Product Monograph - Fluzone Quadrivalent (Sanofi Vaccines Canada, 15 mcg / 15 mcg / 15 mcg / 15 mcg, 30 mcg / 30 mcg / 30 mcg / 30 mcg)
1 INDICATIONS
- FLUZONE® Quadrivalent is indicated for active immunization against influenza caused by the specific strains of influenza virus contained in the vaccine in adults and children 6 months of age and older.
- Although the current influenza vaccine can contain one or more of the antigens administered in previous years, annual vaccination using the current vaccine is necessary because immunity declines in the year following vaccination.
- The National Advisory Committee on Immunization (NACI) encourages annual influenza vaccination for all Canadians 6 months of age and older who have no contraindications.
- The vaccine should be offered to both children and adults up to and even after influenza virus activity is documented in a community.
1.1 Pediatrics
- Pediatrics (6 months – 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of FLUZONE® Quadrivalent in pediatric patients have been established. Therefore, Health Canada has authorized an indication for pediatric use.
1.2 Geriatrics
- Geriatrics (≥60 years of age): The safety and efficacy in individuals 60 years of age and older were assessed in clinical trials (see 14 CLINICAL TRIALS).
2 CONTRAINDICATIONS
FLUZONE® Quadrivalent should not be administered to anyone with a history of severe allergic reaction to egg protein or any component of the vaccine or after previous administration of the vaccine or a vaccine containing the same components or constituents. (See 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.)
4 DOSAGE AND ADMINISTRATION
4.2 Recommended Dose and Dosage Adjustment
Table 1: Recommended Influenza Vaccine Dosage, by Age
| Age Group | Dose | No. of Doses |
|---|---|---|
| 6 through 35 months | 0.25 mL* or 0.5 mL** | 1 or 2*** |
| 3 through 8 years | 0.5 mL | 1 or 2*** |
| ≥9 years | 0.5 mL | 1 |
* In clinical studies conducted by Sanofi Pasteur children 6 through 35 months of age received 0.25 mL dose.
** NACI recommends that children 6 through 35 months of age should be given a full dose (0.5 mL) of influenza vaccine.
***Previously unvaccinated children 6 months to <9 years of age require 2 doses of seasonal influenza vaccine with an interval of 4 weeks. Eligible children <9 years of age who have properly received one or more doses of seasonal influenza vaccine in the past are recommended to receive one dose per season thereafter.
Fractional doses (doses of less volume than indicated for each age group in Table 1 above) should not be given. The effect of fractional doses on the safety and efficacy has not been determined.
4.4 Administration
Administration Route Related Precautions:
Do not administer by intravascular injection: ensure that the needle does not penetrate a blood vessel.
FLUZONE® Quadrivalent should not be administered into the buttocks.
Inspect for extraneous particulate matter and/or discolouration before use. If these conditions exist, the product should not be administered.
Administer the vaccine intramuscularly. The preferred site is into the deltoid muscle in adults and children >1 year of age. The preferred site for infants and young children (<1 year of age) is the anterolateral aspect of the mid-thigh (vastus lateralis muscle).
If using a vial, SHAKE THE VIAL WELL to uniformly distribute the suspension before withdrawing each dose. When administering a dose from a stoppered vial, do not remove either the stopper or the metal seal holding it in place. Aseptic technique must be used for withdrawal of each dose.
Aseptic technique must be used for withdrawal of each dose from a multidose vial. A maximum of 10 total doses (0.5 mL) can be withdrawn from a multidose vial. To prevent disease transmission, use a separate sterile needle and syringe or sterile disposable unit for each individual patient and for each entry into a multidose vial. The same needle and/or syringe must never be used to re-enter a multidose vial to withdraw vaccine even when it is to be used for inoculation of the same patient. This may lead to contamination of the vial contents and nosocomial infection of patients who subsequently receive vaccine from the vial.
If using a prefilled syringe, SHAKE THE PREFILLED SYRINGE WELL to uniformly distribute the suspension before administering each dose.
Aseptic technique must be used. Use a separate, sterile syringe and needle, or a sterile disposable unit, for each individual patient to prevent disease transmission. Needles should not be recapped and should be disposed of according to biohazard waste guidelines.
Give the patient a permanent personal immunization record. In addition, it is essential that the physician or nurse record the immunization history in the permanent medical record of each patient. This permanent office record should contain the name of the vaccine, date given, dose, manufacturer and lot number.
4.5 Missed Dose
For eligible children 6 months to 8 years of age: if a child’s second dose is missed, it can be given at any time.
5 OVERDOSAGE
| For management of a suspected drug overdose, contact your regional poison control centre. |
|---|
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.
Table 2: Dosage Forms, Strengths, Composition and Packaging
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Intramuscular injection | Dosage Form: Suspension for injection. Active Ingredients: Each 0.5 mL dose is formulated to contain 15 μg of hemagglutinin (HA) of each strain listed below: Each 0.25 mL dose is formulated to contain 7.5 μg of hemagglutinin (HA) of each strain listed below: A/Victoria/4897/2022 (H1N1)pdm09 - like strain (A/Victoria/4897/2022, IVR-238) A/Thailand/8/2022 (H3N2)-like strain (A/California/122/2022, SAN-022) B/Austria/1359417/2021 - like strain (B/Michigan/01/2021, wild type) B/Phuket/3073/2013-like strain (B/Phuket/3073/2013, wild type) | 0.5 mL dose: ≤100 μg formaldehyde, up to 0.5 mL sodium phosphate buffered, isotonic sodium chloride solution and ≤250 µg Triton® X-100. 0.25 mL dose: ≤50 μg formaldehyde, up to 0.25 mL sodium phosphate buffered, isotonic sodium chloride solution and ≤125 µg Triton® X-100. 0.01% w/v thimerosal in multidose presentation only (25 µg mercury/0.5 mL dose) |
This vaccine complies with the World Health Organization (WHO) recommendation (Northern Hemisphere) for the 2024 – 2025 season.
Antibiotics and gelatin are not used in the manufacture of FLUZONE® Quadrivalent.
