs: 
i) systemic glucocorticoids ≥ 10 mg prednisone per day ii) 
cytotoxic drugs b) Investigational drugs within 30 days before, or 
planned during, the study c) Blood products within 3 months 
before, or planned during, the study d) Influenza vaccine within 6 
months before the study or planned during the study e) Other 
vaccines within 30 days before, or planned during, the study. 
4. Any serious disease such as: cancer, autoimmune disease, 
advanced arteriosclerotic disease or complicated diabetes mellitus, 
chronic obstructive pulmonary disease (COPD) that requires 
oxygen therapy, acute or progressive hepatic disease, acute or 
progressive renal disease, or congestive heart failure, as judged by 
the PI/SI. 
5. An acute illness, which occurred within 1 week before first 
vaccination, as judged by the PI/SI, or body temperature greater 
than: for participants age 50-59 37.9ºC (axillary or forehead) or 
38.4 ºC (oral), or 38.9ºC (ear/tympanic or rectal); for participants 
of age 60 or more, greater than 37.2ºC (axillary or forehead) or 
37.7 ºC (oral), or 38.2ºC (ear/tympanic or rectal), which occurred 
within 1 week before first vaccination. 
6. Anatomical deficiencies which exclude possibility of taking NP 
swab or throat and nasal swab.  

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7. Women who are breastfeeding or planning pregnancy during the 
period of the study. 
8. Institutionalized subjects or subjects unable to come to the study 
site as expected by the Protocol. 
PROTOCOL 
SYNOPSIS 
 
Test and reference 
product administration 
 
Original wording 
Administered twice intramusculary at 21 days interval (acceptable 
range: 21-30 days) 
New wording 
Administered twice intramuscularly at 21 days interval 
(recommended range: 21-30 days) 
Duration of treatment 
 
Original wording 
For the subset of Cohort 2 participants who will attend 3 visits for 
immunogenicity testing for lot-to-lot consistency, the duration is 
37±3 days. The total duration of this trial for each subject will be 
approximately 8 months and up to 2 years of follow-up (planned are 
2 consecutive flu seasons for cohort 1 participants). Shall the optional 
study extension occurred (subject to future protocol amendment), 
cohort 1 participants will have no obligation to continue their follow 
up thru Year 3. 
New wording 
Cohort 2 participants will attend 3 site visits.  Subset of Cohort 2 
participants will attend , including additional Visit 3 for 
immunogenicity testing, and remaining Cohort 2 participants will 
have the third visit as safety assessment focused site visit. The Visit 3 
is planned 14±2 days after Visit 2 day. The total duration of this trial 
for each subject will be up to 1 year. Shall the optional study 
extension have occurred for the purpose of follow up on efficacy 
(subject to future protocol amendment), the participants will have no 
obligation to continue their follow up thru Year 3 
Criteria for evaluation 
 
Original wording 
(a nasal and throat sample will be collected if the participant object 
NP swab collection), 
New wording 
(a nasal and throat sample can be collected as alternative method) 
Original wording 
2. Reduced Severity of influenza illness  
Reduction of either qRT-PCR or Culture-confirmed influenza 
illness severity: The time to all symptoms alleviation/fever 
resolution (“alleviation/resolution”), which can be defined as 
the first time point at which all of the following influenza 
symptoms (body aches (myalgia and/or arthralgia), cough, 
fatigue/tiredness, headache, nasal congestion/ runny nose/ 
sputum production, wheezing or difficult breathing, chills and 
sore throat) were absent and fever had resolved, with both 
(resolution of the symptoms and fever) maintained for at least 
one day.  

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3. To assess the durability of vaccine efficacy over a second 
influenza season. 
 
4. Percentage of subjects having ILI symptoms in the 
experimental and control group 
 
5. To assess in at least a subset of samples in season 2 the 
consistency of manufacturing between 3 batches of M-001 
according to their T cell responses by ICS and FACS analysis for 
IFN-g production in PBMCs. 
New wording 
2. Reduced Severity of influenza illness  
Reduction of either qRT-PCR or Culture-confirmed influenza 
illness severity: The reduction due to M-001 in the average 
number of days with respiratory or systemic symptoms during the 
first laboratory-confirmed influenza illness episode.  
3. The percentage of subjects having ILI symptoms in the 
experimental and control group 
4. The change from baseline in the percentage of CD4+ 
lymphocytes producing Th1 cytokine (e.g. INF-γ) in response to 
any of the 9 peptides in M-001.  This endpoint will be assessed 
within a randomly selected subset of participants from pre-
selected sites participating to the substudy in Year 2.  
Original wording 
Exploratory endpoints: 
 
Incidence of secondary respiratory tract infections leading to a 
prescription for antibiotic therapy  
 
Incidence of clinic visits associated with the ILI episode (≥15 
days after dosing until epidemiological influenza levels are low as 
defined by the medical director); A possibility of multiple visits 
per subject; each visit will be counted once in the analysis. 
New wording 
Exploratory endpoints: 
 
Incidence of antibiotics use due to post-influenza secondary  
infections of respiratory tract 
Statistical methods 
 
Original wording 
For the primary analysis of vaccine efficacy (VE), the efficacy of M-
001 after a first influenza season will be estimated 
(…) 
Determination of sample size for lot consistency:  
The endpoint for assessing lot consistency will be the percentage of 
CD4+ lymphocytes producing INF-γ in response to any of the 9 
peptides in M-001. Based on preliminary immunogenicity data, the 
percentage of CD4+ lymphocytes is approximately normally 
distributed with a mean of 25% and standard deviation 12%. 

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Assuming an equivalence margin of 5%, 250 subjects per lot would 
need to be enrolled to have 90% probability that the 95% confidence 
interval for the difference in mean percentage for each of 3 pair-wise 
comparisons falls between -5% and 5% when there is no true 
difference. Assuming, that no more than 10% of samples are not 
evaluable, 275 subjects per lot will be targeted. 
New wording 
For the primary analysis of vaccine efficacy (VE), the efficacy of M-
001 after a first influenza season in each cohort will be estimated 
(…) 
Determination of sample size for the CMI substudy:The endpoint 
for assessing immune response to the vaccine will be the change from 
baseline in the percentage of CD4+ lymphocytes producing Th1 
cytokine (e.g. INF-γ) in response to any of the 9 peptides in M-001. 
Based on preliminary immunogenicity data, the percentage of CD4+ 
lymphocytes is approximately normally distributed with a mean of 
25% and standard deviation 12%.  A sample size of 210 M-001 
subjects will provide an estimate of the change from baseline in 
percentage of CD4+ lymphocytes producing e.g. INF-γ with a 
precision (1/2 width of the 95% CI) at most 2% . 
Table 1 
 
Description of changes 
Trial Design tables for Cohort 1 and 2 split between two separate 
tables (Table 1 and 2). 
Headers changed from: 
Season 1 
Interim report issued after season 1 Season 2 
Interim or final report issued after season 2 
To: 
Year 1 
Interim data analysis after Year 1 
And  
Year 2 (flu season 2019/2020) 
 
In addition, updated subheaders and added Visit 3 column. Deleted 
column reflecting season 2 for cohort 1 subjects. 
 
In addition: 
Graph updated to reflect decision tree for after flu season 2 
completion timepoint. 
Updated text below the graph: 
Original wording:  
Flexible enrollment scheme according to interim reports that will be 
issued after seasons 1 and 2. Flu season 3 is not planned. If decided 
that it is needed, protocol amendment will be issued and submitted 
for relevant approvals. 
 1 the cutoff will be at most 82 and will be defined precisely in the 
DSMB charter 

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New wording:  
Flexible enrollment scheme according to interim data review that will 
be available after Year 1 and 2. Flu season 3 (Year 3) is not planned. 
If decided that it is needed after Year 2, protocol amendment will be 
issued and submitted for relevant approvals. 
1 the cutoff will be at most 182 and will be defined precisely in the 
DSMB charter 
* In subset of subjects – visits at selected sites with collection of 
blood for CMI assessment at Visit 1 and 3. Visit 3 should take place 
in 14 days +/-2 since date of Visit 2. 
Table 2 Schedule of 
Events for Cohort 1 
 
Description of changes 
Changed to Table 3. 
Deleted: Both passive and active surveillance for cohort 1 subjects 
will be replicated during second season (passive one starting on 
September 15, 2019). 
 
Original wording: 
A combination of deep nasal and throat swab will be sampled from 
participant that will not allow for or cannot have NP swab collection, 
however NP swab is preferred. The process will be replicated for 
cohort 1 during second season 
(…) 
At any time during the study a disease burdenand concomitant 
medications in association withILI, and for up to 30 days following 
the start of a qualifying ILI symptoms. 
 
New wording: 
At any time during the study a disease burdenand concomitant 
medications in association withILI, and for up to 30 days following 
the start of a qualifying ILI symptoms.  
(…) 
At any time during the study a disease burden and concomitant 
medications in association with respiratory disease, ILI or AE, and 
for up to 30 days following the start of a qualifying ILI symptoms. 
Table 3 Schedule of 
Events for Cohort 2 
 
Description of changes 
Changed to Table 4. 
Updated headers 
Added Visit 3 details 
Minor corrections made to list of procedures on Visit 2 
Updated wording of headers narrowing the contents fo season 2 
instead of season 1 and 2. 
 
Original wording: 

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A nasal and throat swab will be sampled from participant that will 
not allow NP swab collection 
(…) 
At any time during the study year disease burden data and 
concomitant medications in association with ILI, and for up to 30 
days following the start of a qualifying ILI symptoms. 
New wording: 
A nasal and throat swab will be sampled from participant that will 
not allow NP swab collection. Swabs collection period starting on 
September 15, 2019 
(…) 
At any time during the study year disease burden data and 
concomitant medications in association with respiratory disease, ILI 
or AE, and for up to 30 days following the start of a qualifying ILI 
symptoms. 
 
Denotes under the Tables 
with schedule of events 
 
Description of changes 
Added two positions: 
9 In subset of subjects – visit at site with collection of blood for CMI assessment 
at Visit 1 and 3. For remaining subjects only– site visit or - if site visit not 
feasible - phone call. Blood sampling applicable only for on site visits in a subset 
of subjects participating in the CMI assessment. 
10 If indicated by medical interview on period between Visit 1 and 2 
 
Original wording: 
Note: within exploratory outcome measures, endpoints and objectives: “dosing” 
to be understood as second vaccination received.; “≥15 days after” is to be 
understood as ≥15 days after the vaccination, including the day of the 
vaccination. 
New wording: 
Note: within exploratory outcome measures, endpoints and objectives: “dosing” 
to be understood as second vaccination received (unless second dose will not be 
administered to given subject); “≥15 days after” is to be understood as ≥15 days 
after the vaccination, including the day of the vaccination. 
 
2.
 
