A Randomized, Observer-blind, Placebo-controlled, Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent Virus-Like Particles Influenza Vaccine in Adults 18-64 Years of Age
Phase: PHASE3
Conditions: Virus Diseases, RNA Virus Infections, Respiratory Tract Diseases, Respiratory Tract Infections, Influenza
Sponsor: Medicago

 
 
Confidential Information 
Information in this protocol is confidential and should not be disclosed, other than to those directly involved in the 
execution or the ethical review of the study, without written authorization from Medicago R&D Inc. (herein after 
known as “Medicago”), and its affiliates. This study will be conducted in accordance with applicable Good Clinical 
Practice (GCP) guidelines, the United States Code of Federal Regulations (CFR), and International Conference on 
Harmonization (ICH) guidelines. 
 
Clinical Protocol 
A Randomized, Observer-blind, Placebo-controlled, Multicenter, Phase 3 Study to Assess 
the Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent VLP 
Influenza Vaccine in Adults 18-64 Years of Age 
 
CP-PRO-QVLP-012; Phase 3 
 
Plant-Derived Quadrivalent VLP Influenza Vaccine 
 
 
 
Name of Sponsor: 
Medicago R&D Inc. 
1020 route de l’Église, bureau 600 
Québec (Qc), Canada G1V 3V9 
 
 
 
 
 
 
 
 
Status: 
Final version 3.1 
 
 
Date: 
13 September 2017 
 
 
 

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COORDINATING INVESTIGATOR SIGNATURE 
Study Title: 
A Randomized, Observer-blind, Placebo-controlled, Multicenter, Phase 3 
Study to Assess the Efficacy, Safety, and Immunogenicity of a Plant-
Derived Quadrivalent VLP Influenza Vaccine in Adults 18-64 Years of 
Age 
 
I have read the version 3.1 (dated 13 September, 2017) Protocol No. CP-PRO-QVLP-012 titled, 
“A Randomized, Observer-blind, Placebo-controlled, Multicenter, Phase 3 Study to Assess the 
Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent VLP Influenza Vaccine 
in Adults 18-64 Years of Age”. 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative and I agree to accept the responsibility to act as Coordinating 
Investigator for this study. 
 
Coordinating Investigator: 
 
 
Signature 
 
 
 
 
Date (YYYY-MM-DD) 
 
 
 

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INVESTIGATOR AGREEMENT 
I have read the version 3.1 (dated 13 September, 2017) Protocol No. CP-PRO-QVLP-012 titled, 
“A Randomized, Observer-blind, Placebo-controlled, Multicenter, Phase 3 Study to Assess the 
Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent VLP Influenza Vaccine 
in Adults 18-64 Years of Age”. 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the ethical review of the study, without 
prior written authorization from Medicago. It is, however, permissible to discuss information 
contained in this protocol with a subject in order to obtain consent once Institutional Review 
Board (IRB) approval is obtained. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation (ICH) guidelines, Good Clinical 
Practice (GCP), Investigational New Drug (IND) regulations, and other applicable regulatory 
requirements. 
I understand that the Sponsor may decide to suspend or prematurely terminate this study at any 
time for whatever reason and that such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate my 
intention immediately in writing to the Sponsor. 
Principal Investigator: 
Name (typed or 
printed): 
 
Institution and 
Address: 
 
 
 
 
 
Telephone Number: 
 
 
 
Signature 
 
Date (YYYY-MM-DD) 
 
Note: If the address or the telephone number of the Investigator changes during the course of 
the study, written notification will be provided by the Investigator to the Sponsor, and a 
protocol amendment will not be required. 
 

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TABLE OF CONTENTS 
SIGNATURES ................................................................................................................................ 2 
COORDINATING INVESTIGATOR SIGNATURE .................................................................... 3 
INVESTIGATOR AGREEMENT.................................................................................................. 4 
TABLE OF CONTENTS ................................................................................................................ 5 
LIST OF TABLES .......................................................................................................................... 9 
SYNOPSIS .................................................................................................................................... 10 
ABBREVIATIONS ...................................................................................................................... 22 
1 
INTRODUCTION ................................................................................................................. 24 
1.1 
Quadrivalent VLP Influenza Vaccine ............................................................................ 25 
1.2 
Pre-clinical Studies ......................................................................................................... 25 
1.3 
Clinical Studies .............................................................................................................. 25 
1.3.1 
Safety Overview...................................................................................................... 26 
1.3.2 
Immunogenicity Overview ..................................................................................... 27 
1.4 
Overall Rationale for the Study ...................................................................................... 29 
2 
OBJECTIVES ........................................................................................................................ 29 
2.1 
Primary Objectives ......................................................................................................... 29 
2.2 
Secondary Objectives ..................................................................................................... 29 
2.3 
Exploratory Objectives ................................................................................................... 30 
3 
STUDY ADMINISTRATIVE STRUCTURE ...................................................................... 30 
4 
STUDY DESIGN AND RATIONALE ................................................................................. 31 
4.1 
Overview of Study Design ............................................................................................. 31 
4.2 
Rationale of Study Design.............................................................................................. 32 
4.2.1 
Randomization ........................................................................................................ 32 
4.2.2 
Observer-blinding ................................................................................................... 33 
4.2.3 
Age Group Stratification ......................................................................................... 33 
4.2.4 
Dose Selection ........................................................................................................ 33 
4.2.5 
Study Duration ........................................................................................................ 33 
4.2.6 
Efficacy Assessments.............................................................................................. 33 
5 
STUDY POPULATION ........................................................................................................ 33 
5.1 
Inclusion Criteria ............................................................................................................ 33 
5.2 
Exclusion Criteria ........................................................................................................... 34 

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5.3 
Prior and Concomitant Therapy ..................................................................................... 36 
5.4 
Prohibited Therapy ......................................................................................................... 37 
6 
TREATMENT ALLOCATION AND BLINDING .............................................................. 37 
6.1 
Randomization ............................................................................................................... 37 
6.2 
Blinding .......................................................................................................................... 38 
7 
DOSAGE AND ADMINISTRATION .................................................................................. 38 
8 
SPECIMENS AND CLINICAL SUPPLIES ......................................................................... 39 
8.1 
Management of Samples ................................................................................................ 39 
8.2 
Clinical Supplies ............................................................................................................ 39 
9 
TREATMENT COMPLIANCE ............................................................................................ 39 
10 STUDY EVALUATIONS ..................................................................................................... 39 
10.1 Study Procedures ............................................................................................................ 39 
10.1.1 
Overview ................................................................................................................. 39 
10.1.2 
Screening/Vaccination (Visit 1) .............................................................................. 40 
10.1.3 
Day 1 and Day 8 (Telephone Contact) ................................................................... 43 
10.1.4 
Surveillance for Respiratory Illness ........................................................................ 44 
10.1.5 
Day 21 ..................................................................................................................... 45 
10.1.6 
End of Surveillance (Telephone Contact) ............................................................... 46 
10.2 Efficacy .......................................................................................................................... 46 
10.2.1 
Efficacy Evaluations ............................................................................................... 46 
10.2.2 
Efficacy Endpoints .................................................................................................. 48 
10.3 Safety .............................................................................................................................. 49 
10.3.1 
Evaluations .............................................................................................................. 49 
10.3.2 
Pregnancy ................................................................................................................ 51 
10.3.3 
Safety Endpoints ..................................................................................................... 51 
10.4 Immunogenicity ............................................................................................................. 52 
10.4.1 
Immunogenicity Evaluations .................................................................................. 52 
10.4.2 
Immunogenicity Endpoints ..................................................................................... 52 
11 SUBJECT COMPLETION/WITHDRAWAL ...................................................................... 53 
11.1 Temporary Contraindications ......................................................................................... 53 
11.2 Screening Failures .......................................................................................................... 53 
11.3 Removal of Subjects from Treatment or Assessment .................................................... 54 

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11.3.1 
Follow-up of Discontinuations ............................................................................... 54 
11.3.2 
Lost to Follow-up Procedures ................................................................................. 54 
11.4 Interruption of the Study ................................................................................................ 54 
12 STATISTICAL METHODS.................................................................................................. 55 
12.1 Analysis Populations ...................................................................................................... 55 
12.1.1 
Safety Analysis Set ................................................................................................. 55 
12.1.2 
Full Analysis Set ..................................................................................................... 55 
12.1.3 
Per Protocol Set....................................................................................................... 55 
12.2 Sample Size Determination ............................................................................................ 56 
12.3 Efficacy Analyses ........................................................................................................... 56 
12.3.1 
Analysis of Primary Endpoint ................................................................................. 56 
12.3.2 
Analysis of Secondary Endpoints ........................................................................... 57 
12.3.3 
Analysis of Exploratory Endpoints ......................................................................... 57 
12.4 Baseline and Subject Disposition ................................................................................... 58 
12.5 Safety Analyses .............................................................................................................. 58 
12.5.1 
Analysis of Secondary Endpoints ........................................................................... 58 
12.5.2 
Analysis of Exploratory Endpoint .......................................................................... 58 
12.6 Immunogenicity Analyses .............................................................................................. 59 
12.6.1 
Analysis of Secondary Endpoints ........................................................................... 59 
12.6.2 
Analysis of Exploratory Endpoint .......................................................................... 59 
13 ADVERSE EVENT REPORTING ....................................................................................... 59 
13.1 Definitions ...................................................................................................................... 60 
13.1.1 
Serious Adverse Events .......................................................................................... 60 
13.1.2 
Adverse Events ....................................................................................................... 60 
13.1.3 
Adverse Events of Special Interest ......................................................................... 61 
13.1.4 
New Onset of Chronic Disease ............................................................................... 62 
13.1.5 
Expectedness of an Adverse Drug Reaction ........................................................... 62 
13.1.6 
Initial SAE Reporting by the Investigator .............................................................. 62 
13.1.7 
Follow-up Reporting by the Investigator ................................................................ 63 
13.1.8 
Reporting of SAEs Occurring after Surveillance Period or Study Termination ..... 63 
13.1.9 
Causal Relationship ................................................................................................ 63 
13.1.10 Reporting of SAEs to Health Authorities and IRB ................................................. 64 

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14 INVESTIGATIONAL PRODUCT INFORMATION .......................................................... 64 
14.1 Identity of Investigational Product ................................................................................. 64 
14.1.1 
Study Vaccine Composition ................................................................................... 64 
14.1.2 
Placebo .................................................................................................................... 65 
14.1.3 
Preparation and Administration of Study Vaccine ................................................. 65 
14.1.4 
Preparation, Handling, Storage, and Precautions for Use ....................................... 66 
14.2 Packaging ....................................................................................................................... 66 
14.3 Labeling .......................................................................................................................... 66 
14.4 Drug Accountability ....................................................................................................... 66 
15 STUDY-SPECIFIC MATERIALS........................................................................................ 67 
16 ETHICAL ASPECTS ............................................................................................................ 67 
16.1 Study-Specific Design Considerations ........................................................................... 67 
16.2 Regulatory Ethics Compliance ....................................................................................... 68 
16.2.1 
Investigator Responsibilities ................................................................................... 68 
16.2.2 
Independent Ethics Committee or Institutional Review Board .............................. 68 
16.2.3 
Informed Consent.................................................................................................... 70 
16.2.4 
Privacy of Personal Data ......................................................................................... 70 
17 ADMINISTRATIVE REQUIREMENTS ............................................................................. 70 
17.1 Protocol Amendments .................................................................................................... 70 
17.2 Regulatory Documentation ............................................................................................ 71 
17.2.1 
Regulatory Approval/Notification .......................................................................... 71 
17.3 Source Documentation ................................................................................................... 71 
17.4 Case Report Form Completion ....................................................................................... 72 
17.5 Quality Control (Study Monitoring) .............................................................................. 72 
17.6 Quality Assurance .......................................................................................................... 72 
17.7 Record Retention ............................................................................................................ 72 
17.8 Study Completion/Termination ...................................................................................... 73 
17.8.1 
Study Completion ................................................................................................... 73 
17.8.2 
Study Termination .................................................................................................. 73 
17.9 Registration of Clinical Studies and Disclosure of Results............................................ 74 
18 REFERENCES ...................................................................................................................... 74 
19 APPENDICES ....................................................................................................................... 76 

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19.1 Appendix 1 – Sample Ruler to Measure Local Reactions ............................................. 76 
19.2 Appendix 2 – Burden of Disease Questionnaire ............................................................ 77 
19.3 Appendix 3 – Subject Memory Aid ............................................................................... 79 
19.4 Appendix 4 – Acceptable Contraceptive Methods ......................................................... 84 
 
LIST OF TABLES 
Table 1 Time and Events Schedule: General Information ............................................................ 20 
Table 2 Time and Events Schedule: Respiratory Illness Onset .................................................... 21 
Table 3 Summary of Design of Clinical Studies Performed to Date with the Quadrivalent 
Influenza VLP Vaccine ..................................................................................................... 26 
Table 4 Study Administrative Structure ....................................................................................... 30 
Table 5 Estimated Blood Volume Drawn ..................................................................................... 40 
Table 6 Severity Grades for Solicited Local and Systemic Reactions .......................................... 49 
 
 
 

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SYNOPSIS 
Sponsor: 
Medicago R&D Inc. 
Investigational Product: 
Plant-Derived Quadrivalent VLP Influenza Vaccine 
(Quadrivalent VLP Influenza Vaccine) 
Active Substance(s): 
Mix of recombinant H1, H3, and two B hemagglutinin proteins 
expressed as virus-like particles (VLPs) for the 2017-2018 
influenza virus strains 
Control Product: 
Placebo: phosphate buffered saline (PBS) 
Protocol Title: 
A Randomized, Observer-blind, Placebo-controlled, 
Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and 
Immunogenicity of a Plant-Derived Quadrivalent VLP Influenza 
Vaccine in Adults 18-64 Years of Age 
Protocol Number: 
CP-PRO-QVLP-012 
Development Phase: 
Phase 3 
Study Center(s): 
The study will be conducted at multiples sites in several 
countries. 
Study Rationale: 
This Phase 3 study is intended to assess the efficacy of the 
Quadrivalent VLP Influenza Vaccine during the 2017-2018 
influenza season in healthy adults 18 to 64 years of age. One 
dose of Quadrivalent VLP Influenza Vaccine (30 µg/strain) or 
of placebo will be administered to approximately 10,000 
subjects. 
Planned Study Period: 
The Day 0 (screening/vaccination) visit will occur between 
August and September 2017 for North America and Europe and 
approximately the beginning of November 2017 for Asia. A 
follow up call will be performed at the end of the surveillance 
period, approximately April 30th, 2018 (the duration of 
surveillance period may be adjusted, based on the observed 
epidemiology during the season in participating countries). 
Throughout the influenza season, the number of laboratory 
confirmed influenza cases will be monitored and reviewed on a 
regular basis by the independent biostatistical team from the 
CRO. In the event that an insufficient number of cases are 
reported, the study will be either continued or extended into 
another season to enrol more subjects. A protocol amendment 
will be issued to address changes to the enrolment plan in case 

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of an insufficient number of cases. 
Study Objectives 
  Primary Objective: 
• To evaluate the efficacy, relative to placebo, of a single dose 
of the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain, against protocol-defined respiratory illness due 
to laboratory-confirmed influenza caused by vaccine-matched 
strains. 
  Secondary Objectives: 
Efficacy: 
• To evaluate the efficacy, relative to placebo, of a single dose 
of the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain, against protocol-defined respiratory illness due 
to any laboratory-confirmed influenza strain; 
• To evaluate the efficacy, relative to placebo, of a single dose 
of the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain, against laboratory-confirmed protocol-defined 
influenza-like illness (ILI) caused by vaccine-matched strains. 
• To evaluate the efficacy, relative to placebo, of a single dose 
of the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain, against laboratory-confirmed protocol-defined 
influenza-like illness (ILI) caused by any influenza viral 
types/subtypes (matched, mismatched, and un-typed). 
• To evaluate the efficacy, relative to placebo, of a single dose 
of the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain, as measured by the incidence of subjects 
presenting with symptoms of protocol-defined ILI, regardless 
of laboratory results. 
Safety: 
• To assess the safety and tolerability, relative to placebo, of a 
single dose of the Quadrivalent VLP Influenza Vaccine given 
at a dose of 30 µg/strain. 
Immunogenicity: 
• To assess, in a subset of 400 subjects, the immunogenicity of 
a single dose of Quadrivalent VLP Influenza Vaccine given at 
a dose of 30 µg/strain, as measured by hemagglutination 
inhibition (HI) assay, microneutralization (MN) assay, and 
single radial hemolysis (SRH) assay against homologous and 
heterologous (HI only) influenza strains. 
  Exploratory Objectives: 
Efficacy: 
• To evaluate per age stratum the efficacy, relative to placebo, 
of a single dose of the Quadrivalent VLP Influenza Vaccine 
given at a dose of 30 µg/strain, against laboratory-confirmed 
influenza illness caused by vaccine-matched strains; 

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• To evaluate the efficacy, relative to placebo, of a single dose 
of the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain against mismatched influenza strains; 
• To determine the efficacy, relative to placebo, of a single dose 
of the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain, as measured by the incidence of subjects 
presenting with symptoms of protocol-defined respiratory 
illness, regardless of laboratory results. 
Immunogenicity: 
• To assess the cell-mediated immune (CMI) response against 
homologous and heterologous strains on Days 0 and 21 in a 
subset of 400 subjects (same subset as the immunogenicity 
subset). 
Safety: 
• To evaluate respiratory illness outcome, occurrences of 
pneumonia, new onset or exacerbations of cardio-respiratory 
conditions, and health care utilization of subjects administered 
the Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain relative to subjects administered the placebo. 
Number of Planned 
Subjects: 
Approximately 10,000 subjects are planned for randomization in 
a 1:1 ratio to receive the Quadrivalent VLP Influenza Vaccine at 
a dose of 30 µg/strain or the placebo. Within the two treatment 
groups, subjects will be stratified by site and two age groups (18 
to 49 years of age and 50 to 64 years of age in a 1:1 ratio). 
Individuals will be randomly assigned to a treatment group by 
use of an interactive randomization system. 
Sample Size 
Determination: 
The sample size of approximately 10,000 subjects (5,000 
subjects per treatment group) was selected based on the 
assumption that the Quadrivalent VLP Influenza Vaccine would 
have a vaccine efficacy (VE) of at least 70 % and that the 
influenza attack rate in unvaccinated subjects (ARU) would be 
2 % or greater for laboratory-confirmed influenza caused by 
vaccine-matched strains. The sample size was chosen to have 
90 % power to determine whether the lower bound of the two-
sided 95 % confidence interval (CI) for the primary endpoint 
(VE) would be greater than 40 %, assuming a 10 % attrition 
rate. 
If the ARU is lower than 2 %, but greater than or equal to 1.5 %, 
this sample size will have an 80 % power to determine whether 
the lower bound of the two-sided 95 % CI for the primary 
endpoint (VE) would be greater than 40 %, assuming a 10 % 

