Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent Virus-Like Particles Influenza Vaccine in Adults

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.

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).

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.

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 be able to read, understand, and sign the informed consent form (ICF);
complete study-related procedures; and communicate with the study staff at visits and
by phone;

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 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 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;

- 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;

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).

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 rheumatoid arthritis, systemic lupus erythematosus,
Crohn's disease, and inflammatory bowel disease) or any confirmed or suspected
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 intramuscular 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 intramuscular 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);

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
nasopharyngeal 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 ≤ 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 hear
rate ≤ 45 in highly trained athletes);

22. Presence of any febrile illness (including an oral temperature ≥ 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.