Adjuvanted Seasonal Recombinant Quadrivalent Virus-Like Particles (QVLP) Influenza Vaccine in Adults 65 Years of Age and Older

A Randomized, Partially-Blinded, Active Comparator-Controlled, Dose-Ranging, Safety, Tolerability, and Immunogenicity Phase 1/2 Study of an Adjuvanted Seasonal Recombinant Quadrivalent VLP Influenza Vaccine in Adults 65 Years of Age and Older

This randomized, partially-blinded, active comparator-controlled was conducted at multiple sites globally. The composition of QVLP used in this study includes a mix of recombinant H1, H3, and two B hemagglutinin proteins expressed as VLPs and is based on the 2020-2021 influenza virus strains.

In this study, 3 dose levels (15 μg/strain, 30 μg/strain, and 45 μg/strain) of QVLP were planned to be tested in combination with 2 dose levels of AS03 adjuvant (full and half dose) in a single-dose regimen to select a dose level of QVLP and adjuvant dose level-combination that is safe and effective for further development.

Participants participated in this study for up to approximately 13 months, during which the first visit was scheduled for screening (up to 7 days in advance of vaccine administration) and the second visit on Day 0 was scheduled for vaccine administration. Telephone contacts were made on Day 1, Day 8, and monthly (starting after Day 28) until the end of the study for safety assessments, including concomitant medication use review. Blood draws at the clinic site for key safety assessments were made on Day 3, and Day 28 and for key immunogenicity assessments on Day 0, Day 28, Day 182 (6-month follow-up), and Day 365 (12-month follow-up).

In this study, a partially-blinded design was applied whereby the following individuals did not have access to treatment allocation (i.e. remained "blind") throughout the entire study duration: the participants, the Investigators and all personnel involved in the clinical conduct of the study (except the staff involved in the preparation and administration of the study vaccine, the quality assurance auditor, and quality control reviewers), Medicago clinical staff and medical staff involved in safety evaluations (e.g. causality assessments), and all personnel involved in sample analysis at the central and testing laboratories.

A total of 209 participants were randomized to the study, divided into 8 groups receiving different adjuvant dose level-combinations of QVLP or Fluzone HD Quad (60 µg/strain). The majority of participants (126 participants) received QVLP 30 μg/strain with full dose AS03 (42 participants), QVLP 30 μg/strain unadjuvanted (41 participants) or Fluzone HD Quad (43 participants), while in 5 other groups with 83 participants enrolled in total the enrollment was discontinued prematurely due to recruitment challenges caused by COVID-19 pandemic.

Inclusion Criteria:

1. Participants read, understood, and signed the informed consent form prior to participating in the study; participants also completed study-related procedures and communicated with the study staff at visits and by phone during the study;
2. Male and female participants 65 years of age and older at the Vaccination visit (Visit 2);
3. Participants had a body mass index (BMI) < 30 kg/m2 at the Vaccination visit (Visit 2);
4. Participants were considered by the Investigator to be reliable and likely to cooperate with the assessment procedures and be available for the duration of the study;
5. Participants were non-institutionalized (e.g. not living in rehabilitation centers or old-age homes; living in an elderly community was acceptable) and had 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 Investigator and determined by medical history, physical examination, serology, clinical chemistry and hematology tests, urinalysis, and vital signs. Investigator discretion was permitted with this inclusion criterion;

Note: Participants with a pre-existing chronic disease were allowed to participate if the disease was stable and, according to the Investigator's judgment, the condition was unlikely to confound the results of the study or pose additional risk to the participant by participating in the study. Stable disease was generally defined as no new onset or exacerbation of pre-existing chronic disease 3 months prior to vaccination. Based on the Investigator's judgment, participants with more recent stabilization of a disease were also eligible.

Exclusion Criteria:

1. According to the Investigator's opinion, significant acute or chronic, uncontrolled medical or neuropsychiatric illness. Acute disease was defined as presence of any moderate or severe acute illness with or without a fever within 48 hours prior to the Vaccination visit (Visit 2). "Uncontrolled" was defined as:

   • Requiring a new medical or surgical treatment during the 3 months prior to study vaccine administration;
   • Required any significant change in a chronic medication (i.e. drug, dose, frequency) during the 3 months prior to study vaccine administration due to uncontrolled symptoms or drug toxicity unless the innocuous nature of the medication change met the criteria outlined in inclusion criterion #5 and was appropriately justified and documented by the Investigator. Note: Investigator discretion was permitted with this exclusion criterion.