FLUZONE® Quadrivalent is supplied as a clear to slightly opalescent suspension in a vial or prefilled syringe.
FLUZONE® Quadrivalent [Influenza Virus Vaccine Quadrivalent Types A and B (Split Virion)] for intramuscular use, is a sterile suspension containing four strains of influenza viruses propagated in embryonated chicken eggs, inactivated with formaldehyde, concentrated and purified by zonal centrifugation on a sucrose gradient, split with Triton® X-100, further purified and then suspended in sodium phosphate-buffered isotonic sodium chloride solution. The FLUZONE® Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration.
The type and amount of viral antigens contained in FLUZONE® Quadrivalent conform to the current requirements of the World Health Organization (WHO). The strains for the 2024 - 2025 season are: A/Victoria/4897/2022 (H1N1)pdm09 - like strain, A/Thailand/8/2022 (H3N2) - like strain, B/Austria/1359417/2021 - like strain and B/Phuket/3073/2013-like strain.
Packaging
FLUZONE® Quadrivalent is supplied in single dose prefilled syringes and multidose vials.
The vials and syringes are made of Type 1 glass. The container closure system for all presentations of FLUZONE® Quadrivalent does not contain latex (natural rubber). FLUZONE® Quadrivalent is considered safe for use in persons with latex allergies.
FLUZONE® Quadrivalent is available in packages of:
1 x 5 mL (Multidose) vial
10 x 0.5 mL (Single Dose) syringes without attached needle
Not all pack sizes may be marketed.
7 WARNINGS AND PRECAUTIONS
General
Before administration of FLUZONE® Quadrivalent, health-care providers should inform the recipient or parent/guardian of the recipient of the benefits and risks of immunization, inquire about the recent health status of the recipient, review the recipient’s history concerning possible hypersensitivity to the vaccine or similar vaccines, previous immunization history, the presence of any contraindications to immunization and comply with any local requirements regarding information to be provided to the recipient/guardian before immunization.
As with any vaccine, immunization with influenza vaccine may not protect 100% of individuals.
Influenza virus is remarkably unpredictable in that significant antigenic changes may occur from time to time. It is known that FLUZONE® Quadrivalent, as now constituted, is not effective against all possible strains of influenza virus. Protection is limited to those strains of virus from which the vaccine is prepared or against closely related strains.
Febrile or Acute Disease: Persons with serious acute febrile illness usually should not be vaccinated until their symptoms have abated. Those with mild non-serious febrile illness (such as mild upper respiratory tract infections) may be given influenza vaccine.
Hematologic
Because any intramuscular injection can cause injection site hematoma, in persons with any bleeding disorders, such as hemophilia or thrombocytopenia, or in persons on anticoagulant therapy, intramuscular injections with FLUZONE® Quadrivalent should not be administered to persons unless the potential benefits outweigh the risk of administration. If the decision is made to administer any product by intramuscular injection to such persons, it should be given with caution, with steps taken to avoid the risk of hematoma formation following injection.
NACI has recommendations for giving vaccinations to persons with bleeding disorders.
Immune
As with all products, epinephrine hydrochloride solution (1:1,000) and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. Health-care providers should be familiar with current recommendations for the initial management of anaphylaxis in non-hospital settings including proper airway management. For instructions on recognition and treatment of anaphylactic reactions see the current edition of the Canadian Immunization Guide or visit the Health Canada website.
As each dose may contain traces of formaldehyde and Triton® X-100 which are used during vaccine production, caution should be exercised when the vaccine is administered to subjects with hypersensitivity to one of these substances. (See 2 CONTRAINDICATIONS.) The multidose vial presentation contains thimerosal as a preservative. Thimerosal has been associated with allergic reactions.
According to NACI, egg-allergic individuals may be vaccinated against influenza without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration including immunization setting.
Immunocompromised persons (whether from disease or treatment) may not achieve the expected immune response. Nevertheless, as recommended by NACI, the possibility of lower efficacy should not prevent immunization in those at high risk of influenza-associated morbidity, since protection is still likely to occur.
Neurologic
Guillain-Barré syndrome (GBS) has been reported after influenza vaccination. However, it is not known whether influenza vaccination specifically might increase the risk for recurrence of GBS. Therefore, NACI and the US Advisory Committee on Immunization Practices (ACIP) state it is prudent to avoid vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination. (See 8 ADVERSE REACTIONS.)
7.1 Special Populations
7.1.1 Pregnant Women
Animal reproductive studies have not been conducted with FLUZONE® Quadrivalent. It is also not known whether FLUZONE® Quadrivalent can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Data on the use of this vaccine in pregnant women are limited. FLUZONE® Quadrivalent should be given to pregnant women only if clearly needed and following an assessment of the risks and benefits. However, there is no evidence to suggest a risk to the fetus or the pregnancy from maternal immunization with FLUZONE® Quadrivalent.
NACI states that influenza vaccination is recommended for pregnant women.
Pregnancy Registry
Sanofi Pasteur Inc. is conducting a prospective pregnancy exposure registry to collect data on pregnancy outcomes and newborn health status following vaccination with FLUZONE® Quadrivalent during pregnancy. Healthcare providers are encouraged to enroll women who receive FLUZONE® Quadrivalent during pregnancy in Sanofi Pasteur Inc.'s vaccination pregnancy registry by calling 1-888-621-1146.
7.1.2 Breast-feeding
It is not known whether FLUZONE® Quadrivalent is excreted in human milk. Caution must be exercised when FLUZONE® Quadrivalent is administered to a nursing mother.
NACI states that influenza vaccination is considered safe for breastfeeding women.
7.1.3 Pediatrics
The use of FLUZONE® Quadrivalent in infants under 6 months of age is not recommended.
8 ADVERSE REACTIONS
8.1 Adverse Reaction Overview
Adverse event information is derived from clinical trials with FLUZONE® Quadrivalent and worldwide post-marketing experience with trivalent influenza vaccine (FLUZONE®).