BACKGROUN
D INFORMATION 
AND SCIENTIFIC 
RATIONALE 
 
2.2. 
Rationale 
 
Original wording: 
In addition, long term efficacy (up to 2 seasons) will be assessed.  
Lot-to-lot consistency between three batches (produced by Cytovance 
(OK, US) and by BiondVax (IL) will be evaluated. To compare the 3 
lots in terms of immunogenicity, participants in season 2019/20 will 
be vaccinated with the 3 M-001 batches (equally randomized, 1:1:1 

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for each batch). Blood samples will be collected from 825 
participants receiving M-001 (275 participants for each batch) and 
from 100 participants receiving the placebo (to maintain the 
blinding). The blood samples from all 925 participants will be 
collected at baseline (visit 1) and 16±3 days after the second 
immunization (visit 3).  Lots consistency will be confirmed by 
comparing cell mediated immune parameters in the samples from the 
experimental groups only. 
New wording: 
Cell-mediated immunity expected to be induced by the M-001 will 
also be evaluated based on samples from subset of participants from 
Cohort 2.  Blood samples will be collected from approximately 263 
participants receiving M-001 and 87  participants receiving the 
placebo (to maintain the blinding). The blood samples from all 350  
participants will be collected at baseline (visit 1) and on Visit 3 -14 ± 
2 days after the day of the Visit 2 (second vaccination). 
Original wording: 
Six previous trials in which approximately 460 participants received 
M-001 intramuscularly have been completed to date (see Investigator 
Brochure). 
(…) 
Bruising can sometimes occur due to the vaccination procedure. 
New wording: 
Six previous trials in which approximately 460 participants received 
M-001 intramuscularly have been completed to date in addition to 
2027 who participated in season 1 of the current trial (see 
Investigator Brochure). 
(…) 
Bruising can sometimes occur due to the vaccination procedure. 
There were no treatment related SAEs. 
3. 
OBJECTIVES 
 
3.1. 
Study Objectives  
Original wording 
Clinical efficacy 
 
Compare the occurrence of culture confirmed influenza in 
the M-001 experimental group vs. placebo caused by any 
influenza A or B virus in association with a protocol defined 
ILI. 
 
Reduced Severity of either qRT-PCR or culture -confirmed 
influenza illness by the time to all symptoms 
alleviation/fever resolution (“alleviation/resolution”).  
 
To assess the durability of vaccine efficacy over a second 
influenza season. 
 
To assess proportion of subjects having ILI symptoms in the 
experimental or control group. 
Immunogenicity and lots consistency 

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To assess in at least a subset of samples in season 2 the 
consistency of manufacturing between 3 batches of M-001 
according to their T cell responses by IFN-g production in 
PBMCs. 
(…) 
3.1.3 Exploratory Objectives  
 
Incidence of secondary respiratory tract infections leading to 
a prescription for antibiotic therapy declared by the 
participant 
 
Incidence of clinic visits associated with the ILI episode 
(≥15 days after dosing until epidemiological influenza levels 
are low as defined by the medical director); A possibility of 
multiple visits per subject; each visit will be counted once in 
the analysis. 
 
Incidence of hospitalization associated with the ILI (≥15 
days after dosing until epidemiological levels of influenza 
are low as defined by the medical director) 
 
Incidence of death due to influenza-like illness (≥15 days 
after dosing until epidemiological levels of influenza are low 
as defined by the medical director) with or without 
confirmation by viral culture and qRT-PCR analysis 
 
To determine the specific influenza strains in confirmed flu 
cases in experimental and control group  
 
 
New wording 
Clinical efficacy 
 
Compare the occurrence of culture confirmed influenza in 
the M-001 experimental group vs. placebo caused by any 
influenza A or B virus in association with a protocol defined 
ILI. 
 
Assess reduction of severity of either qRT-PCR or culture -
confirmed influenza illness by the reduction due to M-001 in 
the average number of days with respiratory or systemic 
symptoms during the first laboratory-confirmed influenza 
illness episode. 
 
To assess proportion of subjects having ILI symptoms in the 
experimental or control group. 
Immunogenicity 
 To assess in at least a subset of samples in season 2 the 
change from baseline in the percentage of CD4+ 

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lymphocytes producing Th1 cytokine (e.g. INF-γ) in 
response to any of the 9 peptides in M-001.  This endpoint 
will be assessed within a randomly selected subset of 
participants from pre-selected sites participating to the 
substudy in Year 2. 
(…) 
3.1.3. Exploratory Objectives  
• 
Incidence of antibiotics use due to post-influenza secondary 
infections of respiratory tract  as evidenced with medical records or 
declared by the participant 
 
• 
Incidence of hospitalization associated with the ILI (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director). 
• 
Incidence of death due to influenza-like illness (≥15 days 
after dosing until epidemiological levels of influenza are low as 
defined by the medical director) with or without confirmation by 
viral culture or qRT-PCR analysis. 
• 
To determine the specific influenza strains in confirmed flu 
cases in experimental and control group 
Decription of changes 
Study outcome measures changed accordingly to reflect changes in 
text defining study endpoints and study objectives as indicated in the  
Summary of Changes above. 
4. 
STUDY 
DESIGN 
 
Original wording: 
Subjects will be assigned randomly to 1 of 2 treatment arms (4815 
per study arm during the study) to receive two doses of the M-001 
vaccine or placebo (saline).  Group A will receive two doses of M-
001, each containing 1 mg of M-001, on Day 0 and 22.  Group B will 
receive saline placebo on the same days.  
(…) 
In cohort 2, immunogenicity testing will be performed and will 
include performing CMI assays on blood samples obtained 
immediately at baseline (Day 0) and on samples collected on Days 37 
from a subset of 275 participants randomly selected from 
experimental group receiving each of the 3 batches used in the trial 
(total of 825). Cell mediated immune responses to influenza antigens, 
including epitopes represented in the M-001 vaccine, will be assessed 
at baseline (Day 0), at 16 days after the second M-001 vaccination 
(Day 37).   
The duration of this trial for each subject will be approximately 8 
months (reflecting time between vaccination and end of the flu 

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season as stated in the protocol) and up to additional 2 years of 
follow up. 
For additional details on study procedures and evaluations and study 
schedule by study visits/days, see Sections 7 and 8 as well as Table  
and Table 3 – Schedule of events.  
 
New wording: 
Subjects will be assigned randomly to 1 of 2 treatment arms (6000 
per study arm during the study) to receive two doses of the M-001 
vaccine or placebo (saline).  Group A will receive two doses of M-
001, each containing 1 mg of M-001, on Day 0 and 22.  Group B will 
receive saline placebo on the same days. 
(…) 
In cohort 2, immunogenicity testing will be performed and will 
include performing CMI assays on blood samples obtained 
immediately at baseline (Day 0) and on samples collected on Visit 3 
(referred to as Day 36, taking place 14±2 days since day of the 
administration of second dose of the vaccine/placebo).  At sites 
participating in the CMI sub-study, data will be obtained from a 
subset of approximately 263 participants randomly selected from the 
experimental group and from a subset of 87 participants randomly 
selected from the placebo group. Cell mediated immune responses to 
influenza antigens, including epitopes represented in the M-001 
vaccine, will be assessed at baseline (Day 0, before vaccination), and 
at 14±2 days since day of the administration of second dose of the 
vaccine/placebo (Day 36).   
The duration of this trial for each subject will be up to 1 year 
(reflecting time between vaccination and end of the flu season as 
stated in the protocol). 
For additional details on study procedures and evaluations and study 
schedule by study visits/days, see Sections 7 and 8 as well as Table 3 
and Table 4 – Schedule of events. 
5. 
STUDY 
ENROLLMENT AND 
WITHDRAWAL 
 
Description of changes 
Inclusion and exclusion criteria updated as indicated above. 
Clarification added to the last Exclusion Criterion: 
(…)  Institutionalized* subjects unable to come to the study site as 
expected by the Protocol. 
*except for institutionalization without subsequent overnight stays 
5.3. 
Treatment 
Assignment Procedures 
 
Original wording 
Once consented and upon entry of demographic data and confirmation 
of eligibility for this trial, the subject will be enrolled. A total of 9,630 

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subjects will be randomly assigned to one of 2 arms: experimental and 
control.   
The investigator will not be provided with randomization codes. The 
codes will be maintained within the IWRS, which has the functionality 
to allow the investigator to break the blind for an individual subject, if 
necessary. 
New wording 
For season 2, the randomization will be further stratified by sub-study 
participation (i.e. Yes or No).  
For the CMI substudy, 350 subjects from sites participating to the sub-
study (sub-study sites) are randomly chosen among 700 sub-study sites 
subjects with appoximately 263 subjects selected at random from 350 
M-001 sub-study sites subjects and approximately 87 from 350 
placebo sub-study sites subjects.  
Once consented and upon entry of demographic data and confirmation 
of eligibility for this trial, the subject will be enrolled. A total of 12,000 
subjects will be randomly assigned to one of 2 arms: experimental and 
control.  A total of 700 subjects will be randomly chosen to participate 
to the sub-study, with approximately 263 subjects selected at random 
from 350 M-001 sub-study sites subjects and approximately 87 from 
350 placebo sub-study sites subjects. 
The investigator will not be provided with randomization codes. The 
codes will be maintained within the IWRS, which has the functionality 
to allow the investigator to break the blind for an individual subject, if 
necessary. 
5.3.2. Masking 
Procedures 
 
Original wording 
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 will be blinded to treatment assignment. 
Separate unblinded laboratory personnel will be assigned if needed. 
(…) 
The site unblinded staff member will be responsible for preparing the 
syringe and covering it or making it (the content) in other way not 
visible for the subject before its administration to keep the subject 
blinded. This un-blinded staff member will not participate in the 
assessment of respiratory illnesses or ILI, or in the collection of 
safety information. 
 
