Safety and Immunogenicity of Fluzone® Quadrivalent Vaccine Administered to Healthy Children

• Sponsor: Sanofi Pasteur, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02915302
• Collaborator: (none)
• Enrollment: 1,950
• Locations: 36
• Arms: 2
• Duration (Months): 5.4
• Patients Per Site: 54.2
• Patients Per Site Per Month: 10.1

Study Details

Study Description

Brief Summary

The aim of the study was to describe the safety and immunogenicity of a 0.5-mL dose (15 μg hemagglutinin [HA] per strain) of Fluzone Quadrivalent vaccine in children 6 to <36 months of age.

Primary objective:

• To compare the rate of any fever (temperature ≥100.4 degrees Fahrenheit [38.0 degrees Celsius) following a 0.5-mL dose of Fluzone Quadrivalent vaccine to that following a 0.25-mL dose of Fluzone Quadrivalent vaccine during the 7 days after either vaccination (Dose 1 and Dose 2 combined) in participants 6 to < 36 months of age.

Secondary objective:

• To compare antibody responses induced by a 0.5-mL dose of Fluzone Quadrivalent vaccine to those induced by a 0.25-mL dose of Fluzone Quadrivalent vaccine as assessed by geometric mean titer (GMT) ratios and seroconversion rate differences after the final vaccination in participants 6 to < 36 months of age.

Other objectives:

• To describe the safety of 2 different dose levels of the 2016-2017 formulation of Fluzone Quadrivalent vaccine in participants 6 to < 36 months of age.

• To describe the immunogenicity of 2 different dose levels of the 2016-2017 formulation of Fluzone Quadrivalent vaccine in participants 6 months to < 36 months of age.

• To submit available sera from approximately 30 participants to the Center for Biologics Evaluation and Research for further analysis by the World Health Organization, the Centers for Disease Control and Prevention, and the FDA to support formulation recommendations for subsequent influenza vaccines.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Biological: Fluzone Quadrivalent vaccine, No Preservative; Biological: Fluzone Quadrivalent vaccine, No Preservative	Phase 4

Detailed Description

All participants received 1 intramuscular dose of Fluzone Quadrivalent vaccine during Visit

1. For participants, for whom 2 doses of influenza vaccine were recommended per Advisory Committee on Immunization Practices (ACIP) guidance, a second dose of Fluzone Quadrivalent vaccine (of the same volume as the first dose) was administered during Visit 2 (28 days after Visit 1).

Solicited adverse event (AE) information was collected for 7 days after each vaccination, unsolicited AE information was collected from Visit 1 to Visit 2 or to Visit 3 for participants receiving 2 doses of study vaccine. Serious adverse event (SAE) information was collected for 28 days after each vaccination.

Immunogenicity was evaluated in a planned subset of 1600 randomly selected participants prior to vaccination on Day 0 (Visit 1) and at Day 28 after the final vaccination.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1950 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Safety and Immunogenicity of Fluzone® Quadrivalent Vaccine Administered to Healthy Children 6 to < 36 Months of Age
• Study Start Date: Sep 23, 2016
• Actual Primary Completion Date: Mar 6, 2017
• Actual Study Completion Date: Mar 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Fluzone Quadrivalent Vaccine, 0.25-mL Participants received a 0.25-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.25-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Biological: Fluzone Quadrivalent vaccine, No Preservative; 0.25-mL (Pediatric Dose), Intramuscular (2016-2017 formulation); Other Names: Fluzone® Quadrivalent Influenza Vaccine
Experimental: Fluzone Quadrivalent Vaccine, 0.5-mL Participants received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.5-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Biological: Fluzone Quadrivalent vaccine, No Preservative; 0.5-mL, Intramuscular (2016-2017 formulation); Other Names: Fluzone® Quadrivalent Influenza Vaccine

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Fever (Fever Rate) Following Vaccination With Fluzone Quadrivalent Vaccine [Within 7 days after any vaccination]

   Fever rate was defined as percentage of participants with fever (temperature >=100.4 degrees Fahrenheit [38.0 degrees Celsius]) following vaccination with Fluzone Quadrivalent vaccine.

