6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
In adults who received FLULAVAL, the most common (≥10%) solicited local adverse reactions were pain (51%), redness (13%), and swelling (11%); the most common (≥10%) solicited systemic adverse events were fatigue (20%), headache (18%), and muscle aches/arthralgia (18%).
In children 3 through 17 years of age who received FLULAVAL, the most common (≥10%) solicited local adverse reaction was pain (56%). In children 3 through 4 years of age, the most common (≥10%) solicited systemic adverse events were irritability (25%), drowsiness (19%), and loss of appetite (16%). In children 5 through 17 years of age, the most common (≥10%) systemic adverse events were muscle aches (24%), headache (17%), and fatigue (17%).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of FLULAVAL could reveal adverse reactions not observed in clinical trials.
FLULAVAL in Adults: Safety data was obtained from 3 randomized, controlled trials, one of which was a placebo-controlled efficacy study. In these trials, 9,836 subjects were randomized to receive either FLULAVAL (5,114 subjects in the safety analysis), FLUZONE, a US‑licensed trivalent, inactivated influenza vaccine, manufactured by Sanofi Pasteur SA (894 subjects in the safety analysis), or placebo (3,828 subjects in the safety analysis), intramuscularly. In these studies, solicited events were collected for 4 days (i.e., 30 minutes post-vaccination through the next 3 days). Unsolicited adverse events that occurred within 22 days of vaccination (day 0‑21) were recorded based on spontaneous reports or in response to queries about changes in health status.
Study 1 (Immunogenicity): Safety information was collected in a randomized, controlled US study. This study included 1,000 adults 18 through 64 years of age who were randomized to receive FLULAVAL (N = 721) or a US‑licensed trivalent, inactivated influenza vaccine (N = 279). Among recipients of FLULAVAL, 57% were female; 91% of subjects were white and 9% were of other racial/ethnic groups. The mean age of subjects was 38 years; 80% were 18 through 49 years of age and 20% were 50 through 64 years of age.
Study 2 (Immunogenicity Non-Inferiority): Safety information was collected in a randomized, double-blind, active-controlled US study. The study included 1,225 adults ≥50 years of age randomized to receive FLULAVAL (N = 610) or a US‑licensed trivalent, inactivated influenza vaccine (N = 615). In the total population, 57% were female; 95% of subjects were white and 5% were of other racial/ethnic groups. The mean age of subjects was 66 years; 46% were 50 through 64 years of age, 41% were 65 through 79 years of age, and 13% were ≥80 years of age.
Study 3 (Efficacy): Safety information was collected in a double-blind, placebo-controlled US study. The study included 7,658 adults 18 through 49 years of age randomized to receive FLULAVAL (N = 3,807) or placebo (N = 3,851). In the total population, 61% were female; 84% of subjects were white, 10% black, 2% Asian, and 4% were of other racial/ethnic groups. The mean age of subjects was 33 years.
Solicited Adverse Events: Solicited local adverse reactions and systemic adverse events collected for 4 days (day of vaccination and the next 3 days) are presented in Table 2.