Because FLUZONE® Quadrivalent does not contain infectious viral particles, it cannot cause influenza.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
The safety of FLUZONE® Quadrivalent was evaluated in 3,307 study participants in 3 clinical trials in the U.S. (1,223 children 6 through 35 months of age, 1,669 children 3 through 8 years of age, 190 adults ≥18 years of age, and 225 adults ≥65 years of age). For children requiring a second dose as per the U.S. ACIP guidelines, the doses were administered approximately 4 weeks apart. The most common injection-site reaction in children and adults occurring after vaccine administration was pain. The most frequent systemic reaction in infants and toddlers (6 through 35 months) was irritability, while myalgia was the most frequent systemic reaction reported in children (3 through 8 years) and adults.
Within 6 months post-vaccination, there was one serious adverse event thought to be caused by vaccination with FLUZONE® Quadrivalent: a 13-month-old who experienced croup 3 days post-first vaccination; the subject recovered within 18 days without sequelae and continued in the study. There were no deaths considered to be caused from vaccination for any of the subjects.
The frequency of the solicited injection site and systemic reactions reported in the trials are shown in Table 3.
Table 3: Percentage of Solicited Injection-Site Reactions and Systemic Adverse Events in Children and Adults After Vaccination with FLUZONE® Quadrivalent
Infants & Toddlers 6 through 35 months* N = 1,223 | Children 3 through 8 years* N = 1,669 | Adults ≥18 years† N = 190 | Adults ≥65 years* N = 225 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Injection site reactions | ||||||||||||
| Pain | 57.0‡ | 66.6 | 47.4 | 32.6 | ||||||||
| Tenderness | 54.1§ | - | - | - | ||||||||
| Erythema | 37.3 | 34.1 | 1.1 | 2.7 | ||||||||
| Swelling | 21.6 | 24.8 | 0.5 | 1.8 | ||||||||
| Induration | - | - | 0.5 | - | ||||||||
| Ecchymosis | - | - | 0.5 | - | ||||||||
| Systemic reactions | ||||||||||||
| Myalgia | 26.7‡ | 38.6 | 23.7 | 18.3 | ||||||||
| Headache | 8.9‡ | 23.1 | 15.8 | 13.4 | ||||||||
| Malaise | 38.1‡ | 31.9 | 10.5 | 10.7 | ||||||||
| Irritability | 54.0§ | - | - | - | ||||||||
| Crying-abnormal | 41.2§ | - | - | - | ||||||||
| Drowsiness | 37.7§ | - | - | - | ||||||||
| Appetite loss | 32.3§ | - | - | - | ||||||||
| Vomiting | 14.8§ | - | - | - | ||||||||
| Shivering | - | - | 2.6 | - | ||||||||
| Fever | 14.3 | 7.0 | 0.0 | 1.3 | ||||||||
* Injection site and systemic reactions were collected from Day 0 to Day 7 after vaccination † Injection site and systemic reactions were collected from Day 0 to Day 3 after vaccination ‡ Assessed in children 24 months through 35 months of age § Assessed in children 6 months through 23 months of age | ||||||||||||
8.5 Post-Market Adverse Reactions
Currently, there are no post-marketing data available for FLUZONE® Quadrivalent.
The following additional events have been reported during the post-approval use of trivalent influenza vaccine (FLUZONE®). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.
Eye Disorders
Ocular hyperemia
Blood and Lymphatic System Disorders
Thrombocytopenia, lymphadenopathy
Immune System Disorders
Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria and angioedema).
Nervous System Disorders
Guillain-Barré syndrome, convulsions, febrile convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell’s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, paraesthesia
Vascular Disorders
Vasculitis, vasodilatation, flushing
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea, pharyngitis, rhinitis
Skin and Subcutaneous Tissue Disorders
Stevens-Johnson syndrome, rash, cough, wheezing, throat tightness
General Disorders and Administration Site Conditions
Asthenia/fatigue, pain in extremity, chest pain
Gastrointestinal Disorders
Vomiting
Health professionals should report any adverse occurrences temporally related to the administration of the product in accordance with local requirements (See PATIENT MEDICATION INFORMATION , Reporting Side Effects for Vaccines).
9 DRUG INTERACTIONS
9.4 Drug-Drug Interactions
Immunosuppressive treatments may interfere with the development of the expected immune response. (See 7 WARNINGS AND PRECAUTIONS.)
Concomitant Vaccine Administration:
No studies regarding the concomitant administration of inactivated influenza vaccine and other vaccines have been conducted with FLUZONE® Quadrivalent.
NACI states that influenza vaccine may be given at the same time as other vaccines. The same limb may be used if necessary, but different sites on the limb should be chosen. Different administration sets (needle and syringe) must be used.
FLUZONE® Quadrivalent must not be mixed in the same syringe with other parenterals.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
The inoculation of antigen prepared from inactivated influenza virus stimulates the production of specific antibodies. Protection is afforded only against those strains of virus from which the vaccine is prepared or closely related strains.
Immunity to the surface antigens, particularly the hemagglutinin, reduces the likelihood of infection. Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza. Furthermore, antibody to one antigenic type or subtype of influenza virus might not protect against infection with a new antigenic variant of the same type or subtype. Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and is the reason for annually reassessing the need to change one or more of the recommended strains for influenza vaccines.
Each year's quadrivalent influenza vaccine contains four virus strains (two type A and two type B) representing the influenza viruses that are believed likely to circulate in the coming winter. The selection of these strains conforms to the requirements of the World Health Organization. The antigenic characteristics of current and emerging influenza virus strains provide the basis for selecting the strains included in each year’s vaccine.
10.2 Pharmacodynamics
Seroprotection is generally obtained within 2 to 3 weeks.
10.3 Pharmacokinetics
No pharmacokinetic studies have been performed.
Duration of Effect
Protection against influenza post-vaccination persists throughout the influenza season for which the vaccine is indicated.
11 STORAGE, STABILITY AND DISPOSAL
Store at 2° to 8°C. Do not freeze. Discard product if exposed to freezing. Protect from light. Do not use vaccine after expiration date.
12 SPECIAL HANDLING INSTRUCTIONS
A multidose vial of FLUZONE® Quadrivalent which has been entered and stored at 2° to 8°C may be used up to the expiry date indicated on the vial label.
