Vaccine Information: BOOSTRIX (Page 3 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

BOOSTRIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Vaccination of female rabbits and rats with BOOSTRIX had no effect on fertility. [See Use in Specific Populations (8.1).]

14 CLINICAL STUDIES

The efficacy of the tetanus and diphtheria toxoid components of BOOSTRIX is based on the immunogenicity of the individual antigens compared with U.S.-licensed vaccines using established serologic correlates of protection. The efficacy of the pertussis components of BOOSTRIX was evaluated by comparison of the immune response of adolescents and adults following a single dose of BOOSTRIX to the immune response of infants following a 3-dose primary series of INFANRIX. In addition, the ability of BOOSTRIX to induce a booster response to each of the antigens was evaluated.

14.1 Efficacy of INFANRIX

The efficacy of a 3-dose primary series of INFANRIX in infants has been assessed in 2 clinical studies: A prospective efficacy trial conducted in Germany employing a household contact study design and a double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy sponsored by the National Institutes of Health (NIH) (for details see INFANRIX prescribing information). Serological data from a subset of infants immunized with INFANRIX in the household contact study were compared with the sera of adolescents and adults immunized with BOOSTRIX [see Clinical Studies (14.2, 14.3)]. In the household contact study, the protective efficacy of INFANRIX in infants against WHO-defined pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was calculated to be 89% (95% CI: 77%, 95%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52%, 78%) and against ≥7 days of paroxysmal cough was 81% (95% CI: 68%, 89%) (for details see INFANRIX prescribing information).

14.2 Immunological Evaluation in Adolescents

In a multicenter, randomized, controlled study conducted in the United States, the immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration of a single dose of vaccine to adolescent subjects (aged 10 to 18 years). Of the subjects enrolled in this study, approximately 76% were aged 10 to 14 years and 24% were aged 15 to 18 years. Approximately 98% of participants in this study had received the recommended series of 4 or 5 doses of either DTwP or a combination of DTwP and DTaP in childhood. The racial/ethnic demographics were as follows: white 85.8%, black 5.7%, Hispanic 5.6%, Oriental 0.8%, and other 2.1%.

Response to Tetanus and Diphtheria Toxoids

The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with Td vaccine are shown in Table 6. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) and booster response rates were comparable between BOOSTRIX and the comparator Td vaccine.

Table 6. Antibody Responses to Tetanus and Diphtheria Toxoids following BOOSTRIX Compared with Td Vaccine in Adolescents Aged 10 to 18 Years (ATP Cohort for Immunogenicity)
Td = Tetanus and Diphtheria Toxoids, Adsorbed manufactured by MassBiologics.ATP = According-to-protocol; CI = Confidence Interval.a Measured by ELISA.b Booster response: In subjects with pre-vaccination <0.1 IU/mL, post-vaccination concentration ≥0.4 IU/mL. In subjects with pre-vaccination concentration ≥0.1 IU/mL, an increase of at least 4 times the pre-vaccination concentration.c Seroprotection rate or booster response rate to BOOSTRIX was non-inferior to Td (upper limit of 2-sided 95% CI on the difference for Td minus BOOSTRIX ≤10%).d Non-inferiority criteria not prospectively defined for this endpoint.

Antibodies

n

% ≥0.1 IU/mLa

(95% CI)

% ≥1.0 IU/mLa

(95% CI)

% Booster Responseb

(95% CI)

Anti-tetanus

BOOSTRIX

2,469-2,516

Pre-vaccination

97.7 (97.1, 98.3)

36.8 (34.9, 38.7)

Post-vaccination

100 (99.8, 100)c

99.5 (99.1, 99.7)d

89.7 (88.4, 90.8)c

Td

817-834

Pre-vaccination

96.8 (95.4, 97.9)

39.9 (36.5, 43.4)

Post-vaccination

100 (99.6, 100)

99.8 (99.1, 100)

92.5 (90.5, 94.2)

Anti-diphtheria

BOOSTRIX

2,463-2,515

Pre-vaccination

85.8 (84.3, 87.1)

17.1 (15.6, 18.6)

Post-vaccination

99.9 (99.7, 100)c

97.3 (96.6, 97.9)d

90.6 (89.4, 91.7)c

Td

814-834

Pre-vaccination

84.8 (82.1, 87.2)

19.5 (16.9, 22.4)

Post-vaccination

99.9 (99.3, 100)

99.3 (98.4, 99.7)

95.9 (94.4, 97.2)

Response to Pertussis Antigens

The booster response rates of adolescents to the pertussis antigens are shown in Table 7. For each of the pertussis antigens the lower limit of the 2-sided 95% CI for the percentage of subjects with a booster response exceeded the pre-defined lower limit of 80% for demonstration of an acceptable booster response.

Table 7. Booster Responses to the Pertussis Antigens following BOOSTRIX in Adolescents Aged 10 to 18 Years (ATP Cohort for Immunogenicity)
ATP = According-to-protocol; CI = Confidence Interval; PT = Pertussis toxin; FHA = Filamentous hemagglutinin; PRN = Pertactin.a Booster response: In initially seronegative subjects (<5 EL.U./mL), post-vaccination antibody concentrations ≥20 EL.U./mL. In initially seropositive subjects with pre-vaccination antibody concentrations ≥5 EL.U./mL and <20 EL.U./mL, an increase of at least 4 times the pre-vaccination antibody concentration. In initially seropositive subjects with pre-vaccination antibody concentrations ≥20 EL.U./mL, an increase of at least 2 times the pre-vaccination antibody concentration.

Pertussis Antibodies

n

BOOSTRIX

% Booster Responsea (95% CI)

Anti-PT

2,677

84.5 (83.0, 85.9)

Anti-FHA

2,744

95.1 (94.2, 95.9)

Anti-PRN

2,752

95.4 (94.5, 96.1)

The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX in the U.S. adolescent study (N = 2,941 to 2,979) were compared with the GMCs observed in infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age (N = 631 to 2,884). Table 8 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least 1 pertussis antigen; the majority of subjects in the study of INFANRIX had anti-PT serology data only). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated [see Clinical Studies (14.1)]. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-PRN antibody concentrations observed in adolescents 1 month after a single dose of BOOSTRIX were non-inferior to those observed in infants following a primary vaccination series with INFANRIX.

Table 8. Ratio of GMCs to Pertussis Antigens following 1 Dose of BOOSTRIX in Adolescents Aged 10 to 18 Years Compared with 3 Doses of INFANRIX in Infants (Total Immunogenicity Cohort)
GMC = Geometric mean antibody concentration, measured in ELISA units; CI = Confidence Interval; PT = Pertussis toxin; FHA = Filamentous hemagglutinin; PRN = Pertactin.Number of subjects for GMC evaluation for BOOSTRIX: Anti-PT = 2,941, anti-FHA = 2,979, and anti-PRN = 2,978.Number of subjects for GMC evaluation for INFANRIX: Anti-PT = 2,884, anti-FHA = 685, and anti-PRN = 631.a GMC following BOOSTRIX was non-inferior to GMC following INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX >0.67).

Pertussis Antibodies

GMC Ratio: BOOSTRIX/INFANRIX

(95% CI)

Anti-PT

1.90 (1.82, 1.99)a

Anti-FHA

7.35 (6.85, 7.89)a

Anti-PRN

4.19 (3.73, 4.71)a

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