Vaccine Information: FLUARIX QUADRIVALENT 2019/2020 (Page 3 of 5)

14.1 Efficacy against Influenza

The efficacy experience with FLUARIX is relevant to FLUARIX QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions [see Description (11)].

The efficacy of FLUARIX was evaluated in a randomized, double-blind, placebo-controlled trial conducted in 2 European countries during the 2006-2007 influenza season. Efficacy of FLUARIX, containing A/New Caledonia/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 influenza virus strains, was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects aged 18 through 64 years (mean age: 40 years) were randomized (2:1) to receive FLUARIX (n = 5,103) or placebo (n = 2,549) and monitored for influenza-like illnesses (ILI) starting 2 weeks post-vaccination and lasting for approximately 7 months. In the overall population, 60% of subjects were female and 99.9% were white. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as at least one general symptom (fever ≥100°F and/or myalgia) and at least one respiratory symptom (cough and/or sore throat). After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated (Table 7).

Table 7. FLUARIX (Trivalent Formulation): Attack Rates and Vaccine Efficacy against Culture-Confirmed Influenza A and/or B in Adults (Total Vaccinated Cohort)
a There were no vaccine matched culture-confirmed cases of A/New Caledonia/20/1999 (H1N1) or B/Malaysia/2506/2004 influenza virus strains with FLUARIX or placebo.b Vaccine efficacy for FLUARIX exceeded a pre-defined threshold of 35% for the lower limit of the 2-sided 95% Confidence Interval (CI).c Of the 22 additional cases, 18 were unmatched and 4 were untyped; 15 of the 22 cases were A (H3N2) (11 cases with FLUARIX and 4 cases with placebo).

Attack Rates (n/N)

Vaccine Efficacy

N

n

%

%

Lower Limit

Upper Limit

Antigenically Matched Strainsa

FLUARIX

5,103

49

1.0

66.9b

51.9

77.4

Placebo

2,549

74

2.9

All Culture-Confirmed Influenza (Matched, Unmatched, and Untyped)c

FLUARIX

5,103

63

1.2

61.6b

46.0

72.8

Placebo

2,549

82

3.2

In a post-hoc exploratory analysis by age, vaccine efficacy (against culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains) in subjects aged 18 through 49 years was 73.4% (95% CI: 59.3, 82.8) (number of influenza cases: FLUARIX [n = 35/3,602] and placebo [n = 66/1,810]). In subjects aged 50 through 64 years, vaccine efficacy was 13.8% (95% CI: ‑137.0, 66.3) (number of influenza cases: FLUARIX [n = 14/1,501] and placebo [n = 8/739]). As the trial lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown.

The efficacy of FLUARIX QUADRIVALENT was evaluated in Trial 7, a randomized, observer-blind, non-influenza vaccine-controlled trial conducted in 13 countries in Asia, Europe, and Central America during the 2011-2012 and 2012-2013 Northern Hemisphere influenza seasons, and from 2012 to 2014 during influenza seasons in subtropical countries. Healthy subjects aged 6 through 35 months (mean age: 22 months) were randomized (1:1) to receive FLUARIX QUADRIVALENT (n = 6,006) or a non-influenza control vaccine (n = 6,012). In the overall population, 51% were male; 27% were white, 45% were Asian, and 28% were of other racial/ethnic groups. Children aged 12 months and older with no history of influenza vaccination and children younger than 12 months received 2 doses of FLUARIX QUADRIVALENT or the Non-Influenza Active Comparator vaccine approximately 28 days apart. Children aged 12 months and older with a history of influenza vaccination received one dose.

The influenza virus strain composition of FLUARIX QUADRIVALENT administered in each of the 5 study cohorts followed the World Health Organization (WHO) recommendations (which included 2nd B strain from 2012 onwards) for each influenza season associated with a particular cohort.

Efficacy of FLUARIX QUADRIVALENT was assessed for the prevention of reverse transcriptase polymerase chain reaction (RT-PCR)-confirmed influenza A and/or B disease, due to any seasonal influenza strain, compared with non-influenza control vaccines. Influenza disease included episodes of influenza-like illness (ILI, i.e., fever ≥100.4°F with any of the following: cough, runny nose, nasal congestion, or breathing difficulty) or a consequence of influenza virus infection (acute otitis media or lower respiratory illnesses). Among subjects with RT-PCR-positive influenza A and/or B disease, subjects were further prospectively classified based on the presence of adverse outcomes associated with influenza infection: fever >102.2°F, physician-diagnosed acute otitis media, physician-diagnosed lower respiratory tract illness, physician-diagnosed serious extra-pulmonary complications, hospitalization in the intensive care unit, or supplemental oxygen required for more than 8 hours. Subjects were monitored for influenza disease by passive and active surveillance starting 2 weeks post-vaccination and lasting for approximately 6 months. After an episode of ILI, lower respiratory illness, or acute otitis media, nasal swabs were collected and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens were further tested in cell culture and by antigenic characterization to determine whether the viral strains matched those in the vaccine. Vaccine efficacy for subjects with RT-PCR confirmed and culture-confirmed vaccine matching strains (According-to-Protocol (ATP) cohort for efficacy – time to event) is presented in Table 8.