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attrition rate. 
In the event of an insufficient number of events, a protocol 
amendment will be issued. 
Study Population: 
Healthy male and female subjects 18 to 64 years of age and with 
no clinically significant disease at the time of vaccination will 
be included in this study. 
Dosage and 
Administration: 
On Day 0, subjects will receive one intramuscular (IM) injection 
into the deltoid region of the arm of 0.5 mL of 30 µg/strain of 
the Quadrivalent VLP Influenza Vaccine or placebo. 
Study Design: 
This is a randomized, observer-blind, placebo-controlled, 
multicenter, Phase 3 efficacy study. 
The influenza strain composition of the Quadrivalent VLP 
Influenza Vaccine will be based on the 2017-2018 
recommended World Health Organization (WHO) strains for 
vaccination. 
Subjects will participate in this study for approximately eight to 
ten months, during which a first visit will be scheduled on Day 0 
for screening and vaccine administration. A phone contact will 
be made on Days 1 and 8, specifically for review of the subject’s 
safety and concomitant medication data. A visit at the 
investigator site will occur on Day 21 for immunogenicity 
assessments (CMI, HI, MN, and SRH) for a subset of 400 
subjects from pre-defined sites in North America. From Day 14 
until the end of the surveillance period, subjects will be 
instructed to report symptoms meeting the definition of a new or 
worsening respiratory illness and ILI (passive surveillance). In 
addition, active surveillance will be performed during this same 
period: symptoms of a new or worsening respiratory illness and 
ILI will be solicited a minimum of three times per week. At least 
one of these contacts each week will be through a scripted 
telephone call, with the remaining contacts via text messaging; a 
higher proportion of telephone contacts may be used if deemed 
appropriate by the clinic site (e.g. difficulty in obtaining 
responses via text messaging). A final phone contact will be 
made at the end of the follow up period for a safety assessment. 
Efficacy Evaluations: 
Following randomization and vaccination, subjects will be 
instructed to report respiratory symptoms from Day 14 until the 
end of the surveillance period (passive surveillance). During the 
period from Day 14 post-vaccination until the end of the 
surveillance period, the site will collect nasopharyngeal (NP) 
swabs (two per subject per event) for any subject who reports 

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any respiratory illness. Respiratory illness will be defined as the 
occurrence of a new onset of one or more of the following 
symptoms that persist(s) for or reoccur(s) after a period of at 
least 12 hours: 
• Sneezing; 
• Stuffy or runny nose (nasal congestion); 
• Sore throat; 
• Cough; 
• Sputum production; 
• Wheezing; 
• Difficulty breathing. 
The swabs will be collected within 36 hours (preferably within 
24 hours) of the reporting of a respiratory illness. 
One swab will be submitted for analysis by multiplex reverse 
transcription polymerase chain reaction (RT-PCR). The second 
swab will be used for influenza virus culture, serosubtyping, 
detailed antigenic characterization, and vaccine match analysis 
of the isolates only in the event of a positive RT-PCR result. 
A positive RT-PCR result will be considered a laboratory-
confirmed case of influenza. Any respiratory illness must be 
followed up for 30 days following the start date (through the 
planned active surveillance contacts), using a phone script. At 
the end of the 30-day follow-up, subjects will complete a disease 
burden questionnaire (Section 19.2); subjects will be provided 
with a memory aid (Section 19.3) that they can use during the 30 
days to facilitate accurate reporting at the end of the follow-up 
period. 
Some degree of site investigator discretion will be permitted in 
defining new episodes (e.g. a non-productive cough and fatigue 
persisting for ten days from one episode, with a new onset of 
myalgia, headache, and sore throat would constitute the onset of 
a valid new episode). 
ILI will also be monitored during the study, but the presence of 
a respiratory illness symptom as described above will be the 
trigger for swab collection. A subject will be considered to have 
ILI if he/she meets the protocol-defined ILI (≥ 14 days post-
vaccination) conditions: 
• At least one of the following respiratory symptoms: 
• 
Sore throat; 
• 
Cough; 
• 
Sputum production; 

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• 
Wheezing; 
• 
Difficulty breathing; 
AND  
• At least one of the following systemic symptoms: 
• 
Fever (defined as temperature > 99.0 °F or > 37.2 °C); 
• 
Chills; 
• 
Tiredness; 
• 
Headache; 
• 
Myalgia. 
The subjects will also be given a reminder aid listing the 
symptoms of respiratory illness and systemic symptoms and 
contact information for the study site. 
Active surveillance will also be performed, during which 
respiratory and systemic symptoms will be solicited. Subjects 
will be contacted a minimum of three times per week (at least 
one of these contacts each week will be through a scripted 
telephone call, with the remaining contacts via text messaging).  
Safety Evaluations: 
Safety and tolerability endpoints will include immediate 
complaints (15 minutes post-vaccination), solicited local and 
systemic reactions (up to seven days post-vaccination), 
treatment-emergent adverse events (TEAEs) up to Day 21, and 
serious adverse events (SAEs), adverse events (AEs) leading to 
withdrawal, and new onset of chronic diseases (NOCDs) up to 
the end of the surveillance period. 
Subjects will be observed at the study site for 15 minutes 
following vaccination, during which they will be given an oral 
digital thermometer and instructions on how to measure and 
record their solicited local and systemic reactions for the first 
seven days after vaccination and to record AEs during the first 
21 days after vaccination. 
During the surveillance period, subjects will be instructed to 
collect and report any SAEs, NOCDs, concomitant medication 
use, or change in their health status. A questionnaire will be 
completed for subjects with respiratory illness regarding disease 
burden and health care resource utilization. Surveillance will be 
performed during visits to the clinic and/or home visits, as 
applicable. 
The site will make a final telephone call to each subject at the 
end of the surveillance period. Final information about 
respiratory illness outcome, occurrences of pneumonia, and new 

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onset or exacerbations of cardio-respiratory conditions, health 
care utilization, medication use, SAEs, and NOCDs will be 
collected and the termination record will be completed. 
Immunogenicity 
Evaluations: 
Immunogenicity will be evaluated by the immune response 
induced in a subset of 400 subjects (300 from the VLP vaccine 
group and 100 from the placebo group) as measured by the 
serum HI, MN, and SRH antibody titers on Day 0 and Day 21.  
A blood sample for exploratory CMI analyses will be collected 
on Days 0 and 21 for a subset of 400 subjects (the same subset 
as for HI, MN, and SRH analysis). 
The North American sites selected for immunogenicity sample 
collection for this subset of 400 subjects will be pre-defined 
prior to study start and will target providing a representative age 
distribution.  The subjects identified for the immunogenicity 
analyses will be also be stratified by age group (1:1 ratio). 
Primary Endpoint: 
Efficacy: 
• Occurrences of protocol-defined respiratory illness due to 
laboratory-confirmed influenza (≥ 14 days post-vaccination) 
caused by influenza viral types/subtypes that are matched 
(and/or antigenically similar) to the strains covered in the 
vaccine formulation. 
Secondary Endpoints: 
Efficacy: 
• Occurrences of protocol-defined respiratory illness due to 
laboratory-confirmed influenza (≥ 14 days post-vaccination) 
caused by any influenza viral types/subtypes (matched, 
mismatched, and un-typed); 
• Occurrences of laboratory-confirmed influenza (according to 
protocol defined ILI) illnesses (≥ 14 days post-vaccination) 
caused by influenza viral types/subtypes that are matched 
(and/or antigenically similar) to the strains covered in the 
vaccine formulation; 
• Occurrences of laboratory-confirmed influenza (according to 
protocol defined ILI) illnesses (≥ 14 days post-vaccination) 
caused by any influenza viral types/subtypes (matched, 
mismatched, and un-typed); 
• Occurrences of protocol-defined ILI ≥ 14 days post-
vaccination (confirmed or not). 
Safety: 
• Percentage, intensity, and relationship to vaccination of 
immediate complaints (15 minutes post-vaccination); 

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• Percentage, intensity, and relationship to vaccination of 
solicited local and systemic signs and symptoms (for seven 
days following study vaccine administration); 
• Percentage, intensity, and relationship of TEAEs for 21 days 
following study vaccine administration; 
• Occurrences of deaths, SAEs, AEs leading to withdrawal, and 
NOCDs up to the end of the surveillance period. 
Immunogenicity (subset of subjects): 
• HI antibody response induced by the Quadrivalent VLP 
Influenza Vaccine against the homologous and heterologous 
influenza strains on Days 0 and 21 will be assessed in a subset 
of 400 subjects (300 who received the VLP vaccine and 100 
who received the placebo). HI antibody titers will be analyzed 
using the following parameters: geometric mean titers (GMT), 
seroconversion (SC) rate, seroprotection (SP) rate, and 
geometric mean fold rise (GMFR); 
• MN antibody response induced by the Quadrivalent VLP 
Influenza Vaccine against the homologous influenza strains 
on Days 0 and 21, in a subset of subjects, will be analyzed 
using the following parameters: GMT, SC rate, and GMFR; 
• SRH antibody response induced by the Quadrivalent VLP 
Influenza Vaccine against the homologous strains on Days 0 
and 21, will be analysed using the following parameters: 
geometric mean area (GMA), SC rate, SP rate, and GMFR. 
Exploratory Endpoints: 
Efficacy: 
• Occurrences, per age stratum, of laboratory-confirmed 
influenza illnesses (≥ 14 days post-vaccination) caused by 
influenza viral types/subtypes that are matched (and/or 
antigenically similar) to the strains covered in the vaccine 
formulations, according to protocol-defined respiratory 
illness; 
• Occurrences of laboratory-confirmed influenza illnesses (≥ 14 
days post-vaccination) caused by mismatched influenza viral 
strains, according to protocol-defined respiratory illness; 
• Occurrences of respiratory illnesses ≥ 14 days post-
vaccination (confirmed or not). 
Safety: 
• Information on respiratory illness outcome, occurrences of 
pneumonia, new onset or exacerbations of cardio-respiratory 
conditions, and health care utilization during the entire trial 
follow up period. 

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Immunogenicity (subset of subjects): 
• CMI response induced by the Quadrivalent VLP Influenza 
Vaccine against homologous and heterologous strains on Day 
21 (subset of 400 subjects). 
Statistical Methods: 
Populations: 
Statistical analyses will be performed on pre-defined population 
sets (the safety analysis set, the full analysis set, and the per 
protocol set) according to the Statistical Analysis Plan (SAP). 
The analyses of all efficacy endpoints will be performed using 
the efficacy per protocol (PP) population and the full analysis 
set (FAS) population. The analysis in the PP will be considered 
the primary analysis for these objectives. 
All safety analyses will be performed using the safety analysis 
set (SAS). 
The immunogenicity analyses will be performed using a subset 
of the PP that includes only subjects with valid immunogenicity 
samples collected within the specified time window. 
 
Statistical Analyses: 
In general, categorical data will be summarized using the 
number and percent of subjects in each category and continuous 
data will be summarized using descriptive statistics (mean or 
geometric mean, median, SD, minimum, and maximum). 
Immunogenicity endpoints will also be compared between the 
vaccine group and the placebo group. 
Efficacy Analyses: 
For the primary endpoint, vaccine efficacy (VE) will be 
evaluated as the relative risk of vaccinated versus unvaccinated 
subjects to become infected with laboratory-confirmed influenza 
caused by one or more vaccine-matched strains in a timeframe 
of 14 or more days following vaccination (i.e. the proportion of 
subjects with one or more episodes of respiratory illness shown 
to be caused by viral types/subtypes that are matched and/or 
antigenically similar to the strains covered in the vaccine 
formulation), as per the following formula: 
VE=(1-ARV/ARU)*100 % 
Where: 
ARV = attack rate in vaccinated subjects; and 
ARU = attack rate in unvaccinated subjects. 

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The VE success criterion for the primary endpoint is defined as 
a > 40 % lower limit of the two-sided 95 % CI against vaccine-
matched influenza strains. VE against all influenza strains and 
against mismatched strains will also be calculated. 
Safety Analyses: 
Safety endpoints will be tabulated, listed, and compared with the 
placebo group using descriptive statistics. 
Immunogenicity Analyses: 
For the immunogenicity analysis of the HI assays against the 
homologous strains, the point estimates and the corresponding 
two-sided 95 % CI will be calculated to determine if the Center 
for Biologics Evaluation and Research (CBER) criteria for 
licensure for influenza vaccine are met. 
 
 
 

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ABBREVIATIONS 
ACIP 
Advisory Committee on Immunization Practices 
AE 
adverse event 
ANOVA 
analysis of variance 
ARU 
attack rate in unvaccinated subjects 
ARV 
attack rate in vaccinated subjects 
BMI 
body mass index 
BP 
blood pressure 
CBER 
Center for Biologics Evaluation and Research 
CI 
confidence interval 
CMI 
cell-mediated immune (response) 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GMA 
geometric mean area 
GMFR 
geometric mean fold rise or seroconversion factor 
GMT 
geometric mean titer 
HI 
hemagglutination inhibition 
HR 
heart rate 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ILI 
influenza-like illness 
IM 
intramuscular 
IEC 
independent ethics committee 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
microneutralization 
NACI 
National Advisory Committee on Immunization 
NOCD 
new onset of chronic disease 
OT 
oral temperature 
PBMC 
peripheral blood mononuclear cell 
PP 
per protocol 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SAS® 
Statistical Analysis System® 

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SC 
seroconversion 
SP 
seroprotection 
SRH 
single radial hemolysis 
TEAE 
treatment-emergent adverse event 
VE 
vaccine efficacy 
VLP 
virus-like particle 
WHO 
World Health Organization 
US 
United States 
 
 
 

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1 
INTRODUCTION 
Seasonal influenza is a potentially serious infection associated with a wide range of clinical 
outcomes across the entire human lifespan. The influenza virus genome is an eight-segment 
single-stranded RNA with high potential for in situ recombination and mutations for host 
adaptation. Two segments code for the hemagglutinin (H) and neuraminidase (N) antigens that 
play an essential role in virus infectivity. At present, 17 hemagglutinin and ten neuraminidase 
subtypes are known in bird populations and some subtypes routinely circulate in humans, such as 
the H1N1, H3N2, and B influenza viruses. When a new subtype acquires the capacity for human-
to-human transmission, this can give rise to a major pandemic like the one caused by an H1N1 
strain in 1918 referred to as the Spanish flu. Antibodies that bind to the hemagglutinin molecule 
can prevent or modify infection and are the basis on which influenza vaccines are formulated 
every year. 
Despite continuing advances in understanding of the immune response to natural infection and 
immunization, the disease remains a major cause of morbidity and mortality worldwide. In the 
United States (US) alone, influenza is responsible for approximately 36,000 deaths per year and 
the WHO estimates that influenza causes three to five million cases of severe illness and 250,000 
to 500,000 deaths per year (Palache, 2011). Influenza is also responsible for a massive economic 
burden, with a total cost for each winter influenza season estimated at over 87 billion dollars 
(Molinari et al., 2007) in the US alone. 
The main strategy for prevention and control of seasonal and pandemic influenza is still 
vaccination. In 2012, the Advisory Committee on Immunization Practices (ACIP) issued the first 
recommendation of national universal seasonal influenza vaccination (Osterholm et al., 2012). 
Licensure of influenza vaccines is based either on efficacy studies or on surrogate correlates of 
protection. The latter are primarily based on their ability to induce HI titers. Despite the 
existence of these surrogate correlates of protection, recent reviews and meta-analyses suggest 
that the overall efficacy of licensed trivalent vaccines is highly variable and depends, among 
other factors, on the ‘match’ between circulating strains and the strains used for vaccine 
production. One such analysis produced efficacy estimates from 43 % to 89 % in well-matched 
seasons and from 38 % to 85 % in poorly-matched seasons (< 25 % of isolates matched the 
vaccine strains) (DiazGranados et al., 2012), suggesting that there is still great room for 
improvement. 
For the 2012-2013 influenza season, vaccine efficacy numbers were particularly discouraging. 
When stratified by age group, the overall vaccine efficacy against influenza A and B viruses 
ranged from 27 % in persons 65 and older to 64 % in children (aged six months to 17 years old). 
When specific strains and age groups were examined (e.g. H3N2 in the elderly), efficacy 
estimates could be as low as 9 % (95 % CI: -84 % to 55 %). Preliminary efficacy estimates for 
the H3N2 strain in the on-going 2014-2015 influenza season are even lower: hovering at or even 
below 0 % due to a significant mismatch between vaccine and circulating strains (Skowronski et 
al., 2015). 

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1.1 
Quadrivalent VLP Influenza Vaccine 
Medicago R&D Inc. has developed a plant-derived system (Nicotiana benthamiana) for transient 
expression of two Type A and two Type B influenza strains to produce the Quadrivalent VLP 
Influenza Vaccine intended for active immunization for the prevention of influenza disease 
caused by the influenza A subtype viruses and type B virus strains covered in the vaccine. This 
vaccine may be able to address some limitations of the currently licensed vaccines: 
• The hemagglutinin proteins in each monovalent VLP is based on the genetic sequence of 
circulating human influenza viruses selected by the WHO; in contrast, influenza strains 
grown in embryonic eggs or tissue culture tend to mutate for optimal growth in these 
substrates; 
• Medicago’s clinical trial program has revealed that plant-made VLP vaccines induce long-
lasting and cross-reactive T cell responses that could be pivotal for protection against both 
matched and diverse influenza strains, particularly in the elderly who often derive 
significant benefit from vaccination despite little evidence of a humoral response 
(McElhaney, 2011). 
Nicotiana benthamiana is a non-transgenic plant that is a distant wild relative from Australia of 
the tobacco plant, Nicotiana tabacum. The transfer vector used to move targeted DNA constructs 
into the plant cells is the bacterium Agrobacterium tumefaciens. This vector then directs the 
expression of the protein(s) of interest, in this case the hemagglutinin protein. The hemagglutinin 
proteins are assembled into trimers in the intracellular secretory pathway, aligned at the plant 
plasma membrane via a transmembrane domain, and finally bud out of the plant plasma 
membrane in the form of VLPs. Thus, the viral hemagglutinin proteins are anchored in a lipid 
bilayer of plant cell origin. The VLPs accumulate in the space between the plasma membrane 
and plant cell wall. 
1.2 
Pre-clinical Studies 
Medicago has conducted several preclinical studies in rats with monovalent, trivalent, and 
quadrivalent formulations. All strains included in the quadrivalent vaccine are immunogenic at 
doses ranging from 0.001 to 10 μg in the rat model. 
For more comprehensive preclinical information regarding the safety and toxicity of the 
Quadrivalent VLP Influenza Vaccine, refer to the current Investigator’s Brochure (IB). 
1.3 
Clinical Studies 
Under the clinical development program for the Quadrivalent VLP Influenza Vaccine, Medicago 
has conducted five clinical trials to date (CP-Q12VLP-004, CP-Q13VLP-007, CP-Q13VLP-008, 
CP-Q14VLP-009, and CP-Q14VLP-010). Study designs and statuses are summarized in Table 3. 