A maximum of 10 total doses (0.5 mL dose) can be withdrawn from the multidose vial.
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper name:
FLUZONE® Quadrivalent [Influenza Virus Vaccine Quadrivalent Types A and B (Split Virion)]
For the 2024 - 2025 season FLUZONE® Quadrivalent contains the following strains:
A/Victoria/4897/2022 (H1N1)pdm09 - like strain (A/Victoria/4897/2022, IVR-238)
A/Thailand/8/2022 (H3N2)-like strain (A/California/122/2022, SAN-022)
B/Austria/1359417/2021 - like strain (B/Michigan/01/2021, wild type)
B/Phuket/3073/2013 - like strain (B/Phuket/3073/2013, wild type)
Product Characteristics:
FLUZONE® Quadrivalent, Influenza Virus Vaccine Quadrivalent Types subtypes A and types B (Split Virion) for intramuscular use, is a sterile suspension prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified on a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a nonionic surfactant (Triton® X-100 - a registered trademark of Union Carbide, Co.) producing ‘split-virus’. The split-virus is then further purified by ultrafiltration and diluted to appropriate sodium phosphate-buffered isotonic sodium chloride solution. The FLUZONE® Quadrivalent process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration.
FLUZONE® Quadrivalent has been standardized according to USPHS (US Public Health Service) requirements for the 2024 – 2025 influenza season and is formulated to contain 60 micrograms (µg) hemagglutinin (HA) per 0.5 mL dose, in the recommended ratio of 15 µg HA of each strain. The multidose presentation of FLUZONE® Quadrivalent contains the preservative thimerosal (mercury derivative; 25 µg mercury/0.5 mL dose).
FLUZONE® Quadrivalent, after shaking well, is clear to slightly opalescent in colour.
14 CLINICAL TRIALS
14.1 Clinical Trials by Indication
Influenza In Adults And Children 6 Months Of Age And Older
Three clinical trials were conducted in the United States (see Table 4 ) with FLUZONE® Quadrivalent formulated using the strains A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage.
Table 4: Summary of Demographics and Study Design of the Trials with FLUZONE® Quadrivalent
| Study | Study Design | Dosage and Route of Administration | Study Participants N = Number | Mean & Age Range | Gender N = number Males/Females | |
| Randomized | Immuno-genicity* | |||||
| QIV04 | Randomized, observer-blinded, active-controlled, multicentre comparative trial with FLUZONE® Quadrivalent, 2010-2011 TIV and investigational TIV. | 1 Dose at Visit 1; a second dose at Visit 2 if required as per ACIP guidance 0.25 mL I.M (6 through 35 months) 0.5 mL I.M. (3 through 8 years) | N = 4363† | N = 3520 | 49.8 (6.0, 117.3) (months) | N = 2210/2153 |
| GRC43 | Randomized, open-label, active-controlled, multicentre comparative trial with FLUZONE® Quadrivalent, 2009-2010 TIV and 2008-2009 TIV. | 1 Dose 0.5 mL I.M. | N = 570 | N = 565 | 55.6 (18.0, 89.7) (years) | N = 187/383 |
| QIV03 | Randomized, active-controlled, multicentre comparative trial with FLUZONE® Quadrivalent, 2010-2011 TIV and | 1 Dose 0.5 mL I.M. | N = 675 | N = 660 | 72.7 (65.0, 94.6) (years) | N = 299/376 |
| Study | Study Design | Dosage and Route of Administration | Study Participants N = Number | Mean & Age Range | Gender N = number Males/Females |
| Randomized | Immuno-genicity* | ||||
| investigational TIV. | |||||
* Per-protocol population. † One subject was not included in any age by-age analysis, although she received QIV and was randomized. | |||||
Study Results: SAFETY
Children 6 Months Through 8 Years of Age
In clinical trial QIV04, children 6 months through 35 months of age received one or two 0.25 mL doses of either FLUZONE® Quadrivalent, 2010-2011 TIV, or investigational TIV, and children 3 years through 8 years of age received one or two 0.5 mL doses of either FLUZONE® Quadrivalent, 2010-2011 TIV, or investigational TIV. For participants requiring two doses, the doses were administered approximately 4 weeks apart. The safety analysis set included 1,841 children 6 months through 35 months of age and 2,506 children 3 years through 8 years of age. Table 5 and Table 6 summarize solicited injection-site reactions and systemic adverse events reported within 7 days post-vaccination via diary cards.
