Clinical trial NCT04622592: Adjuvanted Seasonal Recombinant Quadrivalent Virus-Like Particles (QVLP) Influenza Vaccine in Adults 65 Years of Age and Older
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Influenza
Keywords: vaccine
safety
immunogenicity
plant-made
virus-like particle
hemagglutinin
Lead sponsor: Medicago
Sponsor class: INDUSTRY
First posted: 2020-11-10
Enrollment: 209
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Geometric Mean Titers (GMTs) of Hemagglutination Inhibition (HI) Antibody Response for Each Homologous Influenza Strain on Day 0
timeFrame: Day 0 (pre-vaccination)
measure: GMTs of HI Antibody Response for Each Homologous Influenza Strain on Day 28
timeFrame: Day 28
measure: Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Homologous Influenza Strain on Day 28
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Homologous Influenza Strain on Day 28
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Geometric Mean Fold Rise (GMFR) Measured by HI Antibody Response for Each Homologous Influenza Strain (Day 28/Day 0)
timeFrame: Day 0 (pre-vaccination), Day 28
measure: Number of Participants With at Least One Immediate Adverse Event (AE)
timeFrame: Up to 30 minutes post-vaccination
measure: Number of Participants With at Least One Immediate AE of Grade 1, 2, 3, or 4
timeFrame: Up to 30 minutes post-vaccination
measure: Number of Participants With at Least One Immediate AE Related to Vaccination
timeFrame: 30 minutes post-vaccination
measure: Number of Participants With at Least One Solicited Local or Systemic AE From Day 0 up to Day 7
timeFrame: Day 0 (pre-vaccination) up to Day 7
measure: Number of Participants With at Least One Solicited Local or Systemic AE of Grade 1, 2, 3, or 4 From Day 0 up to Day 7
timeFrame: Day 0 (pre-vaccination) up to Day 7
measure: Number of Participants With at Least One Unsolicited AE From Day 0 up to Day 28
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Number of Participants With at Least One Unsolicited AE of Grade 1, 2, 3, or 4 From Day 0 up to Day 28
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Number of Participants With at Least One Unsolicited AE Related to Vaccination From Day 0 up to Day 28
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Number of Participants With at Least One Serious Adverse Events (SAE) From Day 1 up to Day 28
timeFrame: Day 1 up to Day 28
measure: Number of Participants With at Least One AE Leading to Withdrawal From the Study From Day 1 up to Day 28
timeFrame: Day 1 up to Day 28
measure: Number of Participants With at Least One Adverse Event of Special Interest (AESI) From Day 1 up to Day 28
timeFrame: Day 1 up to Day 28
measure: Number of Participants With at Least One Medically Attended AE (MAAE) From Day 1 up to Day 28
timeFrame: Day 1 up to Day 28
measure: Number of Participants With at Least One New Onset Clinical Disease (NOCD) From Day 1 up to Day 28
timeFrame: Day 1 up to Day 28
measure: Number of Participants With the Occurrence of Death From Day 1 up to Day 28
timeFrame: Day 1 up to Day 28
measure: Number of Participants With at Least One SAE From Day 29 up to Day 182
timeFrame: Day 29 up to Day 182
measure: Number of Participants With at Least One AE Leading to Withdrawal From the Study From Day 29 up to Day 182
timeFrame: Day 29 up to Day 182
measure: Number of Participants With at Least One AESI From Day 29 up to Day 182
timeFrame: Day 29 up to Day 182
measure: Number of Participants With at Least One MAAE From Day 29 up to Day 182
timeFrame: Day 29 up to Day 182
measure: Number of Participants With at Least One New NOCD From Day 29 up to Day 182
timeFrame: Day 29 up to Day 182
measure: Number of Participants With an Occurrence of Death From Day 29 up to Day 182
timeFrame: Day 29 up to Day 182
measure: Number of Participants With at Least One SAE From Day 183 up to Day 365
timeFrame: Day 183 up to the end of study (Day 365)
measure: Number of Participants With at Least One AE Leading to Withdrawal From the Study From Day 183 up to Day 365
timeFrame: Day 183 up to the end of study (Day 365)
measure: Number of Participants With at Least One AESI From Day 183 up to Day 365
timeFrame: Day 183 up to the end of study (Day 365)
measure: Number of Participants With at Least One MAAE From Day 183 up to Day 365
timeFrame: Day 183 up to the end of study (Day 365)
measure: Number of Participants With at Least One NOCD From Day 183 up to Day 365
timeFrame: Day 183 up to the end of study (Day 365)
measure: Number of Participants With an Occurrence of Death From Day 183 up to Day 365
timeFrame: Day 183 up to the end of study (Day 365)
measure: Number of Participants With Clinically Significant Abnormal Urine, Hematological, and Blood Biochemistry Values on Day 0
timeFrame: Day 0 (pre-vaccination)
measure: Number of Participants With Clinically Significant Abnormal Urine, Hematological, and Blood Biochemistry Values on Day 3
timeFrame: Day 3
measure: Number of Participants With Clinically Significant Abnormal Urine, Hematological, and Blood Biochemistry Values on Day 28
timeFrame: Day 28
Secondary outcomes:
measure: GMTs of HI Antibody Response for Each Homologous Influenza Strain on Day 182 and Day 365
timeFrame: Day 182, Day 365
measure: Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Homologous Influenza Strain on Day 182 and Day 365
timeFrame: Day 0 (pre-vaccination) up to Day 182 and up to Day 365
measure: Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Homologous Influenza Strain on Day 182 and Day 365
timeFrame: Day 0 (pre-vaccination) up to Day 182 and up to Day 365
measure: GMFR Measured by HI Antibody Response for Each Homologous Influenza Strain (Day 182/Day 0 and Day 365/Day 0)
timeFrame: Day 0 (pre-vaccination), Day 182, Day 365
measure: GMTs of HI Antibody Response for Each Heterologous Influenza Strain
timeFrame: Day 0 (pre-vaccination), Day 28