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Table 3 Summary of Design of Clinical Studies Performed to Date with the Quadrivalent 
Influenza VLP Vaccine 
Study / Status 
Phase Design 
Population 
N 
Treatment groups 
CP-Q12VLP-004 / 
Completed 
1-2 
Single-center, observer-
blind, randomized, dose-
ranging, placebo-controlled 
study 
Healthy adults 18 to 
49 years of age, 
both genders 
90 (active; ratio 
1:1:1); 
30 (placebo) 
3 μg VLP; 
9 μg VLP; 
15 μg VLP; 
placebo 
CP-Q13VLP-007 / 
Completed 
2A 
Multicenter, observer-blind, 
randomized, dose-ranging, 
placebo-controlled study 
Healthy adults 18 to 
49 years of age, 
both genders 
225 (active; ratio 
1:1:1); 
75 (placebo) 
15 µg VLP; 
30 µg VLP; 
60 µg VLP; 
placebo 
CP-Q13VLP-008 / 
Completed 
2 
Multicenter, observer-blind, 
randomized, dose-ranging, 
placebo-controlled study  
Healthy subjects of 
50 years of age or 
older, both genders 
375 (active; ratio 
1:1:1:1:1); 
75 (placebo) 
15 µg VLP; 
30 µg VLP; 
60 µg VLP; 
7.5 µg VLP + Alhydrogel®; 
15 µg VLP + Alhydrogel®; 
placebo 
CP-Q14VLP-009 / 
Clinic portion 
completed 
2 
Multicenter, observer-blind, 
randomized, dose ranging, 
active-comparator clinical 
study 
Healthy adults aged 
18 to 64 years, both 
genders 
604 (active; ratio 
1:1); 
296 (active 
comparator) 
15 µg VLP; 
30 µg VLP; 
15 µg/strain dose of 
FluLaval® Tetra 
CP-Q14VLP-010 / 
Clinic portion 
completed 
2 
Multicenter, observer-blind, 
randomized, dose ranging, 
active-comparator clinical 
study 
Healthy subjects of 
65 years of age or 
older, both genders 
499 (active; ratio 
1:1); 
250 (active 
comparator 1) 
252 (active 
comparator 2) 
30 µg VLP; 
60 µg VLP; 
15 µg/strain dose of 
FluLaval® Tetra; 
60 µg/strain dose of Fluzone® 
High Dose 
Overall, a total of 1,793 normal healthy subjects have received a single dose of the Quadrivalent 
Influenza VLP vaccine: 1,106 subjects aged from 18 to 64 years and 687 subjects 65 years of age 
and older. 
An overview of the available safety and immunogenicity findings from these studies are 
summarized in Section 1.3.1 and Section 1.3.2, respectively. For detailed information on these 
findings, please refer to the current version of the IB. 
1.3.1 Safety Overview 
This section summarizes the safety data obtained to date from the five clinical trials performed to 
date (CP Q12VLP-004, CP-Q13VLP-007, CP-Q13VLP-008, CP Q14VLP-009, and CP 
Q14VLP-010); see Table 3 for a description of the basic design of these studies, status, and 
exposure. 
No deaths were reported for either the adults (N = 1,106) or the elderly subjects (N = 687) 
administered the Quadrivalent VLP Influenza vaccine. A total of 21 SAEs were reported for 
subjects who received the Quadrivalent VLP Influenza vaccine: 18 for subjects who received a 
single dose of non-adjuvanted VLP vaccine (all dose levels combined, N = 1,642) and three for 
subjects who received a single dose of adjuvanted VLP vaccine (both dose levels combined, 
N = 151). None were considered by the Investigator to be vaccine-related. No subject withdrew 

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from any of the studies due to a TEAE and none of the NOCDs reported for subjects who 
received the VLP vaccine were considered to be vaccine-related. 
The incidence of local and systemic reactions observed within seven days post-vaccination in the 
five studies was consistent with the known safety profile for commercial influenza vaccines. The 
most frequently reported unsolicited TEAEs included nasopharyngitis, upper respiratory tract 
infection, aspartate aminotransferase increased (minor increase), headache, and oropharyngeal 
pain; no notable differences in the incidence of these events were observed between the VLP 
groups and the active comparators or placebo groups. No safety issues and no notable trends 
were observed with respect to vital signs, clinical laboratory, or physical examinations in any of 
the five studies conducted. 
As a precaution, subjects were monitored for TEAEs with a hypersensitivity component. Based 
on the data from the five studies conducted to date, there is no evidence of anaphylactic reactions 
associated with use of the Quadrivalent VLP Influenza Vaccine in humans: a small number of 
subjects had potential hypersensitivity reactions judged to be related to vaccine administration 
(no more than 0.3 % of subjects in any given VLP treatment group experienced one of these 
events) and the events were distributed fairly evenly among treatment groups, including the 
placebo and the active comparator groups. However, since severe reactions are considered to be 
an important potential risk (based on the theoretical risk that using plants for the production of 
biotherapeutics may induce hypersensitivity) the sponsor will continue to require that appropriate 
medical treatment and supervision are available to manage any possible anaphylactic reactions. 
Safety results from the five clinical trials performed to date show that the Quadrivalent VLP 
Influenza Vaccine was well-tolerated, with a safety profile similar to that of the active 
comparators and to the placebo for systemic reactions and TEAEs. 
1.3.2 Immunogenicity Overview 
This section summarizes the immunogenicity data obtained from the studies conducted to date 
with an adult population (up to 64 years of age): four clinical trials (CP-Q12VLP-004, CP-
Q13VLP-007, CP-Q13VLP-008, and CP-Q14VLP-009). Studies CP-Q12VLP-004, CP-
Q13VLP-007, and CP-Q14VLP-009 were conducted in an adult-only population (18 to 49 years 
for the first two studies and 18 to 64 years for CP-Q14VLP-009) and CP-Q13VLP-008 was 
conducted in a combined adult and elderly population (50 years and older); see Table 3 for a 
description of the basic design of these studies and exposure. 
1.3.2.1 Antibody Response 
Overall, the immunogenicity data from the studies conducted to date show that the Quadrivalent 
Influenza VLP Vaccine induced a strong antibody response in healthy adults (18 to 64 years). 
The 30 μg/strain dose level appeared to be the lowest dose to consistently meet the CBER 
criteria and the lowest dose to be the most comparable with the commercial licensed vaccines. 
As a result, the 30 μg/strain dose level has been selected for evaluation during this Phase 3 
efficacy study to be conducted in an adult population. 

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A summary of the Day 21 HI response data for the 30 μg/strain dose level is presented below: 
• In the combined immunogenicity results of the CP-Q13VLP-007 (all subjects) and CP-
Q13VLP-008 (50 to 64 years old strata), the 30 μg/strain dose level met the CHMP criteria 
for SC rate, SP rate, and GMFR for all four tested influenza strains and the CBER criteria 
for both SC rate and SP rate against all four homologous strains; 
• In study CP-Q14VLP-009, conducted in adults aged from 18 to 64 years, the 30 μg/strain 
VLP vaccine met the CBER criteria for both SC rate and SP rate, as well as the CHMP 
criterion for GMFR against all four homologous strains tested. 
For all of these studies, the HI response may have been underestimated due to the limited 
availability of assay reagents unaffected by the use of eggs for production (even when cell-based 
reagents are available, their history often includes an initial expansion in embryonic-eggs). These 
reagents often include mutations of glycosylation site loss in the receptor binding domain, which, 
in turn can affect the assay results, particularly for the B strains. In consequence, the ability of 
the VLP vaccine to elicit an HI response against the B strains may have been underestimated. 
Further assessment of the humoral immune response induced by the VLP vaccine included MN 
and SRH assays. No correlates of protection are currently available for these two assays and, as a 
result, data interpretation is limited. However, for both assays, the VLP vaccine showed notable 
Day 0 to Day 21 increases in GMT against all four of the homologous strains and the overall 
pattern of responses confirms the 30 μg/strain dose selected for this Phase 3 study. 
In addition to the results above, HI and MN data from the studies conducted to date show that the 
Quadrivalent VLP Influenza Vaccine also elicits some cross-protective antibodies against 
heterologous influenza strains (current IB version). 
1.3.2.2 Plant Glycans 
Plant glycoproteins contain structural motifs not found on human glycoproteins (e.g. core β1-2 
xylose and α1-3fucose). Since some of these motifs occur on known plant allergens, one 
theoretical risk of using plants for production of biotherapeutics was the induction of 
hypersensitivity. Medicago monitored allergic symptoms and the humoral response to plant 
glycans in previous clinical trials; based on the results obtained from these studies, in which 
there were no observed trends suggestive of safety concerns (current IB version), there is no need 
to include assessment of plant glycans in this study. Medicago will continue to monitor allergic-
like reactions in this study. 
1.3.2.3 Cell-mediated Immune Response 
In order to further define immune response induced by the VLP vaccine, the CMI response was 
measured in a small subset of subjects in the five studies. In spite of the small sample sizes, a 
clear and consistent vaccine-related Day 21 poly-functional CD4+ T cell response was observed 
with the VLP vaccine against all four homologous strains in all studies and in both the adult and 
elderly populations. Overall, the 30 μg/strain dose level showed the highest response of the VLP 
vaccines; in contrast, an active comparator (FluLaval® Tetra) showed only a minimal response 

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against the H1N1 and H3N2 strains, although significant Day 0 to Day 21 differences were 
detected for most parameters against the two B strains for this vaccine. Further, the CMI 
response induced by the VLP vaccines appeared to be both durable (up to Day 201) and cross-
reactive. 
1.4 
Overall Rationale for the Study 
This Phase 3 study is intended to assess the efficacy of the Quadrivalent VLP Influenza Vaccine 
during the 2017-2018 influenza season in healthy adults 18-64 years of age. One dose of 
Quadrivalent VLP Influenza Vaccine (30 µg/strain) or of placebo will be administered to 
approximately 10,000 subjects. This study will support the licensure of the vaccine in the US, 
Canada, and Europe in the general adult population for whom ACIP and National Advisory 
Committee on Immunization (NACI) recommend annual influenza vaccination. 
2 
OBJECTIVES 
2.1 
Primary Objectives 
• To evaluate the efficacy, relative to placebo, of a single dose of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain, against protocol-defined respiratory 
illness due to laboratory-confirmed influenza caused by vaccine matched strains. 
2.2 
Secondary Objectives 
Efficacy: 
• To evaluate the efficacy, relative to placebo, of a single dose of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain, against protocol-defined respiratory 
illness due to any laboratory-confirmed influenza strains; 
• To evaluate the efficacy, relative to placebo, of a single dose of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain, against laboratory-confirmed protocol-
defined influenza-like illness (ILI) caused by vaccine-matched strains; 
• To evaluate the efficacy, relative to placebo, of a single dose of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain, against laboratory-confirmed protocol-
defined influenza-like illness (ILI) caused by any influenza viral types/subtypes (matched, 
mismatched, and un-typed). 
• To evaluate the efficacy, relative to placebo, of a single dose of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain, as measured by the incidence of subjects 
presenting with symptoms of protocol-defined ILI, regardless of laboratory results. 
Safety: 
• To assess the safety and tolerability, relative to placebo, of a single dose of the 
Quadrivalent VLP Influenza Vaccine given at a dose of 30 µg/strain. 
Immunogenicity: 

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• To assess, in a subset of 400 subjects, the immunogenicity of a single dose of Quadrivalent 
VLP Influenza Vaccine given at a dose of 30 µg/strain or placebo, as measured by 
hemagglutination inhibition (HI) assay, microneutralization (MN) assay, and single radial 
hemolysis (SRH) assay against homologous and heterologous (HI only) influenza strains. 
2.3 
Exploratory Objectives 
Efficacy: 
• To evaluate per age stratum, the efficacy, relative to placebo, of a single dose of the 
Quadrivalent VLP Influenza Vaccine given at a dose of 30 µg/strain, against laboratory-
confirmed influenza caused by vaccine-matched strains; 
• To evaluate the efficacy, relative to placebo, of a single dose of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain against mismatched influenza strains; 
• To evaluate the efficacy, relative to placebo, of a single dose of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain, as measured by the incidence of subjects 
presenting with symptoms of protocol-defined respiratory illness, regardless of laboratory 
results. 
Immunogenicity: 
• To assess the cell-mediated immune (CMI) response against homologous and heterologous 
strains on Days 0 and 21 in a subset of 400 subjects (same subset as the immunogenicity 
subset). 
Safety: 
• To evaluate respiratory illness outcome, occurrences of pneumonia, new onset or 
exacerbations of cardio-respiratory conditions, and health care utilization of subjects 
administered the Quadrivalent VLP Influenza Vaccine given at a dose of 30 µg/strain, 
relative to subjects administered the placebo. 
3 
STUDY ADMINISTRATIVE STRUCTURE 
Table 4 Study Administrative Structure 
Role 
Name and Address 
Sponsor 
Medicago R&D Inc. 
1020, route de l’Église, bureau 600, 
Sainte-Foy (Qc) Canada G1V 3V9 
 
 
PPD

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4 
STUDY DESIGN AND RATIONALE 
4.1 
Overview of Study Design 
This randomized, observer-blind, placebo-controlled multicenter, Phase 3 study will be 
conducted at multiple sites. The composition of the Quadrivalent VLP Influenza Vaccine to be 
used in this study includes a mix of recombinant H1, H3, and two B hemagglutinin proteins 
expressed as VLPs for the 2017-2018 influenza virus strains (see Investigational Product 
Management Manual). 
Approximately 10,000 healthy male and female subjects aged 18 to 64 years will be randomized 
in a 1:1 ratio into one of two parallel treatment groups, such that approximately 5,000 subjects 
will receive the Quadrivalent VLP Influenza Vaccine at a dose of 30 µg/strain and approximately 
5,000 subjects will receive the placebo. Within the two treatment groups, subjects will be 
stratified by site and two age groups (18-49 years of age and 50-64 years of age in a 1:1 ratio). 
A basic outline of the study design is presented in Figure 1. 
 
Figure 1 Flowchart of Study Procedures 
Subjects will participate in this study for approximately eight to ten months, during which a first 
visit will be scheduled on Day 0 for screening and vaccine administration. Subjects will be 
instructed on how to record reactions, adverse events, concomitant medication use, and 
respiratory illness symptoms in their memory aid and eDiary (electronic data capture system), as 
applicable. A phone contact will be made on Days 1 and 8, specifically for review of the 
subject’s safety and concomitant medication data. A visit will occur on Day 21 for a subset of 
400 subjects for serology sampling and immunogenicity assessments (CMI, HI, MN, and SRH). 
From Day 14 until the end of the surveillance period, subjects will be instructed to report 
symptoms meeting the definition of a new or worsening respiratory illness and ILI (passive 
surveillance). In addition, active surveillance will be performed during this same period: 
symptoms of a new or worsening respiratory illness and ILI will be collected a minimum of three 

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times per week (at least one of these contacts each week will be through a scripted telephone 
call, with the remaining contacts via text messaging). A final phone contact will be made at the 
end of the surveillance period (approximately 30 April 2018; however, the duration of 
surveillance period may be adjusted, based on the observed epidemiology during the season in 
participating countries) for a safety assessment. 
Reports of respiratory illness within the specified window will be followed up for the collection 
of information regarding symptoms, concomitant medication use, and disease burden and the 
collection of two nasopharyngeal swabs. Figure 2 outlines the process to be followed for reports 
of respiratory illness. 
 
Figure 2 Flowchart of Process of Respiratory Illness Report 
Throughout the influenza season, the number of laboratory-confirmed influenza cases will be 
monitored and reviewed on a regular basis by selected members of Medicago and the CRO. In 
the event of an insufficient number of reported cases, the extension of enrollment or the 
extension of the study will be addressed in a protocol amendment. 
4.2 
Rationale of Study Design 
4.2.1 Randomization 
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (e.g. demographic and 
baseline characteristics) are evenly balanced across treatment groups and age strata, and to 
enhance the validity of statistical comparisons across treatment groups. 