Table 2. FLULAVAL: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events Within 4 Daysa of Vaccination in Adults (Total Vaccinated Cohort)
|
Percentage of Subjects Reporting Event
|
Study 1b
18 Through 64 Years of Age
|
Study 2b
50 Years of Age and Older
|
Study 3b
18 Through 49 Years of Age
|
FLULAVAL
|
Comparatorc
|
FLULAVAL
|
Comparatorc
|
FLULAVAL
|
Placebo
|
N = 721
|
N = 279
|
N = 610
|
N = 615
|
N = 3,783
|
N = 3,828
|
Local Adverse Reactions
|
-
- Pain
|
24
|
31
|
25
|
32
|
51
|
14
|
-
- Redness
|
11
|
10
|
10
|
11
|
13
|
6
|
-
- Swelling
|
10
|
10
|
7
|
9
|
11
|
3
|
Systemic Adverse Events
|
-
- Headache
|
18
|
17
|
11
|
12
|
18
|
19
|
-
- Fatigue
|
17
|
15
|
12
|
13
|
20
|
18
|
-
- Muscle achesd
|
13
|
16
|
11
|
10
|
18
|
10
|
-
- Fever (≥99.5°F (37.5°C)
|
11
|
10
|
1
|
1
|
3
|
1
|
-
- Malaise
|
10
|
10
|
6
|
7
|
9
|
6
|
-
- Sore throat
|
9
|
9
|
5
|
6
|
9
|
9
|
-
- Reddened eyes
|
6
|
5
|
4
|
7
|
7
|
6
|
-
- Cough
|
6
|
7
|
5
|
6
|
8
|
7
|
-
- Chills
|
5
|
2
|
3
|
6
|
4
|
4
|
-
- Chest tightness
|
3
|
1
|
2
|
2
|
3
|
3
|
-
- Facial swelling
|
1
|
1
|
1
|
2
|
1
|
1
|
-
- Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available.
a 4 days included day of vaccination and the subsequent 3 days.
b Study 1: NCT01389479; Study 2: NCT00232947; Study 3: NCT00216242.
c US‑licensed trivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur SA).
d For Study 2 and Study 3, includes muscle aches and arthralgia.
Unsolicited Adverse Events: The incidence of unsolicited adverse events in the 21 days post-vaccination was comparable for FLULAVAL and the active comparator in Study 1 (16% and 15%, respectively) and in Study 2 (18% and 21%, respectively). In Study 3, the incidence of unsolicited adverse events was comparable for the groups (21% for FLULAVAL and 19% for placebo).
Unsolicited adverse events defined as reported with FLULAVAL in >1.0% of subjects are described as follows: Study 1: Cough, headache, and pharyngolaryngeal pain; Study 2: Diarrhea, headache, and nasopharyngitis; and Study 3: Pharyngolaryngeal pain, headache, fatigue, cough, injection site pain, upper respiratory tract infection, musculoskeletal pain, nasopharyngitis, injection site erythema and discomfort.
Serious Adverse Events (SAEs): In Study 1, no SAEs were reported. In Study 2, 3% of subjects receiving FLULAVAL and 3% of subjects receiving the active comparator reported SAEs. In Study 3, 1% of subjects receiving FLULAVAL and 1% of subjects receiving placebo reported SAEs. In the 3 clinical trials, the rates of SAEs were comparable between groups and none of the SAEs were considered related to vaccination.
FLULAVAL in Children:Study 4 (Immunogenicity Non-Inferiority): An observer-blind, active-controlled US study evaluated subjects 3 through 17 years of age who received FLULAVAL (N = 1,055) or FLUZONE (N = 1,061), a US‑licensed trivalent, inactivated influenza vaccine, manufactured by Sanofi Pasteur SA. In the overall population, 53% were male; 78% of subjects were white, 12% were black, 2% were Asian, and 8% were of other racial/ethnic groups. The mean age of subjects was 8 years. Children 3 through 8 years of age with no history of influenza vaccination received 2 doses approximately 28 days apart. Children 3 through 8 years of age with a history of influenza vaccination and children 9 years of age and older received one dose. Solicited local adverse reactions and systemic adverse events were collected for 4 days (day of vaccination and the next 3 days) (Table 3).
