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Boostrix

Boostrix

CLINICAL PHARMACOLOGY

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 lU/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.

Clinical Studies

The efficacy of the tetanus and diphtheria toxoid components of BOOSTRIX is based on the immunogenicity of the individual antigens compared to US-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.

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]. 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-logical 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 (10 to 18 years of age). Of the subjects enrolled in this study, approximately 76% were 10 to 14 years of age and 24% were 15 to 18 years of age. 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 10 to 18 Years of Age (ATP Cohort for Immunogenicity)

  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)
Td 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 two-sided 95% CI on the difference for Td minus BOOSTRIX ≤ 10%).
d Non-inferiority criteria not prospectively defined for this endpoint.

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 two-sided 95% CI for the percentage of subjects with a booster response exceeded the predefined lower limit of 80% for demonstration of an acceptable booster response.

Table 7. Booster Responses to the Pertussis Antigens Following BOOSTRIX in Adolescents 10 to 18 Years of Age (ATP Cohort for Immunogenicity)

  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-pertactin 2,752 95.4 (94.5, 96.1)
ATP = according-to-protocol; CI = Confidence Interval.
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.

The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX in the US adolescent study (N = 2,941-2,979) 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 = 631-2,884). Table 8 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one 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]. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin 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 One Dose of BOOSTRIX in Adolescents 10 to 18 Years of Age Compared With 3 Doses of INFANRIX in Infants (Total Immunogenicity Cohort)

  CMC Ratio: BOOSTRIX/INFANRIX
(95% CI)
Anti-PT 1.90(1.82, 1.99)a
Anti-FHA 7.35 (6.85, 7.89)a
Anti-pertactin 4.19 (3.73, 4.71)a
GMC = geometric mean antibody concentration, measured in ELISA units; CI = Confidence Interval.
Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 2,941, anti-FHA = 2,979, and anti-pertactin = 2,978.
Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 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).

Immunological Evaluation in Adults (19 to 64 Years of Age)

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 SA). 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 patients were 19 to 29 years of age, 33% were 30 to 49 years of age and 34% were 50 to 64 years of age. 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 9. 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 9. Antibody Responses to Tetanus and Diphtheria Toxoids Following One Dose of BOOSTRIX Compared With the Comparator Tdap Vaccine in Adults 19 to 64 Years of Age (ATP Cohort for Immunogenicity)

  N % ≥ 0.1 IU/mLa
(95% CI)
% ≥ 1.0 IU/mLa
(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)
Tdap = Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed manufactured by Sanofi Pasteur SA.
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.

Response to Pertussis Antigens: Booster response rates to the pertussis antigens are shown in Table 10. For the FHA and pertactin 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 10. Booster Responses to the Pertussis Antigens Following One Dose of BOOSTRIX in Adults 19 to 64 Years of Age (ATP Cohort for Immunogenicity)

  N BOOSTRIX
% Booster Responsea
(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-pertactin 1,441 93.2(91.8,94.4)c
ATP = according-to-protocol; CI = Confidence Interval.
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 pertactin antigens booster response lower limit of the 95% CI exceeded the predefined limit of 80%.

The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX in the US adult (19 to 64 years of age) study 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. Table 11 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen). 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]. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations observed in adults 1 month after a single dose of BOOSTRIX were non-inferior to those observed in infants following a primary vaccination series with INFANRIX.

Table 11. Ratio of GMCs to Pertussis Antigens Following One Dose of BOOSTRIX in Adults 19 to 64 Years of Age Compared With 3 Doses of INFANRIX in Infants (Total Immunogenicity Cohort)

  CMC Ratio: BOOSTRIX/INFANRIX
(95% CI)
Anti-PT 1.39(1.32, 1.47)a
Anti-FHA 7.46 (6.86, 8.12)a
Anti-pertactin 3.56(3.10,4.08)a
GMC = geometric mean antibody concentration; CI = Confidence Interval.
Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 1,460, anti-FHA = 1,472, and anti-pertactin = 1,473.
Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631.
a BOOSTRIX was non-inferior to INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX ≥ 0.67).

Immunological Evaluation in the Elderly (65 Years of Age and Older)

The US elderly (65 years of age and older) study, a randomized, observer-blinded study, evaluated the immunogenicity of BOOSTRIX (N = 887) compared with a US-licensed comparator Td vaccine (N = 445) (Sanofi Pasteur SA). 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 of age; 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 and Pertussis Antigens: Immune responses to tetanus and diphtheria toxoids and pertussis antigens 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 12).

Table 12. Immune Responses to Tetanus and Diphtheria Toxoids Following BOOSTRIX or Comparator Td Vaccine in the Elderly 65 Years of Age and Older (ATP Cohort for Immunogenicity)

  BOOSTRIX
(N = 844-864)
Td
(N = 430-439)
Anti-T
  % ≥ 0.1IU/mL(95%CI) 96.8 (95.4, 97.8)a 97.5 (95.6, 98.7)
  % ≥ 1.0IU/mL(95%CI) 88.8 (86.5, 90.8)a 90.0 (86.8, 92.6)
Anti-D
  % ≥ 0.1IU/mL(95%CI) 84.9 (82.3, 87.2)a 86.6 (83.0, 89.6)
  % ≥ 1.0IU/mL(95%CI) 52.0 (48.6, 55.4)b 51.2(46.3,56.0)
Td = Tetanus and Diphtheria Toxoids Adsorbed, a US-licensed Td vaccine, manufactured by Sanofi Pasteur SA.
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.