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4.2.2 Observer-blinding 
Observer-blinded treatment will be used to reduce potential bias during data collection and 
evaluation of the clinical endpoints. 
4.2.3 Age Group Stratification 
Subjects under each treatment group will be stratified by site and two age groups (18 to 49 years 
and 50 to 64 years in a 1:1 ratio). The use of a 1:1 ratio in this study provides equal weight to 
both age groups to facilitate a better comparison between the two strata and to allow for possible 
extrapolation of results to an elderly population. 
4.2.4 
Dose Selection 
The dose of 30 µg/strain was selected based on data from previous studies as the lowest dose to 
consistently meet the CBER criteria and the lowest dose to be the most comparable with the 
commercial licensed vaccines. 
4.2.5 
Study Duration 
The duration of this study will be approximately eight to ten months post-vaccination for all 
subjects. 
4.2.6 
Efficacy Assessments 
The efficacy endpoint defined for this study (RT-PCR-confirmed influenza caused by influenza 
viral types/subtypes that are matched or similar to the strains covered in the vaccine formulation) 
is standard to demonstrate influenza vaccine efficacy. 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study; no protocol waivers are allowed: 
1. Subjects must have read, understood, and signed the informed consent form (ICF) prior to 
participating in the study; subjects must also complete study-related procedures and 
communicate with the study staff at visits and by phone during the study; 
2. Subject must have a body mass index (BMI) below 40 kg/m2; 
3. Subjects are considered by the Investigator to be reliable and likely to cooperate with the 
assessment procedures and be available for the duration of the study; 
4. Male and female subjects must be 18 to 64 (has not yet had his/her 65th birthday) years of 
age, inclusive, at the Screening/Vaccination visit (Visit 1); 
5. Subjects must be in good general health prior to study participation, with no clinically 
relevant abnormalities that could jeopardize subject safety or interfere with study 
assessments, as assessed by the Principal Investigator or sub-Investigator (thereafter 

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referred as Investigator) and determined by medical history, physical examination, and vital 
signs; 
Note: Subjects with a pre-existing chronic disease will be allowed to participate if the 
disease is stable and, according to the Investigator’s judgment, the condition is unlikely to 
confound the results of the study or pose additional risk to the subject by participating in the 
study. Stable disease is generally defined as no new onset or exacerbation of pre-existing 
chronic disease three months prior to vaccination. Based on the Investigator’s judgment, a 
subject with more recent stabilization of a disease could also be eligible. 
6. Female subjects must have a negative urine pregnancy test result at the 
Screening/Vaccination visit (Visit 1); 
7. Female subjects of childbearing potential must use an acceptable method of birth control, as 
defined in Appendix 4 (Section 19.4); 
8. Non-childbearing females are defined as: 
• 
Surgically-sterile (defined as bilateral tubal ligation, hysterectomy or bilateral 
oophorectomy performed more than one month prior to vaccination); or 
• 
Post-menopausal (absence of menses for 24 consecutive months and age consistent with 
natural cessation of ovulation). 
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in this study; 
no protocol waivers are allowed: 
1. Any subject whose medical condition(s) is sufficiently severe that annual influenza 
vaccination would be routinely recommended in the jurisdiction of recruitment, as per the 
Investigator’s judgement; 
2. According to the Investigator’s opinion, history of significant acute or chronic, uncontrolled 
medical or neuropsychiatric illness. ‘Uncontrolled’ is defined as: 
• 
Requiring a new medical or surgical treatment during the three months prior to study 
vaccine administration unless the criteria outlined in inclusion criterion no. 5 can be met 
(i.e. the Investigator can justify inclusion based upon the innocuous nature of 
medical/surgical events and/or treatments); 
• 
Requiring any significant change in a chronic medication (i.e. drug, dose, frequency) 
during the three months prior to study vaccine administration due to uncontrolled 
symptoms or drug toxicity unless the innocuous nature of the medication change meets 
the criteria outlined in inclusion criterion no. 5 and is appropriately justified by the 
Investigator. 
3. Any medical or neuropsychiatric condition or any history of excessive alcohol use or drug 
abuse which, in the Investigator’s opinion, would render the subject unable to provide 
informed consent or unable to provide valid safety observations and reporting; 
4. Any autoimmune disease other than hypothyroidism on stable replacement therapy 
(including, but not limited to rhematoid arthritis, systemic lupus erythematosus, Crohn’s 
disease, and inflammatory bowel disease) or any confirmed or suspected 

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immunosuppressive condition or immunodeficiency including known or suspected human 
immunodeficiency virus (HIV), Hepatitis B or C infection, the presence of 
lymphoproliferative disease; 
5. History of chronic pulmonary (including asthma, bronchopulmonary dysplasia, and cystic 
fibrosis) or cardiovascular (except isolated hypertension), renal, hepatic, neurologic, 
hematologic (including anemia and hemoglobinopathy), or metabolic disorders (including 
diabetes mellitus); 
6. Because this is a placebo-controlled study, any subjects in close contact with individuals 
considered to be at high risk for developing influenza-related complications (individuals 
considered at high risk for complications include adults and children who have chronic 
pulmonary or cardiovascular [except isolated hypertension], renal, hepatic, neurologic, 
hematologic, or metabolic disorders [including diabetes mellitus]), ; 
7. Administration or planned administration of any non-influenza vaccine within 30 days prior 
to randomization up to blood sampling on Day 21. Immunization on an emergency basis 
will be evaluated case-by-case by the Investigator; 
8. Administration of any adjuvanted or investigational influenza vaccine within one year prior 
to randomization or planned administration prior to the completion of the study; 
9. Administration of any ‘standard’, non-adjuvanted influenza vaccine (e.g. live attenuated 
trivalent/quadrivalent inactivated influenza vaccine or split trivalent/quadrivalent 
inactivated influenza vaccine administered by intranasal, intradermal, or IM route) within 
six months prior to randomization and up to completion of the study; 
10. Use of any investigational or non-registered product within 30 days or five half-lives, 
whichever is longer, prior to randomization or planned use during the study period. Subjects 
may not participate in any other investigational or marketed drug study while participating 
in this study until after the study; 
11. Treatment with systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or 
equivalent) per day for more than seven consecutive days or for 10 or more days in total, 
within one month of study vaccine administration; any other cytotoxic or 
immunosuppressant drug, or any immunoglobulin preparation within three months of 
vaccination and until the completion of the study. Low doses of nasal or inhaled 
glucocorticoids are allowed. Topical steroids are permitted; 
12. Any significant disorder of coagulation including, but not limited to, treatment with 
warfarin derivatives or heparin. Persons receiving prophylactic anti-platelet medications 
(e.g. low-dose aspirin [no more than 325 mg/day]), and without a clinically apparent 
bleeding tendency are eligible. Subjects treated with new generation drugs that do not 
increase the risk of IM bleeding (e.g. clopidogrel) are also eligible; 
13. History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine  or 
tobacco; 
14. History of anaphylactic allergic reactions to plants or plants components; 
15. Use of antihistamines with systemic absorption for more than 14 days in the four weeks 
prior to vaccination or use of antihistamines 48 hours prior to study vaccination (the use of 
topical antihistamines and nasal or inhaled steroids is acceptable); 

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16. Use of prophylactic medications (e.g. acetaminophen/paracetamol, aspirin, naproxen, or 
ibuprofen) within 24 hours of randomization to prevent or pre-empt symptoms due to 
vaccination. Any subject discovered to have taken a prophylactic medication to prevent or 
pre-empt symptoms due to vaccination within the 24 hours prior to planned randomization 
must be delayed until at least the 24 hours period is met; 
17. Planned use of influenza antiviral treatment medication before the collection of NP swabs 
(e.g. oseltamivir, zanamivir, rapivab); 
18. Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at 
the injection site that may interfere with injection site reaction rating; 
19. Subjects who have received a blood transfusion within 90 days prior to study vaccination; 
20. Any female subject who has a positive or doubtful pregnancy test result prior to vaccination 
or who is lactating; 
21. Subjects with abnormal vital signs (systolic blood pressure [BP] > 140 mmHg and/or 
diastolic BP ≥ 90 mmHg, heart rate [HR] ≤ 45 beats/min and ≥ 100 beats/min) evaluated by 
an Investigator to be clinically significant. A subject with abnormal vital signs results may 
be included in the study based on Investigator’s judgment (e.g. a resting HR ≤ 45 in highly-
trained athletes); 
22. Presence of any febrile illness (including an oral temperature [OT] ≥ 38.0 ˚C within 24 
hours prior to vaccination. Such subjects may be re-evaluated for enrolment after resolution 
of illness; 
23. Cancer or treatment for cancer within three years prior to study vaccine administration. 
Persons with a history of cancer who are disease-free without treatment for three years or 
more are eligible. However, individuals with conditions such as treated and uncomplicated 
basal cell carcinoma of the skin or non-treated, non-disseminated local prostate cancer may 
be eligible; 
24. Subjects identified as an Investigator or employee of the Investigator or clinical site with 
direct involvement in the proposed study, or identified as an immediate family member 
(i.e. parent, spouse, natural or adopted child) of the Investigator or employee with direct 
involvement in the proposed study or any employee of Medicago; 
25. Subjects with a history of Guillain-Barré Syndrome. 
5.3 
Prior and Concomitant Therapy 
Any new or changed medications reported by the subject post-vaccination and through to the end 
of the study will be recorded in the electronic case report form (eCRF) as a concomitant 
medication. Since AEs may be secondary to new medications, the Investigator will explore the 
reasons for the change or for the new medication intake and document these AEs, if any. 
Concomitant medications must be reported in the eCRF (reason for use, dates of administration, 
dosage, and route) if the use meets the following conditions: 
• Within 30 days preceding vaccination: any treatments and/or medications specifically 
contraindicated (e.g. influenza vaccines, any immunoglobulins or other blood products, or 
any immune modifying drugs, etc.); 

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• From randomization to Day 21, inclusive: any medication (including, but not limited to, 
over-the-counter medicines such as aspirin or antacids), vitamins, and mineral supplements; 
• From Day 22 to the end of the study, inclusive: any concomitant medication(s) 
administered to treat a NOCD (see Section 13.1.4 for definition of NOCD), SAE, or AE 
leading to withdrawal; any concomitant medication used to treat an AE that occurred before 
Day 21 and that is still being used afterwards (i.e. on-going use); and any concomitant 
medications used to treat a protocol-defined respiratory illness or ILI; 
• Any concomitant medication used to treat conditions reported as medical history; 
• Any investigational medication or vaccine; any vaccine not foreseen in the study protocol. 
Please refer to the eCRF completion guidelines for details of data entry requirements. 
Given that an important objective of this study is to evaluate the tolerability of the study vaccine, 
the use of prophylactic medications to prevent or pre-empt symptoms due to vaccination is 
specifically prohibited up to Day 7 (end of collection of solicited symptoms). A prophylactic 
medication is a medication administered in the absence of ANY symptom and in anticipation of 
a reaction to the vaccination (e.g. an antipyretic is considered to be prophylactic when it is given 
in the absence of fever or any other symptoms, to prevent fever from occurring, vitamins used to 
boost immune system, etc.). 
The use of influenza antiviral treatment (e.g. oseltamivir, zanamivir, rapivab) is not permitted 
until the NP swab is collected. 
5.4 
Prohibited Therapy 
Please refer to Section 5.2 (exclusion criteria numbers 4, 7, 8, 9, 10, 11, 12, 15, 16, 17, and 23) 
for details on medications or therapies prohibited prior to randomization, prior to NP swab 
collection, and/or during the conduct of this study. 
6 
TREATMENT ALLOCATION AND BLINDING 
6.1 
Randomization 
Randomization will be stratified by site and age group (18 to 49 years of age and 50 to 64 years 
of age in a 1:1 ratio). Subjects will be randomized to one of two treatment groups, based on a 
computer-generated randomization schedule prepared by or under the supervision of Medicago 
before the study. 
Potential study subjects will be screened and assigned a subject number. Once all screening 
procedures, including Day 0 pre-randomization procedures, have been completed and the study 
eligibility is confirmed by the Investigator, the randomization numbers will be allocated to 
subjects within the appropriate treatment group by the randomization system. 
Once a randomization number has been assigned, it will not be re-used for any reason. No 
subjects will be randomized into the study more than once. If a randomization number is 
allocated incorrectly, no attempt will be made to remedy the error once the study vaccine has 

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been dispensed: the subject will continue on the study with the assigned randomization number 
and associated treatment. The study staff will notify the Sponsor Contact as soon as the error is 
discovered without disclosing the study vaccine administered. Admission of subsequent eligible 
subjects will continue using the next unallocated number in the sequence. 
The randomization number and treatment will be recorded along with the six-digit subject 
number for each subject in the investigational product accountability log. The Investigator will 
not be provided with randomization codes, but it will be possible to unblind the treatment in an 
emergency situation. 
6.2 
Blinding 
This is an observer-blind study: the subjects, the Investigators, and those responsible for study 
endpoint evaluations or review or analysis of the study data will not have access to the 
randomization codes. Any code break will be documented and reported to Medicago (or its 
designee) in a timely manner. In a medical emergency, the Investigator may unblind the 
treatment for that subject without prior consultation with the Sponsor. In such an event, the 
Investigator will need to contact the responsible Medical Officer as soon as possible after the 
unblinding to discuss the case. 
Although there may be some visual differences in the VLP vaccine and placebo preparations, the 
site staff involved in the preparation and administration of the treatments will not be involved in 
any activity that could introduce a bias, such as the evaluations of respiratory symptoms, ILI, 
AEs, or reactogenicity of the subjects following vaccination. 
This study is blinded through to the end of the surveillance period of the last subject. The 
RT-PCR samples corresponding to influenza cases that might lead to the unblinding of the 
randomization code, will not be available during the course of the study to any investigator or 
any person directly involved in the clinical conduct of the study (including data cleaning and 
data analysis) except the independent biostatistical team from the contract research organization 
(CRO) and selected individuals from Medicago and the CRO. The selected individuals will 
review the number of influenza cases to allow for discussion of the clinical data and critical 
business decisions (e.g. extension of recruitment for another season) prior to study completion. It 
is anticipated that approximately five people from Medicago and the CRO will have access to the 
number of cases in a blinded manner. Also, the central laboratories and the staff at the clinical 
site (except the staff involved in the preparation/administration of the study vaccine, the quality 
assurance auditor, and the quality control reviewers) will remain blinded throughout the entire 
study duration. 
7 
DOSAGE AND ADMINISTRATION 
On Day 0, subjects will receive one IM injection, into the deltoid region of the non-dominant 
arm (if possible), of their assigned treatment (30 μg/strain of Quadrivalent VLP Influenza 
Vaccine or placebo). The volume of injection will be 0.5 mL for both the vaccine and placebo. 

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8 
SPECIMENS AND CLINICAL SUPPLIES 
8.1 
Management of Samples 
A urine sample will be collected during the screening/vaccination visit for a dipstick pregnancy 
test to be performed during the same visit for females of childbearing potential. 
Between vaccination and the end of the surveillance period, NP swabs will be collected from any 
subject who reports a new or a worsening respiratory illness (as defined in Section 10.2.1); these 
swabs will be collected each time a subject reports such an event (i.e. multiple collections may 
be required from a subject). Two swabs will be collected per subject per event. 
On Days 0 and 21, a blood sample for CMI (peripheral blood mononuclear cell [PBMC] assay) 
and humoral immunity analysis will be collected for a pre-defined subset of 400 subjects. 
Refer to the Study Procedure Manual for complete information on the handling, storage, and 
shipment of all laboratory samples. 
8.2 
Clinical Supplies 
Each study center will be provided with supplies for NP swabs and selected centers will be 
provided with serologic supplies (e.g. aliquot tubes, aliquot labels, aliquot storage, shipping 
boxes, and accompanying manifests). Sites will be authorized to use their own materials if 
agreed to by Medicago (or its designee). 
9 
TREATMENT COMPLIANCE 
Treatment compliance is expected to be 100 %, since the study treatments will be administered 
IM at each Investigator site by site staff. In addition, the Investigator or designated study center 
personnel will maintain a log of all study treatments dispensed and returned during the study. 
Study drug supplies for each subject will be inventoried and accounted for throughout the study 
(refer to Study Procedures Manual for details). 
10 STUDY EVALUATIONS 
10.1 Study Procedures 
10.1.1 Overview 
The Time and Events Schedule: General Information (see Table 1) summarizes the frequency 
and timing of scheduled assessments applicable to this study. 
The Time and Events Schedule: Respiratory Illness Onset (see Table 2) summarizes the 
frequency and timing of scheduled assessments associated with the onset of a respiratory illness 
(as defined in Section 10.2.1). 
Most subjects will have no blood sampled; the subset of subjects included in the immunogenicity 
analyses and who complete the study will have blood volumes drawn of 120 mL (Table 5). 

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Table 5 Estimated Blood Volume Drawn 
Type of Sample 
Volume per Sample (mL) 
Number of Samples per 
Subject 
Total Volume of Blood 
per Subject (mL) 
CMI response 
50 
2* 
100* 
HI, MN, and SRH titers 
10 
2* 
20* 
* Day 0 and Day 21 samples to be collected for a pre-defined subset of 400 subjects. 
10.1.2 Screening/Vaccination (Visit 1) 
Emergency equipment must be available on site and appropriate treatment must be instituted as 
soon as possible in the event of anaphylaxis or any other immediate hypersensitivity reaction. 
The Investigator will be on-site on vaccine administration days and for the duration of the 
observation period for the last subject dosed on that day. The Investigator will be available on 
call for the remainder of the study. A physician should be immediately available at the clinical 
site to administer treatment or to apply procedures for any immediate AEs/SAEs. 
10.1.2.1 Prior to Vaccination 
The following procedures will be performed on Day 0 (Visit 1) prior to vaccination: 
• Review and proceed with the signature of the ICF. The Investigator or his/her designee, 
will fully inform the subject of the nature and scope of the study, potential risks and 
benefits of participation, and the study procedures involved and will answer all questions 
prior to requesting the subject’s signature on the ICF. The subject’s consent must be 
obtained prior to performing any study-related procedures; this must be clearly recorded 
and a copy of the signed ICF retained in the source documents. A copy of the ICF must be 
provided to the subject; 
• Collect and review demographics (gender, date of birth, age, race, and ethnicity) and body 
measurements (BMI, weight [kg or lbs], and height [cm or inches]) data. BMI is to be 
calculated as body weight (kg) divided by the square of height (m); the BMI result will be 
rounded to one decimal place using the standard convention. For the measurement of body 
weight, subjects will be lightly clothed, without shoes; 
• Collect and review medical history, including the grade of any medical conditions. The 
medical history should record significant problems active at the time of screening and 
present within the preceding six months. Problems that have been clinically inactive for 
more than six months preceding screening, but which might alter the subject’s current or 
future medical management, should also be noted (e.g. known mitral valve prolapse or a 
remote history of a seizure disorder); 
• Review and record current and previous medication use (up to 30 days prior to study 
vaccine administration); 
• Record influenza vaccinations received within 24 months prior to the administration of the 
study vaccine; 

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• Perform a vital signs measurement, including resting BP, HR, and OT. OT will be collected 
in degrees Celsius or Fahrenheit using a digital thermometer. The OT measurement should 
not be collected immediately following consumption of a hot or cold beverage or after 
smoking. The BP will be taken after the subject has been in a seated position as per the 
site’s standard procedure. The BP should be taken by cuff (manual or automated are both 
acceptable). BP and HR may be repeated once if judged necessary. All measurements 
(including any repeats) will be recorded in the source documents. Inclusion of subjects with 
an out-of-range BP or HR measurement will be based on the Investigator’s judgment; 
• Perform a history- or symptom-directed physical examination. The physical exam will be 
performed by the Investigator; 
• Collect a urine sample for female subjects of childbearing potential and perform a urine 
dipstick pregnancy test. No study vaccine must be administered to a childbearing potential 
female until a negative result is obtained and documented; 
• Review the inclusion and exclusion criteria and determine the subject’s eligibility to 
participate in this study. The eligibility must be confirmed by the Investigator; 
• Register the subject in the interactive voice/web response system (IRT); the subject’s 
treatment group will be automatically assigned by this system; 
• Subjects for humoral and Day 0 CMI immunogenicity analyses only: collect baseline blood 
samples for CMI, HI, MN, and SRH assessments and prepare and store these samples until 
shipment to the analytical laboratory. 
10.1.2.2 Vaccination 
Once all pre-vaccination procedures have been completed and subject eligibility determined, the 
study vaccine will be administered (on Day 0) IM into the deltoid muscle of the non-dominant (if 
possible) arm. A 25 gauge needle of one inch or 2.5 cm in length should be used for vaccination 
for subjects with a BMI under 35; for subjects with a BMI of 35 and over, the use of a 25 gauge 
needle (when available) of 1.5 inches or 3.8 cm in length is required to reach the muscle. For 
subjects with BMI greater than or equal to 35, if the longer 25 gauge needle is not available, then 
a long 23 gauge needle (1.5 inches; 3.8 cm) can be used. In order to prevent possible 
confounding of vaccination site reactions, whenever possible, blood samples will not be 
collected from the same arm as the one used for vaccination. The arms used, both for blood 
collection and vaccination, will be documented in the source documents. 
10.1.2.3 Fifteen Minutes Post-vaccination 
The following safety observation procedures will be performed for all subjects immediately 
following study vaccine administration: 
• Subjects will remain in the clinic for at least 15 minutes post-vaccination for observation. 
The observation period will include an assessment of immediate solicited local and 
systemic reactions. Any unusual signs or symptoms reported during the initial 15 minutes 
post-vaccination will result in continued close monitoring. Based on their condition, 