Table 5: Percentage of Solicited Injection-Site Reactions and Systemic Adverse Events Within 7 Days After Vaccination with FLUZONE® Quadrivalent, 2010-2011 TIV, and Investigational TIV in Children 6 Months Through 35 Months of Age (Safety Analysis Set)*
| FLUZONE® Quadrivalent N = 1223† | 2010-2011 TIV N = 310† | Investigational TIV N = 308† | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | ||||||||||
| Injection-site reactions | ||||||||||||||||||
| Pain** | 57.0 | 10.2 | 1.0 | 52.3 | 11.5 | 0.8 | 50.3 | 5.4 | 2.7 | |||||||||
| Tenderness†† | 54.1 | 11.3 | 1.9 | 48.4 | 8.2 | 1.9 | 49.7 | 10.3 | 0.0 | |||||||||
| Erythema | 37.3 | 1.5 | 0.2 | 32.9 | 1.0 | 0.0 | 33.3 | 1.0 | 0.0 | |||||||||
| Swelling | 21.6 | 0.8 | 0.2 | 19.7 | 1.0 | 0.0 | 17.3 | 0.0 | 0.0 | |||||||||
| Systemic reactions | ||||||||||||||||||
| Fever‡‡ | 14.3 | 5.5 | 2.1 | 16.0 | 6.6 | 1.7 | 13.0 | 4.1 | 2.0 | |||||||||
| Malaise** | 38.1 | 14.5 | 4.6 | 35.2 | 14.8 | 4.7 | 32.4 | 12.8 | 6.8 | |||||||||
| Myalgia** | 26.7 | 6.6 | 1.9 | 26.6 | 9.4 | 1.6 | 25.0 | 6.8 | 2.7 | |||||||||
| FLUZONE® Quadrivalent N = 1223† | 2010-2011 TIV N = 310† | Investigational TIV N = 308† | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | ||||||||||
| Headache** | 8.9 | 2.5 | 0.6 | 9.4 | 3.9 | 0.0 | 12.2 | 4.7 | 0.0 | |||||||||
| Irritability†† | 54.0 | 26.4 | 3.2 | 52.8 | 20.1 | 3.1 | 53.5 | 22.9 | 2.8 | |||||||||
| Crying-abnormal†† | 41.2 | 12.3 | 3.3 | 36.5 | 8.2 | 1.9 | 29.9 | 10.4 | 2.1 | |||||||||
| Drowsiness†† | 37.7 | 8.4 | 1.3 | 32.1 | 3.8 | 0.6 | 31.9 | 5.6 | 0.7 | |||||||||
| Appetite loss†† | 32.3 | 9.1 | 1.8 | 33.3 | 5.7 | 1.9 | 25.0 | 8.3 | 0.7 | |||||||||
| Vomiting†† | 14.8 | 6.2 | 1.0 | 11.3 | 4.4 | 0.6 | 13.9 | 6.3 | 0.0 | |||||||||
* The safety analysis set includes all persons who received study vaccine
† N is the number of subjects in the safety analysis set
‡ Grade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site tenderness: cries and protests when injection-site is touched; Injection-site erythema, Injection-site swelling: ≥2.5 cm to <5 cm; Fever: ≥38.5°C to ≤39.5°C (>101.3°F to ≤103.1°F) (6 months through 23 months); ≥38.5°C to ≤38.9°C (≥101.2°F to ≤ 102.0°F) (24 months through 35 months); Malaise, Myalgia, and Headache,: some interference with activity; Irritability: requiring increased attention; Crying abnormal: 1 to 3 hours; Drowsiness: not interested in surroundings or did not wake up for a feed/meal; Appetite lost: missed 1 or 2 feeds/meals completely; Vomiting: 2 to 5 episodes per 24 hours
§ Grade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site tenderness: cries when injected limb is moved, or the movement of the injected limb is reduced; Injection-site erythema, Injection-site swelling,: ≥5 cm; Fever: >39.5°C (>103.1°F) (6 months through 23 months); ≥39.0°C (≥ 102.1ºF) (24 months through 35 months); Malaise, Myalgia, and Headache: Significant; prevents daily activity; Irritability: inconsolable; Crying abnormal: >3 hours; Drowsiness: sleeping most of the time or difficult to wake up; Appetite lost: refuses ≥3 feeds/meals or refuses most feeds/meals; Vomiting: ≥6 episodes per 24 hours or requiring parenteral hydration
** Assessed in children 24 months through 35 months
†† Assessed in children 6 months through 23 months of age
‡‡ Fever - Any Fever: ≥38.0°C (≥100.4°F). The percentage of temperature measurements that were taken by axillary, rectal, or oral routes, or not recorded for the 3 vaccine groups combined were 41.0%, 35.4%, 23.4%, and 0.2%, respectively for Dose 1; and 38.4%, 36.0%, 25.6%, and 0.1%, respectively for Dose 2
Table 6: Percentage of Solicited Injection-Site Reactions and Systemic Adverse Events Within 7 Days After Vaccination with FLUZONE® Quadrivalent, 2010-2011 TIV, and Investigational TIV in Children 3 Years Through 8 Years of Age (Safety Analysis Set)*
FLUZONE® Quadrivalent N = 1669† | 2010-2011 TIV N = 424† | Investigational TIV N = 413† | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | |||||||
| Injection-site reactions | |||||||||||||||
| Pain | 66.6 | 15.8 | 2.1 | 64.6 | 9.5 | 2.0 | 63.8 | 11.6 | 2.8 | ||||||
| Erythema | 34.1 | 2.9 | 1.8 | 36.8 | 3.4 | 1.2 | 35.2 | 2.5 | 1.8 | ||||||
| Swelling | 24.8 | 2.8 | 1.4 | 25.4 | 1.5 | 1.2 | 25.9 | 2.5 | 1.8 | ||||||
| Systemic reactions | |||||||||||||||
| Fever** | 7.0 | 2.1 | 2.1 | 7.1 | 2.2 | 1.2 | 7.6 | 2.8 | 0.8 | ||||||
| Headache | 23.1 | 6.8 | 2.2 | 21.2 | 5.1 | 2.7 | 24.4 | 7.5 | 2.0 | ||||||
| Malaise | 31.9 | 11.2 | 5.5 | 32.8 | 11.4 | 5.6 | 33.4 | 10.8 | 5.0 | ||||||
| Myalgia | 38.6 | 12.2 | 3.3 | 34.1 | 9.0 | 2.7 | 38.4 | 11.1 | 2.8 | ||||||
* The safety analysis set includes all persons who received study vaccine
† N is the number of subjects in the safety analysis set
‡ Grade 2 - Injection-site pain: sufficiently discomforting to interfere with normal behavior or activities; Injection-site erythema, Injection-site swelling,: ≥2.5 cm to <5 cm; Fever: ≥38.4°C to ≤38.9°C (≥101.2°F to ≤102.0°F); Headache, Malaise, and Myalgia: some interference with activity
§ Grade 3 - Injection-site pain: incapacitating, unable to perform usual activities; Injection-site erythema, Injection-site swelling ≥5 cm; Fever: ≥39.0°C (≥102.1°F); Headache, Malaise, and Myalgia: Significant; prevents daily activity
** Fever - Any Fever indicates ≥38.0°C (≥100.4°F). The percentage of temperature measurements that were taken by oral, axillary, or rectal routes, or not recorded for the 3 vaccine groups combined were 85.1%, 14.4%, 0.3%, and 0.2%, respectively for Dose 1; and 86.2%, 13.4%, 0.3%, and 0.1%, respectively for Dose 2
Within 6 months post-vaccination, a total of 41 (1.4%) recipients in the FLUZONE® Quadrivalent group, 7 (1.0%) recipients in the 2010-2011 TIV group, and 14 (1.9%) recipients in the investigational TIV group, experienced at least one SAE. There were three serious adverse events thought to be caused by vaccination: one in the FLUZONE® Quadrivalent group (13-month-old who experienced croup 3 days post-first vaccination), one in the 2010-2011 TIV group (4-year-old who experienced a febrile seizure one day post-first vaccination), and one in the investigational TIV group (11-month-old who experienced a febrile seizure on the day of second vaccination). There were no deaths considered to be caused by vaccination.