New wording 
Subjects, investigators, and study personnel performing any study-
related assessments following study injection, as well as collecting 

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swab specimends or blood samples, will be blinded to study group 
and treatment assignment to both: M-001 or placebo. Laboratory 
personnel will be blinded to treatment assignment. Separate 
unblinded laboratory personnel will be assigned if needed. 
(…) 
The site unblinded staff member will be responsible for preparing the 
syringe and covering it or making it (the content) in other way not 
visible for the subject before its administration to keep the subject 
blinded. This un-blinded staff member will not participate in the 
assessment of respiratory illnesses or ILI, or in the collection of 
safety information. 
5.3.3. Reasons for 
Withdrawal and 5.3.5 
Termination of Study 
 
Original wording 
Termination of the study 
(…) 
Although the study Sponsor has every intention of completing the 
study, it reserves the right to terminate the study at any time for 
New wording 
• 
Termination of the study or the study cohort. 
(…) 
Although the study Sponsor has every intention of completing the 
study, it reserves the right to terminate the study or the study cohort 
at any time for 
6. 
STUDY 
INTERVENTION/INV
ESTIGATIONAL 
PRODUCT 
 
6.1. 
Study Product 
Description 
To 
6.4. 
Assessment of 
Subject Compliance 
with Study 
Intervention/ 
Investigational Product 
 
Original wording 
Placebo (normal saline) will be sourced from the European Union 
(marketed product). It will be labelled and distributed by Klifo A/S.  
M-001 
M-001 is supplied as a sterile, cloudy-white suspension in single-
dose vials of volume sufficient to dose 1 mg of M-001 (1mg is a 
single dose). 
Each vial contains a fill volume (less than 1 mL) of concentration 
provided in the study manual for respective product batch that should 

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be transferred to a 1mL syringe for injection according to the study 
manual. It contains no preservative (i.e. non-thimerosal). 
Volume of the product containing 1mg of M-001 (1 mg of M-001 is 
the dose to be administered per each vaccination) will be provided in 
the study manual for respective product batch. 
Study product must be stored at 2°C to 8°C. Do not freeze.  
Placebo (Normal Saline) 
0.9% Sodium Chloride, USP, Ph.Eur. 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 will be stored according to storage conditions defined 
in product-specific Summary of Product Characteristics.  
(…) 
M-001 investigational influenza vaccine product: 
The 1 mg of M-001 dose will be administered as a single 
intramuscular injection according to the study manual. The M-001 
will be provided in vials as described in paragraph 6.1.1 of the 
protocol. 
 
Visually inspect M-001 vaccine vial upon receipt and prior to use. 
After shaking, 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 until the suspension 
looks homogeneous, then it should be transferred to a syringe. 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).   
Normal Saline (Placebo): 
The saline placebo dose will be administered as a single 
intramuscular injection. Exact volume to be injected will be defined 
in the study manual and will be equal to the volume of the M-001 
defined for the active treatment (M-001) study arm. 
The saline will be provided in vials as described in paragraph 6.1.1 of 
the protocol. 
(…) 
The syringe containing the dose of study vaccine (or placebo) will be 
inverted a few times before administered 
(…) 

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Aseptic technique will be used for the preparation and administration 
of each dose of study vaccine using a disposable sterile needle 
appropriate in length and size for each subject and a disposable sterile 
1 mL syringe. 
(…) 
If a subject’s study vaccination (study dose 2) is deferred, vaccination 
should be rescheduled to occur within the acceptable protocol-
specified window for that visit (22 + 9 days). 
(…) 
After receipt of the M-001 and placebo vials, the site 
(…) 
Used and unused vials of M-001 
(…) 
Study product will be administered to subjects by a blinded vaccine 
administrator 
New wording 
Placebo (normal saline) will be provided by BiondVax. Packaging, 
labeling and distribution will be performed by Klifo A/S.  
M-001 
In Season 1, M-001 is supplied as a sterile, cloudy-white suspension 
in single-dose vials of volume sufficient to dose 1 mg of M-001 (1mg 
is a single dose). 
Each vial contains a fill volume (less than 1 mL) of concentration 
provided in the study manual for respective product batch that should 
be transferred to a 1mL syringe for injection according to the study 
manual. It contains no preservative (i.e. non-thimerosal). 
Volume of the product containing 1mg of M-001 (1 mg of M-001 is 
the dose to be administered per each vaccination) will be provided in 
the study manual for respective product batch. 
 
In Season 2, M-001 is supplied in single-dose pre-filled syringes 
containing 1mg of M-001. Each syringe contains a fill volume (0.6 
mL) of concentration provided in the study manual for respective 
product batch that should injected according to the study manual. It 
contains no preservative (i.e. non-thimerosal). 
 
Study product must be stored at 2°C to 8°C. Do not freeze.  
Placebo (Normal Saline) 
0.9% Sodium Chloride, USP, Ph.Eur. 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 in single-dose ready to 
use syringes, containing 0.6 mL.  The solution may contain 
hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 

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5.3, range 4.5-7.0). The normal saline will be stored according to 
storage conditions defined in product-specific Summary of Product 
Characteristics. 
(…) 
M-001 investigational influenza vaccine product: 
The 1 mg of M-001 dose will be administered as a single 
intramuscular injection according to the study manual. The M-001 
will be provided in vials (Season 1) or syringes (in Season 2) as 
described in paragraph 6.1.1 of the protocol. 
 
Visually inspect M-001 vaccine vial (Season 1)/ ready to use syringe  
(Season 2) upon receipt and prior to use. After shaking, the 
suspension will be cloudy white in appearance.  For season 2, if the 
M-001 vaccine precipitated, it should be re-suspended by tapping on 
the pre-filled syringe strongly with the finger or by intensive 
shaking 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).   
Normal Saline (Placebo): 
The saline placebo dose will be administered as a single 
intramuscular injection. Exact volume to be injected will be defined 
in the study manual and will be equal to the volume of the M-001 
defined for the active treatment (M-001) study arm. 
The saline will be provided in ready to use syringes as described in 
paragraph 6.1.1 of the protocol. 
(…) 
The syringe containing the dose of study vaccine (or placebo) will be 
inverted a few times, and the air bubble removed before administered 
(…) 
Aseptic technique will be used for the preparation and administration 
of each dose of study vaccine/placebo using a disposable sterile 
needle appropriate in length and size for each subject. 
(…) 
If a subject’s second study vaccination (study dose 2) cannot occur 
on Day 22, vaccination should be rescheduled to occur within the 
expected protocol-specified window for that visit (Day 22 + 9 days), 
if possible. 
(…) 
After receipt of the M-001 and placebo vials or syringes, 
(…) 
Used and unused vials or syringes of M-001 
(…) 

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Study product will be administered to subjects by an unblinded 
vaccine administrator 
6.5. 
Concomitant 
Medications/Treatment
s 
 
Original wording 
Administration of any medications, therapies, or vaccines will be 
recorded on the appropriate data collection form. Concomitant 
medications will include all current medications and medications 
taken within 3 months days prior to Day 0 through approximately 
Day 43. After Day 43 only concomitant medications relevant for 
respiratory illness as per PI judgment, 
(…) 
. Prescription and over-the-counter drugs will be included as well as 
herbals, vitamins and supplements. In addition, information on 
receipt of other influenza or non-influenza study vaccines will be 
solicited at each clinic visit or phone call by PI/SI or delegated study 
site personnel, and, if confirmed, such vaccination will be reported in 
the eCRF. 
(…) 
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 
medications per the Subject Exclusion Criteria (see Section 5.2). 
(…) 
contraceptives are permitted. 
 
New wording 
Administration of any medications, therapies, or vaccines will be 
recorded on the appropriate data collection form. Concomitant 
medications will include at least all current medications and 
medications taken within 3 months prior to Day 0 through 
approximately Day 43 or 21 days after second vaccination day 
whichever occurs later. After Day 43 (or 21 days after V2 day) only 
concomitant medications relevant for background chronic respiratory 
illness as per PI judgment, 
(…) 
Prescription and over-the-counter drugs will be included as well as 
herbals, vitamins and supplements. In addition, information on 
receipt of other influenza or non-influenza study vaccines will be 
solicited at each subject’s visit at the site or phone call by PI/SI or 
delegated study site personnel, and, if confirmed, such vaccination 
will be reported in the eCRF. Past use of influenza vaccinations 
should be recorded for at least 3 years prior to study entry. 
(…) 
Medications that might interfere with the evaluation of the 
investigational product should not be used unless absolutely 

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necessary. However, as the study concerns elderly population use of 
such medications cannot be excluded. Medications in this category 
include the prohibited medications per the Subject Exclusion Criteria 
(see Section 5.2). 
(…) 
contraceptives are permitted. 
Medications which require relatively frequent dose adjustments, like 
insulin, hormones, anti-inflammatory or pain relieve medications, are 
considered as stable treatment for a chronic condition for the purpose 
of Inclusion Criterion number 3 compliance assessment as long as the 
treatment (regular or p.r.n.) has been continued for at least 3 months 
prior to first vaccination. Switch within the same therapeutic class or 
type of treatment is not automatically considered as an unstable 
treatment but is subject to PI’s assessment and decision. 
7. 
STUDY 
SCHEDULE 
 
Original wording 
7. 
STUDY SCHEDULE  
7.1. 
Enrollment/Baseline (Visit 1, Day 0, Dose 1, Clinic Visit)  
• 
(…). 
•.  Subject receipt of licensed seasonal influenza vaccine, and 
approximate date of vaccination will be recorded on the appropriate 
data collection form, if known. 
• 
(…) 
• 
All concomitant medications taken within 3 months prior to 
signing the ICF will be recorded on the appropriate data collection 
form prior to the first study vaccination. 
• 
(…) 
• 
A targeted physical examination may be performed prior to 
the first study vaccination by a study clinician, if indicated based on 
review of complete medical history. 
• 
(…) 
• 
Approximately 40 mL of venous blood will be collected prior 
to the first study vaccination for isolation of PBMCs from a subset 
from Cohort 2 intended for CMI testing. 
• 
(…) 
• 
(…). 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 encouraged to take their temperature 
around the same time each day for 8 days post vaccination (day of the 
vaccination inclusive). 
(…). The participants will be instructed to return the completed diary, 
covering period between Visit 1 and Visit 2 to the site for Visit 2. 
 
7.2. 
Second Vaccination  

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7.2.1. Visit 2, Day 22, Clinic Visit (22 days [+9 days] post first 
study vaccination day) 
• 
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. 
•(…) 
• 
If indicated by review of memory aid, obtain vital signs 
• 
Measure oral temperature. 
• 
A targeted physical examination may be performed by a study 
physician, if indicated based on review of interim medical history. 
• 
(…). 
• 
(…)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 in a stamped 
envelope 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. (…) The participants that are 
required for visit 3 will be notified and will be requested to bring the 
diary on visit 3. 
 
7.2.2. Visit 3, Day 37, Clinic Visit (16 days [±3 days] post second 
study vaccination for subset of subjects from Cohort 2, in season 
2019/20)  
• 
Study personnel will review the memory aid information with 
subjects and assess and record all solicited events / unsolicited 
AEs/SAEs and concomitant medications on the appropriate data 
collection form.  
• 
Counsel women of childbearing potential on contraception 
and avoidance of pregnancy. 
• 
A targeted physical examination and vital signs collection 
may be performed by a study clinician if indicated based on review 
of interim medical history. 
• 
(…) 
• 
Approximately 40 mL of venous blood will be collected for 
isolation of PBMCs from a subset of subjects from Cohort 2. 
 