Table 3. FLULAVAL: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events Within 4 Daysa of First Vaccination in Children 3 Through 17 Years of Ageb (Total Vaccinated Cohort)
|
FLULAVAL
%
|
Active Comparatorc
%
|
|
3 Through 17 Years of Age
|
Local Adverse Reactions
|
N = 1,042
|
N = 1,026
|
Pain
|
56
|
53
|
Redness
|
4
|
5
|
Swelling
|
4
|
5
|
|
3 Through 4 Years of Age
|
Systemic Adverse Events
|
N = 293
|
N = 279
|
Irritability
|
25
|
27
|
Drowsiness
|
19
|
19
|
Loss of appetite
|
16
|
13
|
Fever ≥100.4°F (38.0°C)
|
5
|
3
|
|
5 Through 17 Years of Age
|
Systemic Adverse Events
|
N = 750
|
N = 747
|
Muscle aches
|
24
|
23
|
Headache
|
17
|
15
|
Fatigue
|
17
|
17
|
Arthralgia
|
8
|
10
|
Shivering
|
6
|
5
|
Fever ≥100.4°F (38.0°C)
|
5
|
4
|
Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available.
a 4 days included day of vaccination and the subsequent 3 days.
b Study 4: NCT00980005.
c US‑licensed trivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur SA).
In children who received a second dose of FLULAVAL or the comparator vaccine, the incidences of adverse events following the second dose were generally lower than those observed after the first dose.
The incidence of unsolicited adverse events that occurred within 28 days (day 0-27) of any vaccination reported in subjects who received FLULAVAL (N = 1,055) or FLUZONE (N = 1,061) was 40% and 37%, respectively. The unsolicited adverse events that occurred most frequently (≥0.1% of subjects for FLULAVAL) and considered possibly related to vaccination included diarrhea, influenza-like illness, injection site hematoma, injection site rash, injection site warmth, rash, upper abdominal pain, and vomiting. The rates of SAEs were comparable between groups (0.9% and 0.6% for FLULAVAL and the comparator, respectively); none of the SAEs were considered related to vaccination.
6.2 Postmarketing Experience
In addition to reports in clinical trials, the following adverse events have been identified during postapproval use of FLULAVAL. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their incidence rate or establish a causal relationship to the vaccine. Adverse events described here are included because: a) they represent reactions which are known to occur following immunizations generally or influenza immunizations specifically; b) they are potentially serious; or c) the frequency of reporting.
Blood and Lymphatic System Disorders: Lymphadenopathy.
Eye Disorders: Eye pain, photophobia.
Gastrointestinal Disorders: Dysphagia.
General Disorders and Administration Site Conditions: Chest pain, injection site inflammation, asthenia, injection site rash, abnormal gait, injection site bruising, injection site sterile abscess.
Immune System Disorders: Allergic reactions including anaphylaxis, angioedema.
Infections and Infestations: Rhinitis, laryngitis, cellulitis.
Musculoskeletal and Connective Tissue Disorders: Muscle weakness, arthritis.
Nervous System Disorders: Dizziness, paresthesia, hypoesthesia, hypokinesia, tremor, somnolence, syncope, Guillain-Barré syndrome, convulsions/seizures, facial or cranial nerve paralysis, encephalopathy, limb paralysis.
Psychiatric Disorders: Insomnia.
Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea, dysphonia, bronchospasm, throat tightness.
Skin and Subcutaneous Tissue Disorders: Urticaria, pruritus, sweating.
Vascular Disorders: Flushing, pallor.
11 DESCRIPTION
FLULAVAL, Influenza Vaccine, for intramuscular injection, is a trivalent, split-virion, inactivated influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs. Each of the influenza viruses is produced and purified separately. The virus is inactivated with ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation, and disrupted with sodium deoxycholate.
FLULAVAL is a sterile, opalescent, translucent to off-white suspension in a phosphate-buffered saline solution that may sediment slightly. The sediment resuspends upon shaking to form a homogeneous suspension.
FLULAVAL has been standardized according to USPHS requirements for the 2014‑2015 influenza season and is formulated to contain 45 micrograms (mcg) hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 3 strains: A/California/7/2009 NYMC X‑179A (H1N1), A/Texas/50/2012 NYMC X-223A (H3N2), and B/Massachusetts/2/2012 NYMC BX-51B.