2. Any confirmed or suspected current immunosuppressive condition or immunodeficiency, including cancer, human immunodeficiency virus, hepatitis B or C infection (participants with a history of cured hepatitis B or C infection without any signs of immunodeficiency at present time were allowed). Investigator discretion was permitted with this exclusion criterion;

3. Current autoimmune disease requiring systemic treatment (such as rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis). Investigator discretion was permitted with this exclusion criterion, and participants were eligible to participate with appropriate written justification in the source document (i.e. participants with a history of autoimmune disease who were disease-free without treatment for 3 years or more, or on stable thyroid replacement therapy, mild psoriasis [i.e. a small number of minor plaques requiring no systemic treatment], etc.);

4. Administration of any non-influenza vaccine within 30 days prior to the Vaccination visit (Visit 2); planned administration of any vaccine up to Day 28 of the study. Immunization on an emergency basis during the study was evaluated on case-by-case basis by the Investigator.

   Note: Administration of an authorized COVID-19 vaccine prior to or during the study was acceptable;

5. Administration of influenza vaccine within 6 months prior to the Vaccination visit (Visit 2) or planned administration of influenza vaccine (other than the study vaccine) up to completion of the study;

6. Administration of any adjuvanted or investigational influenza vaccine within 1 year prior to randomization or planned administration prior to the completion of the study;

7. Use of any investigational or non-registered product within 30 days or five half-lives, whichever is longer, prior to the Vaccination visit (Visit 2) or planned use during the study period. Participants who were in a prolonged post-administration observation period of another investigational or marketed drug clinical study, for which there was no ongoing exposure to the investigational or marketed product and all scheduled on-site visits were completed, were allowed to take part in this study, if all other eligibility criteria were met;

8. Administration of any medication or treatment that may alter the vaccine immune responses, such as:

   • Systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or equivalent) per day for more than 7 consecutive days or for 10 or more days in total, within 1 month prior to the Vaccination visit (Visit 2). Inhaled, nasal, intraarticular, ophthalmic, dermatological, and other topical glucocorticoids were permitted;
   • Cytotoxic, antineoplastic or immunosuppressant drugs - within 36 months prior to the Vaccination visit (Visit 2);
   • Any immunoglobulin preparations or blood products, blood transfusion - within 6 months prior to the Vaccination visit (Visit 2);

9. Use of any prescription antiviral drugs with the intention of COVID-19 prophylaxis, including those that were thought to be effective for prevention of COVID-19 but had not been licensed for this indication, within 1 month prior to the Vaccination visit (Visit 2);

10. Participants at high risk of contracting SARS-CoV-2/COVID-19 infection, including, but not limited to, individuals with known close contact with:

    • anyone residing in, visiting, or working at a health care or long-term care institution (i.e. long-term care facilities, acute care hospitals, rehabilitation hospitals, mental health hospitals, emergency departments);
    • anyone with laboratory-confirmed SARS-CoV-2/COVID-19 infection within 2 weeks prior to vaccine administration;
    • anyone who traveled outside the country for any duration within 30 days before the study vaccination;

11. History of allergy to any of the constituents of QVLP, any components of Fluzone HD Quad, the adjuvant AS03, egg, or tobacco;

12. History of anaphylactic allergic reactions to plants or plants components (including fruits and nuts);

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

14. Personal or family (first-degree relatives) history of narcolepsy;

15. Use of prophylactic medications (e.g. antihistamines [H1 receptor antagonists], nonsteroidal anti-inflammatory drugs [NSAIDs], systemic and topical glucocorticoids, non-opioid and opioid analgesics) within 24 hours prior to the Vaccination visit (Visit 2) to prevent or pre-empt symptoms due to vaccination;

16. Had a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at the injection site that could interfere with injection site reaction rating. Investigator discretion was permitted with this exclusion criterion;

17. Participants identified as an Investigator or employee of the Investigator or clinical site with direct involvement in this 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 this study, or any employees of Medicago.