Lot-to-lot Consistency of a Plant-Derived Quadrivalent Virus-Like Particles Influenza Vaccine in Healthy Adults

A Randomized, Observer-blind, Multicenter, Phase 3 Study to Evaluate the Lot Consistency, Immunogenicity, and Safety of a Plant-Derived Quadrivalent VLP Influenza Vaccine in Healthy Adults 18-49 Years of Age

This Phase 3 study is intended to assess the clinical lot-to-lot consistency in manufacturing by evaluating and comparing the immunogenicity of three consecutively manufactured lots of the Quadrivalent Virus-Like Particles (VLP) Influenza Vaccine, during the 2016-2017 influenza season, in healthy adults 18-49 years of age. A single dose of one of three consecutive lots of Quadrivalent VLP Influenza Vaccine (30 µg/strain) will be administered to 1,200 participants.

This randomized, observer-blind, multicenter, Phase 3 lot consistency study will be conducted at multiple sites in Canada. The composition of the Quadrivalent VLP Influenza Vaccine used in this study includes two influenza A virus strains and two influenza B virus strains based on the 2016-2017 recommended strains for vaccination in the Northern hemisphere.

1,200 healthy male and female participants aged 18 to 49 years will be randomized in a 1:1:1 ratio to one of three lots of the Quadrivalent VLP Influenza Vaccine (30 μg/strain). Participant will participate in this study for approximately 21 days, during which a first visit will be scheduled on Day 0 for screening, eligibility assessment, and vaccine administration; and on Day 21 for blood sample collection for immunogenicity assessment.

Inclusion Criteria:

Participants must meet all of the following inclusion criteria to be eligible for participation in this study; no protocol waivers are allowed:

1. Participants must be considered by the Investigator to be reliable and likely to cooperate with the assessment procedures and be available for the duration of the study;

2. Participants have a body mass index (BMI) ≤ 40.0 kg/m^2 on Day 0 (pre-vaccination);

3. Participants must be in good general health prior to study participation with no clinically relevant abnormalities that could jeopardize participant 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: Participants 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 participant by participating in the study. Stable disease is generally defined as no new onset or exacerbation of pre-existing chronic disease six months prior to vaccination. Based on the Investigator's judgment, a participant with a more recent stabilization of a disease could also be eligible.

4. Female participants must have a negative urine pregnancy test result at the Screening/Vaccination visit (Visit 1);

5. Female participants 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 the duration of the study. Abstinent participants should be asked what method(s) they would use, should their circumstances change, and participants 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 a sterilized partner (at least one year prior to vaccination);
   • Credible self-reported history of heterosexual vaginal intercourse abstinence until at least the Day 21 visit;
   • Female partner.

6. 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:

Participants who meet any of the following criteria will be excluded from participating in this study; no protocol waivers are allowed:

1. 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 six months prior to study vaccine administration unless the criteria outlined in inclusion criterion no. 3 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.

2. Any medical or neuropsychiatric condition or any history of excessive alcohol use or drug abuse which, in the Investigator's opinion, would render the participant unable to provide informed consent or unable to provide valid safety observations and reporting;

3. Any autoimmune disease other than hypothyroidism with stable replacement therapy; or any confirmed or suspected immunosuppressive condition or immunodeficiency including known or suspected human immunodeficiency virus (HIV), hepatitis B or C infection, or the presence of lymphoproliferative disease;

4. Administration or planned administration of any non-influenza vaccine within 30 days prior to randomization and up to blood sampling on Day 21. Immunization on an emergency basis will be evaluated case-by-case by the Investigator;

5. Administration of any adjuvanted or investigational influenza vaccine within 24 months prior to randomization or planned administration prior to the completion of Day 21;

6. Administration of any "standard", non-adjuvanted influenza vaccine (e.g. live attenuated trivalent/quadrivalent inactivated influenza vaccine intranasal or split trivalent/quadrivalent inactivated influenza vaccine by either intradermal or IM route) within 24 months prior to randomization and up to completion of the Day 21 visit;

7. Use of any investigational or non-registered product within 30 days prior to randomization or planned use during the study period. Participants may not participate in any other investigational or marketed drug study while participating in this study until the Day 21 visit. Participation in observational studies is permitted;

8. Treatment with systemic glucocorticoids at a dose exceeding 10 milligrams (mg) of prednisone (or the equivalent) per day for more than seven consecutive days or for ten or more days in total, within one month of study vaccine administration; or any other cytotoxic or immunosuppressant drug, or any immunoglobulin preparation within three months of vaccination and until the completion of the Day 21 visit. Low doses of nasal or inhaled glucocorticoids and topical steroids are permitted;

9. 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. Participants treated with new generation drugs that do not increase the risk of IM bleeding (e.g. clopidogrel) are also eligible.

10. History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine or a tobacco allergy;

11. History of anaphylactic allergic reactions to plants or plants components;

12. Any history of serious asthma (e.g. status asthmaticus, hospitalization for asthma control) in the last three years;

13. Use of antihistamines 48 hours prior to study vaccination;

14. The 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. Participant 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-hour period is met;

15. Participants who have a dermatological condition at the injection site that may interfere with injection site reaction rating;

16. Participant who have received a blood transfusion within 90 days prior to study vaccination;

17. Any female participant who has a positive or doubtful pregnancy test result prior to vaccination or who is lactating;

18. Presence of any febrile illness (including oral temperature (OT) ≥ 38.0 ˚C within 24 hours prior to vaccination). Such participants may be re-evaluated for enrolment after resolution of illness;

19. Cancer or treatment for cancer within three years of study vaccine administration. Participants with a history of cancer who are disease-free without treatment for three years or more are eligible. Individuals with treated and uncomplicated basal cell carcinoma of the skin or with non-treated, non-disseminated local prostate cancer are eligible;

20. Participants 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. Immediate family members of the Investigator or employees of a clinical site can participate in the study at another clinical site, as long as the Investigator or employees are not involved in the study at that site;

21. Participant with a history of Guillain-Barré syndrome.