The prefilled syringe is formulated without preservatives and does not contain thimerosal. Each 0.5-mL dose from the multi-dose vial contains 50 mcg thimerosal (<25 mcg mercury); thimerosal, a mercury derivative, is added as a preservative.
Each 0.5-mL dose of either presentation may also contain residual amounts of ovalbumin (≤0.3 mcg), formaldehyde (≤25 mcg), sodium deoxycholate (≤50 mcg), α-tocopheryl hydrogen succinate (≤240 mcg), and polysorbate 80 (≤665 mcg) from the manufacturing process. Antibiotics are not used in the manufacture of this vaccine.
The tip caps and plungers of the prefilled syringes are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex.
14 CLINICAL STUDIES
The effectiveness of FLULAVAL was demonstrated based on clinical endpoint efficacy data for FLULAVAL QUADRIVALENT (Influenza Vaccine), clinical endpoint efficacy data for FLULAVAL, and on an evaluation of serum HI antibody responses to FLULAVAL. FLULAVAL QUADRIVALENT, an inactivated influenza vaccine that contains the hemagglutinins of two influenza A subtype viruses and two influenza type B viruses, is manufactured according to the same process as FLULAVAL.
14.1 Efficacy Against Influenza
Efficacy Trial in Children: The efficacy of FLULAVAL QUADRIVALENT was evaluated in Study 5, a randomized, observer-blind, non-influenza vaccine-controlled study conducted in 3 countries in Asia, 3 in Latin America, and 2 in the Middle East/Europe during the 2010-2011 influenza season. Healthy subjects 3 through 8 years of age were randomized (1:1) to receive FLULAVAL QUADRIVALENT (N = 2,584), containing A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/4/2006 (Yamagata lineage) influenza strains, or HAVRIX® (Hepatitis A Vaccine) (N = 2,584), as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years.
Efficacy of FLULAVAL QUADRIVALENT was assessed for the prevention of reverse transcriptase polymerase chain reaction (RT-PCR)-positive influenza A and/or B disease presenting as influenza-like illness (ILI). ILI was defined as a temperature ≥100°F in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose, or nasal congestion. Subjects with ILI (monitored by passive and active surveillance for approximately 6 months) had nasal and throat swabs collected and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens were further tested in cell culture. Vaccine efficacy was calculated based on the ATP cohort for efficacy (Table 4).
Table 4. FLULAVAL QUADRIVALENT: Influenza Attack Rates and Vaccine Efficacy Against Influenza A and/or B in Children 3 Through 8 Years of Agea (According to Protocol Cohort for Efficacy)
|
-
- Nb
|
-
- nc
|
-
- Influenza Attack Rate % (n/N)
|
-
- Vaccine Efficacy
-
- % (CI)
|
-
- All RT-PCR-Positive Influenza
|
-
- FLULAVAL QUADRIVALENT
|
-
- 2,379
|
-
- 58
|
-
- 2.4
|
-
- 55.4d
-
- (95% CI: 39.1, 67.3)
|
-
- HAVRIXe
|
-
- 2,398
|
-
- 128
|
-
- 5.3
|
-
- –
|
-
- All Culture-Confirmed Influenzaf
|
-
- FLULAVAL QUADRIVALENT
|
-
- 2,379
|
-
- 50
|
-
- 2.1
|
-
- 55.9
-
- (97.5% CI: 35.4, 69.9)
|
-
- HAVRIXe
|
-
- 2,398
|
-
- 112
|
-
- 4.7
|
-
- –
|
-
- Antigenically Matched Culture-Confirmed Influenza
|
-
- FLULAVAL QUADRIVALENT
|
-
- 2,379
|
-
- 31
|
-
- 1.3
|
-
- 45.1g
-
- (97.5% CI: 9.3, 66.8)
|
-
- HAVRIXe
|
-
- 2,398
|
-
- 56
|
-
- 2.3
|
-
- –
|
CI = Confidence Interval; RT-PCR = reverse transcriptase polymerase chain reaction.
