Vaccine Information: BOOSTRIX (Page 3 of 5)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tetanus

Tetanus is a condition manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2 A level ≥0.1 IU/mL by ELISA has been considered as protective.

Diphtheria

Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL, measured by neutralization assays, is the lowest level giving some degree of protection; a level of 0.1 IU/mL by ELISA is regarded as protective.3 Diphtheria antitoxin levels ≥1.0 IU/mL by ELISA have been associated with long-term protection.3

Pertussis

Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood.

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

14.1 Effectiveness of BOOSTRIX, INFANRIX, and PEDIARIX

Effectiveness of BOOSTRIX

The effectiveness 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 effectiveness of the pertussis components of BOOSTRIX was evaluated by comparison of the immune response of adolescents and adults following an initial dose of BOOSTRIX to the immune response of infants following a 3-dose primary series of INFANRIX or by comparison of the immune response of adults following an additional dose of BOOSTRIX to the immune response of infants following a 3-dose primary series of PEDIARIX. In addition, the ability of BOOSTRIX to induce a booster response to each of the antigens was evaluated.

Efficacy of INFANRIX Against Pertussis

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). 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).

Immune Responses to Pertussis Antigens of PEDIARIX Compared with INFANRIX

The diphtheria, tetanus, and pertussis components in PEDIARIX are the same as those in INFANRIX. The effectiveness of the pertussis component of PEDIARIX was determined in clinical trials by comparison to antibody responses to INFANRIX (for details see PEDIARIX prescribing information).

Immune Responses to Pertussis Antigens of BOOSTRIX Compared with INFANRIX or PEDIARIX

Although a serologic correlate of protection for pertussis has not been established, serological data from a subset of infants immunized with a 3-dose primary series of INFANRIX in the German household contact study were compared with the sera of adolescents and adults immunized with an initial dose of BOOSTRIX [see Clinical Studies (14.2)]. Serological data from infants immunized with a 3-dose primary series of PEDIARIX in an additional pediatric study were compared with the sera of adults immunized with an additional dose of BOOSTRIX [see Clinical Studies (14.3)]. The GMCs to each of the pertussis antigens 1 month following a dose of BOOSTRIX were compared with the GMCs of infants following INFANRIX administered at 3, 4, and 5 months of age or were compared with the GMCs of infants following PEDIARIX administered at 2, 4, and 6 months of age. The majority of subjects in the study of INFANRIX had only anti-PT serology data.

14.2 Immunological Evaluation following an Initial Dose of BOOSTRIX

Adolescents (Aged 10 to 18 years)

In a multicenter, randomized, observer-blinded, 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 8. 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 8. 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 9. 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 9. 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 were compared with the GMCs of a subset of infants following a 3-dose primary series of INFANRIX in the German household contact study [see Clinical Studies (14.1)]. Table 10 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least 1 pertussis antigen). 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 infants following a primary vaccination series with INFANRIX.

Table 10. 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.n = Number of subjects for GMC evaluation.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

BOOSTRIX

(n)

INFANRIX

(n)

GMC Ratio: BOOSTRIX/INFANRIX

(95% CI)

Anti-PT

2,941

2,884

1.90 (1.82, 1.99)a

Anti-FHA

2,979

685

7.35 (6.85, 7.89)a

Anti-PRN

2,978

631

4.19 (3.73, 4.71)a

Adults (Aged 19 to 64 Years)

A multicenter, randomized, observer-blinded study, conducted in the United States, evaluated the immunogenicity of BOOSTRIX compared with the licensed comparator Tdap vaccine (Sanofi Pasteur). Vaccines were administered as a single dose to subjects (N = 2,284) who had not received a tetanus-diphtheria booster within 5 years. The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration. Approximately 33% of subjects were aged 19 to 29 years, 33% were aged 30 to 49 years, and 34% were aged 50 to 64 years. Among subjects in the combined vaccine groups, 62% were female; 84% of subjects were White, 8% Black, 1% Asian, and 7% were of other racial/ethnic groups.