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subjects may be asked to remain in the clinic for their safety for more than 15 minutes after 
vaccination (the reason will be recorded in the source documents). All data (including the 
assessment of solicited local and systemic reactions) will be recorded in the source 
documents during and after the observation period. Refer to Section 10.3.1 for details 
regarding the assessment of AEs and/or solicited local and systemic reactions; 
• During the observation period, subjects will be provided with a measurement device 
template for measuring (in mm) solicited local reactions of erythema (redness) and swelling 
and an oral digital thermometer for recording daily temperature (in degrees Celsius or 
Fahrenheit). Subjects will be shown how to enter their data in their eDiary. Each subject 
will be provided with the following instructions on the measurements they are to make: 
• 
How to collect his/her OT in degrees Celsius or Fahrenheit with the provided digital 
thermometer: 
• 
From the evening of Day 0 to the evening of Day 7, the subject will measure his/her OT 
at approximately the same time each evening and will record the results; 
• 
The OT should not be collected immediately following consumption of a hot or cold 
beverage or after smoking. 
• 
The subject is to also take his/her OT if he/she feels feverish and to record the highest 
temperature of the day. In the event that a temperature ≥ 38.0 °C or ≥ 100.4 °F is 
obtained, the subject will be allowed to take over-the-counter antipyretics 
(e.g. acetaminophen/paracetamol, aspirin, naproxen, or ibuprofen) and will be advised 
to increase the frequency of OT measurements to approximately every four hours, until 
he/she is no longer febrile (fever is defined as a temperature of ≥ 38.0 ºC or ≥ 100.4 °F). 
The subject is to document medication intake, which will be reviewed by the site 
personnel; 
• 
How to measure any solicited local reactions, including erythema (redness) and swelling 
diameter at the injection site using the measurement template supplied for this purpose; 
subjects will also be requested to evaluate pain at the injection site. Local reactions will 
be assessed every day starting in the evening of Day 0 and up to the evening of Day 7 and 
the results will be recorded. The severity of solicited local reactions will be graded 
according to the Food and Drug Administration (FDA) Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (FDA, 2007), as presented in Table 6. 
• 
How to grade, on a daily basis from the evening of Day 0 through to the evening of 
Day 7, each of the solicited systemic reactions and their severity (as per the same 
guidance used for solicited local reactions; see Table 6) (FDA, 2007) and to record the 
worst grade of the day for each of these solicited systemic reaction. The instructions will 
include how to examine and grade swelling in the neck and axilla and to record any 
unusual feeling and/or swelling; 
• 
Subjects will be advised that they will be asked about the occurrence of any symptoms or 
events requiring medical attention and the use of any concomitant medication during the 
21-day post-vaccination period and until the end of the surveillance period; 

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• 
Subjects will be instructed to contact the clinical site for any unsolicited AEs and/or 
solicited local and systemic reactions of greater than Grade 2 (moderate). Based on their 
condition, the Investigator may request that the subject return to the clinic for evaluation; 
• 
Subjects will be advised on emergency contact information and instructions for 
contacting study personnel. Subjects will be advised to immediately contact the 
Investigator (or his/her designee) in the event of an SAE or a medical emergency. 
Subjects will be provided with a phone contact number and be instructed to call if any 
suspected reaction to the vaccination is felt to be significant or of concern; 
• 
Subjects will be advised to notify their health care professional(s) (e.g. primary care 
physician) that they are participating in a clinical research study of an influenza vaccine; 
• After the 15-minute observation period (allowed window of + 15 minutes) is completed, 
measure vital signs (BP, HR, and OT) as described in Section 10.3.1.4. Any out-of-range 
measurements will be assessed by the Investigator (or his/her designee) and any further 
action will be determined upon his/her medical decision; 
• Instruct the subjects to perform measurements of local and systemic reactions at 
approximately the same time each day from Day 0 to Day 7 (preferably in the evening); 
• Provide appointments (date and time) for the next planned visit to the clinical site (Day 21) 
and also for the Days 1 and 8 phone contacts and passive and active surveillance periods; 
• The subject will be released from the clinical site once all Day 0 post-vaccination 
procedures have been completed and the subject is in stable condition. 
10.1.3 Day 1 and Day 8 (Telephone Contact) 
The following procedures will be performed during the phone contact (acceptable interval of 
+ 1 day for Day 1 and ± 1 day for Day 8): 
• Ask the subjects about any difficulties in recording their data, any change in health, any 
visits to health care facilities and/or medical practitioners, and any use of concomitant 
medications. Record the information in the source documents; 
• For any unsolicited AEs and/or solicited local and systemic reactions of greater than 
Grade 2 (moderate), the Investigator should be informed within 48 hours of the time the 
clinical site is made aware of the event. The Investigator may request that the subject return 
to the clinic for evaluation; 
• Advise subjects to immediately contact the Investigator (or his/her designee) in the event of 
any AE that requires medical attention. Subjects will be provided with a phone contact 
number and be instructed to call if any suspected reaction to the vaccination is felt to be 
significant or of concern; 
• Remind the subjects how to measure and record any solicited local and systemic reactions. 
Subjects should also be reminded to record any changes in health, including changes in 
AEs and changes in medications; 

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• Remind subjects to immediately report any new or a worsening respiratory illness, as 
defined in Section 10.2.1. Ensure that subjects have the reminder aid listing the respiratory 
illness symptoms and contact information for the study site; 
• Remind subjects to immediately report any symptoms that meet the definition of an ILI, as 
defined in Section 10.2.1. Ensure that subjects have the reminder aid listing the symptoms 
of ILI and contact information for the study site; 
• Remind subjects of their next appointment (date and time) for the clinical visit and/or the 
next phone contact. Subjects will also be reminded to record their data in the electronic 
system in a timely manner. 
In the event that a subject cannot be reached via phone, he/she may be contacted by text message 
or via email (if these contacts are available). However, the phone should be the initial and 
preferred means of communication. 
10.1.4 Surveillance for Respiratory Illness 
From Day 14 following randomization and vaccination, passive and active surveillance will be 
performed until the end of the end of the surveillance period: 
• Passive surveillance: subjects will be instructed to contact the clinical site within 24 hours 
in case of any new or worsening respiratory illness as defined in Section 10.2.1; 
• Active surveillance: subjects will be contacted a minimum of three times per week. At least 
one of these contacts each week will be through a scripted telephone call, with the 
remaining contacts via text messaging; a higher proportion of telephone contacts may be 
used if deemed appropriate by the clinic site (e.g. difficulty in obtaining responses via text 
messaging). 
Note: An episode of respiratory illness is considered to extend from the first day of the first 
symptom to the last day of the last symptom. In most cases, a new episode can only begin 
after resolution of all symptoms of the previous episode, with a separation of a seven-day 
symptom-free interval between episodes. However, some degree of site investigator discretion 
will be permitted in defining new episodes (e.g. a non-productive cough and fatigue persisting 
for ten days from one episode, with a new onset of myalgia, headache, and sore throat would 
constitute the onset of a valid new episode). 
If a subject reports a new or worsening respiratory illness: 
• 
Collect information regarding the respiratory illness, including all applicable symptoms 
and the onset date: 
• 
The onset date is defined as the first date when one or more of the qualifying 
symptoms (see above) occurred and persisted for at least 12 hours; 
• 
Symptoms collected should also include the presence or absence of concurrent 
systemic symptoms (i.e. fever, feverishness [feeling of warmth], chills [shivering], 
tiredness [fatigue], headache, myalgia [muscle aches], nausea, vomiting, or diarrhea); 
• 
Collect information on any associated concomitant medication use; 

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• 
Schedule a time when the subject can return to the clinic site for the collection of NP 
swabs. The NP swabs are to be collected within 36 hours (preferably within 24 hours) 
after reporting of the respiratory symptoms; 
• Respiratory illnesses that start on or after Day 14 will be followed up for 30 days after the 
illness start date, including occurrences of any of the following in association with any 
respiratory illness: pneumonia (clinical diagnosis), new onset or exacerbations of pre-
existing cardio-respiratory conditions, hospitalizations, emergency room visits, and non-
routine medical office visits, as well as the diagnoses associated with those instances. This 
follow-up will be conducted via the planned active surveillance contacts (telephone and 
text messaging). Information from more than 30 days from respiratory illness onset does 
not need to be collected. As part of this follow up, the following information will be 
needed: 
• 
Collect any new information regarding the evolution of the respiratory illness, including 
symptoms and any associated concomitant medication use; 
• 
Collect data regarding the end date (if resolved). The end date is defined as the date on 
which the last symptom resolved; 
• 
Collect information regarding disease burden and health care information: 
• 
Document whether the illness required consultation at a clinic or with a general 
practitioner or family physician and if so, how many consultations; 
• 
Document whether the illness required consultation at an emergency department and if 
so, how many consultations; 
• 
Document whether the illness required hospitalization and if so, for how many days; 
• 
Document any other medical interventions associated with the illness; 
• 
Document whether the illness resulted in missed work days and if so, how many; 
• 
Document any disease sequelae (including long-term); 
• Ask subjects if they have any ILI symptoms, as defined in Section 10.2.1; 
• Ensure subjects have the reminder aid listing the symptoms of ILI and contact information 
for the study site. 
In case a subject cannot be reached via phone, he/she may be contacted by text message or via 
email (if these contacts are available). However, other than for planned text message contacts, 
the phone should be the initial and preferred means of communication. 
10.1.5 Day 21 
For all subjects a safety follow-up will be performed on or shortly after Day 21 (- 2/+ 3 days): 
• Review the subject’s safety data and ensure all updates on concomitant medication usage 
and any changes in the subject’s health (AEs, SAEs, or NOCDs) are recorded 
appropriately; 

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• Advise the subjects to immediately contact the Investigator or his/her designee, in the event 
of any AE that requires a visit to an emergency room and/or hospitalization; 
• Remind the subjects of their next phone contact. 
Note: This safety follow-up will be performed during one of the surveillance telephone 
contacts either on or shortly after Day 21. For the subset of subjects participating in the CMI 
and humoral immunity assessment, this follow-up can be done during the Day 21 visit. 
The following procedures will be performed during the Day 21 (- 2/+ 3 days) visit for the subset 
of 400 subjects included in the immunogenicity analyses: 
• Collect blood samples for CMI, HI, MN, and SRH assessments and prepare and store these 
samples until shipment to the analytical laboratory; 
• Perform Day 21 safety follow-up (as described above) if it is to be done during this visit. 
Note: This visit might replace one of the phone contacts planned for that week. 
10.1.6 End of Surveillance (Telephone Contact) 
The following procedures will be performed during the end of surveillance telephone contact 
(approximately 30 April 2018 (the duration of surveillance period may be adjusted, based on the 
observed epidemiology during the season in participating countries); acceptable interval of ± 3 
days): 
• Record updates on any change in the subject’s health and report any SAEs or NOCDs; 
• Record updates on any changes in concomitant medications used to treat conditions 
reported in the subject’s medical history, AEs that started before Day 21 and were still 
ongoing after Day 21, SAEs, AEs leading to withdrawal from the study, or NOCDs as well 
as prohibited medication use (if any); 
• Confirm that the subject has continued to comply with protocol requirements (e.g. no use of 
prohibited concomitant medications, use of an adequate contraceptive method, reporting of 
any respiratory illness or ILI symptoms). 
Any subject who withdraws consent from the study will be asked to participate in the final 
telephone contact within two weeks of withdrawal, if the subject agrees. 
10.2 Efficacy 
10.2.1 Efficacy Evaluations 
Following randomization and vaccination, subjects will be instructed to report respiratory 
symptoms and symptoms meeting the definition of ILI from Day 14 until the end of the 
surveillance period (passive surveillance). The subjects will be given a reminder aid listing the 
symptoms of respiratory illness and ILI and contact information for the study site. During this 
same period, active surveillance will also be performed: respiratory illness symptoms will be 
solicited a minimum of three times per week. At least one of these contacts each week will be 
through a scripted telephone call, with the remaining contacts via text messaging; a higher 

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proportion of telephone contacts may be used if deemed appropriate by the clinical site 
(e.g. difficulty in obtaining responses via text messaging). 
A respiratory illness will be defined as the occurrence of a new onset of one or more of the 
following symptoms that persist(s) for or reoccur(s) after a period of at least 12 hours: 
• 
Sneezing; 
• 
Stuffy or runny nose (nasal congestion); 
• 
Sore throat; 
• 
Cough; 
• 
Sputum production; 
• 
Wheezing; 
• 
Difficulty breathing. 
An episode is considered to extend from the first day of the first symptom to the last day of the 
last symptom. As outlined in Section 10.1.4, in most instances a new episode can only begin 
after resolution of all symptoms of the previous episode, with a separation of a seven-day 
symptom-free interval between episodes. 
Within 36 hours (preferably within 24 hours) after the reporting of a respiratory illness, the clinic 
site will collect nasopharyngeal (NP) swabs from the subject (two per subject per event). The 
swabs must be collected prior to the use of any influenza antiviral treatment medication 
(e.g. oseltamivir, zanamivir, rapivab). If the respiratory illness starts prior to Day 14, swabs are 
not to be collected, even if symptoms persist beyond Day 14. One swab will be submitted for 
analysis by multiplex RT-PCR. In the event of a positive RT-PCR result (positive for A or B 
strains), the second swab will be used to attempt to isolate the virus or for additional cell-culture 
testing (typing, subtyping, and strain identification and genetic sequencing using HI assay 
against a panel of known standard ferret reference antisera to different viral strains) to determine 
if the virus detected is matched or similar to any of the strains covered in the vaccine formulation 
for the respective season. A positive RT-PCR result will be considered a laboratory-confirmed 
case of influenza. Any respiratory illness must be followed up for 30 days following the start 
date; this follow up will be conducted via the planned active surveillance contacts (telephone and 
text messaging), using a script. At the end of the 30-day follow up, a questionnaire regarding 
disease burden due to the respiratory illness will be completed (Section 19.2); subjects will be 
provided with a memory aid (Section 19.3) for use over the 30 days, to facilitate accurate 
reporting at the end of the follow-up period. 
ILI will also be monitored during this study. A subject will be considered to have protocol-
defined ILI if the following two conditions are both met between Day 14 and the end of the 
surveillance period: 
• He/she has at least one of the following pre-defined respiratory symptoms: 
• 
Sore throat; 
• 
Cough; 

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• 
Sputum production; 
• 
Wheezing; or 
• 
Difficulty breathing; 
AND 
• He/she has at least one of the following systemic symptoms: 
• 
Fever (defined as a temperature > 37.2 °C or > 99.0 °F); 
• 
Chills; 
• 
Tiredness; 
• 
Headache; or 
• 
Myalgia. 
10.2.2 Efficacy Endpoints 
10.2.2.1 Primary Endpoint 
• Occurrences of protocol-defined respiratory illness due to laboratory-confirmed influenza 
(≥ 14 days post-vaccination) caused by influenza viral types/subtypes that are matched 
(and/or antigenically similar) to the strains covered in the vaccine formulation. 
10.2.2.2 Secondary Endpoints 
• Occurrences of protocol-defined respiratory illness due to laboratory-confirmed influenza 
(≥ 14 days post-vaccination) caused by any influenza viral types/subtypes (matched, 
mismatched, and un-typed); 
• Occurrences of laboratory-confirmed influenza (according to protocol defined ILI) illnesses 
(≥ 14 days post-vaccination) caused by influenza viral types/subtypes that are matched 
(and/or antigenically similar) to the strains covered in the vaccine formulation; 
• Occurrences of laboratory-confirmed influenza (according to protocol defined ILI) illnesses 
(≥ 14 days post-vaccination) caused by any influenza viral types/subtypes (matched, 
mismatched, and un-typed); 
• Occurrences of protocol-defined ILI ≥ 14 days post-vaccination (confirmed or not). 
10.2.2.3 Exploratory Endpoints 
• Occurrences, per age stratum, of laboratory-confirmed influenza (≥ 14 days post-
vaccination) caused by influenza viral types/subtypes that are matched (and/or antigenically 
similar) to the strains covered in the vaccine formulations, according to protocol-defined 
respiratory illness; 
• Occurrences of laboratory-confirmed influenza illnesses (≥ 14 days post-vaccination) 
caused by mismatched influenza viral strains, according to protocol-defined respiratory 
illness; 

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• Occurrences of respiratory illness ≥ 14 days post-vaccination (confirmed or not). 
10.3 Safety 
10.3.1 Evaluations 
Safety and tolerability will be evaluated by solicited local and systemic reactions (immediate 
complaints within 15 minutes post-vaccination and reactions up to seven days post-vaccination), 
unsolicited AEs up to 21 days post-vaccination, and SAEs and NOCDS up to the end of the 
surveillance period. 
10.3.1.1 Solicited Local and Systemic Reactions 
Subjects will be monitored for both solicited local reactions (erythema, swelling, and pain at the 
injection site) and solicited systemic reactions (fever, headache, fatigue, muscle aches, joint 
aches, chills, a feeling of general discomfort, swelling in the axilla, and swelling in the neck) 
from the time of vaccination through Day 7. While the subjects remain in the clinic following 
vaccine administration, staff will monitor them for local and systemic reactions; after release 
from the clinic facility, from the evening of Day 0 to the evening of Day 7, subjects will measure 
and record their local and systemic reactions in their eDiary. 
The intensity of the solicited local and systemic reactions will be graded as: mild (1), moderate 
(2), severe (3) or potentially life threatening (4) (please refer to Table 6). Their causal 
relationship with the study vaccine will be assessed by the Investigator (definitely not related, 
probably not related, possibly related, probably related or definitely related); see Section 13.1.9 
for a definition of these causal relationships. 
Table 6 Severity Grades for Solicited Local and Systemic Reactions 
Symptoms 
Severity 
None 
Grade 1  
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially life-
threatening) 
Injection Site Reactions (Local Reactions) 
Erythema (redness) 
< 25 mm 
25 - 50 mm 
51 - 100 mm 
> 100 mm 
Necrosis or 
exfoliative 
dermatitis  
Swelling 
< 25 mm 
25 - 50 mm and 
does not interfere 
with activity 
51 – 100 mm or 
interferes with 
activity 
> 100 mm or 
prevents daily 
activity  
Necrosis 
Pain 
None 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever for more 
than 24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Solicited Systemic Reactions 
Fever (ºC or ºF) 
 
< 38.0 ºC 
< 100.4 ºF 
38.0 - 38.4 ºC 
100.4 - 101.1 ºF 
38.5 - 38.9 ºC 
101.2 - 102.0 ºF 
39.0 - 40.0 ºC 
102.1 - 104.0 ºF 
> 40.0 ºC 
> 104.0 ºF 

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Symptoms 
Severity 
None 
Grade 1  
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially life-
threatening) 
Headache 
None 
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever for more 
than 24 hours or 
some interference 
with activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Fatigue  
None 
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Muscle aches 
None 
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Joint aches, chills, 
feeling of general 
discomfort or 
uneasiness (malaise), 
swelling in the axilla, 
swelling in the neck 
None 
No interference 
with activity 
Some interference 
with activity not 
requiring medical 
intervention  
Prevents daily 
activity and 
requires medical 
intervention  
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
10.3.1.2 Adverse Events 
All AEs occurring within 21 days after vaccination will be reported in the “Adverse Event” 
screen in the subject’s eCRF, irrespective of intensity or whether or not they are considered to be 
vaccination-related. Thereafter, from Day 22 to the end of the surveillance period, SAEs, AEs 
leading to withdrawal, and NOCDs will be monitored and reported in the eCRF. 
The intensity of AEs will be graded as: mild (1), moderate (2), severe (3) or potentially life 
threatening (4), according to the FDA Guidance for Industry (FDA, 2007). Their causal 
relationship with the study vaccine will be assessed by the Investigator (definitely not related, 
probably not related, possibly related, probably related or definitely related); see Section 13.1.9 
for a definition of these causal relationships. 
10.3.1.3 Clinical Laboratory Tests 
As part of screening procedures, a urine sample will be collected for female subjects of 
childbearing potential for a urine dipstick pregnancy test that will be performed prior to the 
eligibility assessment on Day 0. 
10.3.1.4 Vital Signs 
Vital signs measurements (resting BP, HR, and OT) will be performed as part of screening 
procedures (prior to eligibility assessment on Day 0) and after the post-vaccination surveillance 
period. 