7.3. 
Follow up period for safety and efficacy:  
Safety surveillance: 
(…) 
Passive efficacy surveillance: Following randomization and 
vaccinations, subjects will be instructed to contact the site if they 
experience symptoms of a respiratory illness during the annual 
surveillance periods, from Day 14 after second vaccination day until 

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15 May of the following year. Another period of follow up will take 
place in the influenza season that follows (total of 2 years follow up). 
Active efficacy surveillance will be performed from November 15th 
until the week of 30 March the following year, the most likely period 
of influenza virus circulation in the Northern Hemisphere. Another 
period of follow up will take place in the influenza season that 
follows (total of 2 years follow up).  
The participants will be contacted by a dedicated study staff twice a 
week between approximately November 15th through March 30th; 
Another period of follow up may take place in the influenza season 
that follows (up to 2 years follow up).  
Participants will be contacted as described above by non-site study 
staff to monitor for influenza-like illness (ILI).; participants identified 
this way as potentially having ILI will be followed up by relevant 
study site personnel to confirm if the participant’s symptoms and 
signs meet study ILI definition. 
During the period from Day 14 after second vaccination day until 30 
April of the following year (or longer if decided by the medical 
director based on actual influenza season duration), the site will 
arrange for an NP/nasal and throat swab to be collected if the subject 
experiences a new onset of the above mentioned symptoms of ILI 
(that persist for or reoccur after a period of at least 12 hours). 
(…)  
 
NP/nasal and throat swab collection: 
NP swab (or nasal and throat swab) specimens will be collected 
during the period from Day 14 after second vaccination until 30 April 
of the following year (or longer if decided by the medical director 
based on actual influenza season duration), within 24 hours from ILI 
being reported to or identified by study personnel and up to 4 days of 
the onset of ILI symptoms for confirmation of influenza virus (…) 
 
The end of influenza season will be defined for each participating 
country by the Medical director based on national surveillance 
and study data. 
The Sponsor's Responsible Medical Director will base the decision 
on the following criteria: 
(…) 
 
If the 2 criteria are met for the region/zone where the research site is 
located, the site will be instructed to continue obtaining NP/nasal and 
throat swabs if subjects report a new respiratory illness. 
 
(…) 
 

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After 30th of April, passive surveillance will continue, with subjects 
expected to call the research site to report the occurrence of any new 
respiratory illness symptoms. 
(…) 
 
ILI follow-up calls:  
Any ILI must be followed up for up to 30 days following the start 
date or until resolved. Site personnel will follow up the participant 
with ILI at 10±3 days after ILI start date. Follow up information on 
symptoms associated with the ILI will be collected by study staff 
through a telephone call performed at 10±3 days (and up to 30 days) 
(unless collected at unscheduled clinic visit at relevant time point) 
following the illness start date.  
 
Laboratory testing for the confirmation of influenza:  
All NP/nasal and throat swab specimens will be submitted for 
analysis by polymerase chain reaction (qRT-PCR), and when the 
result is found positive, another aliquot from such specimen will be 
also examined by culture confirmation test. Typing and subtyping of 
the influenza virus will be performed with PCR based method. 
(…).  
 
7.4. 
Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ 
Electronic Communication (180 days +/-14 post last study 
vaccination)  
Subjects will be contacted by phone or electronic communication 
(e.g., email, text message) to query for safety events.  Subjects will 
be asked to provide positive responses to the follow-up by phone. 
(…) 
7.5. 
Follow Up Period for Efficacy Season 2  
Participants from cohort 1 who did not withdraw during season 1 
(2018-2019) will be followed up for ILI during the subsequent season 
(2019-2020), to define the duration of the protection unless during 
initial call for the season 2 a participant decides not to continue or is 
determined as being not able to comply with the study protocol. 
Passive and active surveillance will take place as detailed for season 
1 (see 7.3).  
Passive surveillance will take place between September 15, 2019 and 
May 15, 2020. 
Active surveillance will take place between November 15, 2019 and 
March 30, 2020. During this period, the dedicated study staff will 
contact the participants twice a week to monitor for ILI symptoms as 
detailed above in 7.3. (Follow up calls in season 2019/20 will be for 
all 9,630 participants).  
(…) 
7.7. 
Early Termination Visit  

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(…) 
• 
If indicated by interim medical history, perform physical 
examination and obtain vital signs including oral temperature. 
Subjects must not eat or drink anything hot or cold, or smoke within 
10 minutes prior to taking oral temperature. 
• 
(…). 
• 
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 last study vaccination day. 
• 
A targeted physical examination may be performed by a study 
clinician licensed to make medical diagnoses, 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, day of the vaccination inclusive ). 
 
7.8. 
Unscheduled Visit  
(…). 
• 
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 day. 
• 
(…). 
• 
If deemed as relevant and/or needed, perform physical 
examination and obtain vital signs including oral temperature. 
Subjects must not eat or drink anything hot or cold, or smoke within 
10 minutes prior to taking oral temperature. 
• 
(…). 
New wording 
7.1. 
Enrollment/Baseline (Visit 1, Day 0, Dose 1, Site Visit)  
• 
(…) 
• 
History of receipt of licensed seasonal influenza vaccine(s) 
from at least last 3 years, and approximate date of vaccination will be 
recorded on the appropriate data collection form, if known. 
• 
(…) 
• 
All concomitant medications taken before signing the ICF (at 
minimum those taken within 3 months prior to it, if applicable) will 
be recorded on the appropriate data collection form prior to the first 
study vaccination. 
• 
(…) 
• 
Standard physical examination (PE) will be performed on day 
0 prior to the first study vaccination. If subject’s medical history is 
known based on medical records (but not if there are no medical 
records available at all), a limited, targeted physical examination may 
be performed instead of standard scope PE prior to the first study 
vaccination by a study clinician, however in any case neurologic 
component of PE and physical examination of head/upper respiratory 
tract must be performed. Except for neurologic, head and upper 

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respiratory tract physical examination, for other body systems only 
findings relevant from the study perspective and not obvious from 
medical history need to recorded in the eCRF 
• 
(…) 
• 
Approximately 40 mL of venous blood will be collected prior 
to the first study vaccination for isolation of PBMCs from a subset 
from Cohort 2 intended for CMI testing (applicable only for selected 
study sites). 
• 
(…) 
• 
In study sites participating in CMI assessment, additional, 
nested randomization is planned to assign certain number of subjects 
to one of the subset substudy groups. 
• 
(…). The study vaccination site will be examined, and 
observed reactions, AEs, SAEs (as applicable) will be assessed and 
recorded on the appropriate data collection form prior to discharge 
from the clinic. 
• 
(…). Subjects will be encouraged to take their temperature on 
the vaccination day in the evening and then at selected approximately 
the same time each day for next 7 days after the vaccination day.  
(…)  
The participants will be instructed to return the completed diary, 
covering period between Visit 1 and Visit 2 to the site for Visit 2, and 
to bring their study thermometer with them to the Visit 2. 
 
7.2. 
Second Vaccination  
7.2.1. Visit 2, Day 22, Site Visit (22 days [+9 days] post first study 
vaccination day) 
• 
Study personnel will review the memory aid information with 
subjects and assess and record all solicited, reported reactions, AEs, 
SAEs (as applicable) and concomitant medications on the appropriate 
data collection form. 
• 
(…) 
• 
If indicated by review of memory aid or recent medical 
history, obtain vital signs 
• 
A targeted physical examination should be performed by a 
study physician if assessed as needed based on medical interview 
concerning period between Visit 1 and Visit 2 . 
• 
(…). 
• 
(…) The study vaccination site for Dose 2 will be examined, 
and any reactions, AEs or SAEs (as applicable) 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 (paper diaries) 
in a stamped envelope to record daily oral temperature, solicited 
injection site and systemic reactions, any unsolicited AEs, and 
concomitant medications. Subjects will be encouraged to take their 

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temperature on the vaccination day in the evening and then at 
selected approximately the same time each day for next 7 days after 
the vaccination day. (…) The participants that are  coming for visit 3 
to the site will be requested to bring the diary to that visit. 
 
7.2.2. Visit 3, Day 36, Site Visit (14 days [±2 days] post second 
study vaccination day(visit 3 - in season 2019/20 only)  
• 
This is a visit in study site for the subset of subjects selected 
for immunogenicity evaluation and site visit or a phone call (if site 
visit is not feasible) for the rest of the participants. The following #4 
and #6 points refer to those actually visiting the clinic: 
• 
Study personnel will review the memory aid information with 
subjects and assess and record all solicited events / unsolicited 
reactions, AEs, SAEs and concomitant medications on the 
appropriate data collection form.  
• 
Counsel women of childbearing potential on contraception 
and avoidance of pregnancy. 
• 
[site visits only] A targeted physical examination and/or vital 
signs collection may be performed by a study clinician if assessed as 
needed based on review of recent medical history. 
• 
(…) 
• 
[site visits only] Approximately 40 mL of venous blood will 
be collected for isolation of PBMCs from a subset of subjects from 
Cohort 2. 
7.3. 
Follow up period for safety and efficacy:  
Safety surveillance: 
(…) 
Passive efficacy surveillance: Following randomization and 
vaccinations, subjects will be instructed to contact the site if they 
experience symptoms of a respiratory illness or influenza-like illness 
during the annual surveillance periods defined as from Day 14 after 
second vaccination day or from September 15 (the later of them) until 
15 May of the following year. 
Active efficacy surveillance will be performed from November 15th 
(in Season 1) or from December 1st (in Season 2) until the week of 
30 March the following year, the most likely period of influenza 
virus circulation in the Northern Hemisphere.  
The participants will be contacted by a dedicated study staff up to 
twice a week between approximately November 15th through March 
31st .  
Participants will be contacted as described above by non-site study 
staff to monitor for influenza-like illness (ILI).; participants identified 
this way as potentially having ILI will be followed up by relevant 
study site personnel to confirm if the participant’s symptoms and 
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ILI is NOT to be understood as condition caused specifically by 
influenza virus. The etiology of ILI may be very different, and only 
after analysis of swabs taken from subjects , the presence or absence 
of influenza virus in swab sample can be determined. Hence, even if 
it is suspected that ILI is caused by e.g. a bacteria, or by some other 
virus than influenza virus, such ILI remains valid reason for swab 
collection, also because in some cases there may be a superinfection 
or parallel infection with influenza virus. 
However, if an Investigator is sure that an ILI-qualifying 
symptom/sign comes purely from underlying chronic condition (e.g. 
arthritis, COPD, asthma), including also the severity of the 
symptoms/signs, or belongs to clinical presentation of another, 
known, completely non-infectious condition (e.g. toxicity, injury, 
cancer), then it is understood that the investigator may decide to NOT 
recognize the case as meeting ILI criteria, and to NOT qualify the 
subject for swab collection. The rationale behind disqualifying such 
cases from ILI is preference for avoidance of exposing subjects to 
swab collection procedure in case when it is absolutely sure a priori 
that infectious etiology of the symptoms/signs is highly unlikely. 
During the period from Day 14 after second vaccination day (not 
earlier than from September 15th) until 30 April of the following year 
(or longer if decided by the medical director based on actual 
influenza season duration), the site will arrange for an NP/nasal and 
throat swab to be collected if the subject experiences a new onset of 
the above mentioned symptoms of ILI (that persist for or reoccur 
after a period of at least 12 hours). 
(…)  
 
NP/nasal and throat swab collection: 
NP swab (or nasal and throat swab) specimens will be collected 
during the period from Day 14 after second vaccination day (but not 
earlier than from September 15th) until 30 April of the following year 
(or longer if decided by the medical director based on actual 
influenza season duration), within 24 hours from ILI being reported 
to or identified by study personnel and up to 4 days of the onset of 
ILI qualifying symptom(s) for confirmation of influenza virus (…) 
 
 
 
 
The end of influenza season will be defined for each participating 
country by the Medical director based on national surveillance 
and study data. 
The Sponsor's Responsible Medical Director will base the decision 
on the following criteria: 
(…)  

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If the 2 criteria are met for the region/zone where the research site is 
located, the site will be instructed to continue obtaining NP/nasal and 
throat swabs if a subject has a new influenza-like illness. 
 