Response to Tetanus and Diphtheria Toxoids: The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with the comparator Tdap vaccine are shown in Table 11. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) were comparable between BOOSTRIX and the comparator Tdap vaccine.

Table 11. Antibody Responses to Tetanus and Diphtheria Toxoids following 1 Dose of BOOSTRIX Compared with the Comparator Tdap Vaccine in Adults Aged 19 to 64 Years (ATP Cohort for Immunogenicity)
Tdap = Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed manufactured by Sanofi Pasteur.ATP = According-to-protocol; CI = Confidence Interval.a Measured by ELISA.b Seroprotection rates for BOOSTRIX were non-inferior to the comparator Tdap vaccine (lower limit of 95% CI on the difference of BOOSTRIX minus Tdap ≥-10%).c Non-inferiority criteria not prospectively defined for this endpoint.

Antibodies

% ≥0.1 IU/mLa

% ≥1.0 IU/mLa

n

(95% CI)

(95% CI)

Anti-tetanus

BOOSTRIX

1,445-1,447

Pre-vaccination

95.9 (94.8, 96.9)

71.9 (69.5, 74.2)

Post-vaccination

99.6 (99.1, 99.8)b

98.3 (97.5, 98.9)b

Tdap

727-728

Pre-vaccination

97.2 (95.8, 98.3)

74.7 (71.4, 77.8)

Post-vaccination

100 (95.5, 100)

99.3 (98.4, 99.8)

Anti-diphtheria

BOOSTRIX

1,440-1,444

Pre-vaccination

85.2 (83.3, 87.0)

23.7 (21.5, 26.0)

Post-vaccination

98.2 (97.4, 98.8)b

87.9 (86.1, 89.5)c

Tdap

720-727

Pre-vaccination

89.2 (86.7, 91.3)

26.5 (23.3, 29.9)

Post-vaccination

98.6 (97.5, 99.3)

92.0 (89.8, 93.9)

Response to Pertussis Antigens: Booster response rates to the pertussis antigens are shown in Table 12. For the FHA and PRN antigens, the lower limit of the 95% CI for the booster responses exceeded the pre-defined limit of 80% demonstrating an acceptable booster response following BOOSTRIX. The PT antigen booster response lower limit of the 95% CI (74.9%) did not exceed the pre-defined limit of 80%.

Table 12. Booster Responses to the Pertussis Antigens following 1 Dose of BOOSTRIX in Adults Aged 19 to 64 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.b The PT antigen booster response lower limit of the 95% CI did not exceed the pre-defined limit of 80%.c The FHA and PRN antigens booster response lower limit of the 95% CI exceeded the pre-defined limit of 80%.

Pertussis Antibodies

BOOSTRIX

% Booster Responsea

n

(95% CI)

Anti-PT

1,419

77.2 (74.9, 79.3)b

Anti-FHA

1,433

96.9 (95.8, 97.7)c

Anti-PRN

1,441

93.2 (91.8, 94.4)c

The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX were compared with the GMCs of a subset of infants following a 3-dose primary series of INFANRIX in the German household contact study [see Clinical Studies (14.1)]. Table 13 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least 1 pertussis antigen). Anti-PT, anti-FHA, and anti-PRN antibody concentrations observed in adults 1 month after a single dose of BOOSTRIX were non-inferior to those infants following a primary vaccination series with INFANRIX.

Table 13. Ratio of GMCs to Pertussis Antigens following 1 Dose of BOOSTRIX in Adults Aged 19 to 64 Years Compared with 3 Doses of INFANRIX in Infants (Total Immunogenicity Cohort)
GMC = Geometric mean antibody concentration; CI = Confidence Interval; PT = Pertussis toxin; FHA = Filamentous hemagglutinin; PRN = Pertactin.n = Number of subjects for GMC evaluation.a BOOSTRIX was non-inferior to INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX ≥0.67).