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OT will be collected in degrees Celsius or Fahrenheit using a digital thermometer. The OT 
measurement should not be collected immediately following consumption of a hot or cold 
beverage or after smoking. 
BP will be taken after the subject has been in a seated position as per the site’s standard 
procedure. BP should be taken by cuff (manual or automated are both acceptable). BP and HR 
may be repeated once if judged necessary. All measurements (including any repeats) will be 
recorded in the source documents. 
10.3.1.5 Physical Examinations 
A history- or symptom-directed physical examination will be performed by the Investigator as 
part of screening procedures (prior to eligibility assessment on Day 0). 
10.3.2 Pregnancy 
Female subjects who become pregnant during the study will be followed for safety. The 
Investigator, or his/her designee, will collect pregnancy information on any subject who becomes 
pregnant while participating in this study. The Investigator or his/her designee will record 
pregnancy information on the Pregnancy Report Form (for the template of the form, refer to 
Study Procedures Manual) and submit it to the Sponsor Safety Contact (see Section 13.1.6) 
within 24 hours of learning of a subject's pregnancy. The subject will be followed to determine 
the outcome of the pregnancy. At the end of the pregnancy, whether full-term or premature, 
information on the status of the mother and child will be forwarded to the Sponsor Safety 
Contact, if available. Generally, follow-up will be no longer than six to eight weeks following 
the estimated delivery date. 
While pregnancy itself and elective termination of a pregnancy for non-medical reasons are not 
considered to be an AE/SAE, any pregnancy complication or elective termination of a pregnancy 
for medical reasons will be recorded in the Pregnancy Report Form or as an SAE and will be 
followed. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Furthermore, any SAE occurring as a result of a post-study pregnancy and considered 
reasonably related in time to receipt of the investigational product by the Investigator, will be 
reported to the Sponsor Safety Contact. While the Investigator is not obligated to actively seek 
this information from former study subjects, he/she may learn of a pregnancy through 
spontaneous reporting. Information on pregnancies identified during the screening phase/prior to 
vaccine administration do not need to be collected; this information need not be communicated 
to Medicago (or its designee). 
10.3.3 Safety Endpoints 
10.3.3.1 Secondary Endpoints 
• Percentage, intensity, and relationship to vaccination of immediate complaints (15 minutes 
post-vaccination); 

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• Percentage, intensity, and relationship to vaccination of solicited local and systemic signs 
and symptoms (for seven days following study vaccine administration); 
• Percentage, intensity, and relationship of TEAEs for 21 days following study vaccine 
administration; 
• Occurrences of deaths, SAEs, AEs leading to withdrawal, and NOCDs up to the end of the 
surveillance period. 
10.3.3.2 Exploratory Endpoint 
• Information on respiratory illness outcome, occurrences of pneumonia, new onset or 
exacerbations of cardio-respiratory conditions, and health care utilization during the entire 
trial follow up period. 
10.4 Immunogenicity 
10.4.1 Immunogenicity Evaluations 
Immunogenicity will be evaluated by the humoral immune response (HI, MN, and SRH assays) 
and the CMI response induced in subjects on Days 0 and 21 in a subset of 400 subjects (300 
from the VLP vaccine group and 100 from the placebo group) from selected sites. The North 
American sites selected for this subset of 400 subjects will be pre-defined prior to study start and 
will target providing a representative age distribution. 
10.4.2 Immunogenicity Endpoints 
10.4.2.1 Secondary Endpoints 
• HI antibody response induced by the Quadrivalent VLP Influenza Vaccine against the 
homologous and heterologous influenza strains on Days 0 and 21 in a subset of 400 
subjects. HI antibody titers will be analyzed as follows: 
• 
GMTs of HI antibody on Days 0 and 21; 
• 
SC rate: the proportion of subjects in a given treatment group with either a ≥ 4-fold 
increase in reciprocal HI titers between Day 0 and Day 21 or a rise of undetectable HI 
titer (i.e. < 10) pre-vaccination (Day 0) to an HI titer of ≥ 40 on Day 21; 
• 
SP rate: the proportion of subjects in a given treatment group attaining a reciprocal HI 
titer of ≥ 40 on Day 21 (the percentage of vaccine recipients with a serum HI titer of at 
least 1:40 following vaccination); 
• 
GMFR: the geometric mean of the ratio of GMTs (Day 21/Day 0). 
The immunogenicity endpoints for all four homologous influenza antigens will be evaluated 
according to the CBER criteria. 
• MN antibody response induced by the Quadrivalent VLP Influenza Vaccine against the 
homologous influenza strains on Days 0 and 21, in the subset of 400 subjects, will be 
analysed as follows: 

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• 
GMTs of MN antibody on Days 0 and 21; 
• 
SC rate on Day 21 (as defined above for HI); 
• 
GMFR (Day 21/Day 0). 
• SRH antibody response induced by the Quadrivalent VLP Influenza Vaccine against the 
homologous strains on Days 0 and 21 in a subset of 400 subjects, will be analysed as 
follows: 
• 
GMAs of SRH antibody on Days 0 and 21; 
• 
SC rate: proportion of subjects in a given treatment group showing at least 50 % increase 
in GMA between Days 0 and 21; 
• 
SP rate: the proportion of subjects in a given treatment group attaining an area diameter 
≥ 25 mm2 following vaccination (Day 21); 
• 
GMFR: the geometric mean of the ratio of GMAs (Day 21/Day 0). 
10.4.2.2 Exploratory Endpoint 
• CMI response induced by the Quadrivalent VLP Influenza Vaccine against homologous 
and heterologous strains on Day 21 (in the subset of 400 subjects). 
11 SUBJECT COMPLETION/WITHDRAWAL 
11.1 Temporary Contraindications 
Some exclusion criteria that render subjects ineligible for the study may be temporary in nature: 
• Temperature ≥ 38.0 ºC or ≥ 100.4 ºF within 24 hours prior to randomization; 
• Acute cold symptoms such as upper respiratory tract infection symptoms, with or without 
fever, that resolve at least 48 hours prior to randomization. 
Following the resolution of such conditions, a subject may be considered eligible by the 
Investigator and be enrolled in the study. 
11.2 Screening Failures 
Screening failures are subjects who have signed the study-specific ICF but are not eligible for 
enrolment (subjects who were not randomized), due to failure on one or more of the inclusion or 
exclusion criteria or because the subject withdrew consent prior to randomization. Eligible/not 
treated subjects are subjects that have signed the ICF and are eligible for enrolment, but were 
either not randomized or randomized and not treated. 
Recording of screening failures and eligible/not treated subjects will be carried out in the study 
records maintained at the participating clinical sites. Neither of these subject classes will receive 
a safety follow-up. 
A screening failure subject can be rescreened once, with prior authorization from Medicago or its 
designee. If the subject is rescreened, a new subject number will be allocated. 

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11.3 Removal of Subjects from Treatment or Assessment 
Subjects will be advised that they are free to withdraw from the study at any time without 
prejudice to their future medical care by the physician or the institution. Subjects who withdraw 
or are withdrawn from the study after vaccination will not be replaced. 
Every reasonable effort will be made to ensure that each subject complies with the protocol and 
completes all study visits. However, a subject may withdraw or be withdrawn from participation 
if: 
• The subject withdraws consent; 
• The subject displays non-compliance to the terms of their participation in the clinical study 
(based on Investigator’s or Medicago’s [or its designee’s] opinion); 
• Safety reasons as judged by the Investigator and/or Medicago (or its designee); 
• Medicago or the regulatory authority(ies) terminates the clinical study. 
Withdrawal subjects will be those who leave the study before the end of the surveillance period, 
for whatever reason; withdrawal subjects will not be replaced. Any subject who withdraws 
consent from the study will be asked to participate in the final telephone contact within two 
weeks of withdrawal, if the subject agrees. The procedures performed for the final assessment 
will comprise those for the end of surveillance telephone contact, if permitted by the subject. All 
withdrawal subjects must be reported to Medicago (and/or its designee). The reason for 
withdrawal should be documented in the subjects’ records and in the appropriate section of the 
eCRF. The eCRF must be completed up to and including the time of the drop-out/final 
assessment. 
11.3.1 Follow-up of Discontinuations 
All subjects who receive a study vaccine will be followed for safety until the end of the 
surveillance period, if permitted by the subject. 
11.3.2 Lost to Follow-up Procedures 
Every attempt will be made to contact study subjects who are lost to follow-up. At least three 
contacts will be attempted and recorded in the source documents. As a last resort, one registered 
letter requesting contact with the site will be sent to any subject with whom the clinic staff no 
longer has contact. All attempts at contact will be documented in the subject’s source documents. 
11.4 Interruption of the Study 
The Investigator (in consultation with Medicago [or its designee]), Medicago, or Regulatory 
Authorities may interrupt or terminate this study for any reason. The Investigator will 
immediately, on discontinuance of the clinical study at the clinical site, inform both the study 
subjects and the Institutional Review Board (IRB) responsible for the study of the 
discontinuance, provide them with reasons for the discontinuance and advise them in writing of 
any potential health risks to the subjects themselves or to other persons. It is Medicago’s (or its 

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designee’s) responsibility to report discontinuance of the study to the local regulatory agencies 
within the appropriate timeframe, providing them with the reasons for the discontinuance and 
advising them in writing of any potential health risks to the study subjects or to other persons. 
Medicago (or its designee) must then inform the Investigator that the appropriate notifications 
were done. 
12 STATISTICAL METHODS 
A general description of the statistical methods used to analyze the efficacy, safety, and 
immunogenicity data is outlined below. Complete details will be provided in the SAP, which will 
be finalized prior to database lock. 
12.1 Analysis Populations 
12.1.1 Safety Analysis Set 
The SAS is defined as all subjects who received either the Quadrivalent VLP Influenza Vaccine 
or the placebo. All safety analysis will be performed using the SAS, according to the treatment 
the subjects actually received. 
12.1.2 Full Analysis Set 
The FAS will consist of the subset of subjects in the SAS who were successfully contacted at 
least once during the surveillance period. Subjects who received the wrong treatment will be 
analyzed as randomized. 
12.1.3 Per Protocol Set 
The PP set will consist of the subjects who participated in the study until at least the end of the 
peak period (approximately the end of February for Europe and North America) or for at least 
five months or until the end of the surveillance period (other countries); had no major protocol 
deviations related to subject eligibility, the ability to develop a valid immune response, 
prohibited medication use, or the efficacy analyses; and who received the vaccine or placebo. 
Major protocol deviations will be identified and documented during a blinded data review prior 
to database lock and confirmed at the time of database lock. The PP set will be the primary 
analysis population for the efficacy and immunogenicity endpoints. Subjects who received the 
wrong treatment, but for whom the treatment received can be unequivocally confirmed, will be 
analyzed as treated, provided they have no other deviations that compromise their data. 
The analyses of all efficacy endpoints will be performed using the efficacy PP population and the 
FAS population. 
The immunogenicity PP set will consist of the subset of subjects who participated in the 
immunogenicity portion of the study, who had a Day 21 immunogenicity sample collection; who 
had no major deviations related to subject eligibility, the ability to develop a valid immune 
response, prohibited medication use, or the immunogenicity analyses; and who received the 
vaccine or placebo. Subjects who received the wrong treatment, but for whom the treatment 

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received can be unequivocally confirmed, will be analyzed as treated, provided they have no 
other deviations that compromise their data. 
12.2 Sample Size Determination 
The sample size of approximately 10,000 subjects (5,000 subjects per treatment group) was 
selected based on the assumption that the Quadrivalent VLP Influenza Vaccine would have a VE 
of at least 70 % and that the ARU would be 2 % or greater for laboratory-confirmed influenza 
caused by vaccine-matched strains. The sample size was chosen to have 90 % power to 
determine whether the lower bound of the two-sided 95 % CI for the primary endpoint would be 
greater than 40 %, assuming a 10 % attrition rate. 
If the ARU is lower than 2 %, but greater than or equal to 1.5 %, this sample size will have an 
80 % power to determine whether the lower bound of the two-sided 95 % CI for the primary 
endpoint (VE) would be greater than 40 %, assuming a 10 % attrition rate. 
A protocol amendment will be issued to address changes to the enrolment plan in the event of 
insufficient ARU. 
12.3 Efficacy Analyses 
Efficacy endpoints are described in Section 10.2.2. 
All descriptive and inferential statistical analyses will be performed using Statistical Analysis 
System® (SAS®) software (version 9.3 or higher). Details of the statistical analyses are provide 
in the SAP. 
Analyses of primary and secondary endpoints will include each group as a whole as well as 
comparisons by age strata (18 to 49 years and 50 to 64 years). 
12.3.1 Analysis of Primary Endpoint 
The primary efficacy endpoint is defined in Section 10.2.2.1. 
For the primary endpoint, VE will be evaluated as the relative risk of vaccinated (30 µg/strain 
VLP vaccine) and unvaccinated (placebo) subjects to become infected with protocol-defined 
respiratory illness caused by one or more vaccine-matched strains in a timeframe of 14 or more 
days following vaccination (i.e. the proportion of subjects with one or more episodes of 
respiratory illness shown to be caused by viral types/subtypes that are matched and/or 
antigenically similar to the strains covered in the vaccine formulation). 
VE will be calculated using the following formula: 
VE=(1-ARV/ARU)*100 % 
Where: 
  ARV = attack rate in vaccinated subjects; and 
  ARU = attack rate in unvaccinated subjects. 

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The VE success criterion is defined as a > 40 % lower limit of the two-sided 95 % CI. 
12.3.2 Analysis of Secondary Endpoints 
The secondary efficacy endpoints are defined in Section 10.2.2.2. 
VE will be calculated for the following endpoints, using the same formula indicated for the 
primary efficacy analysis: 
• The relative risk of vaccinated (30 µg/strain VLP vaccine) and unvaccinated (placebo) 
subjects to become infected with protocol-defined respiratory illness caused by any 
influenza strain in a timeframe of 14 days or more following vaccination (i.e. the 
proportion of subjects with one or more episodes of respiratory illness shown to be caused 
by any influenza strain [matched, mismatched, and un-typed with the strains covered in the 
vaccine formulation]); 
• The relative risk of vaccinated (30 µg/strain VLP vaccine) and unvaccinated (placebo) 
subjects to become infected with laboratory-confirmed ILI caused by one or more vaccine-
matched strains in a timeframe of 14 or more days following vaccination (i.e. the 
proportion of subjects with one or more episodes of ILI shown to be caused by viral 
types/subtypes that are matched and/or antigenically similar to the strains covered in the 
vaccine formulation); 
• The relative risk of vaccinated (30 µg/strain VLP vaccine) and unvaccinated (placebo) 
subjects to present with ILI in a timeframe of 14 days or more following vaccination, 
regardless of the laboratory results (i.e. the proportion of subjects with at least one episode 
of protocol-defined ILI). 
12.3.3 Analysis of Exploratory Endpoints 
The exploratory efficacy endpoints are defined in Section 10.2.2.3. 
VE will be calculated for the following endpoints, using the same formula indicated for the 
primary efficacy analysis: 
• The relative risk, per age stratum, of vaccinated (30 µg/strain VLP vaccine) versus 
unvaccinated (placebo) subjects with laboratory-confirmed influenza caused by one or 
more vaccine-matched strains in a timeframe of 14 days or more following vaccination 
(i.e. the proportion of subjects in each age stratum with one or more episodes of respiratory 
illness shown to be caused by viral types/subtypes that are matched and/or antigenically 
similar to the strains covered in the vaccine formulation); 
• The relative risk of vaccinated (30 µg/strain VLP vaccine) and unvaccinated (placebo) 
subjects to become infected with laboratory-confirmed influenza caused by a mismatched 
influenza strain in a timeframe of 14 days or more following vaccination (i.e. the 
proportion of subjects with one or more episodes of respiratory illness shown to be caused 
by viral types/subtypes that are not antigenically similar to the strains covered in the 
vaccine formulation); 

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• The relative risk of vaccinated (30 µg/strain VLP vaccine) and unvaccinated (placebo) 
subjects to present with respiratory illness symptoms in a timeframe of 14 days or more 
following vaccination regardless of the laboratory results (i.e. the proportion of subjects 
with at least one episode of protocol-defined respiratory illness). 
12.4 Baseline and Subject Disposition 
Demographic data and influenza immunization history will be presented in listings and 
summarized by treatment. Continuous variables including age, weight, height, and BMI will be 
summarized with mean, median, standard deviation, minimum, and maximum. Count and 
percentage of subjects will be presented for categorical variables such as sex, race, ethnicity, and 
immunization history. 
The number of subjects in different study disposition statuses will be summarized by number 
and, when applicable, percentage (based on vaccinated subjects). Subjects’ 
completion/discontinuation status will be listed (including subject identifier, date of 
completion/early discontinuation and, for those who discontinued early, the specific reason(s) for 
discontinuation). 
12.5 Safety Analyses 
The safety endpoints are defined in Section 10.3.3. 
12.5.1 Analysis of Secondary Endpoints 
The secondary safety endpoints are defined in Section 10.3.3.1. 
Safety and tolerability endpoints (immediate complaints, solicited local and systemic reactions, 
and TEAEs, deaths, SAEs, AEs leading to subject withdrawal, and NOCDs) will be summarized 
by treatment using descriptive statistics. 
The original terms used in the eCRFs by Investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®). All eCRF reported AEs with onset 
post-vaccination will be included in the safety analyses. 
Special attention will be given to those subjects who die, who discontinue from the study due to 
an AE, who experience an SAE (e.g. summaries, listings, and narrative preparation may be 
provided, as appropriate), or who experience an allergic or allergic-like reaction (see 
Section 13.1.3). 
Analyses of secondary safety endpoints will include each group as a whole as well as 
comparisons by age strata (18 to 49 years and 50 to 64 years). 
12.5.2 Analysis of Exploratory Endpoint 
The exploratory safety endpoint is defined in Section 10.3.3.2. 
The occurrences of medical visits, hospitalizations, and workdays missed will be summarized by 
treatment using descriptive statistics. 