(…) 
 
After 30th of April, passive surveillance will continue, with subjects 
expected to call the research site to report the occurrence of any new 
respiratory illness or influenza-like illness symptoms. 
(…) 
 
ILI follow-up calls:  
Any ILI must be followed up for up to 30 days following the start 
date or until resolved. Site personnel will follow up the participant 
with ILI at 10±3 days after ILI start date. Follow up information on 
symptoms associated with the ILI will be collected by study staff 
through a telephone call performed at 10±3 days (and up to 30 days) 
(unless collected at unscheduled site visit at relevant time point) 
following the illness start date.  
Protocol defined ILI end date is the date when for at least 24 hours 
ILI symptoms are no longer present. Of note, some symptoms may 
persist after ILI for a long time, but the duration of ILI is to be 
determined by presence of symptoms of ILI understood as active 
disease, or “influenza symptom”, contrary to symptoms being part of 
an underlying chronic condition (e.g. COPD, arthritis), and contrary 
to chronic complications and/or sequelae of the ILI. When no clear 
end of ILI can be observed, the PI is requested to make rational 
judgment and determine the ILI end date based on available data and 
his/her experience. It is expected, that normally, ILI should not last 
longer than 2-3 weeks, and in case of suspected  overlapping new 
infection, the two infection episodes should be recognized by PI as 
separate ILI cases.  
 
Laboratory testing for the confirmation of influenza:  
All NP/nasal and throat swab specimens will be submitted for 
analysis by polymerase chain reaction (qRT-PCR), and when the 
result is found positive, and if there is a sufficient content of viruses 
(as determined by Ct value ≤35)” [Ct= cycle threshold] another 
aliquot from such specimen will be also examined by culture 
confirmation test. Typing and subtyping of the influenza virus will be 
performed with PCR based method. 
(…). 
Out of study influenza infection confirmation: in cases when no swab 
collection was performed within study framework, but valid, relevant 
external medical documentation exists confirming recent or ongoing 

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influenza infection (laboratory confirmation – PCR, culture or 
serology - IgM antibodies), such medical documentation will be 
subject to sponsor’s approval as surrogate proofs of influenza 
infection, and if approved as valid, may be taken into account for 
exploratory analyzes. Details of exploratory analyzes will be defined 
in statistical analysis plan. 
 
 
7.4. 
Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ 
Electronic Communication (180 days +/-14 post last study 
vaccination)  
Subjects will be contacted by phone or electronic communication 
(e.g., email, text message) to query for safety events.  In case follow-
up contact is needed based on the responses, subjects will be asked to 
provide further details to the follow-up by phone.  
(…) 
7.5. 
Follow Up Period for Efficacy Season 2  
Passive surveillance will take place between September 15, 2019 and 
May 15, 2020. 
Active surveillance for cohort 2 will take place between December 
1st , 2019 and March 31, 2020. During this period, the dedicated 
study staff will contact the participants up to twice a week to monitor 
for ILI symptoms as detailed above in 7.3. (Follow up calls in season 
2019/20 will be for participants in cohort 2 only).  
As of the end of the season 1, the follow up for Cohort 1 subjects in 
season 2019/2020 is not planned and participation of all Cohort 1 
subjects will be assumed as completed with the end of Season 1, i.e. 
the latest on May 15th except for cases defined elsewhere (e.g. 
ongoing ILI, SAE follow-up). 
(…) 
7.7. 
Early Termination Visit  
(…) 
• 
If indicated by medical history, perform physical examination 
and/or obtain vital signs including oral temperature. Subjects must 
not eat or drink anything hot or cold, or smoke within 10 minutes 
prior to taking oral temperature. 
• 
(…). 
• 
Information regarding reactions recorded in diary/-ies, AEs 
and SAEs will be recorded on the appropriate data collection form. 
Recording of AEs in the EDC will be limited to SAEs if after 21 days 
following the last study vaccination day. 
• 
Examine study vaccination site, and perform post- 
administration reactogenicity assessment (if within 8  days after the 
last study vaccination, day of the vaccination inclusive ). 
 
7.8. 
Unscheduled Visit  

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(…) 
• 
All reactions recorded in diary/-ies, AEs, SAEs will be 
recorded on the appropriate data collection form.  Recording of AEs 
in the EDC will be limited to SAEs if after 21 days after the last 
study vaccination day. 
• 
(…). 
• 
If deemed as relevant and/or needed, perform physical 
examination and/or obtain vital signs including oral temperature. 
Subjects must not eat or drink anything hot or cold, or smoke within 
10 minutes prior to taking oral temperature. 
• 
(…). 
8. 
STUDY 
PROCEDURES/EVAL
UATIONS 
 
Original wording 
8.1. 
Clinical Evaluations 
(…). 
Concomitant Medications: All current medications and medications 
taken within 3 months before Study Day 0 (prescription and over-the-
counter drugs) will be included, as well as vitamins and supplements, 
through 21 days after the last study injection day 
Vital signs: blood pressure, oral temperature and pulse will be 
collected at study visit 1,on early termination visit and as needed at 
the other study visits. Only oral temperature will be measured on visit 
2. 
Height, weight: These parameters will be measured at Day 0 (Visit 
1). 
Targeted Physical Examination: This may be conducted at any study 
visit based on indicated symptoms.  
(…) 
Subject memory aids will be reviewed with the subject for AEs at the 
clinic visit following the first study injection.  (…).  
 
8.2. 
Laboratory Evaluations 
Schedules and volumes of clinical laboratory tests and 
immunogenicity assays are specified in Schedule of events (Table 2). 
  
(…). 
Refer to the relevant instruction included in the relevant study 
manual for further details. 
Detailed instructions for the preparation of NP (or combination of 
nasal and throat swabs) samples are contained in the relevant study 
manual provided to the sites and relevant study personnel. 
 
8.2.3. Special Assays or Procedures  
Cellular (CMI) Studies  

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Assays to measure T cell responses will be performed by a qualified 
laboratory.  Venous blood samples for isolation of PBMCs will be 
collected from a subset of cohort 2, immediately prior to the first 
study vaccination (Day 0, visit 1 in season 2), and 16 days (day of the 
vaccination inclusive) after the second M-001 vaccination (Day 37, 
visit 3, season 2). 
 
8.2.4. Specimen Preparation, Handling, and Shipping  
(…). 
Swab samples will be shipped on ongoing basis or in batches shipped 
regularly (at least once a month) during the course of this study. 
(…) 
Samples for PBMC will be shipped from sites on ongoing basis 
aiming at same day or next day delivery. 
New wording 
8.1. 
Clinical Evaluations 
(…). 
Concomitant Medications: All current medications and medications 
taken within 3 months before Study Day 0 (prescription and over-the-
counter drugs) will be included, as well as vitamins and supplements, 
through 21 days after the last study injection day, unless relevant for 
chronic background respiratory illness, as per PI judgment, or related 
to AE or ILI. 
Vital signs: blood pressure, oral temperature and pulse will be 
collected at study visit 1, and as needed at any other study visits Only 
oral temperature is required to be measured on visit 2. Measurement 
of oral temperature should be performed with thermometers provided 
by the study Sponsor. Oral temperature should be measured by 
keeping the tip of the thermometer under the tongue for sufficient 
amount of time until the temperature reading stabilizes. In cases 
when level of oral temperature seems too low the measurement 
should be repeated and care should be taken to correctly place the tip 
of the thermometer and to keep it under the tongue for sufficient 
amount of time (until the temperature stops growing). 
Height, weight: These parameters will be measured at Day 0 (Visit 
1). 
Physical Examination: On Visit 1 standard physical examination 
should be performed prior to the first study vaccination, but if 
subject’s medical history is known based on medical records, a 
limited, targeted physical examination may be performed instead of 
standard scope PE prior to the first study vaccination by a study 
clinician,  however in any case neurologic component of PE and 
physical examination of head/upper respiratory tract must be 
performed. On visits other than 1 limited, targeted physical 
examination may be performed if assessed by investigator as needed.  
(…) 

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Subject memory aids will be reviewed with the subject for AEs at the 
site visit following the first study injection, and over the phone after 
the second study injection (unless the subject comes to the site for 
Visit 3). (…).  
 
8.2. 
Laboratory Evaluations 
Schedules and volumes of clinical laboratory tests and 
immunogenicity assays are specified in Schedule of events (Table 3 
and 4 in the Synopsis).  
 
(…). 
Detailed instructions for the preparation of NP (or combination of 
nasal and throat swabs) samples are contained in the relevant study 
manual provided to the sites and relevant study personnel. 
 
8.2.3. Special Assays or Procedures  
Cellular (CMI) Studies  
Assays to measure T cell responses will be performed by a qualified 
laboratory.  Venous blood samples for isolation of PBMCs will be 
collected from a subset of cohort 2, immediately prior to the first 
study vaccination (Day 0, visit 1 in season 2), and approximately 15 
days (day of the vaccination inclusive) after the second M-001 
vaccination (Day 36, visit 3, season 2). 
 
8.2.4. Specimen Preparation, Handling, and Shipping  
 
(…. 
Swab samples will be shipped in batches regularly during the course 
of this study. 
(…). 
Samples for PBMC will be shipped from sites on ongoing basis 
aiming at same day or next day delivery, as possible. 
9. 
ASSESSMENT 
OF SAFETY 
 
Original wording 
Unsolicited AEs/SAEs – non-serious AEs/SAEs occurring from the 
time of the study vaccination through approximately 22 days after the 
study vaccination (day of the vaccination inclusive) 
(…) 
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 within study 
periods as described below. 