Pertussis Antibodies

BOOSTRIX

INFANRIX

GMC Ratio: BOOSTRIX/INFANRIX

(n)

(n)

(95% CI)

Anti-PT

1,460

2,884

1.39 (1.32, 1.47)a

Anti-FHA

1,472

685

7.46 (6.86, 8.12)a

Anti-PRN

1,473

631

3.56 (3.10, 4.08)a

Elderly (Aged 65 Years and Older)

The U.S. elderly (aged 65 years and older) study, a randomized, observer-blinded study, evaluated the immunogenicity of BOOSTRIX (n = 887) compared with a U.S.-licensed comparator Td vaccine (n = 445) (Sanofi Pasteur). Vaccines were administered as a single dose to subjects who had not received a tetanus-diphtheria booster within 5 years. Among all vaccine recipients, the mean age was approximately 72 years; 54% were female and 95% were White. The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration.

Response to Tetanus and Diphtheria Toxoids: Immune responses to tetanus and diphtheria toxoids were measured 1 month after administration of a single dose of BOOSTRIX or a comparator Td vaccine. Anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL) were comparable between BOOSTRIX and the comparator Td vaccine (Table 14).

Table 14. Immune Responses to Tetanus and Diphtheria Toxoids following BOOSTRIX or Comparator Td Vaccine in the Elderly Aged 65 Years and Older (ATP Cohort for Immunogenicity)
Td = Tetanus and Diphtheria Toxoids Adsorbed, a U.S.-licensed Td vaccine, manufactured by Sanofi Pasteur.ATP = According-to-protocol; CI = Confidence Interval.a Seroprotection rates for BOOSTRIX were non-inferior to the comparator Td vaccine (lower limit of 95% CI on the difference of BOOSTRIX minus Td ≥-10%).b Non-inferiority criteria not prospectively defined for this endpoint.

Anti-Tetanus and Anti-Diphtheria Titers

BOOSTRIX

Td

(n = 844-864)

(n = 430-439)

Anti-tetanus

% ≥0.1 IU/mL (95% CI)

96.8 (95.4, 97.8)a

97.5 (95.6, 98.7)

% ≥1.0 IU/mL (95% CI)

88.8 (86.5, 90.8)a

90.0 (86.8, 92.6)

Anti-diphtheria

% ≥0.1 IU/mL (95% CI)

84.9 (82.3, 87.2)a

86.6 (83.0, 89.6)

% ≥1.0 IU/mL (95% CI)

52.0 (48.6, 55.4)b

51.2 (46.3, 56.0)

Response to Pertussis Antigens: The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX were compared with the GMCs of a subset of infants following a 3-dose primary series of INFANRIX in the German household contact study [see Clinical Studies (14.1)]. Table 15 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least 1 pertussis antigen). Anti-PT, anti-FHA, and anti-PRN antibody concentrations in the elderly 1 month after a single dose of BOOSTRIX were non-inferior to those of infants following a primary vaccination series with INFANRIX.

Table 15. Ratio of GMCs to Pertussis Antigens following 1 Dose of BOOSTRIX in the Elderly Aged 65 Years and Older Compared with 3 Doses of INFANRIX in Infants (Total Immunogenicity Cohort)
GMC = Geometric mean antibody concentration; CI = Confidence Interval; PT = Pertussis toxin; FHA = Filamentous hemagglutinin; PRN = Pertactin.n = Number of subjects for GMC evaluation.a BOOSTRIX was non-inferior to INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX ≥0.67).

Pertussis Antibodies

BOOSTRIX

INFANRIX

GMC Ratio: BOOSTRIX/INFANRIX

(n)

(n)

(95% CI)

Anti-PT

865

2,884

1.07 (1.00, 1.15)a

Anti-FHA

847

685

8.24 (7.45, 9.12)a

Anti-PRN

878

631

0.93 (0.79, 1.10)a

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