a Study 5: NCT01218308.
b According to protocol cohort for efficacy included subjects who met all eligibility criteria, were successfully contacted at least once post-vaccination, and complied with the protocol-specified efficacy criteria.
c Number of influenza cases.
d Vaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined criterion of >30% for the lower limit of the 2-sided 95% CI.
e Hepatitis A Vaccine used as a control vaccine.
f Of 162 culture-confirmed influenza cases, 108 (67%) were antigenically typed (87 matched; 21 unmatched); 54 (33%) could not be antigenically typed [but were typed by RT-PCR and nucleic acid sequence analysis: 5 cases A (H1N1) (5 with HAVRIX), 47 cases A (H3N2) (10 with FLULAVAL QUADRIVALENT; 37 with HAVRIX), and 2 cases B Victoria (2 with HAVRIX)].
g Since only 67% of cases could be typed, the clinical significance of this result is unknown.
In an exploratory analysis by age, vaccine efficacy against RT-PCR-positive influenza A and/or B disease presenting as ILI was evaluated in subjects 3 through 4 years of age and 5 through 8 years of age; vaccine efficacy was 35.3% (95% CI: ‑1.3, 58.6) and 67.7% (95% CI: 49.7, 79.2), respectively. As the study lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown.
As a secondary objective in the study, subjects with RT-PCR-positive influenza A and/or B were prospectively classified based on the presence of adverse outcomes that have been associated with influenza infection (defined as fever >102.2°F/39.0°C, physician-verified shortness of breath, pneumonia, wheezing, bronchitis, bronchiolitis, pulmonary congestion, croup and/or acute otitis media, and/or physician-diagnosed serious extra-pulmonary complications, including myositis, encephalitis, seizure and/or myocarditis).
The risk reduction of fever >102.2°F/39.0°C associated with RT-PCR-positive influenza was 71.0% (95% CI: 44.8, 84.8) based on the ATP cohort for efficacy [FLULAVAL QUADRIVALENT (n = 12/2,379); HAVRIX (n = 41/2,398)]. The other pre-specified adverse outcomes had too few cases to calculate a risk reduction. The incidence of these adverse outcomes is presented in Table 5.
Table 5. FLULAVAL QUADRIVALENT: Incidence of Adverse Outcomes Associated With RT-PCR-Positive Influenza in Children 3 Through 8 Years of Agea (Total Vaccinated Cohort)b
|
-
- FLULAVAL
-
- QUADRIVALENT
-
- N = 2,584
|
-
- HAVRIXc
-
- N = 2,584
|
-
- Adverse Outcomed
|
-
- Number of Events
|
-
- Number of Subjectse
|
-
- %
|
-
- Number of Events
|
-
- Number of Subjectse
|
-
- %
|
-
- Fever >102.2°F/39.0°C
|
-
- 16f
|
-
- 15
|
-
- 0.6
|
-
- 51f
|
-
- 50
|
-
- 1.9
|
-
- Shortness of breath
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 5
|
-
- 5
|
-
- 0.2
|
-
- Pneumonia
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 3
|
-
- 3
|
-
- 0.1
|
-
- Wheezing
|
-
- 1
|
-
- 1
|
-
- 0
|
-
- 1
|
-
- 1
|
-
- 0
|
-
- Bronchitis
|
-
- 1
|
-
- 1
|
-
- 0
|
-
- 1
|
-
- 1
|
-
- 0
|
-
- Pulmonary congestion
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 1
|
-
- 1
|
-
- 0
|
-
- Acute otitis media
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 1
|
-
- 1
|
-
- 0
|
-
- Bronchiolitis
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- Croup
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- Encephalitis
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- Myocarditis
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- Myositis
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- Seizure
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
-
- 0
|
a Study NCT01218308.
b Total vaccinated cohort included all vaccinated subjects for whom data were available.
c Hepatitis A Vaccine used as a control vaccine.
d In subjects who presented with more than one adverse outcome, each outcome was counted in the respective category.
e Number of subjects presenting with at least one event in each group.
f One subject in each group had sequential influenza due to influenza type A and type B viruses.