Secondary Outcome Measures

1. Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies [28 days post-final vaccination]

   Anti-influenza antibodies were measured using a hemagglutination inhibition (HAI) assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, B Yamagata lineage.

2. Percentage of Participants With Seroconversion (Seroconversion Rate [SCR]) to Influenza Vaccine Antigens [28 days post-final vaccination]

   Anti-influenza antibodies were measured using HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, B Yamagata lineage. SCR was defined as percentage of participants with either a pre-vaccination titer <10 (1/dil) and a post-final vaccination titer >=40 (1/dil), or a pre-vaccination titer >=10 (1/dil) and at least a four-fold increase in post-final vaccination titer.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 35 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Aged 6 to < 36 months of age on the day of first study vaccination (study product administration).

• Born at full term of pregnancy (≥37 weeks) and/or with a birth weight ≥2.5 kg. Note: This inclusion criterion only applies to participants 6 to <12 months of age on the day of the first study visit.

• Informed consent form has been signed and dated by the parent(s) or guardian(s).

• Participant and parent/guardian are able to attend all scheduled visits and to comply with all trial procedures.

Exclusion Criteria:

• Participation at the time of study enrollment (or in the 30 days preceding the first trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure.

• Receipt of any vaccine in the 30 days preceding the first trial vaccination, or 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 2016-2017 season) with either the trial vaccine or another vaccine.

• Receipt of immune globulins, blood, or blood-derived products in the past 3 months.

• Known or suspected congenital or acquired immunodeficiency; 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 vaccine used in the trial or to a vaccine containing any of the same substances.

• Thrombocytopenia, which may 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.

• Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial 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 degrees Fahrenheit [38.0 degrees Celsius]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided.

• Identified as a natural or adopted child of either the Investigator or an employee with direct involvement in the proposed study.

• History of serious adverse reactions 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35205
2		Harrisburg	Arkansas	United States	72432
3		Downey	California	United States	90241
4		Paramount	California	United States	90723
5		Sacramento	California	United States	95815
6		San Diego	California	United States	92111
7		Thornton	Colorado	United States	80233
8		Miami Beach	Florida	United States	33140
9		Miami	Florida	United States	33142
10		Meridian	Idaho	United States	83642
11		Bardstown	Kentucky	United States	40004
12		Metairie	Louisiana	United States	70006
13		Lincoln	Nebraska	United States	68504
14		Lincoln	Nebraska	United States	68505
15		Lincoln	Nebraska	United States	68516
16		Norfolk	Nebraska	United States	68701
17		Omaha	Nebraska	United States	68131
18		Omaha	Nebraska	United States	68134
19		Syracuse	New York	United States	13057
20		Dayton	Ohio	United States	45414
21		Grove City	Ohio	United States	43123
22		Gresham	Oregon	United States	97030
23		Erie	Pennsylvania	United States	16505
24		Charleston	South Carolina	United States	29407
25		Charleston	South Carolina	United States	29414
26		Tullahoma	Tennessee	United States	37388
27		Fort Worth	Texas	United States	76107
28		Houston	Texas	United States	77055
29		Layton	Utah	United States	84041
30		Orem	Utah	United States	84057
31		Provo	Utah	United States	84604
32		Roy	Utah	United States	84067
33		South Jordan	Utah	United States	84095
34		West Jordan	Utah	United States	84088
35		Burke	Virginia	United States	22015
36		Anaheim	California	United Kingdom	92804

Sponsors and Collaborators

• Sanofi Pasteur, a Sanofi Company

Investigators

• Study Director: Medical Director, Sanofi Pasteur Inc.

Study Documents (Full-Text)

• Study Protocol - Jun 13, 2016
• Statistical Analysis Plan - Jul 20, 2017

More Information

Publications

None provided.

