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

Respiratory Tract Infections Clinical Trial

Official title:

A Randomized, Observer-blind, Active Comparator-controlled, Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and Immunogenicity of a Plant-derived Quadrivalent VLP Influenza Vaccine in Adults 65 Years of Age and Older

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03739112
• Other study ID #: CP-PRO-QVLP-014
• Status: Completed
• Phase: Phase 3
• Start date: September 18, 2018
• Est. completion date: July 16, 2019

Study information

• Verified date: May 2023
• Source: Medicago
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12794
• Est. completion date: July 16, 2019
• Est. primary completion date: May 17, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 65 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Communicable Diseases
• Infections
• Respiratory Tract Diseases
• Respiratory Tract Infections
• RNA Virus Infections
• Virus Diseases

Intervention

Biological:
• Quadrivalent VLP Vaccine
Single dose of a 30 µg/strain of Quadrivalent VLP Vaccine
• Fluarix Quadrivalent® Comparator Vaccine
Single dose of a 15 µg/strain of Fluarix Quadrivalent® Comparator Vaccine

Locations

Country	Name	City	State
Canada	(Site 103) Q & T Recherche Chicoutimi	Chicoutimi	Quebec
Canada	(Site 105) Q & T Outaouais	Gatineau	Quebec
Canada	(Site 113) Dawson Road Family Medical Clinic	Guelph	Ontario
Canada	(Site 107) Manna Research Inc.	Levis	Quebec
Canada	(Site 109) Manna Research Inc. (Mirabel)	Mirabel	Quebec
Canada	(Site 108) Manna Research	Pointe-Claire	Quebec
Canada	(site 101) Centre de Recherche St-Louis	Québec City	Quebec
Canada	(Site 102) CHU de Québec - Université Laval	Québec City	Quebec
Canada	(Site 110) Alpha Recherche Clinique	Québec City	Quebec
Canada	(Site 104) Q & T Recherche Sherbrooke	Sherbrooke	Quebec
Canada	(Site 110) Manna Research Inc.	Toronto	Ontario
Canada	(Site 106) Colchester Research Group	Truro	Nova Scotia
Canada	(Site 112) Medexa Recherche	Victoriaville	Quebec
Finland	(Site 309) Espoo Vaccine Research Clinic	Espoo
Finland	(Site 303) Helsinki South Vaccine Research Clinic	Helsinki
Finland	(Site 308) Helsinki East Vaccine Research Center	Helsinki
Finland	(Site 301) Jarvenpaa Vaccine Research Clinic	Järvenpää
Finland	(Site 306) Kokkola Vaccine Research Clinic	Kokkola
Finland	(Site 304) Oulu Vaccine Research Clinic	Oulu
Finland	(Site 302) Tampere University Vaccine Research Center	Pori
Finland	(Site 305) Seinaejoki Vaccine Research Clinic	Seinäjoki
Finland	(Site 310) Tampere Vaccine Research Clinic	Tampere
Finland	(Site 307) Turku Vaccine Research Center	Turku
Germany	(Site 410) Emovis GmbH	Berlin
Germany	(Site 418) Klinische Forschung Berlin GbR	Berlin
Germany	(Site 422) Synexus Clinical Research GmbH	Berlin
Germany	(Site 402) Synexus Clinical research GmbH	Bochum
Germany	(Site 409) Gemeinschaftspraxis Dr. med Kleinecke-Pohl	Cologne
Germany	(Site 401) Cardiologicum Dresden & Pirna	Dresden
Germany	(Site 406) Diabetologische Germeinschafts praxis Faulman	Dresden
Germany	(Site 405) Doktor Markus Faghih	Essen
Germany	(Site 407) Klinisches Forschungszentrum Dr. Hagemann am Hausarztzer	Essen
Germany	(Site 414) Unterfrintroper Hausarztzentrum Klinische Forschung	Essen
Germany	(Site 417) Medizentrum Essen-Borbeck	Essen
Germany	(SIte 404) Synexus Clinical Reserach GmbH	Frankfurt
Germany	(Site 411) MedicoKIT GmbH	Goch
Germany	(Site 403) Praxis Dr. Med Cornelia Brauer	Hamburg
Germany	(Site 425) Clinical Research Hamburg	Hamburg
Germany	(Site 408) Germeinsschaftspraxis Dr. med Christiane Klein/Minnich	Künzing
Germany	(Site 420) Synexus Clinical Research GmbH	Leipzig
Germany	(Site 421) SIBAmed Studienzentrum GmbH	Leipzig
Germany	(Site 423) centrum fuer Diagnostik und Gesundheit	Munich
Germany	(Site 413) Dr. Ingomar F.K. Naudts MD Office	Rodgau
Germany	(Site 415) Praxisgemeinschaft Stuhr-Brinkum	Stuhr
Germany	(Site 416) Praxis Dr. med Joachim Sauter	Wangen
Germany	(Site 412) MALU-Medizinische Studien GmbH	Wardenburg
Germany	(Site 424) Medislim GmbH	Weinheim