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Unsolicited AEs will be collected occurring from the time of the 
study vaccination through approximately 22 days after the study 
vaccination (day of the study vaccination inclusive). 
(…) 
Tables numbered 4,5,6,7 
(…) 
inpatient hospitalization or prolongation of existing hospitalization 
(excluding pre-planned elective surgeries or other pre-planned 
hospitalizations), 
(…) 
ILI as AE will be documented if occur within 8 days post vaccination 
(day of the vaccination inclusive). 
(…) 
9.6. 
Efficacy Assessment  
9.6.1. Molecular Detection and Sequencing Methodology (qRT-
PCR): 
(…). 
For samples that are found positive for influenza in the qRT-PCR 
assay, further testing 
by culture confirmation will be performed.  
9.6.2. Influenza Culture and Virus Isolation: 
. 
 
New wording 
Unsolicited AEs/SAEs – unsolicited AEs/SAEs occurring from the 
time of the study vaccination through approximately 22 days after 
each study vaccination (day of the vaccination inclusive)  
(…) 
AEs must be graded for severity and assessed for relationship to 
study product (see definitions below). AEs characterized as 
intermittent require documentation in the subject’s file of onset and 
duration of each episode. It is up to PI’s decision whether the 
episodes are recorded in the eCRF as separate events or under one 
event with comment added on the intermittent (or similar) nature of 
the event. The start and stop date of each reported AE will be 
recorded on the appropriate data collection form and eCRF within 
study periods as described below. 
•Unsolicited AEs – which do not meet SAE criteria, nor ILI, AESI or 
NOCI definition should be reported only until ~22 days post each 
study vaccination, thus - per protocol – such AEs, if they occurred 
later then 22 days post study vaccination day, should not be recorded 
in the AE section of the eCRF. They still need to be documented in 
the subject’s study file at the site. 
(…) 

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Desription of changes: Tables numbered 4,5,6,7 re-numbered as 
5,6,7,8 respectively 
(…) 
inpatient hospitalization or prolongation of existing hospitalization 
(excluding pre-planned elective surgeries or other pre-planned 
hospitalizations; for this option it is not required that they were pre-
planned solely before Visit 1, they might be pre-planned also after 
Visit 1), 
(…) 
ILI will be documented as AE if occurs within 8 days post 
vaccination (day of the vaccination inclusive). 
(…) 
9.6. 
Efficacy Assessment  
9.6.1. Molecular Detection and Sequencing Methodology (qRT-
PCR): 
(…) 
For samples that are found positive for influenza in the qRT-PCR 
assay, further testing 
by culture confirmation will be performed if there is a sufficient 
content of viruses (as determined by Ct value <35)” [Ct= cycle 
threshold].  
 
If swab specimen was not collected but infection with influenza virus 
has been confirmed outside of the study framework and valid medical 
documentation exists confirming such virus identification (e.g. 
hospital discharge), such cases may be recognized by study sponsor 
as valid confirmed influenza cases. Extent to which such results will 
be included in the statistical analyses will be defined in statistical 
analysis plan. 
9.6.2. Influenza Culture: 
 
11. 
STATISTICAL 
CONSIDERATIONS 
 
Original wording 
This section provides an overview of the statistical considerations for 
the design, conduct, and analysis of the phase 3 trial of Multimeric-
001 influenza vaccine. A formal statistical analysis plan will be 
developed and finalized prior to or shortly after enrollment starts in 
Year 1. 
11.1 Study Hypotheses  
(…). 
11.3 Sample Size Considerations 
11.3.1 Study Design  
(…) 

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All doses will be administered IM approximately 21 days apart. All 
subjects from cohort 1 will be followed for up to two consecutive 
influenza seasons with no obligation to continue in season 3 if the 
study is extended to third season with protocol amendment.  
(…)  
A lots consistency study is nested within the second year of the trial. 
In Year 1, a single lot of vaccine produced by Cytovance will be 
used. In Year 2, the lot produced by Cytovance as well as 2 lots 
produced by BiondVax in Israel will be employed. Thus, subjects 
randomized to vaccine in Year 2 will be further randomized 1:1:1 to 
one of the three lots of vaccines. 
A random sample of subjects enrolled in Year 2 will be selected to 
provide blood samples for the lots consistency study. For each 
vaccine lot, 275 (34.4%) of the roughly 800 subjects randomized to 
that lot will be selected. In order to maintain the study blind, 100 
(4.2%) of the roughly 2,400 subjects randomized to placebo will be 
selected and bled as well. For these 925 subjects, blood samples will 
be collected prior to the first study vaccination (Day 0) and 
approximately 16 days (day of the vaccination inclusive) after the 
second vaccination (Day 37). However, T cell responses will be 
measured only in subjects who receive M-001. 
11.3.2 Study Population and Sample Size 
The study population for this clinical trial includes 9,630 males and 
non-pregnant females, ≥50 years old, inclusive, who meet all 
eligibility criteria.  The participants will be recruited from the general 
population. At least half of the participants will be ≥65 years old. 
The study sample size of 9,630 subjects is based on the lower bound 
of the two-sided 95% confidence interval for vaccine efficacy (VE) 
being above 40% with 80% probability when true VE is 62%. It 
assumes 1:1 randomization, a 3% attack rate in the study population, 
and no more than 10% of subjects lost to follow-up or excluded from 
the per protocol population. Under these assumptions, 182 first 
episodes of qRT-PCR -confirmed influenza of any strain occurring at 
least 15 days after the second dose of study vaccine or control and 
prior to the end of the first influenza season will be needed to 
demonstrate efficacy is at least 40%.  
In the event vaccine efficacy for a single influenza season is 
demonstrated, a lot consistency analysis will be performed at the end 
of Year 2. The endpoint for assessing lot consistency will be the 
percentage of CD4+ lymphocytes producing INF-g in response to any 

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of the 9 peptides in M-001 measured at Day 37. Based on preliminary 
immunogenicity data, the percentage of CD4+ lymphocytes is 
approximately normally distributed with a mean of 25% and standard 
deviation of 12%. Assuming an equivalence margin of 5%, 250 
subjects per lot would need to be enrolled to have 90% probability 
that the 95% confidence interval for the difference in mean 
percentage for each of 3 pair-wise comparisons falls between -5% 
and 5% when there is no true difference. Assuming no more than 
10% of samples is missing or not evaluable, 275 subjects per lot will 
be targeted. 
11.3.3 Subject Enrollment and Follow-up 
(…). 
11.4.1 Interim Safety Review  
A DSMB will be convened by the sponsor to review study progress 
and participant, clinical, safety, reactogenicity, and efficacy data as 
described in section 9.5. Once the last subject in Year 1 completes 
the visit that occurs approximately at Day 202, the interim clinical 
database will be cleaned, monitored and locked. The first unblinded 
interim report will be issued to the DSMB at the end of the first 
influenza season of the trial approximately in June 2019). Based on 
the interim safety data, the DSMB may recommend continuing the 
study as planned, stopping the study for safety concerns, or 
modifying the study to ensure study objectives are followed.  
11.4.2 Interim Efficacy Review 
There are no plans to stop the trial for futility or for efficacy at the 
end of Year 1. However if after the first flu season the total number 
of per protocol cases of confirmed influenza infection is substantially 
fewer than 82 cases, the DSMB may recommend increasing the 
sample size for Year 2. The sample size re-estimation plan will be 
detailed in the DSMB charter. (…).  
11.5 Final Analysis Plan 
At the end of Year 2 a clinical study report (CSR) will be prepared 
summarizing the efficacy, safety, reactogenicity, and immunogenicity 
data. The clinical database will be cleaned, monitored, and locked 
prior to analysis.   
A formal statistical analysis plan will be developed and finalized 
prior to start of the study. Any post hoc analyses will be documented 
and clearly indicated in the CSR. 

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11.5.1 Analysis Populations 
(…). 
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 study vaccination not received 
 Second study vaccination received out of window 
 Receipt of non-study licensed live vaccine within 30 
days before or anytime after each study vaccination 
 Receipt of non-study licensed inactivated vaccine 
within 21 days before or anytime after each study 
vaccination day 
 Receipt of non-study influenza vaccine (live or 
inactivated) within 30 days before or anytime after each 
study vaccination 
 Receipt 
of 
immunosuppressive 
therapy 
(e.g., 
corticosteroids) within 30 days before or after each 
study vaccination  
Data from any visit that occurs substantially out of window. 
11.5.2 Analysis of Safety Data 
(…). 
Additionally, solicited events 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 events 
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 

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different study vaccinations (e.g., dose 1 vs. dose 2) will be compared 
using McNemar’s test. 
(…) 
11.5.3 Analysis of Efficacy Data  
For the primary analysis of vaccine efficacy (VE), the efficacy of M-
(…). 
To assess the ability of M-001 to prevent culture or PCR confirmed 
influenza in association with an ILI during a second influenza season 
without revaccination, we will extend the follow-up time for a first 
episode to include a second influenza season. Average vaccine 
efficacy over two seasons will be calculated as 
𝑉𝐸[(0,2)] = 1 −[(𝐶𝑉
∗/ 𝑁𝑉) /(𝐶𝑃
∗/𝑁𝑃)] 
where C*V and C*P are the number of first episodes of influenza 
during 2 years of follow-up meeting the primary case definition in the 
vaccine and placebo group, respectively, and NV and NP are the 
number of per protocol subjects in the vaccine and placebo group, 
respectively. VE(2) assumes loss to follow-up is similar between the 
vaccine and placebo groups. It also assumes subjects will not receive 
a licensed influenza vaccine prior to or during the second season. If 
either assumption is violated, a Cox regression analysis of time to 
first episode over 2 years of follow-up will be performed. In addition 
to an indicator variable for randomization to the vaccine group (Z1), 
the model will include a time dependent variable Z2 that indicates the 
subject is in the vaccine group and under follow-up for a second 
season. Subjects who are known to receive a licensed influenza 
vaccine will be censored at the time of this vaccination. To test 
whether vaccine efficacy is different in the second season, we test 
whether the coefficient associated with Z2 is equal to zero. For the 
Cox model, vaccine efficacy for a first season is estimated by  
𝑉𝐸[(0,1)] = 1 −exp {−𝛽1} 
while vaccine efficacy over the second season is estimated by 
𝑉𝐸[(1,2)] =  1 −exp{−𝛽1 −𝛽2}. 
11.5.4 Analysis of Cell Mediated Immunity Data 

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For each pair of vaccine lots, the pairwise difference in the average 
percentage of CD4+ lymphocytes producing INF-γ in response to any 
of the 9 peptides in M-001 measured at Day 37 and its two-sided 
95% confidence interval will be calculated. The un-pooled estimate 
of the variance of the difference will be used in the construction of 
the confidence intervals. Subjects with missing Day 37 data will be 
excluded. If all three confidence intervals fall within -5% and 5%, lot 
consistency will be demonstrated. 
In the event more than 10% of samples is missing or not evaluable, a 
sensitivity analysis will be performed in which multiple imputation is 
employed to impute missing Day 37 percentage of CD4+ cells. 
Details of the imputation procedure will be described in the statistical 
analysis plan. 
Please see the separate document “Statistical Analysis Plan” for 
additional information. 
11.5.5 Missing Values and Outliers 
(…) 
11.5.6 Statistical Software 
 
New wording 
This section provides an overview of the statistical considerations for 
the design, conduct, and analysis of the phase 3 trial of Multimeric-
001 influenza vaccine. A formal statistical analysis plan will be  
developed and finalized prior to first DSMB meeting for Year 1 
cohort and will be amended to reflect changes made to previous 
version of the protocol. 
11.1 Study Hypotheses  
(…). 
11.3 Sample Size Considerations 
11.3.1 Study Design  
(…) 
 For season 2, stratification will also be performed for participation to 
the sub-study. All doses will be administered IM approximately 21 
days apart (recommended window is 21-30 days). All subjects from 
cohort 1 will be followed for up to two consecutive influenza seasons 
with no obligation to continue in season 3 if the study is extended to 
third season with protocol amendment. It is not planned to extend the 
participation of the cohort 1 subjects beyond season 1.  