• Responsible Party: Sanofi Pasteur, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT02915302
• Other Study ID Numbers: GRC88; U1111-1143-9273
• First Posted: Sep 27, 2016
• Last Update Posted: Mar 29, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Sanofi Pasteur, a Sanofi Company: Influenza; Influenza virus vaccine; Fluzone® Quadrivalent Influenza Vaccine (No Preservative)
• Additional relevant MeSH terms: Influenza, Human; Vaccines

Study Results

Participant Flow

Recruitment Details	Study participants were enrolled in 38 centers in the United States from 23 September 2016 to 02 January 2017.
Pre-assignment Detail	A total of 1950 participants were randomized in the study.

Arm/Group Title	Fluzone Quadrivalent Vaccine, 0.25-mL	Fluzone Quadrivalent Vaccine, 0.5-mL
Arm/Group Description	Participants received a 0.25-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per Advisory Committee on Immunization Practices (ACIP) guidance, a second 0.25-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.5-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.
Period Title: Overall Study
STARTED	955	995
Vaccinated (Safety Analysis Set)	949	992
COMPLETED	890	917
NOT COMPLETED	65	78

Baseline Characteristics

Arm/Group Title	Fluzone Quadrivalent Vaccine, 0.25-mL	Fluzone Quadrivalent Vaccine, 0.5-mL	Total
Arm/Group Description	Participants received a 0.25-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.25-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.5-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Total of all reporting groups
Overall Participants	949	992	1941
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	20.4 (8.75)	20.5 (8.55)	20.5 (8.65)
Sex: Female, Male (Count of Participants)
Female	469 49.4%	495 49.9%	964 49.7%
Male	480 50.6%	497 50.1%	977 50.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	206 21.7%	221 22.3%	427 22%
Not Hispanic or Latino	731 77%	763 76.9%	1494 77%
Unknown or Not Reported	12 1.3%	8 0.8%	20 1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	9 0.9%	10 1%	19 1%
Asian	1 0.1%	8 0.8%	9 0.5%
Native Hawaiian or Other Pacific Islander	4 0.4%	5 0.5%	9 0.5%
Black or African American	178 18.8%	195 19.7%	373 19.2%
White	717 75.6%	725 73.1%	1442 74.3%
More than one race	36 3.8%	43 4.3%	79 4.1%
Unknown or Not Reported	4 0.4%	6 0.6%	10 0.5%
Region of Enrollment (participants) [Number]
United States	949 100%	992 100%	1941 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Fever (Fever Rate) Following Vaccination With Fluzone Quadrivalent Vaccine
Description	Fever rate was defined as percentage of participants with fever (temperature >=100.4 degrees Fahrenheit [38.0 degrees Celsius]) following vaccination with Fluzone Quadrivalent vaccine.
Time Frame	Within 7 days after any vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed using the safety analysis set. Here, 'Number of participants analyzed' = those participants with available data for this endpoint.

Arm/Group Title	Fluzone Quadrivalent Vaccine, 0.25-mL	Fluzone Quadrivalent Vaccine, 0.5-mL
Arm/Group Description	Participants received a 0.25-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.25-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.5-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.
Measure Participants	893	930
Number (95% Confidence Interval) [percentage of participants]	11.31 1.2%	12.15 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	Difference in fever rate was defined as the fever rate following a 0.5-mL dose of Fluzone Quadrivalent vaccine minus the fever rate following a 0.25-mL dose of Fluzone Quadrivalent vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) of the difference in fever rate was <5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Fever Rate
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; -2.13 to 3.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Fever rate: Fluzone Quadrivalent vaccine (0.5-mL vs. 0.25-mL)

2. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies
Description	Anti-influenza antibodies were measured using a hemagglutination inhibition (HAI) assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, B Yamagata lineage.
Time Frame	28 days post-final vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed using Per-protocol (PP) analysis set which included participants who received at least 1 dose of study vaccine and had a valid post-vaccination serologic result for at least 1 strain without any protocol deviations. Here, 'Number Analyzed' = those participants with available data for specified categories.