Thailand	(Site 603) Ramathibodi Hospital, Mahid - Division of Infectious Disease	Bangkok
Thailand	(Site 606) Faculty of Tropical Medicine, Mahidol University	Bangkok
Thailand	(Site 608) Phramongkutklao Hospital	Bangkok
Thailand	(Site 609) Division of Tropical Pediatrics	Bangkok
Thailand	(Site 601) Faculty of Medicine, Chiang Mai University	Chiang Mai
Thailand	(Site 607) Srinagarind Hospital Khon Kaen University	Khon Kaen
Thailand	(Site 605) Golden Jubilee Medical Center	Nakhon Pathom
United States	(Site 219) Heartland Research Associates LLC	Augusta	Kansas
United States	(Site 206) Benchmark Research	Austin	Texas
United States	(Site 218) Tekton Research Inc	Austin	Texas
United States	(Site 213) Advanced Clinical Research	Banning	California
United States	(Site 209) United Medical Associates	Binghamton	New York
United States	(Site 237) PMG Research of Cary LLC	Cary	North Carolina
United States	(Site 230) PMG Research of Charlotte LLC	Charlotte	North Carolina
United States	(Site 208) Sterling Research Group	Cincinnati	Ohio
United States	(Site 233) Sterling Research Group	Cincinnati	Ohio
United States	(Site 245) Rapid Medical Research	Cleveland	Ohio
United States	(Site 202) Aventiv Research Inc	Columbus	Ohio
United States	(Site 239) Alliance for Multispeciality Research	Coral Gables	Florida
United States	(Site 201) Meridian Clinical Research	Dakota Dunes	South Dakota
United States	(Site 217) Regional Clinical Research inc	Endwell	New York
United States	(Site 214) Ventavia Research Group LLC	Fort Worth	Texas
United States	(Site 224) Benchmark Research	Fort Worth	Texas
United States	(Site 222) Research Centers of America	Hollywood	Florida
United States	(Site 247) New orleans Center for Clinical Research	Knoxville	Tennessee
United States	(Site 241) Central Kentucky Reserach Associates	Lexington	Kentucky
United States	(Site 249) Advanced Clinical Research	Meridian	Idaho
United States	(Site 203) Benchmark Research	Metairie	Louisiana
United States	(Site 225) Coastal Clinical Research	Mobile	Alabama
United States	(Site 216) PMG Research of Charleston LLC	Mount Pleasant	South Carolina
United States	(Site 248) Coastal Carolina Research Center	Mount Pleasant	South Carolina
United States	(Site 234) Heartland Research Associates LLC	Newton	Kansas
United States	(Site 226) Meridian Clinical Research LLC	Norfolk	Nebraska
United States	(Site 229) Clinical Research Associates of Tidewater	Norfolk	Virginia
United States	(Site 207) Lynn Institute of Norman	Norman	Oklahoma
United States	(Site 238) Tekton Research	Oklahoma City	Oklahoma
United States	(Site 211) Meridian Clinical Research	Omaha	Nebraska
United States	(Site 221) St-Johns Center for Clinical Research	Ponte Vedra	Florida
United States	(Site 246) Paradigm Clinical Research / Pharmaseek	Redding	California
United States	(Site 251) Meridian Clinical Research	Richmond Hill	Georgia
United States	(Site 205) PMG Research of Rocky Mount LLC	Rocky Mount	North Carolina
United States	(Site 212) Benckmark Research	Sacramento	California
United States	(Site 227) Sundande Clinical Research	Saint Louis	Missouri
United States	(Site 204) Jean Brown Research	Salt Lake City	Utah
United States	(Site 232) Benchmark Research	San Angelo	Texas
United States	(Site 250) Clinical Trials of Texas Inc	San Antonio	Texas
United States	(Site 244) Paradigm Clinical Research Center Inc	San Diego	California
United States	(Site 240) Meridian Clinical Research LLC	Savannah	Georgia
United States	(Site 231) QPS-MRA LLC	South Miami	Florida
United States	(Site 236) PMG Research	Statesville	North Carolina
United States	(Site 223) Clinical Research Atlanta	Stockbridge	Georgia
United States	(Site 201) Clinical Research Consortium	Tempe	Arizona
United States	(Site 220) Advanced Clinical Research	West Jordan	Utah
United States	(Site 242) Paradigm Clinical Research Centers Inc	Wheat Ridge	Colorado
United States	(Site 215) Heartland Research Associates LLC	Wichita	Kansas
United States	(Site 235) Heartland Research Associates LLC	Wichita	Kansas
United States	(Site 228) Research of Winston-Salem	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Medicago