Adults 18 Years of Age and Older
The safety profile of FLUZONE® Quadrivalent was assessed in a total of 190 study participants (≥ 18 years of age) in clinical trial GRC43. The most common solicited injection-site reaction occurring after FLUZONE® Quadrivalent vaccine administration was pain and the most common solicited systemic reaction was myalgia. Solicited reactions usually occurred within the first 2 days after vaccination and typically lasted for 1 to 3 days after onset. The frequency and intensity of the solicited injection-site and systemic reactions reported are presented in Table 7.
In the follow-up period, there were two subjects who experienced serious adverse events; each serious adverse event was considered by the investigator to be unrelated to the study vaccine. No deaths were reported during the trial period.
Table 7: Percentage of Solicited Injection-Site Reactions and Systemic Adverse Events Within 3 Days After Vaccination with FLUZONE® Quadrivalent, 2009-2010 TIV, and 2008-2009 TIV in Adults 18 Years of Age and Older (Safety Analysis Set)*
| FLUZONE® Quadrivalent N = 190† | 2009-2010 TIV N = 190† | 2008-2009 TIV N =190† | |||||||||||||||
| Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | |||||||||
| Injection-site reactions | |||||||||||||||||
| Pain | 47.4 | 6.8 | 0.5 | 52.1 | 7.9 | 0.5 | 43.2 | 6.3 | 0.0 | ||||||||
| Erythema | 1.1 | 0.0 | 0.0 | 1.6 | 0.5 | 0.0 | 1.6 | 0.5 | 0.0 | ||||||||
| Swelling | 0.5 | 0.0 | 0.0 | 3.2 | 0.5 | 0.0 | 1.1 | 0.0 | 0.0 | ||||||||
| Induration | 0.5 | 0.0 | 0.0 | 1.6 | 0.5 | 0.0 | 0.5 | 0.0 | 0.0 | ||||||||
| Ecchymosis | 0.5 | 0.0 | 0.0 | 0.5 | 0.0 | 0.0 | 0.5 | 0.0 | 0.0 | ||||||||
| Systemic reactions | |||||||||||||||||
| Myalgia | 23.7 | 5.8 | 0.0 | 25.3 | 5.8 | 0.0 | 16.8 | 5.8 | 0.0 | ||||||||
| Headache | 15.8 | 3.2 | 0.5 | 18.4 | 6.3 | 0.5 | 18.0 | 4.2 | 0.0 | ||||||||
| Malaise | 10.5 | 1.6 | 1.1 | 14.7 | 3.2 | 1.1 | 12.1 | 4.7 | 0.5 | ||||||||
| Shivering | 2.6 | 0.5 | 0.0 | 5.3 | 1.1 | 0.0 | 3.2 | 0.5 | 0.0 | ||||||||
| Fever** | 0.0 | 0.0 | 0.0 | 0.5 | 0.5 | 0.0 | 0.5 | 0.5 | 0.0 | ||||||||
* The safety analysis set includes all persons who received study vaccine
† N is the number of subjects in the safety analysis set
‡ Grade 2 - Injection-site pain: Some interference with activity; Injection-site erythema, Injection-site swelling, Injection-site induration, and Injection-site ecchymosis: ≥5.1 to ≤10 cm; Fever: ≥38.5°C to ≤38.9°C ( ≥101.2°F to ≤102.0°F); Myalgia, Headache, Malaise, and Shivering: some interference with activity
§ Grade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema, Injection-site swelling, Injection-site induration, and Injection-site ecchymosis: >10 cm; Fever: ≥39.0°C (≥102.1°F); Myalgia, Headache, Malaise, and Shivering: Significant; prevents daily activity
** Fever - Any Fever indicates ≥38.0°C (≥100.4°F). The percentage of temperature measurements that were taken by the oral route was 100.0% in each group
Geriatric Adults 65 Years of Age and Older
A total of 225 study participants (≥ 65 years of age) received FLUZONE® Quadrivalent in clinical trial QIV03. The most common solicited injection-site reaction occurring after FLUZONE® Quadrivalent administration was pain and the most common solicited systemic reaction was myalgia (see Table 8 ). Solicited reactions usually occurred within 3 days of vaccination and typically resolved within 1 to 3 days.
A total of three subjects experienced a serious adverse event; each serious adverse event was considered by the Investigator to be unrelated to study vaccine. There were no deaths in any vaccine group.
