Safety and Immunogenicity of Fluzone® Quadrivalent, Flublok® Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines, 2018-2019 Formulations (GRC90)

• ClinicalTrials.gov Identifier: NCT03617523
• Recruitment Status: Completed
• First Posted: August 6, 2018
• Results First Posted: November 25, 2019
• Last Update Posted: November 25, 2019
• Sponsor: Sanofi Pasteur, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Sanofi Pasteur, a Sanofi Company )

Study Description

Brief Summary:

The primary objectives of this study were:

• To describe the immunogenicity of the 2018-2019 formulation of Fluzone® Quadrivalent vaccine in children 6 to less than (<) 36 months of age and 3 to <9 years of age, and in adults 18 to <65 years of age; the immunogenicity of the 2018-2019 formulation of Flublok® Quadrivalent vaccine in adults 18 to <65 years of age; and the immunogenicity of the 2018-2019 formulation of Fluzone High-Dose vaccine in adults greater than or equal to (>=) 65 years of age.
• To describe the safety of the 2018-2019 formulation of Fluzone Quadrivalent vaccine in children 6 to <36 months of age and 3 to <9 years of age, and in adults 18 to <65 years of age; the safety of the 2018-2019 formulation of Flublok Quadrivalent vaccine in adults 18 to <65 years of age; and the safety of the 2018-2019 formulation of Fluzone High-Dose vaccine in adults >=65 years of age.

Condition or disease	Intervention/treatment	Phase
Influenza	Biological: Fluzone Quadrivalent vaccine, 2018-2019 formulation; Biological: Flublok Quadrivalent vaccine, 2018-2019 formulation; Biological: Fluzone High-Dose vaccine, 2018-2019 formulation	Phase 4

Detailed Description:

Study duration per participant was approximately 21 days for adult participants or 28 days for child participants who received one dose of vaccine, and 56 days for participants who received two doses of vaccine.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 240 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The study was partially randomized. Participants were assigned a vaccine group based on age. Participants in Groups 1, 2, and 5 were not randomly assigned, while participants in Groups 3 and 4 were randomly assigned.
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Safety and Immunogenicity of Fluzone® Quadrivalent, Flublok® Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines, 2018-2019 Formulations
• Actual Study Start Date: September 10, 2018
• Actual Primary Completion Date: November 12, 2018
• Actual Study Completion Date: November 12, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Fluzone Quadrivalent vaccine Group 1: 6 to <36 months; Participants (aged 6 to <36 months) received a 0.25-milliliter (mL) dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.	Biological: Fluzone Quadrivalent vaccine, 2018-2019 formulation; Pharmaceutical form: Suspension for injection Route of administration: Intramuscular
Experimental: Fluzone Quadrivalent vaccine Group 2: 3 to <9 years; Participants (aged 3 to <9 years) received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.	Biological: Fluzone Quadrivalent vaccine, 2018-2019 formulation; Pharmaceutical form: Suspension for injection Route of administration: Intramuscular
Experimental: Fluzone Quadrivalent vaccine Group 3: 18 to <65 years; Participants (aged 18 to <65 years) received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0.	Biological: Fluzone Quadrivalent vaccine, 2018-2019 formulation; Pharmaceutical form: Suspension for injection Route of administration: Intramuscular
Experimental: Flublok Quadrivalent vaccine Group 4: 18 to <65 years; Participants (aged 18 to <65 years) received a 0.5-mL dose of Flublok Quadrivalent vaccine, intramuscularly, at Day 0.	Biological: Flublok Quadrivalent vaccine, 2018-2019 formulation; Pharmaceutical form: Suspension for injection Route of administration: Intramuscular
Experimental: Fluzone High-Dose vaccine Group 5: >=65 years; Participants (aged >=65 years) received a 0.5-mL dose of Fluzone High-Dose vaccine, intramuscularly, at Day 0.	Biological: Fluzone High-Dose vaccine, 2018-2019 formulation; Pharmaceutical form: Suspension for injection Route of administration: Intramuscular

Outcome Measures

Primary Outcome Measures :

