Vaccine Information: Flulaval Quadrivalent 2019/2020 (Page 3 of 4)

14.2 Immunological Evaluation

Adults

Trial 1 was a randomized, double-blind, active-controlled, safety and immunogenicity trial conducted in subjects aged 18 years and older. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 1,246) or one of 2 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, n = 204 or TIV-2, n = 211), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see Adverse Reactions (6.1)].

Immune responses, specifically hemagglutination inhibition (HI) antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoint was GMTs adjusted for baseline, performed on the According-to-Protocol (ATP) cohort for whom immunogenicity assay results were available after vaccination. FLULAVAL QUADRIVALENT was non‑inferior to both TIVs based on adjusted GMTs (Table 8). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 8).

Table 8. Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza Vaccine (TIV) 21 Days Post-vaccination in Adults Aged 18 Years and Oldera (According-to-Protocol Cohort for Immunogenicity)b
CI = Confidence Interval.a Trial 1: NCT01196975.b According-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen.c Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage).d Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage).e Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage).f Non‑inferior to both TIVs based on adjusted GMTs [upper limit of the 2‑sided 95% CI for the GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5]; superior to TIV-1 (B Victoria) with respect to the B strain of Yamagata lineage and to TIV-2 (B Yamagata) with respect to the B strain of Victoria lineage based on adjusted GMTs [lower limit of the 2‑sided 95% CI for the GMT ratio (FLULAVAL QUADRIVALENT/TIV) >1.5].

Geometric Mean Titers Against

FLULAVAL QUADRIVALENTc

TIV-1

(B Victoria)d

TIV-2

(B Yamagata)e

n = 1,245-1,246

(95% CI)

n = 204

(95% CI)

n = 210-211

(95% CI)

A/California/7/2009 (H1N1)

204.6f

(190.4, 219.9)

176.0

(149.1, 207.7)

149.0

(122.9, 180.7)

A/Victoria/210/2009 (H3N2)

125.4f

(117.4, 133.9)

147.5

(124.1, 175.2)

141.0

(118.1, 168.3)

B/Brisbane/60/2008

(Victoria lineage)

177.7f

(167.8, 188.1)

135.9

(118.1, 156.5)

71.9

(61.3, 84.2)

B/Florida/4/2006

(Yamagata lineage)

399.7f

(378.1, 422.6)

176.9

(153.8, 203.5)

306.6

(266.2, 353.3)

Children

Trial 4 was a randomized, observer-blind, active-controlled trial in children aged 6 through 35 months which was conducted in the United States and Mexico. In this trial, subjects received 0.5 mL of FLULAVAL QUADRIVALENT containing 15 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,207); or 0.25 mL of control vaccine FLUZONE QUADRIVALENT (Influenza Vaccine) containing 7.5 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,217) [see Adverse Reactions (6.1)].

Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following completion of vaccination regimen. Previously vaccinated children received one dose and previously unvaccinated children (i.e., unprimed individuals) received 2 doses 4 weeks apart of FLULAVAL QUADRIVALENT or the comparator. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4‑fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to the comparator for all 4 vaccine strains based on adjusted GMTs and seroconversion rates (Table 9).

Table 9. Non-inferiority of FLULAVAL QUADRIVALENT Relative to Comparator Quadrivalent Influenza Vaccine at 28 Days Post-vaccination in Children Aged 6 through 35 Monthsa (According-to-Protocol Cohort for Immunogenicity)b
CI = Confidence Interval.a Trial 4: NCT02242643. b According-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen. c A 0.5-mL dose containing 15 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2), B/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). d A 0.25-mL dose of U.S.-licensed quadrivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.) containing 7.5 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2), B/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). e Non‑inferior to the comparator vaccine based on adjusted GMTs [upper limit of the 2-sided 95% CI for the GMT ratio (comparator/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper limit of the 2‑sided 95% CI on difference of comparator vaccine minus FLULAVAL QUADRIVALENT ≤10%).f Seroconversion defined as a 4‑fold increase in post-vaccination antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.