Table 8: Percentage of Solicited Injection-Site Reactions and Systemic Adverse Events Within 7 Days After Vaccination with FLUZONE® Quadrivalent, 2010-2011 TIV, and Investigational TIV in Adults 65 Years of Age and Older (Safety Analysis Set)*
| FLUZONE® Quadrivalent N = 225† | 2010-2011 TIV N = 225† | Investigational TIV N = 225† | ||||||||||||||||
| Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | Any (%) | Grade 2‡ (%) | Grade 3§ (%) | ||||||||||
| Injection-site reactions | ||||||||||||||||||
| Pain | 32.6 | 1.3 | 0.9 | 28.6 | 2.7 | 0.0 | 23.1 | 0.9 | 0.0 | |||||||||
| Erythema | 2.7 | 0.9 | 0.0 | 1.3 | 0.0 | 0.0 | 1.3 | 0.4 | 0.0 | |||||||||
| Swelling | 1.8 | 0.4 | 0.0 | 1.3 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | |||||||||
| Systemic reactions | ||||||||||||||||||
| Myalgia | 18.3 | 4.0 | 0.4 | 18.3 | 4.0 | 0.0 | 14.2 | 2.7 | 0.4 | |||||||||
| Headache | 13.4 | 1.3 | 0.4 | 11.6 | 1.3 | 0.0 | 11.6 | 1.8 | 0.4 | |||||||||
| Malaise | 10.7 | 4.5 | 0.4 | 6.3 | 0.4 | 0.0 | 11.6 | 2.7 | 0.9 | |||||||||
| Fever** | 1.3 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 0.9 | 0.4 | 0.4 | |||||||||
* The safety analysis set includes all persons who received study vaccine
† N is the number of subjects in the safety analysis set
‡ Grade 2 - Injection-site pain: some interference with activity; Injection-site erythema and Injection-site swelling: ≥5.1 to ≤10 cm; Fever: ≥38.5°C to ≤38.9°C (≥101.2°F to ≤102.0°F); Myalgia, Headache, and Malaise: some interference with activity
§ Grade 3 - Injection-site pain: Significant; prevents daily activity; Injection-site erythema and Injection-site swelling: >10 cm; Fever: ≥39.0°C (≥102.1°F); Myalgia, Headache, and Malaise: Significant; prevents daily activity
** Fever - Any Fever indicates ≥38.0°C (≥100.4°F). The percentage of temperature measurements that were taken by the oral or axillary routes, or not recorded for the 3 vaccine groups combined were 99.8%, 0.2%, and 0.03%, respectively
14.3 Immunogenicity
Immunogenicity of FLUZONE® Quadrivalent in Children 6 Months Through 8 Years of Age
In a multi-center study (QIV04) conducted in the US, 1419 children 6 months through 35 months of age and 2101 children 3 years through 8 years of age were included in the per-protocol analysis set and given one or two 0.25 mL doses or one or two 0.5 mL doses, respectively of FLUZONE® Quadrivalent, 2010-2011 TIV, or investigational TIV. For participants requiring two doses, the doses were administered approximately 4 weeks apart.
HI antibody geometric mean titers (GMTs) following FLUZONE® Quadrivalent were non-inferior to those following TIV for all four strains (see Table 9 ). Seroconversion rates following FLUZONE® Quadrivalent were non-inferior to those following TIV for all four strains (Table 10 ). At 28 days following vaccination the percentages of FLUZONE® Quadrivalent recipients with a serum HI antibody titer of at least 1:40 were 98.6% for H1N1, 99.7% for H3N2, 78.6% for B/Brisbane, and 71.6% for B/Florida.
Table 9: Non-inferiority* of FLUZONE® Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years of Age (Per-protocol Analysis Set)†
| Antigen Strain | FLUZONE® Quadrivalent N = 2339‡ | Pooled TIV§ N = 1181‡ | GMT Ratio (95%CI) | |||||||||
| GMT | GMT | |||||||||||
| A (H1N1) | 1124 | 1096 | 1.03 (0.93; 1.14) | |||||||||
| A (H3N2) | 822 | 828 | 0.99 (0.91; 1.08) | |||||||||
| FLUZONE® Quadrivalent N = 2339‡ | 2010-2011 TIV** N = 582‡ | Investigational TIV†† N = 599‡ | GMT Ratio (95%CI) | |||||||||
| GMT | GMT | GMT | ||||||||||
| B/Brisbane/60/2008 | 86.1 | 64.3 | - | 1.34 (1.20; 1.50) | ||||||||
| B/Florida/04/2006 | 61.5 | - | 58.3 | 1.06 (0.94; 1.18) | ||||||||
* Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (FLUZONE® Quadrivalent divided by TIV) was > 0.66
† Per-protocol analysis set includes all persons who had no study protocol deviations
‡ N is the number of subjects in the per-protocol analysis set
§ Pooled TIV group includes subjects vaccinated with either 2010-2011 TIV or investigational TIV
** 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed
†† Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed
Table 10: Non-inferiority* of FLUZONE® Quadrivalent Relative to TIV for Each Strain by Seroconversion Rates at 28 Days Post-Vaccination, Persons 6 Months Through 8 Years of Age (Per-protocol Analysis Set)†
| Antigen Strain | FLUZONE® Quadrivalent N = 2339‡ | Pooled TIV N = 1181‡ | Difference of Seroconversion Rates (95% CI) | |||||||||||
| Seroconversion** (%) | ||||||||||||||
| A (H1N1) | 92.4 | 91.4 | 0.9 (-0.9;3.0) | |||||||||||
| A (H3N2) | 88.0 | 84.2 | 3.8 (1.4;6.3) | |||||||||||
| FLUZONE® Quadrivalent N = 2339‡ | 2010-2011 TIV†† N = 582‡ | Investigational TIV‡‡ N = 599‡ | Difference of Seroconversion Rates (95% CI) | |||||||||||
| Seroconversion** (%) | ||||||||||||||
| B/Brisbane/60/2008 | 71.8 | 61.1 | - | 10.7 (6.4; 15.1) | ||||||||||
| B/Florida/04/2006 | 66.1 | - | 64.0 | 2.0 (-2.2; 6.4) | ||||||||||
* Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in seroconversion rates (FLUZONE® Quadrivalent minus TIV) was > -10% † Per-protocol analysis set included all persons who had no study protocol deviations ‡ N is the number of subjects in the per-protocol analysis set §Pooled TIV group includes subjects vaccinated with either 2010-2011 TIV or investigational TIV ** Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination titer ≥1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥1:10 †† 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed ‡‡ Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed | ||||||||||||||
In addition, HI antibody GMTs and seroconversion rates following FLUZONE® Quadrivalent were statistically superior to those following TIV for the B strain not contained in each respective TIV.
Immunogenicity of FLUZONE® Quadrivalent in Adults 18 years of Age and Older
In a multi-center study (GRC43) conducted in the US, 565 adults 18 years of age and older (281 subjects 18 through 60 years of age; 284 subjects 61 years of age and older) were included in the per-protocol analysis set and given one dose of FLUZONE® Quadrivalent, 2009-2010 TIV, or 2008-2009 TIV.
HI antibody GMTs following FLUZONE® Quadrivalent were non-inferior to those following TIV for all four strains (see Table 11). At 21 days following vaccination, the percentages of FLUZONE® Quadrivalent recipients with a serum HI antibody titer of at least 1:40 were 92.6% for H1N1, 94.7 for H3N2, 85.3% for B/Brisbane, and 92.1% for B/Florida.