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12.6 Immunogenicity Analyses 
12.6.1 Analysis of Secondary Endpoints 
The secondary immunogenicity endpoints are defined in Section 10.4.2.1.  
For the immunogenicity analysis of the HI assays against the homologous strains, the point 
estimates and the corresponding two-sided 95 % CI will be calculated to determine if the CBER 
criteria for licensure for influenza vaccine are met. The following analyses for the HI assay 
(homologous strains) will be performed on the immunogenicity PP: 
• GMT (Day 21): The point estimates and the corresponding two sided 95 % CI by treatment 
group and strain will be calculated as the antilog of the mean and 95 % CI of log 
transformed titer values; 
• SC rate (Day 0 and Day 21): The point estimates and the corresponding two-sided 95 % CI 
for subjects achieving SC by treatment group and strain will be calculated to determine 
whether the lower bound of the CI will meet or exceed 40 %; 
• SP rate (Day 21): The point estimates and the corresponding two-sided 95 % CI for 
subjects achieving SP by treatment group and strain will be calculated to determine whether 
the lower bound of the CI will meet or exceed 70 %. 
The analyses for the MN and SRH assays (homologous strains) will be performed on the 
immunogenicity PP. The GMTs, GMFRs, and SC rates of the MN antibody assay and the 
GMAs, GMFRs, SC rates, and SP rates for the SRH antibody assay will be compared between 
the treatment groups using descriptive statistics and 95 % CI. For SC rate and SP rate, Fisher’s 
exact tests or chi square tests will be used. GMT and GMFR for MN and GMA and GMFR for 
SRH will be compared using appropriate analysis of variance (ANOVA) models. 
Analyses of secondary immunogenicity endpoints will include each group as a whole as well as 
comparisons by age strata (18 to 49 years and 50 to 64 years). 
12.6.2 Analysis of Exploratory Endpoint 
The exploratory immunogenicity endpoint is defined in Section 10.4.2.2. 
The CMI response will be compared between the treatment groups using appropriate non-
parametric (Wilcoxon) models. Additional details will be provided in the SAP. 
13 ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, Investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. 

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13.1 Definitions 
13.1.1 Serious Adverse Events 
An SAE is any untoward medical occurrence (whether or not considered to be related to the 
study vaccine) that, at any dose: 
• Results in death; 
• Is life-threatening (at the time of the event); 
Note: the term “life-threatening” in the definition of an SAE refers to an event that put the 
subject at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe; 
• Requires inpatient hospitalization (≥ 24 hours) or prolongation of existing hospitalization 
(elective hospitalizations/procedures for pre-existing conditions that have not worsened are 
excluded); 
• Results in persistent or significant disability/incapacity; 
• Is a congenital abnormality/birth defect; 
• Is another medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but that may jeopardize the subject’s health 
or may require an intervention to prevent one of the other outcomes listed in the definition 
above. These events should be considered serious. Examples of such events are intensive 
treatment in an emergency room for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or the development of drug dependency or drug abuse. See 
Section 13.1.6 for initial SAE reporting by the Investigator. 
13.1.2 Adverse Events 
An AE or adverse experience is defined as any untoward medical occurrence in a subject or 
clinical investigation subject who was administered a pharmaceutical product, with or without a 
causal relationship with the treatment. An AE can be any favorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
related to a medicinal product. 
Information such as the date and time of onset and resolution (duration), intensity (defined 
below), seriousness, any required treatment or action taken, outcome, relationship to the 
investigational vaccine, and whether the AE caused withdrawal from the study will be collected. 

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The intensity of all AEs will be graded as mild (1), moderate (2) severe (3), or potentially life 
threatening (4), according to the FDA Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA, 2007) 
and the following definitions: 
Mild (Grade 1): 
The AE is easily tolerated and does not interfere with usual 
activity; 
Moderate (Grade 2): 
The AE interferes with daily activity, but the subject is still able 
to function; 
Severe (Grade 3): 
The AE is incapacitating and the subject is unable to work or 
complete usual activity; 
Potentially life-threatening 
(Grade 4): 
The AE is likely to be life-threatening if not treated in a timely 
manner. 
The Investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the investigational product or not) until the outcome of the AE has been 
determined. 
If any of the solicited local or systemic reactions persist beyond Day 7, these will also be 
recorded as AEs. In this case, the AE start will be set as eight days post-vaccination. The subject 
will be requested to note when the AE resolves and to report this information to the Investigator 
or clinic staff at the next visit at the clinical site or contact. 
The clinical importance of AEs will be determined based upon the Investigator’s judgment. The 
Investigator must ensure that any sample obtained to follow-up on an AE is properly labeled and 
stored. The Investigator and others responsible for care of the subjects should institute any 
supplementary investigations of significant AEs based on the clinical assessment of the likely 
causative factor. This may include seeking the opinion of a specialist in the field of the AE. 
All AEs occurring within 21 days after vaccination must be reported in the “Adverse Event” 
screen in the subject’s eCRF, irrespective of intensity or whether or not they are considered to be 
vaccination-related. Thereafter, from Day 22 through to the end of the surveillance period, SAEs, 
AEs leading to withdrawal, and NOCDs (see Section 13.1.4 for definition) will be monitored and 
reported in the eCRF. Additional details on eCRF entries can be found in the eCRF completion 
guidelines. 
The SAEs and NOCDs will be followed up until complete resolution or stabilization. Follow-up 
of unresolved SAEs, AEs leading to withdrawal, or NOCDs after the end of the surveillance 
period will continue under the discretion of the Investigator. 
13.1.3 Adverse Events of Special Interest 
Based on the data from the five studies conducted to date, there is no evidence of anaphylactic 
reactions associated with use of the Quadrivalent VLP Influenza Vaccine in humans: a small 
number of subjects had potential hypersensitivity reactions judged to be related to vaccine 
administration (no more than 0.3 % of subjects in any given VLP treatment group experienced 
one of these events) and the events were distributed fairly evenly among treatment groups, 

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including the placebo and the active comparator groups. However, since severe reactions are 
considered to be an important potential risk (based on the theoretical risk that using plants for the 
production of biotherapeutics may induce hypersensitivity) the sponsor will continue to require 
that appropriate medical treatment and supervision are available to manage any possible 
anaphylactic reactions. 
To collect additional data on these events, Medicago will closely monitor and assess allergic or 
allergic-like reactions as AEs of special interest. Thus, to collect specific data under this 
protocol, the Investigator should, whenever possible, take a picture of any occurrence of allergic 
or allergic-like reactions and send the anonymized images to Medicago as described in the Study 
Procedure Manual. 
13.1.4 New Onset of Chronic Disease 
In the context of this study, all NOCDs that may plausibly have an allergic, autoimmune or 
inflammatory component are to be reported. Plausibility should be interpreted broadly however; 
the only clear exceptions are degenerative conditions such as osteoarthritis, age-related 
physiologic changes (e.g. benign prostatic hypertrophy) and life-style diseases (e.g. alcohol-
associated cirrhosis, bronchitis in a smoker, etc.). In this context, most cancers, cardiac 
conditions and kidney diseases should be reported. 
NOCDs will be collected from vaccination on Day 0 to the end of the surveillance period and 
reported as an AE or SAE, as applicable. 
13.1.5 Expectedness of an Adverse Drug Reaction 
An “unexpected” adverse reaction is one in which the nature or severity of the event is not 
consistent with information in the current version of the IB. Expedited reporting to the regulatory 
authorities is required if an SAE occurs that is both unexpected and considered possibly, 
probably, or definitely related to the study vaccine. 
13.1.6 Initial SAE Reporting by the Investigator 
SAEs related to pre-treatment study procedures will be reported from the time the ICF is signed. 
All post-vaccination SAEs (treatment-emergent SAEs) will be reported from the time of 
receiving the study vaccine on Day 0 through to the end of the surveillance period (final 
scheduled phone contact). The Investigator (or designee) must report, by phone or email, all 
SAEs, whether considered related to the study vaccine or not, and whether considered 
unexpected or expected (as defined in Section 13.1.1), to Medicago (or its designee) within 24 
hours of the Investigator learning of the event. The Investigator must also complete the AE 
screen of the eCRF page for SAE reporting. If the eCRF is not available, the Investigator must 
use a paper SAE report form, and send, via e-mail, a copy to the Medicago safety e-mail address 
and the appropriate regional (Americas or EU/APAC) e-mail address: 
Medicago Safety e-mail address: 
Medicago-Safety@medicago.com 
Americas SAE e-mail address: 
CCI

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EU/APAC SAE e-mail address: 
 
 
Sponsor Safety Contact: 
 
 
 
 
13.1.7 Follow-up Reporting by the Investigator 
All SAEs, regardless of causality, will be followed as described in Section 13.1.2. When 
appropriate, documentation of any medical tests or examinations performed will be provided to 
document resolution/stabilization of the event. 
13.1.8 Reporting of SAEs Occurring after Surveillance Period or Study Termination 
All SAEs occurring during the safety follow up period will be followed until the end of the 
surveillance period. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE detection 
period (post surveillance period). Active follow-up for AEs or SAEs will continue until the end 
of the surveillance period for all subjects. However, after the end of the surveillance period, if 
the Investigator learns of any SAE, including death, at any time after a subject has been 
discharged from the study, and he/she considers the event to be reasonably related to the 
investigational product, the Investigator will promptly notify the Sponsor Safety Contacts for 
Reporting SAEs. 
13.1.9 Causal Relationship 
The Investigator must make the determination of relationship to the study vaccine for each AE. 
The Investigator should decide whether, in his/her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational vaccine. If there is any 
valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the investigational vaccine and the occurrence of the AE, then the AE 
should be considered “definitely related”, “probably related”, or “possibly related”. Otherwise, if 
no valid reason exists for suggesting a possible relationship, then the AE should be classified as 
“probably not related” or “definitely not related”. The following guidance should be followed: 
Definitely Not 
Related: 
The AE is clearly not related to the administration of the study vaccine. 
Another cause of the event is most plausible; and/or a clinically 
plausible temporal sequence is inconsistent with the onset of the event 
and the study vaccine administration; and/or a causal relationship is 
considered biologically implausible. 
Probably Not 
Related: 
There is no medical evidence to suggest that the AE is related to the 
study vaccine. The event can be readily explained by the subject’s 
underlying medical condition or concomitant therapy or lacks a 
PPD
CCI

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plausible temporal relationship to the study vaccine. 
Possibly Related: 
A direct cause and effect relationship between the study vaccine and the 
AE has not been demonstrated but there is a reasonable possibility that 
the event was caused by the study vaccine. 
Probably Related: 
There probably is a direct cause and effect relationship between the AE 
and the study vaccine. A plausible biologic mechanism and temporal 
relationship exist and there is no more likely explanation. 
Definitely Related: 
There is a direct cause and effect relationship between the AE and the 
study vaccine. Reactions at the injection site (redness, swelling, and 
pain) will automatically be entered as definitely related to the study 
vaccine. 
AE outcomes will be classified as recovered/resolved, not recovered/not resolved, 
recovered/resolved with sequelae, recovering/resolving, or death. 
13.1.10Reporting of SAEs to Health Authorities and IRB 
Medicago or its designee will be responsible for reporting SAEs that are deemed both possibly 
related to the study vaccine and considered to be unexpected (‘unexpected’ refers to events that 
do not appear in the package labeling or in the study vaccine IB) to the regulatory authorities in 
an expedited manner. 
The Investigator will be responsible for reporting the SAEs that meet IRB reporting requirements 
directly to the relevant ethical review board as soon as possible, and will also provide the ethical 
review board with any safety reports prepared by Medicago or its designee. 
All SAEs that are suspected, unexpected serious adverse reactions (SUSARs) should be reported 
to regulatory authorities by phone or by facsimile transmission as soon as possible but, in no 
event, later than seven calendar days for deaths and 15 calendar days for other SAEs after 
Medicago's (or its designee’s) initial receipt of the information. These events should be followed 
to resolution, stabilization, or return to baseline, regardless of conclusion of the study. 
14 INVESTIGATIONAL PRODUCT INFORMATION 
14.1 Identity of Investigational Product 
The study vaccine is a Quadrivalent VLP Influenza Vaccine composed of recombinant H1, H3, 
and two B proteins (hemagglutinin) expressed as VLPs for the 2017-2018 influenza virus strains. 
14.1.1 Study Vaccine Composition 
The Quadrivalent VLP Influenza Vaccine is a sterile transparent to opalescent colorless to 
slightly yellowish liquid suspension consisting of a mix of VLPs from four strains, each bearing 
the hemagglutinin of one of the recommended virus strains , in a phosphate buffered saline 
(PBS) solution (100 mM NaKPO4, 150 mM NaCl) and 0.01 % polysorbate 80 at pH 7.4). The 
Quadrivalent VLP Influenza Vaccine will be supplied in a one-millilitre borosilicate pre-filled 
syringes (type 1). The hemagglutinin protein concentration in the provided syringes will be 

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60 μg/strain/mL in a volume of approximately 0.6 mL; the syringes were designed to deliver 
0.5 mL, for a final dose of 30 μg/strain. 
14.1.2 Placebo 
The control product (placebo) will be composed of a phosphate-buffered saline (PBS) solution 
(100 mM NaKPO4, 150 mM NaCl) and 0.01 % polysorbate 80 at pH 7.4. The placebo will be 
provided in one-millilitre borosilicate pre-filled syringes (type 1). According to the 
randomization scheme, 0.5 mL of placebo will be administered to subjects. 
14.1.3 Preparation and Administration of Study Vaccine 
The study treatment (including both the VLP Vaccine and placebo) will be prepared by 
unblinded staff members at the clinical site as described in the Investigational Product 
Management Manual. The prepared study treatment will subsequently be administered to 
subjects by an unblinded staff member. 
Note: The personnel responsible for treatment preparation can also perform the vaccination (if 
certified and qualified to do it) as this person would already be unblinded. The unblinded staff 
members must not be involved in the evaluation of any AEs or reactogenicity evaluations 
following vaccination. 
The pre-filled syringes to be used for study treatment administration will be handled in a clean 
environment in an aseptic manner for preparation for injection as follows: 
• For the administration of the 30 μg/strain vaccine dose, the site will use a pre-filled syringe 
labelled with study protocol CP-PRO-QVLP-012 and identified with a concentration of 
60 μg/strain/mL and with a dose of 0.5 mL (30 μg/strain); 
• For the administration of the placebo, the site will use a pre-filled syringe labelled with 
study protocol number CP-PRO-QVLP-012 and identified with the word “Placebo” and the 
lot number. 
All study treatments will be administered IM. The needle to be used for the injection should be 
of sufficient length to reach the substance of the muscle. According to randomization scheme, 
subjects will receive either the Quadrivalent VLP Influenza Vaccine (30 μg/strain) or the placebo 
in the deltoid muscle of (preferably) the non-dominant arm. Whenever possible, the injection 
will be given in the opposite arm from which blood samples are drawn, when applicable. 
The dose administered will be recorded in the Investigational Product Accountability Records 
form (refer to Investigational Product Management Manual) by the clinical site, which will be 
separate from the study medication record for drug preparation. After drug accountability 
monitoring and reconciliation has been completed by the site and Clinical Research Associate, 
all study treatments (used and unused syringes) will be destroyed locally upon Medicago’s 
approval or returned to Medicago (or its designee) in accordance with instructions provided in 
the Investigational Product Management Manual. 