Arm/Group Title	Fluzone Quadrivalent Vaccine, 0.25-mL	Fluzone Quadrivalent Vaccine, 0.5-mL
Arm/Group Description	Participants received a 0.25-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.25-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.5-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.
Measure Participants	525	543
A/H1N1	214	310
A/H3N2	221	332
B Victoria	261	348
B Yamagata	243	349

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For A/H1N1 strain, GMT ratio was defined as the GMT after 0.5 mL dose(s) of Fluzone Quadrivalent vaccine divided by the GMT after 0.25 mL dose(s) of Fluzone Quadrivalent vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs was >0.667.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMTs Ratio (A/H1N1)
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95%; 1.19 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	A/H1N1 strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For A/H3N2 strain, GMT ratio was defined as the GMT after 0.5 mL dose(s) of Fluzone Quadrivalent vaccine divided by the GMT after 0.25 mL dose(s) of Fluzone Quadrivalent vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs was >0.667.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMTs Ratio (A/H3N2)
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 1.23 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	A/H3N2 strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For B Victoria lineage strain, GMT ratio was defined as the GMT after 0.5 mL dose(s) of Fluzone Quadrivalent vaccine divided by the GMT after 0.25 mL dose(s) of Fluzone Quadrivalent vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs was >0.667.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMTs Ratio (B Victoria lineage)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 1.10 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments	B Victoria lineage strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For B Yamagata lineage strain, GMT ratio was defined as the GMT after 0.5 mL dose(s) of Fluzone Quadrivalent vaccine divided by the GMT after 0.25 mL dose(s) of Fluzone Quadrivalent vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs was >0.667.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMTs Ratio (B Yamagata lineage)
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 95%; 1.20 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	B Yamagata lineage strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

3. Secondary Outcome

Title	Percentage of Participants With Seroconversion (Seroconversion Rate [SCR]) to Influenza Vaccine Antigens
Description	Anti-influenza antibodies were measured using HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, B Yamagata lineage. SCR was defined as percentage of participants with either a pre-vaccination titer <10 (1/dil) and a post-final vaccination titer >=40 (1/dil), or a pre-vaccination titer >=10 (1/dil) and at least a four-fold increase in post-final vaccination titer.
Time Frame	28 days post-final vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed using the PP analysis set. Here, 'Number Analyzed' = those participants with available data for specified categories.

Arm/Group Title	Fluzone Quadrivalent Vaccine, 0.25-mL	Fluzone Quadrivalent Vaccine, 0.5-mL
Arm/Group Description	Participants received a 0.25-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.25-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.5-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.
Measure Participants	525	543
A/H1N1	78.9 8.3%	84.1 8.5%
A/H3N2	81.9 8.6%	86.2 8.7%
B Victoria	87.2 9.2%	88.6 8.9%
B Yamagata	87.8 9.3%	91.2 9.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For A/H1N1 strain, difference in SCR was defined as SCR after 0.5-mL dose(s) of Fluzone Quadrivalent Vaccine minus SCR after 0.25-mL dose(s) of Fluzone Quadrivalent Vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in SCRs was >-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in SCR (A/H1N1)
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; 0.189 to 10.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	A/H1N1 strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For A/H3N2 strain, difference in SCR was defined as SCR after 0.5-mL dose(s) of Fluzone Quadrivalent Vaccine minus SCR after 0.25-mL dose(s) of Fluzone Quadrivalent Vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in SCRs was >-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in SCR (A/H3N2)
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; -0.283 to 8.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	A/H3N2 strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For B Victoria lineage strain, difference in SCR was defined as SCR after 0.5-mL dose(s) of Fluzone Quadrivalent Vaccine minus SCR after 0.25-mL dose(s) of Fluzone Quadrivalent Vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in SCRs was >-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in SCR (B Victoria lineage)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -2.78 to 5.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	B Victoria lineage strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fluzone Quadrivalent Vaccine, 0.25-mL, Fluzone Quadrivalent Vaccine, 0.5-mL
	Comments	For B Yamagata lineage strain, difference in SCR was defined as SCR after 0.5-mL dose(s) of Fluzone Quadrivalent Vaccine minus SCR after 0.25-mL dose(s) of Fluzone Quadrivalent Vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in SCRs was >-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in SCR (B Yamagata lineage)
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; -0.465 to 7.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	B Yamagata lineage strain: Fluzone Quadrivalent Vaccine (0.5-mL vs. 0.25-mL)