Table 11: Non-inferiority* of FLUZONE® Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 18 Years of Age and Older (Per-protocol Analysis Set)†
| Antigen Strain | FLUZONE® Quadrivalent N = 190‡ | Pooled TIV§ N = 375‡ | GMT Ratio (95%CI) | |||||||||
| GMT | GMT | |||||||||||
| A (H1N1) | 161 | 151 | 1.06 (0.87, 1.31) | |||||||||
| A (H3N2) | 304 | 339 | 0.90 (0.70, 1.15) | |||||||||
| FLUZONE® Quadrivalent N = 190‡ | 2009-2010 TIV** N = 187‡ | 2008-2009 TIV†† N = 188‡ | GMT Ratio (95%CI) | |||||||||
| GMT | GMT | GMT | ||||||||||
| B/Brisbane/60/2008 | 101 | 114 | - | 0.89 (0.70, 1.12) | ||||||||
| B/Florida/04/2006 | 155 | - | 135 | 1.15 (0.93, 1.42) | ||||||||
* Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (FLUZONE® Quadrivalent divided by TIV) was >2/3. Non-inferiority testing for the A strains was performed post-hoc. † Per-protocol analysis set included all persons who had no study protocol deviations ‡ N is the number of subjects in the per-protocol analysis set § Pooled TIV group includes subjects vaccinated with either 2009-2010 TIV or 2008-2009 TIV ** 2009-2010 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed †† 2008-2009 Fluzone TIV containing A/Brisbane/59/2007 (H1N1), A/Uruguay/716/2007 (H3N2), and B/Florida/04/2006 (Yamagata lineage), licensed | ||||||||||||
Immunogenicity of FLUZONE® Quadrivalent in Adults 65 Years of Age and Older
In a multi-center study (QIV03) conducted in the US, 660 adults 65 years of age and older were included in the per-protocol analysis set and given one dose of FLUZONE® Quadrivalent, 2010-2011 TIV, or investigational TIV.
HI antibody GMTs following FLUZONE® Quadrivalent were non-inferior to those following TIV for all four strains (see Table 12) . Seroconversion rates following FLUZONE® Quadrivalent, 2010-2011 TIV, and Investigational TIV are shown in Table 13 .
Table 12: Non-inferiority* of FLUZONE® Quadrivalent Relative to TIV for Each Strain by HI Antibody GMTs at 21 Days Post-Vaccination, Adults 65 Years of Age and Older (Per-protocol Analysis Set)†
| Antigen Strain | FLUZONE® Quadrivalent N = 220‡ | Pooled TIV§ N = 440‡ | GMT Ratio (95%CI) | |||||||||
| GMT | GMT | |||||||||||
| A (H1N1) | 231 | 270 | 0.85 (0.67; 1.09) | |||||||||
| A (H3N2) | 501 | 324 | 1.55 (1.25; 1.92) | |||||||||
| FLUZONE® Quadrivalent N = 220‡ | 2010-2011 TIV** N = 219‡ | Investigational TIV†† N = 221‡ | GMT Ratio (95%CI) | |||||||||
| GMT | GMT | GMT | ||||||||||
| B/Brisbane/60/2008 | 73.8 | 57.9 | - | 1.27 (1.05; 1.55) | ||||||||
| B/Florida/04/2006 | 61.1 | - | 54.8 | 1.11 (0.90; 1.37) | ||||||||
* Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio of GMTs (FLUZONE® Quadrivalent divided by TIV) was >0.66 † Per-protocol analysis set included all persons who had no study protocol deviations ‡ N is the number of subjects in the per-protocol analysis set § Pooled TIV group includes subjects vaccinated with either 2010-2011 TIV or investigational TIV ** 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed †† Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed | ||||||||||||
Table 13: Seroconversion Rates at 21 Days Post-Vaccination of FLUZONE® Quadrivalent Relative to TIV for Each Strain, Adults 65 Years of Age and Older (Per-protocol Analysis Set)*
| Antigen Strain | FLUZONE® Quadrivalent N = 220† | Pooled TIV‡ N = 440† | Difference of Seroconversion Rate (95% CI) | ||||||||||
| Seroconversion§ (%) | |||||||||||||
| A (H1N1) | 65.91 | 69.77 | -3.86 (-11.50; 3.56) | ||||||||||
| A (H3N2) | 69.09 | 59.32 | 9.77 (1.96; 17.20) | ||||||||||
| FLUZONE® Quadrivalent N = 220† | 2010-2011 TIV** N = 219† | Investigational TIV†† N = 221† | Difference of Seroconversion Rate (95% CI) | ||||||||||
| Seroconversion§ (%) | |||||||||||||
| B/Brisbane/60/2008 | 28.64 | 18.72 | - | 9.91 (1.96; 17.70) | |||||||||
| B/Florida/04/2006 | 33.18 | - | 31.22 | 1.96 (-6.73; 10.60) | |||||||||
* Per-protocol analysis set included all persons who had no study protocol deviations † N is the number of subjects in the per-protocol analysis set ‡ Pooled TIV group includes subjects vaccinated with either 2010-2011 TIV or investigational TIV § Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination titer ≥1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥1:10 ** 2010-2011 Fluzone TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage), licensed †† Investigational TIV containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), non-licensed | |||||||||||||
FLUZONE® Quadrivalent induced higher HI antibody GMTs and seroconversion rates to B/Florida compared with those induced by 2010-2011 TIV (not containing B/Florida) and higher GMTs and seroconversion rates to B/Brisbane compared with the investigational TIV (not containing B/Brisbane). At 21 days following vaccination, the percentages of FLUZONE® Quadrivalent recipients with a serum HI antibody titer of at least 1:40 were 91.4% for H1N1, 100.0% for H3N2, 77.7% for B/Brisbane, and 73.2% for B/Florida.
15 MICROBIOLOGY
No microbiological information is required for this drug product.
16 NON-CLINICAL TOXICOLOGY
FLUZONE® Quadrivalent has not been evaluated in non-clinical studies.