Efficacy Trial in Adults: The efficacy of FLULAVAL was evaluated in a randomized, double-blind, placebo-controlled study conducted in the United States during the 2005-2006 and 2006-2007 influenza seasons (Study 3). Efficacy of FLULAVAL was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects 18 through 49 years of age were randomized (1:1); a total of 3,783 subjects received FLULAVAL and 3,828 subjects received placebo [see Adverse Reactions (6.1)]. Subjects were monitored for influenza-like illnesses (ILI) starting 2 weeks post-vaccination and for duration of approximately 7 months thereafter. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as illness sufficiently severe to limit daily activity and including cough, and at least one of the following: Fever >99.9°F, nasal congestion or runny nose, sore throat, muscle aches or arthralgia, headache, feverishness or chills. After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated using the per protocol cohort (Table 6). Of note, the 1.2% attack rate in the placebo group for culture-confirmed, antigenically matched strains was lower than expected, contributing to a wide confidence interval for the estimate of vaccine efficacy.
Table 6. FLULAVAL: Influenza Attack Rates and Vaccine Efficacy Against Culture-Confirmed Influenza in Adults 18 Through 49 Years of Agea (Per Protocol Cohort)
|
-
- Influenza Attack Rates
|
-
- Vaccine Efficacy
|
|
-
- Nb
|
-
- nc
|
-
- % (n/N)
|
-
- %
|
-
- 97.5% CI
-
- Lower Limit
|
-
- Antigenically Matched Strains
|
-
- FLULAVAL
|
-
- 3,714
|
-
- 23
|
-
- 0.6
|
-
- 46.3
|
-
- 9.8d
|
-
- Placebo
|
-
- 3,768
|
-
- 45
|
-
- 1.2
|
-
- –
|
-
- –
|
-
- All Culture-Confirmed Influenza (Matched, Unmatched, and Untyped)
|
-
- FLULAVAL
|
-
- 3,714
|
-
- 30
|
-
- 0.8
|
-
- 49.3
|
-
- 20.3
|
-
- Placebo
|
-
- 3,768
|
-
- 60
|
-
- 1.6
|
-
- –
|
-
- –
|
CI = Confidence Interval.
a Study 3: NCT00216242.
b Per Protocol Cohort for efficacy included subjects with no protocol deviations considered to compromise efficacy data.
c Number of influenza cases.
d Lower limit of the one-sided 97.5% CI for vaccine efficacy against influenza due to antigenically matched strains was less than the pre-defined success criterion of ≥35%.
14.2 Immunological Evaluation
Adults: Study 1 was a randomized, blinded, active-controlled US study performed in healthy adults 18 through 64 years of age (N = 1,000). A total of 721 subjects received FLULAVAL, and 279 received a US‑licensed trivalent, inactivated influenza vaccine, FLUZONE (manufactured by Sanofi Pasteur SA), intramuscularly; 959 subjects had complete serological data and no major protocol deviations [see Adverse Reactions (6.1)].
Analyses of immunogenicity (Table 7) were performed for each hemagglutinin (HA) antigen contained in the vaccine: 1) assessment of the lower bounds of 2‑sided 95% confidence intervals for the proportion of subjects with HI antibody titers of ≥1:40 after vaccination, and 2) assessment of the lower bounds of 2-sided 95% confidence intervals for rates of seroconversion (defined as a 4‑fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40). The pre-specified success criteria for HI titer ≥1:40 was 70% and for seroconversion rate was 40%. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved an HI titer of ≥1:40 exceeded the pre-defined criteria for the A strains. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved seroconversion exceeded the pre-defined criteria for all 3 strains.