Countries where clinical trial is conducted

United States,  Canada,  Finland,  Germany,  Thailand, 

References & Publications (1)

Ward BJ, Makarkov A, Seguin A, Pillet S, Trepanier S, Dhaliwall J, Libman MD, Vesikari T, Landry N. Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18-64 years) and older adults (>/=6 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Occurrences of Protocol-Defined Influenza-Like Illness (ILI) Due to Any Laboratory-Confirmed Influenza Strains	Occurrences of laboratory-confirmed ILI caused by any influenza viral strains was measured by reverse transcriptase polymerase chain reaction (RT-PCR). A participant was considered to have protocol-defined ILI if the participant met at least one of the following pre-defined respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing and at least one of the following systemic symptoms: fever (defined as a temperature > 37.2 °C or > 99.0 °F), chills, tiredness, headache or myalgia. The number of laboratory-confirmed ILI cases caused by any influenza strains are reported.	Day 14 (post-vaccination) up to ~9 months
Secondary	Number of Occurrences of Laboratory Confirmed Protocol-Defined Influenza-Like Illness (ILI) Caused by Vaccine-Matched Influenza Strains	Occurrences of protocol-defined ILI due to laboratory-confirmed influenza caused by influenza viral types/subtypes that were matched (and/or antigenically similar) to the strains covered in the vaccine formulation was measured by sequential RT-PCR & serotyping. The vaccine-matched strains included: homologous A/Michigan/45/2015 [H1N1], homologous A/Singapore/INFIMH-16-0019/2016 [H3N2], homologous B/Colorado/06/2017 and homologous B/Phuket/3073/2013) covered in the vaccine formulation. A participant was considered to have protocol-defined ILI if the participant met at least one of the following pre-defined respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing and at least one of the following systemic symptoms: fever (defined as a temperature > 37.2 °C or > 99.0 °F), chills, tiredness, headache or myalgia. The number of laboratory-confirmed ILI cases caused by vaccine-matched influenza strains (all matched strains) are reported.	Day 14 (post-vaccination) up to ~9 months
Secondary	Number of Occurrences of Protocol-Defined Respiratory Illness Due to Any Laboratory-Confirmed Influenza Strains	Occurrences of protocol-defined respiratory illness due to laboratory-confirmed influenza strain (matched, mismatched, and un-typed) was measured by sequential RT-PCR. A protocol-defined respiratory illness was determined by the occurrence of at least 1 of the following respiratory symptoms: sneezing, stuffy nose, sore throat, cough, sputum production, wheezing, or difficulty breathing. The number of protocol-defined respiratory illness cases caused by any laboratory-confirmed influenza strain (matched, mismatched, and un-typed) are reported.	Day 14 (post-vaccination) up to ~9 months
Secondary	Number of Occurrences of Protocol-Defined Respiratory Illness Vaccine Caused by Vaccine-Matched Influenza Strains	Occurrences of protocol-defined respiratory illness vaccine caused by vaccine-matched influenza strains was measured by sequential RT-PCR & serotyping. The vaccine-matched strains included: homologous A/Michigan/45/2015 [H1N1], homologous A/Singapore/INFIMH-16-0019/2016 [H3N2], homologous B/Colorado/06/2017 and homologous B/Phuket/3073/2013. The protocol-defined respiratory illness was determined by the occurrence of at least 1 of the following respiratory symptoms: sneezing, stuffy nose, sore throat, cough, sputum production, wheezing, or difficulty breathing. The number of protocol-defined respiratory illness cases caused by one or more vaccine-matched strains are reported.	Day 14 (post-vaccination) up to ~9 months
Secondary	Number of Occurrences of Protocol-Defined ILI	Occurrences of protocol-defined ILI that were confirmed or not by laboratory testing were assessed. A participant was considered to have protocol-defined ILI if the participant met at least one of the following pre-defined respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing and at least one of the following systemic symptoms: fever (defined as a temperature > 37.2 °C or > 99.0 °F), chills, tiredness, headache or myalgia. The number of protocol-defined ILI cases (confirmed or not) are reported.	Day 14 (post-vaccination) up to ~9 months
Secondary	Number of Participants With at Least One Immediate Complaints	Immediate complaints were defined as any solicited local or systemic reactions. Solicited local reactions included: erythema, swelling, and pain at the injection site) and solicited systemic reactions included: fever, headache, fatigue, muscle aches, joint aches, chills, a feeling of general discomfort, swelling in the axilla, and swelling in the neck.	15 minutes post vaccination
Secondary	Number of Participants With at Least One Solicited Local and Systemic Reactions	Participants were monitored for both solicited local reactions (erythema, swelling, and pain at the injection site) and solicited systemic reactions (fever, headache, fatigue, muscle aches, joint aches, chills, a feeling of general discomfort, swelling in the axilla, and swelling in the neck) from the time of vaccination through Day 7. Any solicited local or systemic immediate complaint was also included.	Day 0 (post-vaccination) to Day 7
Secondary	Number of Participants With = Severe Solicited Local and Systemic Reaction	Participants were monitored for both solicited local reactions (erythema, swelling, and pain at the injection site) and solicited systemic reactions (fever, headache, fatigue, muscle aches, joint aches, chills, a feeling of general discomfort, swelling in the axilla, and swelling in the neck). The intensity of the solicited reactions was graded as mild (1)-easily tolerated and does not interfere with usual activity; moderate (2)-interferes with daily activity, but the participant is still able to function; severe (3)-incapacitating and the participant is unable to work or complete usual activity or potentially life threatening; (4)-likely to be life-threatening if not treated in a timely manner, according to the Food and Drug Administration (FDA) Guidance for Industry. = Severe events included severe and potentially life-threatening events. Any =severe solicited reactions are reported.	Day 0 (post-vaccination) to Day 7
Secondary	Number of Participants With = Severe Related Solicited Reactions	Participants were monitored for both solicited local reactions (erythema, swelling, & pain at the injection site) & solicited systemic reactions (fever, headache, fatigue, muscle aches, joint aches, chills, a feeling of general discomfort, swelling in axilla, & swelling in neck). The intensity of solicited reactions was graded as mild (1)-easily tolerated and does not interfere with usual activity; moderate (2)-interferes with daily activity, but the participant is still able to function; severe (3)-incapacitating and the participant is unable to work or complete usual activity or potentially life threatening; (4)-likely to be life-threatening if not treated in a timely manner, according to the FDA Guidance for Industry. = Severe events included severe and potentially life-threatening events. Any =severe related (possibly related, probably related, and definitely related to the study treatments [as defined by investigator]) solicited events are reported.	Day 0 (post-vaccination) to Day 7
Secondary	Number of Participants With Unsolicited Treatment-Emergent Adverse Events (TEAEs)	Participants were monitored for unsolicited TEAEs (e.g., nasopharyngitis, upper respiratory tract infection, headache, and pain). An adverse event (AE) or adverse experience was defined as any untoward medical occurrence in a participant or clinical investigation participant who received study drug, with or without a causal relationship with the treatment. An AE was considered treatment-emergent if it began on or after the date and time of Study Day 0 vaccination.	Day 0 (post-vaccination) to Day 21