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Further specific information relating to treatment preparation, storage, and shipment is provided 
in the Investigational Product Management Manual. 
14.1.4 Preparation, Handling, Storage, and Precautions for Use 
The study treatment should be stored in an access-restricted area between 2 ºC and 8 ºC; the 
vaccine should, however, be at room temperature before administration (i.e. the vaccine should 
not be administered cold). In the event of a storage temperature deviation outside of the 
permitted window of 2 ºC to 8 ºC, the study treatment should be quarantined (at the required 
storage temperature) and Medicago (or its designee) contacted immediately. 
Note: The vaccine must NEVER be frozen, since freezing destroys activity; any vaccine that 
has been frozen must not be used. 
Note: The vaccine must NEVER be shaken or vortexed. 
Note: The treatments must NOT be administered intravenously, subcutaneously, or 
intradermally. 
The Investigational Product Management Manual provides additional details on treatment 
preparation, handling and storage. 
14.2 Packaging 
The study drug will be packaged in boxes containing pre-filled syringes of the same treatment. 
14.3 Labeling 
The pre-filled syringes will have a product and study-specific label containing information that 
meets the applicable regulatory requirements. The study dispensing labels will contain dosing 
instructions, treatment, storage conditions, and a unique subject-specific treatment number. 
Blinding measures will be applied to maintain the observer-blindness of the blinded staff and to 
allow identification of the study treatment only by staff involved in the 
preparation/administration of the study vaccine/placebo. 
14.4 Drug Accountability 
The Investigator is responsible for ensuring that all study treatments received at the site are 
inventoried and accounted for throughout the study. The dispensing of study treatment to each 
subject must be documented on the Investigational Product Accountability Records form. 
The study treatments or drugs must be handled in strict accordance with the Investigational 
Product Management Manual and the syringe label and will be stored in a limited access area or 
in a locked cabinet under appropriate environmental conditions. All unused study drugs must be 
available for verification by Medicago’s (or its designee’s) unblinded site monitor during on-site 
monitoring visits. The return of all unused study drugs to Medicago (or its designee) for 
destruction will be documented on the Drug Return Form. When the site is authorized by 
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The study drug should be dispensed under the supervision of the Investigator or a qualified 
member of the investigational staff. The study drug will be supplied only to subjects 
participating in the study. Returned study drugs may not be relabeled or reassigned for use for 
other subjects. The Investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study centers agreed upon with Medicago (or its designee). 
15 STUDY-SPECIFIC MATERIALS 
The Investigator will be provided with the following: 
• eCRF; 
• Source documents (when applicable); 
• Forms and questionnaires for special assessments; 
• Thermometers and measurements template; 
• Study manuals. 
16 ETHICAL ASPECTS 
16.1 Study-Specific Design Considerations 
On-going medical review will be performed by Medicago (or its designee) throughout the 
duration of the study; subjects will be given any new information that may affect their decision 
to continue participation in the study. 
The use of a placebo might raise ethical concerns since these research participants would not be 
receive an effective vaccine that would have decreased their risk of becoming infected with 
seasonal influenza. However, for this study, the use of a placebo control is considered to be 
justified and ethical for a number of reasons: 
1. Although seasonal influenza vaccination is now widely recommended for all individuals 
aged six months and older (who do not have contraindications to the vaccine), the 
individuals at highest risk or with the highest burden of illness from seasonal influenza are 
considered to be individuals ≥ 65 years of age, children under five years of age, and 
individuals with medical conditions that place them at an increased risk for complications 
from influenza (CDC, 2016b; NACI, 2016; WHO, 2016). The population selected for this 
study (adults 18 to 64 years of age) are considered to be at relatively low risk for 
complications from seasonal influenza; 
2. Even in high income countries, a large proportion of the target population typically remains 
unvaccinated (e.g. in the US vaccination is recommended for everyone aged six months and 
older, however, the Centers for Disease Control and Prevention [CDC] reports the amount 
of vaccine distributed for each influenza season to be less than 50 % of the population).  
Based on historical data, the proportion of healthy adults who do not fall into one of the 
major risk categories (for either themselves or their close contacts) and who go 
unvaccinated is lower than that of individuals considered to be at high risk (e.g. 22 % and 
33.5 % of healthy adults were vaccinated against seasonal influenza in Canada in the 2013-
2014 season (Gionet, 2015) and in the US in the 2015-2016 season (CDC, 2016a), 

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respectively. In consequence, a large proportion of the target population of this study would 
likely go unvaccinated, irrespective of this study; 
3. The size of the currently planned placebo-controlled trial (approximately 10,000 subjects) is 
based on an ARU of ≥ 2 % and it is understood that if the ARU falls below 1.5 %, a second 
season may be required in order to have sufficient power for hypothesis testing. The use of 
an active comparator as a control would impact the attack rate estimate that was used in the 
sample size calculation in two ways, both of which could render the trial non-viable in 
terms of cost and/or duration: 
• 
A lower attack rate estimate would be required for an active comparator-controlled 
study design, resulting in an unrealistic sample size to have adequate  power for 
hypothesis testing; 
• 
The attack rate estimate for an active comparator control would be significantly more 
unpredictable, since the efficacy of the currently available seasonal influenza vaccines 
can range greatly from one season to another (DiazGranados et al., 2012). This 
unpredictability can, in turn, independent of an increased sample size, lead to a longer 
study duration in order to achieve sufficient power for hypothesis testing. 
Blood samples will be collected from a subset of subjects for humoral immunogenicity analysis, 
although not all will be analysed. Since blood sample collection is a minimally invasive 
procedure and the amount of blood collected will be a relatively small amount (Table 5), the 
benefits of obtaining this data outweigh the small level of risk associated with the collection of 
samples that may not require analysis. 
16.2 Regulatory Ethics Compliance 
16.2.1 Investigator Responsibilities 
The Investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Conference on Harmonisation (ICH) guidelines on good clinical 
practice (GCP), and applicable regulatory and country-specific requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are reliable. 
16.2.2 Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the Investigator (or Medicago, where required) will provide the 
Independent Ethics Committee (IEC)/IRB with current and complete copies of the following 
documents (as required by local regulations): 
• Final protocol and, if applicable, amendments to the protocol; 
• Sponsor-approved ICF (and any other written materials to be provided to the subjects); 

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• IB (or equivalent information) and amendments/addenda; 
• Sponsor-approved subject recruiting materials; 
• Information on compensation for study-related injuries or payments to subjects for 
participation in the study, if applicable; 
• Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB); 
• Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects; 
• Any other documents that the IEC/IRB requests to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative in nature, with 
no consequences for subjects, data, or study conduct), the ICF, applicable recruiting materials, 
and subject compensation programs, and Medicago (or its designee) has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved. In addition, the Investigator must wait for written confirmation from 
Medicago (or its designee) that the study can be started. 
During the study, the Investigator (or Medicago [or its designee], where required) will send the 
following documents and updates to the IEC/IRB for their review and approval, where 
appropriate: 
• Protocol amendments; 
• Revision(s) to ICF and any other written materials to be provided to subjects; 
• If applicable, new or revised subject recruiting materials approved by Medicago; 
• Revisions to compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable; 
• New edition(s) of the IB and amendments/addenda; 
• Summaries of the study at intervals stipulated in guidelines of the IEC/IRB (at a minimum, 
annually); 
• Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug 
(when applicable); 
• New information that may adversely affect the safety of the subjects or the conduct of the 
study; 
• Deviations from or changes to the protocol to eliminate immediate hazards to subjects; 
• Reports of deaths of subjects under the Investigator’s care; 
• Notification if a new Investigator is responsible for the study at any of the sites; 
• Development Safety Update Report and Line Listings, where applicable; 
• Any other requirements of the IEC/IRB. 

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At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing. At the end of the study, the Investigator (or 
Medicago [or its designee], where required) will notify the IEC/IRB of study completion. 
16.2.3 Informed Consent 
Each subject who participates in the study must first give written consent according to local 
requirements after the nature of the study has been fully explained, including the risks and 
requirements of the study. The consent form must be signed before performing any study-related 
activity. The consent form that is used must have been approved by regulatory authorities, 
Medicago, and the reviewing IEC/IRB. 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 Medicago policy. During the study, subjects will be 
given any new information that may affect their decision to continue their participation in the 
study. They will be told that their consent to participate is voluntary and that it may be 
withdrawn at any time, with no reason given, and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential AEs of the study and who provide their consent voluntarily will be 
enrolled. 
16.2.4 Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to support the development, registration, and future 
marketing of the investigational product. The data must be collected and processed with adequate 
precautions to ensure confidentiality and compliance with applicable data privacy protection 
laws and regulations. Appropriate technical and organizational measures to protect the personal 
data against unauthorized disclosures or access, accidental or unlawful destruction, or accidental 
loss or alteration must be in place. Medicago (or its designee) personnel whose responsibilities 
require access to personal data agree to keep the identity of study subjects confidential. 
17 ADMINISTRATIVE REQUIREMENTS 
17.1 Protocol Amendments 
Neither the Investigator nor Medicago will modify this protocol without a formal amendment. 
All protocol amendments must be issued and approved by Medicago, and signed and dated by 
the Investigator. Protocol amendments must not be implemented without prior IEC/IRB approval 
or when the relevant competent authority has raised any grounds for non-acceptance, except 
when necessary in order to eliminate an immediate hazard to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the Investigator and IEC/IRB must be provided to 
Medicago or its designee. 

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Note that administrative changes may be implemented without prior IRB approval; however, 
the Investigator or Medicago, as applicable, must notify the IRB of any administrative change 
and ensure that IRB acknowledges receipt of the administrative changes. 
The Investigator is responsible for notifying the IRB of all protocol amendments and ensuring 
that the IRB has approved any amendments when local IRBs are used. When a central IRB is 
used, Medicago or its designee will inform the IRB on behalf of the sites. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the Investigator or other physician in attendance will contact the appropriate Medicago 
representative or its designee (see Contact Information pages provided separately). Except in 
emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with Medicago or its designee must be made as soon as possible to 
discuss the situation and to agree on an appropriate course of action. The data recorded in the 
eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances that made a deviation necessary. 
17.2 Regulatory Documentation 
17.2.1 Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, as applicable. A study may not be initiated until all local regulatory 
requirements are met. 
17.3 Source Documentation 
At a minimum, source documentation must be available for the following information: 
• Subject identification, eligibility, and study identification; 
• ICF discussion and date of informed consent; 
• Dates of visits; 
• Results of safety and study procedures as required by the protocol; 
• Record of all reactions, AEs, respiratory illnesses, ILIs, and associated follow ups; 
• Concomitant medication; 
• Drug receipt, dispensing, and return records; 
• Study drug administration information; 
• Date of study completion and reason for early discontinuation of study drug or withdrawal 
from the study, if applicable. 
It is recommended that the author of an entry in the source documents be identifiable. 
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care. Specific 

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details required as source data for the study will be reviewed with the Investigator before the 
study and will be described in the monitoring guidelines (or other equivalent document). 
17.4 Case Report Form Completion 
Electronic case report forms (eCRFs) will be provided for each subject who is randomized and 
receives a dose of study drug. Screening failures will also be entered in an electronic case report 
form; data entered should include date of birth and reason for screening failure. 
Data must be entered into the eCRFs in English. The Investigator must verify that all data entries 
in the eCRFs are accurate and correct. All eCRF entries, corrections, and alterations must be 
made by the Investigator or other authorized study-site personnel. 
17.5 Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and Medicago (or its designee) procedures, the 
site will be contacted prior to the study start to review the protocol and study requirements with 
the clinical study staff. Medicago (or its designee) will review their responsibilities to satisfy 
regulatory, ethical, and company (Medicago) requirements. 
The Investigator or institution, if applicable, will authorize and provide direct access to all 
relevant documents to allow review of the appropriate conduct of the study by Medicago’s (or its 
designee’s) monitor. The Investigator(s) must allocate their time and the time of their staff to the 
monitors, discuss any findings or issues, and take appropriate actions to maintain the quality and 
integrity of the study data and conduct. 
Protocol deviations will be reviewed by Medicago (or its designee) to identify any non-
compliances likely to have a significant effect on the safety and rights of a subject or the 
reliability and robustness of the data generated. These deviations will be included in the clinical 
study report. 
17.6 Quality Assurance 
To ensure compliance with GCP and all other applicable regulatory requirements, Medicago (or 
its designee) may conduct quality assurance assessments and/or an audit of the site. Regulatory 
agencies may conduct regulatory inspections at any time during or after completion of the study. 
If an audit or an inspection is conducted, the Investigator and/or institution (if applicable) must 
agree to grant auditors or inspectors direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss the conduct of the study and any findings or issues, and 
to implement corrective and/or preventative actions to address any findings or issues identified. 
17.7 Record Retention 
Following closure of the study, the Investigator must maintain all site study records in a safe and 
secure location. The records must be easily accessible when needed (e.g. for a Medicago [or its 
designee] audit or regulatory inspection) and must be available for review in conjunction with 
assessment of the facility, supporting systems, and relevant site staff. 

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When permitted by local laws and regulations or institutional policy, some or all of the records 
may be maintained in a format other than a hard copy (e.g. scanned electronic). The Investigator 
must ensure that all reproductions are legible and are a true and accurate copy of the original. 
The Investigator must follow the time period for retaining the site records in order to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by local laws and regulations, Medicago (or its 
designee) standard operating procedures (SOPs), and/or institutional requirements. The 
Investigator must contact Medicago (or its designee) prior to the disposal of any study 
documents at the end of the retention period. 
If the responsible Investigator retires, relocates, or, for any other reason, withdraws from the 
responsibility of keeping the study records, custody must be transferred to another person who 
will accept the responsibility. Medicago (or its designee) must be notified in writing of the name 
and address of the new custodian. Under no circumstance shall the Investigator relocate or 
dispose of any study documents without having obtained prior written approval from Medicago 
(or its designee). 
If it becomes necessary for Medicago or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator must permit access to such reports. 
17.8 Study Completion/Termination 
17.8.1 Study Completion 
The study will be considered to be completed with the last contact with the last subject 
participating in the study. The final data from the investigational site will be sent to Medicago 
(or designee) after completion of the final subject visit at that site. Investigational sites will be 
closed after study completion. An investigational site is considered closed when all required 
documents and study supplies have been collected, all data have been entered, monitored, 
locked, and signed and a site closure visit has been performed. 
17.8.2 Study Termination 
Medicago (or its designee) reserves the right to close the investigational site or terminate the 
study at any time for any reason at the sole discretion of Medicago. Investigational sites will be 
closed after study termination once Medicago (or its designee) has completed all study related 
tasks. Reasons for the early closure of an investigational site by Medicago (or its designee) or the 
Investigator may include, but are not limited to: 
• Failure of the Investigator to comply with the protocol, Medicago’s (or its designee’s) 
procedures, or GCP guidelines; 
• Inadequate recruitment of subjects by the Investigator; 
• Discontinuation of further drug development. 
The Investigator may initiate site closure at any time, provided there is reasonable cause and 

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sufficient notice is given in advance of the intended closure. 
Site closure following an Investigator request can only be performed when all active study 
subjects have completed the study period, Medicago (or its designee) has collected all required 
documents and study supplies, and all data have been entered, monitored and locked. 
17.9 Registration of Clinical Studies and Disclosure of Results 
Study information from this study will be posted on publicly available clinical trial registries in 
countries where applicable and will include information required by law. In addition, the results 
summary will be posted to the same clinical trial registries, to the extent specified by law, and 
will include information required by regulatory authorities. 
18 REFERENCES 
CDC (Producer). (2016a, 19 December 2016). Flu Vaccination Coverage: United States, 2015-
16 Influenza Season. Retrieved from http://www.cdc.gov/flu/fluvaxview/coverage-
1516estimates.htm 
CDC. (2016b). Morbidity and Mortality Weerkly Report: Prevention and Control of Seasonal 
Influenza with Vaccines: Recommendations of the Advisory Committee on 
Immunization Practices — United States, 2016–17 Influenza Season. 
DiazGranados, C., Denis, M., & Plotkin, S. (2012). Seasonal influenza vaccine efficacy and its 
determinants in children and non-elderly adults: a systematic review with meta-analyses 
of controlled trials. Vaccine, 31(1), 49-57.  
FDA. (2007). Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
Gionet, L. (2015). Flu vaccination rates in Canada. (Catalogue no.82-624-X). 
McElhaney, J.E. (2011). Influenza Vaccine Responses in Older Adults. Ageing Res Rev, 10(3), 
379-388. doi:10.1016/j.arr.2010.10.008 
Molinari, N. A., Ortega-Sanchez, I. R., Messonnier, M. L., Thompson, W. W, Wortley, P. M., 
Weintraub, E., & Bridges, C. B. (2007). The annual impact of seasonal influenza in the 
US: measuring disease burden and costs. Vaccine, 25(27), 5086-5096.  
NACI. (2016). An Advisory Committee Statement (ACS) National Advisory Committee on 
Immunization (NACI): Canadian Immunization Guide Chapter on Influenza and 
Statement on Seasonal Influenza Vaccine for 2016-2017. (Cat.: HP37-25E; ISBN: 2371-
5375; Pub.: 160156). 
Osterholm, M., Kelley, N., Sommer, A., & Belongia, E. (2012). Efficacy and effectiveness of 
influenza vaccines: a systematic review and meta-analysis. The Lancet Infectious 
Diseases, 12(1), 36-44.  
Palache, A. (2011). Seasonal influenza vaccine provision in 157 countries (2004-2009) and the 
potential influence of national public health policies. Vaccine, 29(51), 9459-9466.  
Skowronski, D. M., Chambers, C., Sabaiduc, S., De Serres, G., Dickinson, J. A., Winter, A. L., 
Drews, S. J. , Fonseca, K., Charest, H., Gubbay, J. B., Petric, M., Krajden, M., Kwindt, T. 
L., Martineau, C., Eshaghi, A., Bastien, N., & Li, Y. (2015). Interim estimates of 2014/15 
vaccine effectiveness against influenza A(H3N2) from Canada's Sentinel Physician 
Surveillance Network (Vol. 20(4), pp. pii=21022). 

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WHO. (2016). WHO Regional Office for Europe recommendations on influenza vaccination 
during the 2016/2017 winter season. 
 
 

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19 APPENDICES 
19.1 Appendix 1 – Sample Ruler to Measure Local Reactions 
 
 
 

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19.4 Appendix 4 – Acceptable Contraceptive Methods 
Germany 
Female subjects of childbearing potential must use an effective method of contraception for one 
month prior to vaccination and agree to continue employing adequate birth control measures for 
at least 60 days post-vaccination. Moreover, female subjects must have no plan to become 
pregnant for at least two months post-vaccination. The following relationship or methods of 
contraception are considered to be effective: 
• Hormonal contraceptives (e.g. oral, injectable, topical [patch], or estrogenic vaginal ring); 
• Intra-uterine device with or without hormonal release; 
• Sterilized partner (at least one year prior to vaccination); 
• Credible self-reported history of heterosexual vaginal intercourse abstinence until at least 
60 days post-vaccination; 
• Female partner. 
United Kingdom 
Female subjects of childbearing potential must use an effective method of contraception for one 
month prior to vaccination and agree to continue employing adequate birth control measures for 
at least 60 days post-vaccination. Moreover, female subjects must have no plan to become 
pregnant for at least two months post-vaccination. The following relationship or methods of 
contraception are considered to be effective: 
• Hormonal contraceptives (e.g. oral, injectable, topical [patch], or estrogenic vaginal ring); 
• Intra-uterine device with or without hormonal release; 
• Male partner using a condom plus spermicide or sterilized partner (at least one year prior to 
vaccination); 
• Credible self-reported history of heterosexual vaginal intercourse abstinence until at least 
60 days post-vaccination; 
• Female partner. 
All Other Regions 
Female subjects of childbearing potential must use an effective method of contraception for one 
month prior to vaccination and agree to continue employing adequate birth control measures for 
at least 60 days post-vaccination. Moreover, female subjects must have no plan to become 
pregnant for at least two months post-vaccination. Abstinent subjects should be asked what 
method(s) they would use should their circumstances change, and subjects without a well-
defined plan should be excluded. The following relationship or methods of contraception are 
considered to be effective: 
• Hormonal contraceptives (e.g. oral, injectable, topical [patch], or estrogenic vaginal ring); 
• Intra-uterine device with or without hormonal release; 

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• Male partner using a condom plus spermicide or sterilized partner (at least one year prior to 
vaccination); 
• Credible self-reported history of heterosexual vaginal intercourse abstinence until at least 
60 days post-vaccination; 
• Female partner.