Immunogenicity, Safety, and Tolerability of a Plant-Derived Quadrivalent VLP Influenza Vaccine in Elderly Adults

This Phase 2 Quadrivalent VLP Vaccine study is intended to replicate and extend the immunogenicity and safety results obtained in earlier Phase 1-2 and Phase 2 studies. The study is being conducted to evaluate that the immunogenicity profile of the Quadrivalent VLP Vaccine meets the US Center for Biologics Evaluation and Research (CBER) licensure criteria and to evaluate if the immunogenicity and the safety profile of the Quadrivalent VLP Vaccine is acceptable and comparable to that of the FluLaval® Tetra and Fluzone® High-Dose (HD). The study will also help to define the optimal dose in this population, establish potential competitive advantages, and support the design of future studies.

This randomized, observer-blind, multicenter, Phase 2 study will be conducted at multiple sites across the United States and Canada.

The influenza strain composition of the Quadrivalent VLP Vaccine used in this study includes 2 influenza A virus strains (A/California/7/2009 \[H1N1\] and A/Switzerland/9715293/2013 \[H3N2\]) and 2 influenza B virus strains (B/Phuket/3073/2013 \[Yamagata lineage\] and B/Brisbane/60/2008 \[Victoria lineage\]), based on the 2015-2016 recommended World Health Organization (WHO) strains for vaccination in the Northern hemisphere.

Approximately 1000 elderly male and female subjects, aged 65 years or older, will be randomized in a 1:1:1:1 ratio to 1of 4 parallel treatment groups such that 500 subjects receive Quadrivalent VLP Vaccine (250 each for the 30 µg/strain and 60 µg/strain groups), 250 subjects receive FluLaval® Tetra (15 µg/strain) and 250 subjects receive Fluzone® HD (60 µg/strain). Subjects in each group will be stratified into 2 age strata: 65 to 74 years and 75 years old and older, where 70 % of subjects will be enrolled into the 65 to 74 years old age group and 30 % into the 75 years old or older group.

Subjects will participate in this study for approximately 8 months, during which 5 visits will be scheduled, and phone contact will be made on Day 1, Day 8, and every 2 months thereafter for up to 6 months post-Day 21 visit (Day 201). Blood samples will be collected for immunogenicity analyses at Days 0 and 21 for all subjects. Safety laboratory assessments will be performed at Screening, on Day 3 and within 48 hours of Day 3 results availability, for grade 3 or grade 4 abnormalities or if deemed necessary by the investigator or early termination. Subsequent follow-up of clinically significant laboratory abnormalities will be done according to the investigator's discretion.. Subjects will be monitored throughout the study for safety, including the reporting of solicited local and systemic reactions.

Eligibility Criteria:
Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:

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. 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.
3. Male and female subjects must be 65 years of age or older at Screening (Visit 1).
4. Subjects have a body mass index (BMI) of ≥ 18.0 and ≤ 32.4 kg/m2 at Day 0.
5. Subjects must be in good general health prior to study participation (no more than 30 days prior to study vaccine administration) 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, biochemistry, hematology, and urinalysis.

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 6 months prior to immunization. Based on the Investigator's judgment, a subject with more recent stabilization of a disease could also be eligible.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from participating in this study:

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 within one month prior to study vaccine administration;
   * Requiring a change in medication dosage during one month prior to study vaccine administration due to uncontrolled symptoms or drug toxicity, or for chronic diseases, significant change in medication dosage within 6 months prior to study vaccine administration based upon the investigator's judgment (elective dosage adjustments in stable subjects are acceptable).
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 subject unable to provide informed consent or unable to provide valid safety observations and reporting.
3. Any autoimmune disease other than hypothyroidism on 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 up to blood sampling at 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 1 year prior to randomization or planned administration prior to the completion of Day 201.
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 intramuscular \[IM\] route) within 6 months prior to randomization and up to completion of Day 21 visit.
7. Use of any investigational or non-registered product within 30 days or 5 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 Day 201 visit.
8. Treatment with systemic glucocorticoids at a dose exceeding 10 mg of prednisone per day, or equivalent for more than 7 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 3 months of vaccination and until the completion of Day 21 visit. Low doses of nasal or inhaled glucocorticoids are allowed. Topical steroids are permitted.
9. Any significant disorder of coagulation including 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.
10. History of allergy to any of the constituents of the Quadrivalent VLP vaccine (including H1N1, H3N2, B/Bris, and B/Phuket), to any components of the licensed quadrivalent/trivalent vaccine, or tobacco allergy.
11. History of anaphylactic allergic reactions to any food, medication, or bee sting.
12. Any history of serious asthma (e.g., status asthmaticus, hospitalization for asthma control) or recurrent asthma episodes requiring medical attention in the last 3 years (≥ 1 episode/year)
13. Continuous use of antihistamines in the last 4 weeks prior to immunization or use of antihistamines 48 hours prior to study immunization.
14. 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. Subject discovered to have taken a prophylactic medication within the 24 hours prior to planned randomization must be delayed until the 24 hours period is met.
15. Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at injection site that may interfere with injection site reaction rating.
16. Have received a blood transfusion within 90 days prior to study vaccination.
17. Have abnormal Vital Signs defined as: systolic Blood Pressure (BP) \> 140 mmHg and/or diastolic BP ≥ 90mmHg, heart rate ≤ 45 beats/min and ≥ 100 beats/min. Even if one or more vital signs are out of the acceptable ranges, a subject may still be included in the study based on Investigator's judgment (e.g. a resting heart rate ≤ 45 in highly-trained athletes). Presence of any febrile illness (including oral temperature (OT) ≥ 38.0 ˚C within 24 hours prior to immunization). Such subjects may be re-evaluated for enrolment after resolution of illness.
18. Cancer or treatment for cancer within 3 years of study vaccine administration. Persons with a history of cancer who are disease-free without treatment for 3 years or more are eligible. Persons with treated and uncomplicated basal cell carcinoma of the skin are eligible. Person with non-treated, non-disseminated local prostate cancer are eligible.
19. 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 employees of Medicago.
20. Subject with a history of Guillain-Barre Syndrome