Table 7. Immune Responses to Each Antigen 21 Days After Vaccination With FLULAVALa in Adults 18 Through 64 Years of Age (Per Protocol Cohort)b
|
FLULAVAL
N = 692
% of Subjects (95% CI)
|
HI titers ≥1:40
|
Pre-vaccination
|
Post-vaccination
|
A/New Caledonia/20/99 (H1N1)
|
24.6
|
96.5 (94.9, 97.8)
|
A/Wyoming/03/03 (H3N2)
|
58.7
|
98.7 (97.6, 99.4)
|
B/Jiangsu/10/03
|
5.4
|
62.9 (59.1, 66.5)
|
Seroconversionc to:
|
|
A/New Caledonia/20/99 (H1N1)
|
85.6 (82.7, 88.1)
|
A/Wyoming/03/03 (H3N2)
|
79.3 (76.1, 82.3)
|
B/Jiangsu/10/03
|
58.4 (54.6, 62.1)
|
HI – hemagglutination inhibition; CI = Confidence Interval.
a Results obtained following vaccination with FLULAVAL manufactured for the 2004–2005 season.
b Per Protocol Cohort for immunogenicity included subjects with complete pre- and post-dose HI titer data and no major protocol deviations.
c Seroconversion defined as a 4‑fold increase in post-vaccination HI antibody titers from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.
Study 2 (Immunogenicity Non-Inferiority): In a randomized, double-blind, active-controlled US study, immunological non-inferiority of FLULAVAL was compared with a US‑licensed trivalent, inactivated influenza vaccine, FLUZONE, manufactured by Sanofi Pasteur SA. A total of 1,225 adults ≥50 years of age and older in stable health were randomized to receive FLULAVAL or the comparator vaccine intramuscularly [see Adverse Reactions (6.1)].
Analyses of immunogenicity were performed for each HA antigen contained in the vaccines: 1) assessment of the lower bounds of 2‑sided 95% confidence intervals for the geometric mean antibody titer (GMT) ratio (FLULAVAL/comparator), and 2) assessment of the lower bounds of 2‑sided 95% confidence intervals for seroconversion rates (defined as a 4‑fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40). Non-inferiority of FLULAVAL to the comparator vaccine was established for all 6 co-primary endpoints (Table 8). Within each age stratum, immunogenicity results were similar between the groups.
Table 8. Immune Responses to Each Antigen 21 Days After Vaccination With FLULAVAL Versus Comparator Influenza Vaccine in Adults 50 Years of Age and Oldera (Per Protocol Cohort)b
|
FLULAVAL
N = 592
|
Active Comparatorc
N = 595
|
|
-
- GMTs Against
|
GMT
(95% CI)
|
GMT
(95% CI)
|
GMT Ratiod
(95% CI)
|
A/New Caledonia/20/99 (H1N1)
|
113.4
(104.7, 122.8)
|
110.2
(101.8, 119.3)
|
1.03
(0.92, 1.15)
|
A/New York/55/04 (H3N2)
|
223.9
(199.5, 251.3)
|
214.6
(191.3, 240.7)
|
1.04
(0.89, 1.23)
|
B/Jiangsu/10/03
|
82.3
(74.7, 90.6)
|
97.1
(88.2, 106.8)
|
0.85
(0.74, 0.97)
|
-
- Seroconversione to:
|
% of Subjects
(95% CI)
|
% of Subjects
(95% CI)
|
Difference in Seroconversion Ratesf
(95% CI)
|
A/New Caledonia/20/99 (H1N1)
|
34
(30.0, 37.6)
|
32
(28.3, 35.9)
|
2
(-3.7, 7.0)
|
A/New York/55/04 (H3N2)
|
83
(80.3, 86.3)
|
82
(78.4, 84.6)
|
1
(-2.6, 6.1)
|
B/Jiangsu/10/03
|
53
(49.0, 57.1)
|
56
(51.6, 59.6)
|
-3
(-8.3, 3.1)
|
GMT = geometric mean antibody titer; CI = Confidence Interval.