1. Number of Participants (Group 1: Aged 6 to <36 Months) Reporting Solicited Injection Site Reactions and Systemic Reactions [ Time Frame: Within 7 days post any vaccination ]
   A solicited reaction was an adverse event (AE) that was pre-listed in the electronic case report form (eCRF) and considered to be related to vaccination. Solicited injection (Inj.) site reactions: tenderness, erythema and swelling. Solicited systemic reactions: fever, vomiting, crying abnormal, drowsiness, appetite lost and irritability.
2. Number of Participants (Groups 2, 3, 4 and 5: Children Aged 3 to <9 Years and Adults 18 to >=65 Years) Reporting Solicited Injection Site Reactions or Systemic Reactions [ Time Frame: Within 7 days post any vaccination ]
   A solicited reaction was an AE that was pre-listed in the eCRF and considered to be related to vaccination. Solicited injection site reactions: pain, erythema and swelling. Solicited systemic reactions: fever, headache, malaise, and myalgia.
3. Geometric Mean Titers (GMTs) of Antibodies in Children 6 Months to <9 Years of Age (Groups 1 and 2) Receiving Fluzone Quadrivalent Vaccine [ Time Frame: 28 days post-final vaccination ]
   GMT of anti-influenza antibodies were measured using a hemagglutination inhibition (HAI) assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage.
4. Geometric Mean Titers of Antibodies in Adults (Groups 3, 4 and 5) Receiving Either Fluzone Quadrivalent Vaccine, Flublok Quadrivalent Vaccine, or Fluzone High-Dose Vaccine [ Time Frame: Day 21 (post-vaccination) ]
   GMTs of anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage in Groups 3 and 4, and using HAI assay for 3 strains: A/H1N1, A/H3N2 and B Victoria lineage in Group 5.
5. Geometric Mean Titer Ratios (GMTRs) of Antibodies in Children 6 Months to <9 Years of Age (Groups 1 and 2) Receiving Fluzone Quadrivalent Vaccine [ Time Frame: Day 0 (pre-vaccination), 28 days post-final vaccination ]
   GMT of anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage. GMTRs were calculated as the ratio of GMTs post-final vaccination and pre-vaccination.
6. Geometric Mean Titer Ratios of Antibodies in Adults (Groups 3, 4 and 5) Receiving Either Fluzone Quadrivalent Vaccine, Flublok Quadrivalent Vaccine, or Fluzone High-Dose Vaccine [ Time Frame: Day 0 (pre-vaccination), Day 21 (post-vaccination) ]
   GMTs of anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage in Groups 3 and 4, and using HAI assay for 3 strains: A/H1N1, A/H3N2 and B Victoria lineage in Group 5. GMTRs were calculated as the ratio of GMTs post vaccination and pre-vaccination.
7. Percentage of Participants With Seroprotection to Influenza Vaccine Antigens After Vaccination With Fluzone Quadrivalent Vaccine: Groups 1 and 2 [ Time Frame: 28 days post-final vaccination ]
   Anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage. Seroprotection was defined as antibody titer >=40 (1/ dilution) at pre-vaccination and at post-final vaccination.
8. Percentage of Participants With Seroprotection to Influenza Vaccine Antigens After Vaccination With Either Fluzone Quadrivalent Vaccine, Flublok Quadrivalent Vaccine or Fluzone High Dose Vaccine: Group 3, 4 and 5 [ Time Frame: Day 21 (post-vaccination) ]
   Anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage in Groups 3 and 4, and using HAI assay for 3 strains: A/H1N1, A/H3N2 and B Victoria lineage in Group 5. Seroprotection was defined as antibody titer >=40 (1/dilution) at pre-vaccination and at post-final vaccination.
9. Percentage of Participants With Seroconversion to Influenza Vaccine Antigens After Vaccination With Fluzone Quadrivalent Vaccine: Group 1 and 2 [ Time Frame: 28 days post-final vaccination ]
   Anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage. Seroconversion was defined as either a pre-vaccination titer <10 (1/dilution) and a post-final vaccination titer >= 40 (1/dilution) or a pre-vaccination titer >= 10 (1/dilution) and >=4-fold increase in post-final vaccination titer.
10. Percentage of Participants With Seroconversion to Influenza Vaccine Antigens After Vaccination With Either Fluzone Quadrivalent Vaccine, Flublok Quadrivalent Vaccine or Fluzone High Dose Vaccine: Group 3, 4 and 5 [ Time Frame: Day 21 (post-vaccination) ]
    Anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage in Group 3 and 4, and using an HAI assay for 3 strains: A/H1N1, A/H3N2, and B Victoria lineage in Group 5. Seroconversion was defined as either a pre-vaccination titer <10 (1/dilution) and a post-vaccination titer >= 40 (1/dilution) or a pre-vaccination titer >= 10 (1/dilution) and >=4-fold increase in post-vaccination titer.

Eligibility Criteria

• Ages Eligible for Study: 6 Months and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion criteria :

• Aged 6 months to <9 years or >=18 years on the day of first study vaccination (study product administration).
• For participants 6 to <12 months of age, born at full term of pregnancy (>=37 weeks) and with a birth weight >=2.5 kilograms (kg) (5.5 pounds [lbs.]).
• Informed consent form (ICF) had been signed and dated by participants >=18 years of age.
• Assent form had been signed and dated by participants 7 to <9 years of age, and ICF had been signed and dated by parent(s) or guardian(s) for participants 6 months to <9 years of age.
• Participants and parent/guardian (of participants 6 months to <9 years of age) were able to attend all scheduled visits and to comply with all study procedures.

Exclusion criteria:

• Participant was pregnant, or lactating, or of childbearing potential and not using an effective method of contraception or abstinence from at least 4 weeks prior to vaccination and until at least 4 weeks after vaccination. To be considered of non-childbearing potential, a female must be pre-menarche, or post-menopausal for at least 1 year, or surgically sterile.
• Participation at the time of study enrollment (or in the 30 days 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.
• Receipt of any vaccine in the 30 days preceding the first study vaccination, or planned receipt of any vaccine before Visit 2 for participants who received 1 dose of influenza vaccine or Visit 3 for participants who received 2 doses of influenza vaccine.
• Previous vaccination against influenza (in the 2018-2019 influenza season) with either study vaccine or another vaccine.
• Receipt of immune globulins, blood, or blood-derived products in the 3 months preceding planned inclusion.
• Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the 6 months preceding planned inclusion; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the 3 months preceding planned inclusion).
• Known systemic hypersensitivity to any of the vaccine components, or history of a life- threatening reaction to study vaccine or to a vaccine containing any of the same substances.
• Thrombocytopenia, which might be a contraindication for intramuscular vaccination, at the discretion of the Investigator.
• Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination.
• Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
• Current alcohol abuse or drug addiction.
• Chronic illness that, in the opinion of the Investigator, was 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 planned vaccination or febrile illness (temperature >=100.4 degree Fahrenheit [38.0 degree Celsius]). A prospective participant was not included in the study until the condition had resolved or the febrile event had subsided.
• Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study (participants >=18 years of age) or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study (all participants).
• History of serious adverse reaction to any influenza vaccine.
• Personal history of Guillain-Barré 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 developmental delay (at the discretion of the Investigator), neurologic disorder, or seizure disorder.
• Known seropositivity for human immunodeficiency virus, hepatitis B, or hepatitis C.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

United States, Kentucky

Investigational Site Number 8400003

Bardstown, Kentucky, United States, 40004

United States, Louisiana

Investigational Site Number 8400001

Metairie, Louisiana, United States, 70006

United States, Utah

Investigational Site Number 8400002

Salt Lake City, Utah, United States, 84121

Sponsors and Collaborators

Sanofi Pasteur, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi Pasteur, a Sanofi Company

  Study Documents (Full-Text)

Documents provided by Sanofi ( Sanofi Pasteur, a Sanofi Company ):

Study Protocol  [PDF] May 18, 2018

Statistical Analysis Plan  [PDF] March 22, 2019

More Information

• Responsible Party: Sanofi Pasteur, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT03617523
• Other Study ID Numbers: GRC90; U1111-1211-4864 ( Other Identifier: UTN )
• First Posted: August 6, 2018
• Results First Posted: November 25, 2019
• Last Update Posted: November 25, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to participant-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Participant level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Influenza, Human; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Vaccines; Immunologic Factors; Physiological Effects of Drugs