Adverse Events

Time Frame	Adverse event (AE) data were collected from Day 0 (post-vaccination) up to Day 28 post-final vaccination.
Adverse Event Reporting Description	All AEs were presented.
Arm/Group Title	Fluzone Quadrivalent Vaccine, 0.25-mL		Fluzone Quadrivalent Vaccine, 0.5-mL
Arm/Group Description	Participants received a 0.25-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.25-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.		Participants received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second 0.5-mL dose of Fluzone Quadrivalent vaccine was administered at Day 28.
All Cause Mortality
	Fluzone Quadrivalent Vaccine, 0.25-mL		Fluzone Quadrivalent Vaccine, 0.5-mL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/949 (0%)		0/992 (0%)
Serious Adverse Events
	Fluzone Quadrivalent Vaccine, 0.25-mL		Fluzone Quadrivalent Vaccine, 0.5-mL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/949 (0.5%)		5/992 (0.5%)
Infections and infestations
Cellulitis	0/949 (0%)		1/992 (0.1%)
Pneumonia	1/949 (0.1%)		1/992 (0.1%)
Respiratory syncytial virus bronchiolitis	0/949 (0%)		1/992 (0.1%)
Tonsillitis	1/949 (0.1%)		0/992 (0%)
Upper respiratory tract infection	1/949 (0.1%)		0/992 (0%)
Injury, poisoning and procedural complications
Accidental exposure to product by child	0/949 (0%)		1/992 (0.1%)
Metabolism and nutrition disorders
Dehydration	0/949 (0%)		1/992 (0.1%)
Respiratory, thoracic and mediastinal disorders
Bronchial hyperreactivity	1/949 (0.1%)		0/992 (0%)
Skin and subcutaneous tissue disorders
Urticaria chronic	1/949 (0.1%)		0/992 (0%)
Other (Not Including Serious) Adverse Events
	Fluzone Quadrivalent Vaccine, 0.25-mL		Fluzone Quadrivalent Vaccine, 0.5-mL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	698/949 (73.6%)		737/992 (74.3%)
Gastrointestinal disorders
Diarrhoea	54/949 (5.7%)		58/992 (5.8%)
Vomiting	115/949 (12.1%)		109/992 (11%)
General disorders
Crying	302/949 (31.8%)		321/992 (32.4%)
Injection site erythema	210/949 (22.1%)		228/992 (23%)
Injection site pain	430/949 (45.3%)		473/992 (47.7%)
Injection site swelling	117/949 (12.3%)		138/992 (13.9%)
Pyrexia	151/949 (15.9%)		164/992 (16.5%)
Infections and infestations
Upper respiratory tract infection	69/949 (7.3%)		70/992 (7.1%)
Metabolism and nutrition disorders
Decreased appetite	249/949 (26.2%)		267/992 (26.9%)
Nervous system disorders
Somnolence	292/949 (30.8%)		294/992 (29.6%)
Psychiatric disorders
Irritability	431/949 (45.4%)		458/992 (46.2%)
Respiratory, thoracic and mediastinal disorders
Cough	109/949 (11.5%)		107/992 (10.8%)
Rhinorrhoea	74/949 (7.8%)		74/992 (7.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor must have the opportunity to review at least 60 days prior to submission for publication or presentation. If review indicates that potentially patentable subject matter would be disclosed, publication or public disclosure may be delayed for a maximum of an additional 60 days to allow for filing the necessary patent applications.