a Results obtained following vaccination with influenza vaccines manufactured for the 2005‑2006 season.
b Per Protocol Cohort for immunogenicity included subjects with complete pre- and post-dose HI titer data and no major protocol deviations.
c US‑licensed trivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur SA).
d FLULAVAL met non‑inferiority criteria based on GMTs (lower limit of 2‑sided 95% CI for GMT ratio [FLULAVAL/comparator vaccine] ≥0.67).
e Seroconversion defined as a 4‑fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.
f FLULAVAL met non‑inferiority criteria based on seroconversion rates (lower limit of 2‑sided 95% CI for difference of FLULAVAL minus the comparator vaccine ≥‑10%).
Children: In Study 4, the immune response of FLULAVAL (N = 987) was compared to FLUZONE, a US‑licensed trivalent, inactivated influenza vaccine (N = 979), manufactured by Sanofi Pasteur SA, in an observer-blind, randomized study in children 3 through 17 years of age. The immune responses to each of the antigens contained in FLULAVAL formulated for the 2009-2010 season were evaluated in sera obtained after one or 2 doses of FLULAVAL and were compared to those following the comparator influenza vaccine [see Adverse Reactions (6.1)].
The non‑inferiority endpoints were geometric mean antibody titers (GMTs) adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as at least a 4‑fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the According‑to‑Protocol (ATP) cohort. FLULAVAL was non-inferior to the comparator influenza for all strains based on adjusted GMTs and seroconversion rates (Table 9).
Table 9. Immune Responses to Each Antigen 28 Days After Last Vaccination With FLULAVAL Versus Comparator Influenza Vaccine in Children 3 Through 17 Years of Agea (According to Protocol Cohort for Immunogenicity)b
|
FLULAVAL
|
Active Comparatorc
|
|
GMTs Against
|
N = 987
(95% CI)
|
N = 979
(95% CI)
|
GMT Ratiod
(95% CI)
|
A/Brisbane (H1N1)
|
320.9
(298.3, 345.2)
|
329.4
(306.8, 353.7)
|
1.03
(0.94, 1.13)
|
A/Uruguay (H3N2)
|
414.7
(386.5, 444.9)
|
451.9
(423.8, 481.8)
|
1.05
(0.96, 1.13)
|
B/Brisbane
|
213.7
(198.5, 230.1)
|
200.2
(186.1, 215.3)
|
0.93
(0.85, 1.02)
|
Seroconversione to:
|
N = 987
%
(95% CI)
|
N = 978
%
(95% CI)
|
Difference in Seroconversion Ratef
(95% CI)
|
A/Brisbane (H1N1)
|
59.8
(56.6, 62.9)
|
58.2
(55.0, 61.3)
|
-1.6
(-5.9, 2.8)
|
A/Uruguay (H3N2)
|
68.2
(65.2, 71.1)
|
66.2
(63.1, 69.1)
|
-2.0
(-6.1, 2.1)
|
B/Brisbane
|
81.1
(78.5, 83.5)
|
78.6
(75.9, 81.2)
|
-2.4
(-6.0, 1.1)
|
GMT = geometric mean antibody titer; CI = Confidence Interval.
a Results obtained following vaccination with influenza vaccines formulated for the 2009-2010 season.
b According to protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one study vaccine antigen.
c US‑licensed trivalent, inactivated influenza vaccine (Sanofi Pasteur SA).
d FLULAVAL met non‑inferiority criteria based on GMTs (upper limit of 2‑sided 95% CI for GMT ratio [comparator vaccine/FLULAVAL] ≤1.5).
e Seroconversion defined as a 4‑fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.
f FLULAVAL met non‑inferiority criteria based on seroconversion rates (upper limit of 2‑sided 95% CI for difference of the comparator vaccine minus FLULAVAL ≤10%).