measure: Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Heterologous Influenza Strain
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Heterologous Influenza Strain
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: GMFR Measured by HI Antibody Response for Each Heterologous Influenza Strain
timeFrame: Day 0 (pre-vaccination), Day 28
measure: GMTs of Microneutralization (MN) Antibody Response for Each Homologous Influenza Strain
timeFrame: Day 0 (pre-vaccination), Day 28
measure: Percentage of Participants With Seroconversion Measured by MN Antibody Response for Each Homologous Influenza Strain
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: GMFR Measured by MN Antibody Response for Each Homologous Influenza Strain
timeFrame: Day 0 (pre-vaccination), Day 28
measure: GMTs of HI Antibody Response for Each Homologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination), Day 28
measure: Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Homologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Homologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: GMFR Measured by HI Antibody Response for Each Homologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination), Day 28
measure: GMTs of HI Antibody Response for Each Heterologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination), Day 28
measure: Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Heterologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Heterologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: GMFR Measured by HI Antibody Response for Each Heterologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination), Day 28
measure: GMTs of MN Antibody Response for Each Homologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination), Day 28
measure: Percentage of Participants With Seroconversion Measured by MN Antibody Response for Each Homologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: GMFR Measured by MN Antibody Response for Each Homologous Influenza Strain, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination), Day 28
measure: Number of Participants With at Least One Immediate AE, Stratified by Prior Influenza Vaccination Status
timeFrame: Up to 30 minutes post-vaccination
measure: Number of Participants With at Least One Immediate AE of Grade 1, 2, 3, or 4, Stratified by Prior Influenza Vaccination Status
timeFrame: Up to 30 minutes post-vaccination
measure: Number of Participants With at Least One Immediate AE Related to Vaccination, Stratified by Prior Influenza Vaccination Status
timeFrame: Up to 30 minutes post-vaccination
measure: Number of Participants With at Least One Solicited Local or Systemic AE, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 7
measure: Number of Participants With at Least One Solicited Local or Systemic AE of Grade 1, 2, 3, or 4, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 7
measure: Number of Participants With at Least One Unsolicited AE, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Number of Participants With at Least One Unsolicited AE of Grade 1, 2, 3, or 4, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Number of Participants With at Least One Unsolicited AE Related to Vaccination, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination) up to Day 28
measure: Number of Participants With at Least One SAE From Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365
measure: Number of Participants With at Least One AE Leading to Withdrawal From the Study From Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365
measure: Number of Participants With at Least One AESI From Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365
measure: Number of Participants With at Least One MAAE From Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365
measure: Number of Participants With at Least One NOCD From Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365
measure: Number of Participants With the Occurrence of Death From Day 1 up to Day 28, From Day 29 to Day 182, and From Day 183 to Day 365, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 1 up to Day 28, Day 29 up to Day 182, and Day 183 up to Day 365
measure: Number of Participants With Clinically Significant Abnormal Urine, Hematological, and Blood Biochemistry Values on Day 0, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 0 (pre-vaccination)
measure: Number of Participants With Clinically Significant Abnormal Urine, Hematological, and Blood Biochemistry Values on Day 3, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 3
measure: Number of Participants With Clinically Significant Abnormal Urine, Hematological, and Blood Biochemistry Values on Day 28, Stratified by Prior Influenza Vaccination Status
timeFrame: Day 28
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Optimal Sites
state: Alabama
city: Chandler
country: United States
facility: Synexus
state: Arizona
city: San Diego
country: United States
facility: Optimal Sites
state: California
city: Melbourne
country: United States
facility: Optimal Sites
state: Florida
city: Orlando
country: United States
facility: Global AES
state: Florida
city: The Villages
country: United States
facility: Global AES
state: Florida
city: Peoria
country: United States
facility: Optimal Sites
state: Illinois
city: Evansville
country: United States
facility: Synexus
state: Indiana
city: Rockville
country: United States
facility: Optimal Sites
state: Maryland
city: Anderson
country: United States
facility: Vitalink Research
state: South Carolina
city: Columbia
country: United States
facility: Vitalink Research
state: South Carolina
city: Gaffney
country: United States
facility: Vitalink Research
state: South Carolina
city: Union
country: United States
facility: Vitalink Research
state: South Carolina
city: Austin
country: United States
facility: Optimal Sites
state: Texas
Study officials:
affiliation: Medicago
name: Medical Director
role: STUDY_DIRECTOR
References: