Study on a High-Dose Quadrivalent Influenza Vaccine Compared With Standard-Dose Quadrivalent Influenza Vaccine in Children 6 Months Through 35 Months of Age

Study Overview
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Brief Summary
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The primary objective of the study is to compare the clinical efficacy of high-dose quadrivalent influenza vaccine (QIV-HD) to standard-dose quadrivalent influenza vaccine (QIV-SD) in participants 6 months through 35 months of age for the prevention of laboratory-confirmed influenza illness caused by any influenza A or B type. The secondary objectives of the study are: To compare QIV-HD to QIV-SD: in participants 6 months through 35 months of age for the prevention of laboratory-confirmed influenza illness caused by any influenza A or B type using a more stringent threshold in participants 6 months through 35 months of age for the prevention of laboratory-confirmed protocol-defined influenza-like illness caused by viral strains similar to those contained in the vaccine. in participants 6 months through 23 months of age for the prevention of laboratory-confirmed influenza illness caused by any influenza A or B types. To compare hemagglutination inhibition (HAI) immune response of QIV-HD to QIV-SD in participants 6 months through 35 months of age To describe the HAI, seroneutralization (SN), and anti-neuraminidase (NA) immune response To describe the immune response to revaccination in Season 3 (Northern Hemisphere) To describe the safety profile of each vaccine

Detailed Description
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The study is planned to start in the second half of 2020 with the Sentinel Safety Cohort. Following the Sentinel Safety Cohort, the main efficacy cohort will be conducted during the 2021-2022 Northern Hemisphere influenza season (Season 1), the 2021-2022 Southern Hemisphere influenza season (Season 2), and the 2021-2022-2023 Northern Hemisphere influenza season (Season 3). Participants will receive either 1 or 2 doses of the study vaccine depending on whether they were previously influenza vaccinated or previously influenza unvaccinated, respectively. Study duration per participant is approximately 6 to 7 months.

Official Title
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Efficacy, Immunogenicity, and Safety of High-Dose Quadrivalent Influenza Vaccine Compared With Standard-Dose Quadrivalent Influenza Vaccine in Children 6 Months Through 35 Months of Age

Conditions
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Influenza

Intervention / Treatment
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* Biological: Quadrivalent influenza vaccine, high-dose
* Biological: Quadrivalent influenza vaccine, standard dose


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Aged 6 to 35 months on the day of the first study visit Informed consent form has been signed and dated by the parent(s) or guardian(s) and by an independent witness, if required by local regulations. Participant and parent / guardian are able to attend all scheduled visits and to comply with all study procedures. Covered by health insurance if required by local regulations For Season 3 Re-vaccination Cohort: eligible participants must have been enrolled in the Season 1 (2021-2022 Northern Hemisphere season) immunogenicity subset and must have completed all study procedures (ie, blood draws and vaccinations) in Season 1. Exclusion criteria: Participation at the time of study enrollment (or in the 4 weeks preceding the first study vaccination) or planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure. For all participants: Receipt of any vaccine in the 30 days preceding the first study vaccination. For participants in immunogenicity subset: Planned receipt of any vaccine before Visit 2 for participants receiving 1 dose of influenza vaccine or Visit 3 for participants receiving 2 doses of influenza vaccine. Previous vaccination against influenza in the preceding 6 months with either the study vaccine or another influenza vaccine Receipt of immune globulins, blood or blood-derived products in the past 3 months. Known or suspected congenital or acquired immunodeficiency (eg, HIV); or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months). Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any of the same substances. Exception: participants with an egg allergy are allowed to enroll in the study. Thrombocytopenia, bleeding disorder, or receipt of anticoagulants that based on Investigator's judgment contraindicate intramuscular vaccination Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with study conduct or completion. Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0 C [≥ 100.4 F]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided. Identified as natural or adopted child of the Investigator or employee with direct involvement in the proposed study. Personal or family history of Guillain-Barre Syndrome. Any condition that in the opinion of the Investigator would pose a health risk to the participant if enrolled or could interfere with the evaluation of the vaccine. Personal history of clinically significant development delay (at the discretion of the Investigator), neurologic disorder, or seizure disorder. For Season 3 (2022-2023 Northern Hemisphere) main cohort: participants who were enrolled in a previous study season are excluded from Season 3, with the exception of the Re-vaccination Cohort. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 35 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A sentinel safety cohort is selected for collection safety events where QIV-HD will be administered open-label in 100 participants. These subjects will not provide blood samples and will not be followed for influenza-like illness (ILI) surveillance. A re-vaccination cohort will be composed of a subset of approximately 120 participants from Season 1 (2021-2022 Northern Hemisphere) will be re-enrolled and re-randomized in Season 3.The re-vaccination cohort will be included re-randomized to receive either QIV-HD or QIV-SD, will provide blood samples in Season 1 and Season 3, and will not be followed for ILI surveillance during their participation in Season 3.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QIV-HD<br>One injection of QIV-HD on Day 0. For participants for whom 2 doses of influenza vaccine are recommended, a second dose is administered on Day 28. | Biological: Quadrivalent influenza vaccine, high-dose<br>* Pharmaceutical form: suspension for injection in a pre-filled syringe; route of administration: intramuscular<br>|
| Active Comparator: QIV-SD<br>One injection of QIV-SD on Day 0. For participants for whom 2 doses of influenza vaccine are recommended, a second dose is administered on Day 28. | Biological: Quadrivalent influenza vaccine, standard dose<br>* Pharmaceutical form: suspension for injection in a pre-filled syringe; route of administration: intramuscular<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with laboratory-confirmed influenza illness caused by any influenza viral types/subtypes, in association with a protocol-defined influenza-like illness (ILI) | Laboratory-confirmed influenza is a positive influenza result on either polymerase chain reaction (PCR) or viral culture. A protocol-defined ILI is occurrence of fever concurrently with protocol pre-defined clinical symptoms. | From 14 days after the first injection to 6 months after the last injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with ILI laboratory-confirmed as positive for viral strains similar to those contained in the vaccine | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive in participants aged 6 through 23 months for any influenza A or B type | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for any influenza A or B type, according to previous vaccination status | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for viral strains similar to those contained in the vaccine, according to previous vaccination status | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for any influenza A or B type, and associated with acute otitis media (AOM) | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. AOM is based on clinical diagnosis. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for viral strains similar to those contained in the vaccine, and associated with AOM | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. AOM is based on clinical diagnosis. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for any influenza A or B type, and associated with acute lower respiratory infection (ALRI) | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for viral strains similar to those contained in the vaccine, and associated with ALRI | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI PCR-confirmed as positive for viral strains similar to those contained in the vaccine | PCR-confirmed influenza is a positive influenza result on PCR. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI culture-confirmed as positive for viral strains similar to those contained in the vaccine | Culture-confirmed influenza is a positive influenza result on viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI PCR-confirmed as positive for any influenza A or B types | PCR-confirmed influenza is a positive influenza result on PCR. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI culture-confirmed as positive for any influenza A or B types | Culture-confirmed influenza is a positive influenza result on viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for any influenza A or B types and associated with hospitalization | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Number of participants with ILI laboratory-confirmed as positive for viral strains similar to those contained in the vaccine and associated with hospitalization | Laboratory-confirmed influenza is a positive influenza result on either PCR or viral culture. | From 14 days to maximum 6 months after the last injection | 
| Geometric mean titer of influenza vaccine antibodies | Antibody titers are measured by HAI assay. | Day 0 and 28 days after the last vaccination | 
| Number of participants with seroconversion or significant increase of titers | Seroconversion for participants with a pre-vaccination titer < 10 (1/dil): post-injection titer ≥ 40 (1/dil) on 28 days after the last vaccination or significant increase for participants with a pre-vaccination titer ≥ 10 (1/dil): ≥ 4-fold increase from pre- to post-injection titer on 28 days after the last vaccination. Antibody titers are measured by HAI assay. | Day 0 and 28 days after the last vaccination | 
| Number of participants with influenza vaccine antibody titer ≥ 10 (1/dilution [dil]) | Antibody titers are measured by HAI assay. | Day 0 and 28 days after the last vaccination | 
| Influenza vaccine antibody titer ratio | Individual antibody titer ratio 28 days after the last vaccination /Day 0. Antibody titers are measured by HAI assay. | Day 0 and 28 days after the last vaccination | 
| Participant with influenza vaccine antibody titer ≥ 40 (1/dil) | Antibody titers are measured by HAI assay. | Day 0 and 28 days after the last vaccination | 
| Influenza SN antibody titer | Antibody titers will be measured by the SN method | Day 0 and 28 days after the last vaccination | 
| Influenza SN antibody titer ratio | Ratio is calculated as fold increase in serum SN post-vaccination relative to Day 0. Antibody titers are measured by the SN method | 28 days after the last vaccination | 
| Number of participants with influenza SN antibody titer above predefined thresholds | Antibody titers are measured by the SN method. Titers levels assessed are ≥ 20 (1/dil), ≥ 40 (1/dil), and ≥ 80 (1/dil). | 28 days after the last vaccination | 
| Fold-increase in influenza SN antibody titer | Increase of titer [post/pre] ≥2 and ≥ 4. Antibody titers are measured by the SN method. | 28 days after the last vaccination | 
| Detectable influenza SN antibody titer | Detectable antibody titers are ≥ 10 [1/dil] | Day 0 and 28 days after the last vaccination | 
| Anti-NA antibody titer | Antibody titers are measured by enzyme-linked lectin assay | Day 0 and 28 days after the last vaccination | 
| Anti-NA antibody titer ratio | Ratio is calculated as fold increase in anti-NA antibodies post-vaccination relative to Day 0. Antibody titers are measured by enzyme-linked lectin assay. | 28 days after the last vaccination | 
| Number of participants with anti-NA antibody titer above predefined thresholds | Antibody titers are measured by enzyme-linked lectin assay. Titers levels assessed are ≥ 20 (1/dil), ≥ 40 (1/dil), and ≥ 80 (1/dil). | 28 days after the last vaccination | 
| Fold-increase in anti-NA antibody titer | Increase of titer [post/pre] ≥2 and ≥ 4. Antibody titers are measured by enzyme-linked lectin assay. | 28 days after the last vaccination | 
| Detectable anti-NA antibody titer | Detectable antibody titers are ≥ 10 (1/dil). | Day 0 and 28 days after the last vaccination | 
| Number of participants with immediate adverse events | Immediate adverse events includes unsolicited systemic adverse events occuring within 30 minutes after vaccination. | Within 30 minutes after vaccination | 
| Number of participants with solicited injection site and systemic reactions | Injection site reactions: tenderness, erythema, swelling, induration, and bruising. Systemic reactions: fever, vomiting, crying abnormal, drowsiness, appetite lost, and irritability. | Within 7 days after vaccination | 
| Number of participants with unsolicited adverse events | Unsolicited adverse events are events other than solicited reactions. | Within 28 days after vaccination | 
| Number of participants with serious adverse events | Serious adverse events are collected throughout the study. | From Day 0 to Day 180 | 
| Number of participants with adverse events of special interest | Adverse events of special interest are collected throughout the study. | From Day 0 to Day 180 |