The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX were compared with the GMCs of infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age. Table 13 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen). 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]. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations in the elderly (65 years of age and older) 1 month after a single dose of BOOSTRIX were non-inferior to those of infants following a primary vaccination series with INFANRIX.

Table 13. Ratio of GMCs to Pertussis Antigens Following One Dose of BOOSTRIX in the Elderly 65 Years of Age and Older Compared With 3 Doses of INFANRIX in Infants (Total Immunogenicity Cohort)

  CMC Ratio: BOOSTRIX/INFANRIX(95% CI)
Anti-PT 1.07(1.00, 1.1 5)a
Anti-FHA 8.24 (7.45, 9.12)a
Anti-pertactin 0.93 (0.79, 1.1 0)a
GMC = geometric mean antibody concentration; CI = Confidence Interval.
Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 865, anti-FHA = 847, and anti- pertactin = 878.
Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631.
a BOOSTRIX was non-inferior to INFANRIX (lower limit of 95% CI for the GMC ratio of BOOSTRIX/INFANRIX ≥ 0.67).

Concomitant Vaccine Administration

Concomitant Administration With Meningococcal Conjugate Vaccine: The concomitant use of BOOSTRIX and a tetravalent meningococcal (groups A, C, Y, and W-135) conjugate vaccine (Sanofi Pasteur SA) was evaluated in a randomized study in healthy adolescents 11 to 18 years of age. A total of 1,341 adolescents were vaccinated with BOOSTRIX. Of these, 446 subjects received BOOSTRIX administered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects received BOOSTRIX followed by meningococcal conjugate vaccine 1 month later, and 449 subjects received meningococcal conjugate vaccine followed by BOOSTRIX 1 month later.

Immune responses to diphtheria and tetanus toxoids (% of subjects with anti-tetanus and anti-diphtheria antibodies ≥ 1.0 lU/mL by ELISA), pertussis antigens (booster responses and GMCs), and meningococcal antigens (vaccine responses) were measured 1 month (range 30 to 48 days) after concomitant or separate administration of BOOSTRIX and meningococcal conjugate vaccine. For BOOSTRIX given concomitantly with meningococcal conjugate vaccine compared to BOOSTRIX administered first, non-inferiority was demonstrated for all antigens, with the exception of the anti-pertactin GMC. The lower limit of the 95% CI for the GMC ratio was 0.54 for anti-pertactin (pre-specified limit ≥ 0.67). For the anti-pertactin booster response, non-inferiority was demonstrated. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to pertactin.

There was no evidence that BOOSTRIX interfered with the antibody responses to the meningococcal antigens when measured by serum bactericidal assays (rSBA) when given concomitantly or sequentially (meningococcal conjugate vaccine followed by BOOSTRIX or BOOSTRIX followed by meningococcal conjugate vaccine.

Concomitant Administration With FLUARIX (Influenza Virus Vaccine): The concomitant use of BOOSTRIX and FLUARIX was evaluated in a multicenter, open-label, randomized, controlled study of 1,497 adults 19 to 64 years of age. In one group, subjects received BOOSTRIX and FLUARIX concurrently (n = 748). The other group received FLUARIX at the first visit, then 1 month later received BOOSTRIX (n = 749). Sera was obtained prior to and 1 month following concomitant or separate administration of BOOSTRIX and/or FLUARIX, as well as 1 month after the separate administration of FLUARIX.

Immune responses following concurrent administration of BOOSTRIX and FLUARIX were non-inferior to separate administration for diphtheria (seroprotection defined as ≥ 0.1 IU/mL), tetanus (seroprotection defined as ≥ 0.1 IU/mL and based on concentrations ≥ 1.0 IU/mL), pertussis toxin (PT) antigen (anti-PT GMC) and influenza antigens (percent of subjects with hemagglutination-inhibition [HI] antibody titer ≥ 1:40 and ≥ 4-fold rise in HI titer). Non-inferiority criteria were not met for the anti-pertussis antigens FHA and pertactin. The lower limit of the 95% CI of the GMC ratio was 0.64 for anti-FHA and 0.60 for anti-pertactin and the pre-specified limit was ≥ 0.67. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to FHA and pertactin.

REFERENCES

1. Institute of Medicine (IOM). Stratton KR, Howe CJ, Johnston RB, eds. Adverse events associated with childhood vaccines. Evidence bearing on causality. Washington, DC: National Academy Press; 1994.

2. Wassilak SGF, Roper MH, Kretsinger K, and Orenstein WA. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:805-839.

3. Vitek CR and Wharton M. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:139-156.

Last reviewed on RxList: 7/21/2011
This monograph has been modified to include the generic and brand name in many instances.

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