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(…).  
A total of up to 10 sites will be selected to participate to the CMI 
substudy. Blood samples will be collected prior to the first study 
vaccination (Day 0) and approximately 15 days (day of the 
vaccination inclusive) after the second vaccination (Day 36, 14±2 
days since day of the second vaccination) in 350 randomly chosen 
subset of subjects from these sites.  M-001 subjects will be 3 times 
more likely to be selected in the subset than placebo subjects and T 
cell responses will be measured only in subjects who receive M-001. 
11.3.2 Study Population and Sample Size 
The study population for this clinical trial includes 12,000 males and 
non-pregnant females, ≥50 years old, inclusive, who meet all 
eligibility criteria.  The participants will be recruited from the general 
population. At least half of the participants will be ≥65 years old. 
The study sample size of 12,000 subjects is based on the lower bound 
of the two-sided 95% confidence interval for vaccine efficacy (VE) 
being above 40% with 80% probability when true VE is 62%. It 
assumes 1:1 randomization, a 2.41% attack rate in the study 
population, and no more than 10% of subjects lost to follow-up or 
excluded from the per protocol population. Under these assumptions, 
182 first episodes of qRT-PCR -confirmed influenza of any strain 
occurring at least 15 days after the second dose of study vaccine or 
control and prior to the end of the first influenza season will be 
needed to demonstrate efficacy is at least 40%.  
A total of up to 10 sites will be selected to participate to the CMI 
substudy. A total of 350 subjects will be randomly chosen among 700 
subjects from the selected sites: approximately 263 subjects selected 
at random from 350 M-001 subjects and approximately 87 from 350 
placebo subjects; placebo subjects being selected to maintain the study 
blind. Assuming that among the 263 M-001 selected subjects, 210 will 
have valid measurement for the change from baseline in percentage of 
CD4+ lymphocytes producing Th1 cytokine (e.g. INF-γ) in response 
to any of the 9 peptides in M-001, then this endpoint can be estimated 
with a precision of at most 2% (1/2 width of the 95% CI).  
11.3.3 Subject Enrollment and Follow-up 
(…) 
11.4.1 Interim Safety Review  
A DSMB will be convened by the sponsor to review study progress 
and participant, clinical, safety, reactogenicity, and efficacy data as 

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described in section 9.5. Once the last subject in Year 1 completes 
the visit that occurs approximately at Day 202, the clinical database 
will be cleaned, monitored and analyzed in blinded manner. The first 
partly unblinded report will be issued to the DSMB at the end of the 
first influenza season of the trial approximately in June 2019, though 
some data may be requested by DSMB to be provided to them earlier. 
Based on the interim review of safety data, the DSMB may 
recommend continuing the study as planned, stopping the study for 
safety concerns, or modifying the study to ensure study objectives are 
followed.  
11.4.2 Interim Efficacy Review 
There are no plans to stop the trial for futility or for efficacy at the 
end of Year 1. However if after the first flu season the total number 
of per protocol cases of confirmed influenza infection is substantially 
fewer than  there may be a decision made by the Sponsor about 
increasing the sample size for Year 2.  
11.5 Final Analysis Plan 
At the end of Year 2 a clinical study report (CSR) will be prepared 
(unless the study is decided to be continued for Year 3) summarizing 
the efficacy, safety, reactogenicity, and immunogenicity data. The 
clinical database will be cleaned, monitored, and locked prior to 
analysis.   
A formal statistical analysis plan for the efficacy and immunogenicity 
data will be developed and finalized prior to start of the study. Any 
changes to the plan including post hoc analyses will be documented 
and clearly indicated in the CSR. 
11.5.1 Analysis Populations 
(…). 
The per protocol (PP) population includes all subjects in the ITT 
subset satisfying the following criteria: 
 Subject met all protocol-specified inclusion criteria and 
met no exclusion criterion, 
 Subject received both doses of M-001/placebo as 
randomized, in the protocol-specified time frame, and at 
the intended dose level, 
 Subject did not receive M-001/placebo that was not 
properly handled or was otherwise not acceptable for 
administration, 

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 Subject had at least one successful surveillance contact 15 
days or more after the second dose of M-001/placebo, or 
attended at least one ILI visit due to ILI symptoms 
 Subject did not receive a seasonal influenza vaccine 
between randomization and end of the surveillance period 
for Season 1, 
 Subject did not receive a licensed live vaccine within 30 
days of any dose of M-001/placebo, and 
 Subject did not receive a licensed non-live vaccine within 
21 days of any dose of M-001/placebo. 
 
11.5.2 Analysis of Safety Data 
(…) 
Additionally, solicited events will be analyzed by taking the most 
severe response over the follow-up period 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 events 
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) will be compared 
using McNemar’s test. 
(…) 
11.5.3 Analysis of Efficacy Data  
Primary Efficacy Assessment 
For the primary analysis of vaccine efficacy (VE), the efficacy of M-
(…). 
 
Secondary Efficacy Assessments 
The first secondary efficacy assessment will be analyzed using the 
same methodology than the one used for the primary endpoint 
(including the supportive and sensitivity analyses). Notice that samples 
with Ct ≤35 only will be grown for culture. 

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The second secondary efficacy assessment consisting in the between-
group difference in average number of days with respiratory or 
systemic symptoms among subjects with laboratory-confirmed 
influenza illness will be tested in an ANOVA model with vaccine 
group, age category, and season/cohort as main factors.   
The risk ratio for the total number of ILI events during the flu season 
will be compared between the vaccine groups using an overdispersed 
Poisson model with offset being the duration of follow-up in days and 
factors for vaccine group, age category and season/cohort.   
 
All secondary efficacy assessments will be performed on the ITT and 
PP sets. 
Exploratory efficacy assessments: 
For both vaccine groups, the following proportions will be estimated 
with an exact 95% CI within the PP set  
 
Proportions of subjects taking antibiotics due to a post-
influenza (laboratory confirmed) respiratory tract infection 
 
Proportions of subjects who died due to influenza-like 
illness with or without confirmation by viral culture and 
qRT-PCR analysis due to vaccination with M-001 
Between-groups comparisons will be performed using Fisher’s exact 
test. 
For both vaccine groups, the following rates will be estimated on the 
PP set using a 95% CI based on a Poisson model on the number of 
events with duration of follow-up (in days) as offset  
 
 Rate of hospitalizations associated with ILI episodes over 
the flu season  
 
Comparisons between the 2 groups will be performed on the basis of 
an overdispersed Poisson model with group as factor and duration of 
follow-up (in days) as offset. Incidence rate ratios between the 2 
groups will be estimated and their 95% CI provided.  Because it is 
expected that very few hospitalizations cases will occur, no additional 
factor will be included in the Poisson model. 
Descriptive statistics for the specific influenza strains in confirmed flu 
cases in experimental and control groups will also be provided. 

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In addition, the following descriptive statistics will be provided to 
describe the ILI episodes: 
 For the PP set, the distribution of influenza confirmed episodes  
 For the PP set, the distribution of influenza confirmed episodes 
by severity. 
 
Exploratory CMI assessment in substudy: 
A subset of patients will be be enrolled in Season 2 to assess 
immunogenicity:  the average percentage of CD4+ lymphocytes 
producing Th1 cytokine (e.g. INF-γ) in response to any of the 9 
peptides in M-001 measured at Day 36 (14±2 days since day of the 
second vaccination) and its two-sided 95% confidence interval will be 
calculated. Additional exploratory  analyses to be performed on the 
immunogenicity data from these subjects will be detailed in a separate 
SAP for immunogenicity. 
 
11.5.4 Missing Values and Outliers 
(…)  
11.5.5 Statistical Software 
 
14.4. Exclusion of 
Women, Minorities, 
and Children (Special 
Populations) 
 
Original wording 
. 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. 
Males whose female partner has childbearing potential, if not after 
vasectomy, must use condoms   throughout the study treatment and 
for at least up to day 111 of the trial 90 days after the last dose of the 
IMP. 
 
New wording 
. 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. 

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In selected, individual cases, PI, where justified, may accept 
complete abstinence from sexual activity in women not having male 
partner as basis for considering such female subject as of no 
childbearing potential. Rationale for such decision must be available 
and documented. 
Males whose female partner has childbearing potential, if not after 
vasectomy, must use condoms  throughout the study treatment and 
for at least up to day 111 of the trial 90 days after the last dose of the 
IMP. 
15.4. Timing/Reports 
 
Original wording 
The primary clinical study report (CSR) will include clinical, safety, 
reactogenicity, efficacy and cellular immunogenicity data through the 
end of the last follow up period. At this time, the clinical database 
will be cleaned, monitored and locked.  Unblinded analyses of safety, 
reactogenicity, and available PBMCs, including all primary and 
secondary endpoint data will be performed after the clinical database 
is locked. The CSR will be completed when all efficacy data for day 
202 and for the follow up period of season 2 are available. 
New wording 
The primary clinical study report (CSR) will include clinical, safety, 
reactogenicity, efficacy and possibly, cellular immunogenicity data 
through the end of the last follow up period. At this time, the clinical 
database will be cleaned, monitored and locked. Unblinded analyses 
of safety, reactogenicity, and available PBMCs, including all primary 
and secondary endpoint data will be performed after the clinical 
database is locked. The CSR will be completed when all efficacy data 
are available. 
15.6. Protocol 
Deviations 
 
Original wording 
It is the responsibility of the site to use continuous vigilance to 
identify and report deviations within 5 working days of identification 
of the protocol deviation, or within 5 working days of the scheduled 
protocol-required activity.  All deviations must be promptly reported 
to the sponsor.  
New wording 
Sites are expected to maintain vigilance to identify deviations from 
the Protocol and address them as soon as possible including reporting 
of suspected major protocol deviations within 5 working days of its 
identification, or for deviations related to study schedule - within 5 
working days of the scheduled protocol-required activity.  Suspected 
major protocol  deviations must be reported to the sponsor directly or 
to the sponsor’s contracted representative (e.g. clinical research 
monitor or medical monitor). 
 