Secondary	Number of Participants With = Severe Unsolicited TEAEs	Participants were monitored for unsolicited TEAEs (e.g., nasopharyngitis, upper respiratory tract infection, headache, and pain). AE: any untoward medical occurrence in a participant or clinical investigation participant who received study drug, with or without a causal relationship with the treatment. An AE was considered treatment-emergent if it began on or after the date and time of Study Day 0 vaccination. The intensity of the solicited reactions was graded as mild (1)-easily tolerated and does not interfere with usual activity; moderate (2)-interferes with daily activity, but the participant is still able to function; severe (3)-incapacitating and the participant is unable to work or complete usual activity or potentially life threatening; (4)-likely to be life-threatening if not treated in a timely manner, according to the FDA Guidance for Industry. = severe events included severe and potentially life-threatening events. Any = severe unsolicited reactions are reported.	Day 0 (post-vaccination) to Day 21
Secondary	Number of Participants With = Severe Related Unsolicited Reactions	Participants were monitored for unsolicited TEAEs (e.g., nasopharyngitis, upper respiratory tract infection, headache, & pain). AE: any untoward medical occurrence in a participant who received study drug, with or without a causal relationship with treatment. An AE was considered treatment-emergent if it began on or after date & time of Study Day 0 vaccination. Intensity of solicited reactions was graded as mild (1) easily tolerated & not interfere with usual activity; moderate (2) interferes with daily activity, but participant still able to function; severe (3) incapacitating & participant unable to work/complete usual activity/ potentially life threatening; (4) likely to be life-threatening if not treated in a timely manner, according to FDA Guidance for Industry. = severe events included severe & potentially life-threatening events. Any =severe related (possibly, probably, & definitely related to study treatments [as defined by investigator]) unsolicited events are reported.	Day 0 (post-vaccination) to Day 21
Secondary	Number of Participants With at Least One Serious Adverse Event (SAE)	An AE was any untoward medical occurrence in a participant who received study drug, with or without a causal relationship with treatment. An SAE was an AE that resulted in death, was life threatening, resulted in a persistent or significant disability or incapacity, resulted in or prolonged an existing hospitalization, was a congenital anomaly or birth defect, or was another important medical event.	Day 0 to ~9 months
Secondary	Number of Occurrences of Death	The number of participants who died during the study was assessed.	Day 0 up to ~9 months
Secondary	Number of Participants Who Withdrew Due to an AE	An AE or adverse experience was defined as any untoward medical occurrence in a participant or clinical investigation participant who received study drug, with or without a causal relationship with the treatment. An AE can be any favorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to a medicinal product.	Day 0 up to ~9 months
Secondary	Number of Participants With at Least One New Onset Chronic Diseases (NOCDs)	All NOCDs that may plausibly have an allergic, autoimmune or inflammatory component were reported. Plausibility should be interpreted broadly however; the only clear exceptions were degenerative conditions such as osteoarthritis, age-related physiologic changes and life-style diseases. In this context, most cancers, cardiac conditions and kidney diseases should be reported. NOCDs were collected from vaccination on Day 0 to the end of the surveillance period.	Day 0 up to ~9 months
Secondary	Geometric Mean Titers (GMTs) of Hemagglutination Inhibition (HI) Antibody Response for Each Homologous and Heterologous Influenza Strain	GMTs were measured using a HI assay for the homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013, and the heterologous strains: H1N1 = A/Brisbane/59/2007; H3N2 = A/Uruguay/716/2007; B/Malaysia = B/Malaysia/2506/2004; B/Florida = B/Florida/4/2006.	Baseline (Day 0), Day 21
Secondary	Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Homologous and Heterologous Strain	The percentage of participants in a given treatment group with either a = 4-fold increase in reciprocal HI titers between Day 0 and Day 21 or a rise of undetectable HI titer (i.e. < 10) pre-vaccination (Day 0) to an HI titer of = 40 on Day 21 was measured using an HI assay for the homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013, and the heterologous strains: H1N1 = A/Brisbane/59/2007; H3N2 = A/Uruguay/716/2007; B/Malaysia = B/Malaysia/2506/2004; B/Florida = B/Florida/4/2006.	Day 0 (pre-vaccination) to Day 21
Secondary	Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Homologous and Heterologous Strain	The percentage of participants in a given treatment group attaining a reciprocal HI titer of = 40 on Day 21 (the percentage of vaccine recipients with a serum HI titer of at least 1:40 following vaccination) was measured using an HI assay for homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013, and the heterologous strains: H1N1 = A/Brisbane/59/2007; H3N2 = A/Uruguay/716/2007; B/Malaysia = B/Malaysia/2506/2004; B/Florida = B/Florida/4/2006.	Baseline (Day 0), Day 21
Secondary	Geometric Mean Fold Rise (GMFR) of HI Antibody Response for Each Homologous and Heterologous Strain	GMFR, the geometric mean of the ratio of GMTs (Day 21/Day 0), was measured using an HI assay homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013, and the heterologous strains: H1N1 = A/Brisbane/59/2007; H3N2 = A/Uruguay/716/2007; B/Malaysia = B/Malaysia/2506/2004; B/Florida = B/Florida/4/2006.	Baseline (Day 0), Day 21
Secondary	GMTs of Microneutralization (MN) Antibody Response for Each Homologous Strain	GMTs were measured using an MN assay for homologous strains:H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013.	Baseline (Day 0), Day 21
Secondary	Percentage of Participants With Seroconversion Measured by MN Antibody Response for Each Homologous Strain	The percentage of participants in a given treatment group with either a = 4-fold increase in reciprocal MN titers between Day 0 and Day 21 or a rise of undetectable MN titer (i.e. 7.1) pre-vaccination (Day 0) to an MN titer of = 28.3 at Day 21 post-vaccination were measured using an MN assay for homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013.	Day 0 (pre-vaccination) to Day 21
Secondary	GMFR of MN Antibody Response for Each Homologous Strain	GMFR, the geometric mean of the ratio of GMTs (Day 21/Day 0), was measured using an MN assay for H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013.	Baseline (Day 0), Day 21
Secondary	Geometric Mean Areas (GMA) of Single Radial Hemolysis (SRH) Antibody Response for Each Homologous Strain	GMA was measured using an SRH assay for homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013.	Baseline (Day 0), Day 21
Secondary	Percentage of Participants With Seroconversion Measured by SRH Antibody Response for Each Homologous Strain	The percentage of participants in a given treatment group showing at least 50 % increase in GMA between Days 0 and 21 were measured using an SRH assay for homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013.	Day 0 (pre-vaccination) to Day 21
Secondary	Percentage of Participants With Seroprotection Measured by SRH Antibody Response for Each Homologous Strain	The percentage of participants in a given treatment group attaining an area = 25 mm^2 following vaccination (Day 21) were measured using an SRH assay for homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013.	Baseline (Day 0), Day 21
Secondary	GMFR of SRH Antibody Response for Each Homologous Strain	GMFR, the geometric mean of the ratio of GMTs (Day 21/Day 0), was measured using an SRH assay for homologous strains: H1N1 = A/Michigan/45/2015; H3N2 = A/Singapore/INFIMH-16-0019/2016; B/Colorado = B/Colorado/06/2017; B/Phuket = B/Phuket/3073/2013.	Baseline (Day 0), Day 21