Efficacy of a Plant-derived Quadrivalent Virus-like Particle (VLP) Vaccine in the Elderly

This Phase 3 study was intended to assess the relative efficacy of the Quadrivalent VLP Influenza Vaccine during the 2018-2019 influenza season compared to a licensed vaccine in elderly adults 65 years of age and older. One dose of VLP Influenza Vaccine (30 μg/strain) or of Comparator (15 μg/strain) was to be administered to 12,738 participants.

This randomized, observer-blind, active-controlled multicenter, Phase 3 study was conducted at multiple sites. The composition of the Quadrivalent VLP Influenza Vaccine used in this study included a mix of recombinant H1, H3, and two B hemagglutinin proteins expressed as VLPs for the 2018-2019 influenza virus strains.

A total of 12,794 healthy male and female participants aged 65 years and older were randomized in a 1:1 ratio into one of two parallel treatment groups, such that 6,396 participants were randomized to receive the Quadrivalent VLP Influenza Vaccine at a dose of 30 μg/strain and 6,398 participants were randomized to receive the comparator. Within the two treatment groups, participants were stratified by site and two age groups (65-74 years of age and 75 years of age and older in a 2:1 ratio).

Participants participated in this study for approximately nine months, during which a first visit was scheduled on Day 0 for screening and vaccine administration.

Eligibility Criteria:
Inclusion Criteria:

1. Participants must have read, understood, and signed the informed consent form (ICF) prior to participating in the study; participants must also complete study-related procedures and communicate with the study staff at visits and by phone during the study;
2. Participants must have a body mass index (BMI) ≤35 kg/m\^2;
3. 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;
4. Male and female participants must be 65 years of age and older at the Screening/Vaccination visit (Visit 1);
5. Participants must be non-institutionalized (e.g. not living in rehabilitation centres or old-age homes; living in an elderly community is acceptable) and have no acute or evolving medical problems prior to study participation and 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 are 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.

Exclusion Criteria:

1. According to the Investigator's opinion, history of an ongoing acute or evolving medical or neuropsychiatric illness. 'Evolving' was 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.
2. Any medical or neuropsychiatric condition or any history of excessive alcohol use or drug abuse that would render the participant unable to provide informed consent or unable to provide valid safety observations and reporting, including methadone (methadone as treatment for opioid dependence may be acceptable if the participant has been otherwise opioid-free for at least three years);
3. Any autoimmune disease other than hypothyroidism on stable replacement therapy (including, but not limited to rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, type 1 diabetes, 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;
4. Any history of status asthmaticus or ongoing serious problems with asthma, hospitalization for asthma control, or recurrent asthma episodes requiring medical attention in the last three years (one or more episodes per year);
5. 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 was evaluated case-by-case by the Investigator;
6. Administration of any adjuvanted or investigational influenza vaccine within one year prior to randomization or planned administration prior to the completion of the study;
7. 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;
8. 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;
9. Treatment with systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or equivalent) per day for more than seven consecutive days or for ten 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;
10. 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 \[no more than 100 mg/day\]), 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;
11. History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine, any components of the active comparator quadrivalent vaccine, or tobacco;
12. History of anaphylactic allergic reactions to plants or plants components (including fruits and nuts);
13. Use of antihistamines within 48 hours prior to study vaccination;
14. Daily use of large doses of medication for pain control or inflammation (e.g. opioids, nonsteroidal anti-inflammatory drugs \[NSAIDs\]). Use of a singular regular dose either in the morning or at bedtime would not be exclusionary;
15. 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;
16. Planned use of influenza antiviral treatment medication before the collection of nasopharyngeal (NP) swabs (e.g. oseltamivir, zanamivir, rapivab);
17. Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at the injection site that may interfere with injection site reaction rating;
18. Participants who have received a blood transfusion within 90 days prior to study vaccination;
19. Participants with abnormal vital signs (systolic blood pressure \[BP\] ≥ 150 mmHg and/or diastolic BP ≥ 95 mmHg for individuals taking antihypertensive medication and ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg for individuals not taking antihypertensive medication; heart rate \[HR\] ≤ 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 HR ≤ 45 in highly trained athletes);
20. Presence of any febrile illness (including an oral temperature \[OT\] ≥ 38.0 ˚C within 24 hours prior to vaccination;
21. 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;
22. 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) of the Investigator or any employee of Medicago (or their family members);
23. Participants with a history of Guillain-Barré Syndrome.