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List of changes of study protocol version 5.0 vs. study protocol version 
4.0 dated 27Mar2019 
 
Description  
Wording 
Version and Date of the 
protocol 
 
Original Wording 
Version 4.0 final dated 27th March 2019 
New Wording 
Version 5.0 final dated 08th May2019 
INVESTIGATOR’S 
COMPLIANCE 
DECLARATION 
 
Original Wording 
Protocol:  BVX-010, version 4.0 dated 27th March 2019… 
New Wording 
Protocol:  BVX-010, version 5.0 dated 08th May 2019… 
PROTOCOL 
SYNOPSIS PBMC 
(CMI) sub-study 
 
Original Wording 
Approximately two hundred sixty two (263) will be selected…. 
New Wording 
Approximately two hundred sixty three (263) will be selected…. 
PROTOCOL 
SYNOPSIS PBMC  
Primary endpoint 
 
Original Wording 
To assess M-001 Safety by occurrence of unsolicited AEs from 
the time of first study vaccination through 22 days after M-001 
study vaccination (day of the vaccination inclusive). 
New Wording 
To assess M-001 Safety by occurrence of unsolicited AEs from 
the time of first study vaccination through 22 days after each 
study vaccination (day of the vaccination inclusive). 
Table 3:  Schedule of 
Events (Season 1, 
2018/2019 for Cohort 1) 
 
Original Wording 
Study Day…202 
New Wording 
Study Day…202 (180 days after last vaccination day) 
Table 4:  Schedule of 
Events (Season 2, 
2019/2020 for Cohort 2) 
 
Original Wording 
Study Day…202 
New Wording 
Study Day…202 (180 days after last vaccination day) 

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Original Wording 
Passive Surveillance: Subjects will be instructed to contact the 
study site if they experience symptoms of influenza-like illness 
from Day 14 post-second vaccination day but not earlier than 
from September 15th until 15 May the following year 
… 
From Day 14 post second vaccination day, but not earlier than 
from September 15th until 30 April of the following year. 
… 
Swabs collection period starting on September 15, 2019. 
New Wording 
Passive Surveillance: Subjects will be instructed to contact the 
study site if they experience symptoms of influenza-like illness 
from Day 14 post-second vaccination day until 15 May the 
following year 
… 
From Day 14 post second vaccination day, until 30 April of the 
following year.  
… 
  
Original Wording 
# Occurrence of unsolicited AEs will be analyzed from the time of 
first study vaccination through 22 days after M-001 study 
vaccination (day of the vaccination inclusive). 
New Wording 
# Occurrence of unsolicited AEs will be analyzed from the time of 
first study vaccination through 22 days after each study 
vaccination (day of the vaccination inclusive). 
Section 3.1.1 Primary 
Objectives 
 
Original Wording 
To assess M-001 safety by occurrence of unsolicited AEs from the 
time of first study vaccination through 22 days after M-001 study 
vaccination (day of the vaccination inclusive). 
New Wording 
To assess M-001 safety by occurrence of unsolicited AEs from the 
time of first study vaccination through 22 days after each study 
vaccination (day of the vaccination inclusive). 
Section 3.2.1 Primary 
Outcome Measures 
 
Original Wording 
 
Occurrence of solicited injection site and systemic 
reactogenicity events on the day of each study vaccination 
through 8 days after M-001 study vaccination (day of the 
vaccination inclusive) 
 
Occurrence of unsolicited AEs from the time of first study 
vaccination through 22 days after M-001 study vaccination 
(day of the vaccination inclusive) 
New Wording 
 
Occurrence of solicited injection site and systemic 
reactogenicity events on the day of each study vaccination 

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through 8 days after each study vaccination (day of the 
vaccination inclusive) 
• Occurrence of unsolicited AEs from the time of first study 
vaccination through 22 days after each study vaccination 
(day of the vaccination inclusive)  
Section 4.  Study Design 
 
Original Wording 
Unsolicited non-serious AEs collected from the time of each study 
vaccination through approximately 22 days after M-001 study 
vaccination (day of the vaccination inclusive) will be analyzed 
separately. 
New Wording 
Unsolicited non-serious AEs collected from the time of each study 
vaccination through approximately 22 days after each study 
vaccination (day of the vaccination inclusive) will be analyzed 
separately. 
Section 6.5 Concomitant 
Medications/Treatments 
 
Original Wording 
Concomitant medications will include at least all current 
medications and medications taken within 3 months prior to Day 0 
through approximately Day 43 or 21 days after second vaccination 
day whichever occurs later. After Day 43, only concomitant 
medications relevant for background chronic respiratory illness as 
per PI judgment, or related to AE or ILI, will be recorded. 
Subjects who do not receive both M-001 study vaccinations will 
have all concomitant medications collected through approximately 
22 days after the first study vaccination, day of the vaccination 
inclusive, or early termination, whichever occurs first. 
New Wording 
Records of concomitant medications will include at least all 
current medications and medications taken within 3 months prior 
to Day 0 through 21 days after last vaccination day. After this 
period, only concomitant medications relevant for background 
chronic respiratory illness as per PI judgment, or related to AE or 
ILI, will be recorded. Subjects who do not receive both M-
001/placebo study vaccinations will have all concomitant 
medications collected through approximately 22 days after the 
first study vaccination, day of the vaccination inclusive, or early 
termination, whichever occurs first. 
Section 7.3 Follow up 
period for safety and 
efficacy 
 
Original Wording 
Passive efficacy surveillance: Following randomization and 
vaccinations, subjects will be instructed to contact the site if they 
experience symptoms of a respiratory illness or influenza-like 
illness during the annual surveillance periods defined as from Day 
14 after second vaccination day or from September 15 (the later of 
them) until 15 May of the following year. 
… 

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During the period from Day 14 after second vaccination day (not 
earlier than from September 15th) until 30 April of the following 
year (or longer if decided by the medical director based on actual 
influenza season duration), the site will … 
… 
NP/nasal and throat swab collection: 
NP swab (or nasal and throat swab) specimens will be collected 
during the period from Day 14 after second vaccination day (but 
not earlier than from September 15th) until 30 April of the 
following year… 
New Wording 
Passive efficacy surveillance: Following randomization and 
vaccinations, subjects will be instructed to contact the site if they 
experience symptoms of a respiratory illness or influenza-like 
illness during the annual surveillance periods defined as from Day 
14 after second vaccination day until 15 May of the following 
year. 
… 
During the period from Day 14 after second vaccination day until 
30 April of the following year (or longer if decided by the medical 
director based on actual influenza season duration), the site will…  
… 
NP/nasal and throat swab collection: 
NP swab (or nasal and throat swab) specimens will be collected 
during the period from Day 14 after second vaccination day until 
30 April of the following year… 
Section 7.4. Safety 
Follow Up Visit, Visit 4, 
Day 202: Phone Call/ 
Electronic 
Communication (180 
days +/-14 post last 
study vaccination) 
 
Original Wording 
7.4. Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ 
Electronic Communication (180 days +/-14 post last study 
vaccination) 
New Wording 
7.4. Safety Follow Up Visit, Visit 4, Day 202: Phone Call/ 
Electronic Communication (180 days [+/-14 days] post last study 
vaccination day) 
Section 7.5 Follow Up 
Period for Efficacy 
Season 2 
 
Original Wording 
Passive surveillance will take place between September 15, 2019 
and May 15, 2020. 
New Wording 
Passive surveillance will take place starting 14 days after the 
second injection and until May 15, 2020. 

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Section 8.2.3 Special 
Assays or Procedures 
 
Original Wording 
Venous blood samples for isolation of PBMCs will be collected 
from a subset of cohort 2, immediately prior to the first study 
vaccination (Day 0, visit 1 in season 2), and approximately 15 
days (day of the vaccination inclusive) after the second M-001 
vaccination (Day 36, visit 3, season 2). 
New Wording 
Venous blood samples for isolation of PBMCs will be collected 
from a subset of cohort 2, immediately prior to the first study 
vaccination (Day 0, visit 1 in season 2), and approximately 15 
days (day of the vaccination inclusive) after the second study 
vaccination (Day 36, visit 3, season 2). 
Section 9.6.2 Infuenza 
Culture 
 
Original Wording 
9.6.2 Influenza Culture 
New Wording 
9.6.2 Influenza Virus Culture 
 
 
 

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2 http://www.who.int/mediacentre/factsheets/fs211/en/ 
3 Patriarca PA, Cox NJ.  Influenza pandemic preparedness plan for the United States.  J Infect Dis 1997; 176:S4-7. 
4 Center for Disease Control: http://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm 
5 World Health Organization: 
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6 https://www.cdc.gov/flu/about/qa/vaccineeffect.htm 
7 Lambert1 ND, Ovsyannikova1 IG, Pankratz VS, Jacobson RM, Poland GA. Understanding the immune response to 
seasonal influenza vaccination in older adults: a systems biology approach. Expert Review of Vaccines 2012; 11: 985–
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8 Ridenhour BJ, Campitelli MA, Kwong JC, Rosella LC, Armstrong BG, Mangtani P, et al. Effectiveness of inactivated 
influenza vaccines in preventing influenza-associated deaths and hospitalizations among Ontario residents aged ≥65 
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10 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 
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11 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 
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12 Gottlieb T, Ben-Yedidia T. Epitope-based approaches to a universal influenza vaccine. J Autoimmun 2014; 54:15-20. 
13 Lowell GH et al. Back to the future: Immunization with M-001 prior to trivalent influenza vaccine in 2011/12 
enhanced protective immune responses against 2014/15 epidemic strain. Vaccine (2017) 
14 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. 
15 BiondVax Pharmaceuticals Limited. Multimeric-001 Investigator’s Brochure. Edition number 3.  Release Date: 17 
August 2017.  
16 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. 
17 van Doorn E, Liu H, Ben-Yedidia T, Hassin S, Visontai I, Norley S, Frijlink HW, Hak E. Evaluating the 
immunogenicity and safety of a BiondVax-developed universal influenza vaccine (Multimeric-001) either as a 
standalone vaccine or as a primer to H5N1 influenza vaccine: Phase IIb study protocol. Medicine (Baltimore). 2017 
Mar;96(11):e6339. 
18 Ben-Yedidia T et al, Safety and immunogenicity of M-001 as standalone universal influenza vaccine and as a primer 
to H5N1 vaccine: Results of a multicenter, randomized, double-blind and controlled Phase IIb trial. In preparation.   
19 Vesikari T, Beran J, Durviaux S et al. Use of real-time polymerase chain reaction (rtPCR) as a diagnostic tool for 
influenza infection in a vaccine efficacy trial. J Clin Virol 2012; 53:22–28. 
20 https://www.ncbi.nlm.nih.gov/pubmed/19886869 
21  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110927#pone.0110927-Katz1