Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent Virus-Like Particles (VLPs) 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 participants 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 participants will receive the Quadrivalent VLP Influenza Vaccine at a dose of 30 μg/strain and approximately 5,000 participants will receive the placebo. Within the two treatment groups, participants 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).

Participants 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

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

• Participants must have a body mass index (BMI) below 40 kg/m^2;
• Participants 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;
• 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 three months prior to vaccination. Based on the Investigator's judgment, a participant with more recent stabilization of a disease could also be eligible.
• Female participants must have a negative urine pregnancy test result at the Screening/Vaccination visit (Visit 1).
• 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 at least 60 days post-vaccination. Moreover, female participants must have no plan to become pregnant for at least two months post-vaccination. 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 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;
• 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:

• Any participant 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;
• 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.
• 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;
• 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;
• 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);
• Because this is a placebo-controlled study, any participants 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]).
• 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;
• Administration of any adjuvanted or investigational influenza vaccine within one year prior to randomization or planned administration prior to the completion of the study;
• 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;
• 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. Participants may not participate in any other investigational or marketed drug study while participating in this study until after the study;
• 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;
• 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 intramuscular bleeding (e.g. clopidogrel) are also eligible;
• History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine or tobacco;
• History of anaphylactic allergic reactions to plants or plants components;
• 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);
• 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 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 hours period is met;
• Planned use of influenza antiviral treatment medication before the collection of nasopharyngeal swabs (e.g. oseltamivir, zanamivir, rapivab);
• Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at the injection site that may interfere with injection site reaction rating;
• Participants who have received a blood transfusion within 90 days prior to study vaccination;
• Any female participant who has a positive or doubtful pregnancy test result prior to vaccination or who is lactating;
• Participants 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 participant 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);
• Presence of any febrile illness (including an oral temperature ≥ 38.0 ˚C within 24 hours prior to vaccination. Such participants may be re-evaluated for enrolment after resolution of illness;
• 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;

• 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;
• Participants with a history of Guillain-Barré Syndrome.