Table 8. Attack Rates and Vaccine Efficacy against Influenza A and/or B in Children Aged 6 through 35 Monthsa (ATP Cohort for Efficacy – Time to Event)
ATP = According‑to‑Protocol; RT-PCR = Reverse Transcriptase Polymerase Chain Reaction.a Trial 7: NCT01439360.b Number of subjects in the ATP cohort for efficacy – time to event, which included subjects who met all eligibility criteria, who were followed for efficacy and complied with the study protocol until the influenza-like episode.c Number of subjects who reported at least one case in the reporting period.d Vaccine efficacy for FLUARIX QUADRIVALENT met the pre-defined criterion for the lower limit of the 2-sided 97.5% CI (>15% for all influenza).e Children younger than 12 months: pneumococcal 13-valent conjugate vaccine [Diphtheria CRM197 Protein] (Wyeth Pharmaceuticals, Inc.). f Children 12 months and older: HAVRIX (Hepatitis A Vaccine) for those with a history of influenza vaccination; or HAVRIX (Dose 1) and a varicella vaccine (U.S. Licensed Manufactured by Merck & Co., Inc. or Non-U.S. Licensed Manufactured by GlaxoSmithKline Biologicals) (Dose 2) for those with no history of influenza vaccination.g Vaccine efficacy for FLUARIX QUADRIVALENT met the pre-defined criterion of >10% for the lower limit of the 2-sided 95% CI.h Vaccine efficacy for FLUARIX QUADRIVALENT met the pre-defined criterion of >15% for the lower limit of the 2-sided 95% CI.

Nb

nc

Attack Rates (n/N)

Vaccine Efficacy

%

%

Lower Limit

Upper Limit

All RT-PCR-Confirmed Influenza

FLUARIX QUADRIVALENT

5,707

344

6.03

49.8

41.8d

56.8

Non-Influenza Comparatore,f

5,697

662

11.62

-

-

-

All Culture-Confirmed Influenza

FLUARIX QUADRIVALENT

5,707

303

5.31

51.2

44.1g

57.6

Non-Influenza Comparatore,f

5,697

602

10.57

-

-

-

All Antigenically Matched Culture-Confirmed Influenza

FLUARIX QUADRIVALENT

5,707

88

1.54

60.1

49.1h

69.0

Non-Influenza Comparatore,f

5,697

216

3.79

-

-

-

The vaccine efficacy against RT-PCR-confirmed influenza associated with adverse outcomes was 64.6% (97.5% CI 53.2%, 73.5%). The vaccine efficacy against RT-PCR-confirmed influenza associated with adverse outcomes due to A/H1N1, A/H3N2, B/Victoria, and B/Yamagata was 71.4% (95% CI 48.5%, 85.2%), 51.3% (95% CI 32.7%, 65.2%), 86.7% (95% CI 52.8%, 97.9%), and 68.9% (95% CI 50.6%, 81.2%), respectively.

For RT-PCR-confirmed influenza cases associated with adverse outcomes, the incidence of the specified adverse outcomes is presented in Table 9.

Table 9. Incidence of Adverse Outcomes Associated with RT-PCR-Positive Influenza in Children Aged 6 through 35 Monthsa (ATP Cohort for Efficacy- Time to Event)b
ATP = According‑to‑Protocol; RT-PCR = Reverse transcriptase polymerase chain reaction.a Trial 7: NCT01439360.b Number of subjects in the ATP cohort for efficacy – time to event, which included subjects who met all eligibility criteria, who were followed for efficacy and complied with the study protocol until the influenza-like episode.c Children younger than 12 months: pneumococcal 13-valent conjugate vaccine [Diphtheria CRM197 Protein] (Wyeth Pharmaceuticals, Inc.). d Children 12 months and older: HAVRIX (Hepatitis A Vaccine) for those with a history of influenza vaccination; or HAVRIX (Dose 1) and a varicella vaccine (U.S. Licensed Manufactured by Merck & Co., Inc. or Non-U.S. Licensed Manufactured by GlaxoSmithKline Biologicals) (Dose 2) for those with no history of influenza vaccination.e Subjects who experienced more than one adverse outcome, each outcome was counted in the respective category.f Number of subjects with at least one event in a given category.g Analyses considered AOM cases confirmed by otoscopy.h Pneumonia, lower respiratory tract infection, bronchiolitis, bronchitis, or croup infection as per final diagnosis by physician.i Includes myositis, encephalitis or other neurologic condition including seizure, myocarditis/pericarditis or other serious medical condition as per final diagnosis by physician.

Influenza-Associated Symptome

FLUARIX QUADRIVALENT

n = 5,707

Non-Influenza Active Comparatorc,d

n = 5,697

Number of Events

Number of Subjectsf

%

Number of Events

Number of Subjectsf

%

Fever >102.2°F/39°C

62

61

1.1

184

183

3.2

Acute otitis media (AOM)g

5

5

0.1

15

15

0.3

Physician-diagnosed lower respiratory tract illnessh

28

28

0.5

62

61

1.1

Physician-diagnosed serious extra-pulmonary complicationsi

2

2

0

3

3

0.1

Hospitalization in the intensive care unit

0

0

0

0

0

0

Supplemental oxygen required for more than 8 hours

0

0

0

0

0

0

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