Adjusted Geometric Mean Titers Against

FLULAVAL QUADRIVALENTc

Active Comparatord

n = 972-974

n = 980

A/California/07/2009 (H1N1)

99.6e

85.1

A/Texas/50/2012

(H3N2)

99.8e

84.6

B/Massachusetts/02/2012

(Yamagata lineage)

258.1e

167.3

B/Brisbane/60/2008

(Victoria lineage)

54.5e

33.7

Seroconversionf to:

n = 972-974

%

(95% CI)

n = 980

%

(95% CI)

A/California/07/2009 (H1N1)

73.7e

(70.8, 76.4)

67.3

(64.3, 70.3)

A/Texas/50/2012

(H3N2)

76.1e

(73.3, 78.8)

69.4

(66.4, 72.3)

B/Massachusetts/02/2012

(Yamagata lineage)

85.5e

(83.2, 87.7)

73.8

(70.9, 76.5)

B/Brisbane/60/2008

(Victoria lineage)

64.9e

(61.8, 67.9)

48.5

(45.3, 51.6)

Trial 2 was a randomized, double-blind, active-controlled trial conducted in children aged 3 through 17 years. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 878), or one of 2 formulations of a comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 871 or TIV-2 n = 878), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see Adverse Reactions (6.1)].

Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following one or 2 doses of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoints were 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 ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to both TIVs based on adjusted GMTs and seroconversion rates (Table 10). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 10).

Table 10. Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza Vaccine (TIV) at 28 Days Post-vaccination in Children Aged 3 through 17 Yearsa (According-to-Protocol Cohort for Immunogenicity)b
CI = Confidence Interval.a Trial 2: NCT01198756.b According-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen.c Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage).d Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage).e Containing A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage).f Non‑inferior to both TIVs based on adjusted GMTs [upper limit of the 2-sided 95% CI for the GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper limit of the 2‑sided 95% CI on difference of the TIV minus FLULAVAL QUADRIVALENT ≤10%); superior to TIV-1 (B Victoria) with respect to the B strain of Yamagata lineage and to TIV-2 (B Yamagata) with respect to the B strain of Victoria lineage based on adjusted GMTs [lower limit of the 2‑sided 95% CI for the GMT ratio (FLULAVAL QUADRIVALENT/TIV) >1.5] and seroconversion rates (lower limit of the 2‑sided 95% CI on difference of FLULAVAL QUADRIVALENT minus the TIV >10%).g Seroconversion defined as a 4‑fold increase in post-vaccination antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.

Geometric Mean Titers Against

FLULAVAL QUADRIVALENTc

TIV-1

(B Victoria)d

TIV-2

(B Yamagata)e

n = 878

(95% CI)

n = 871

(95% CI)

n = 877-878

(95% CI)

A/California/7/2009 (H1N1)

362.7f

(335.3, 392.3)

429.1

(396.5, 464.3)

420.2

(388.8, 454.0)

A/Victoria/210/2009 (H3N2)

143.7f

(134.2, 153.9)

139.6

(130.5, 149.3)

151.0

(141.0, 161.6)

B/Brisbane/60/2008

(Victoria lineage)

250.5f

(230.8, 272.0)

245.4

(226.9, 265.4)

68.1

(61.9, 74.9)

B/Florida/4/2006

(Yamagata lineage)

512.5f

(477.6, 549.9)

197.0

(180.7, 214.8)

579.0

(541.2, 619.3)

Seroconversiong to:

n = 876

% (95% CI)

n = 870

% (95% CI)

n = 876-877

% (95% CI)

A/California/7/2009 (H1N1)

84.4f

(81.8, 86.7)

86.8

(84.3, 89.0)

85.5

(83.0, 87.8)

A/Victoria/210/2009 (H3N2)

70.1f

(66.9, 73.1)

67.8

(64.6, 70.9)

69.6

(66.5, 72.7)

B/Brisbane/60/2008

(Victoria lineage)

74.5f

(71.5, 77.4)

71.5

(68.4, 74.5)

29.9

(26.9, 33.1)

B/Florida/4/2006

(Yamagata lineage)

75.2f

(72.2, 78.1)

41.3

(38.0, 44.6)

73.4

(70.4, 76.3)

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