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CLINICAL PHARMACOLOGY

Mechanism of Action

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 is the lowest level giving some degree of protection; a level of 0.1 IU/mL is regarded as protective.1

Tetanus: Tetanus is an acute toxin-mediated disease 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.2,3 A level of ≥ 0.1 IU/mL is considered protective.4

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. There is no well established serological correlate of protection for pertussis. The efficacy of the pertussis component of KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) was determined in clinical trials of INFANRIX administered as a 3-dose series in infants (see INFANRIX prescribing information).

Poliomyelitis: Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Neutralizing antibodies against the 3 poliovirus serotypes are recognized as conferring protection against poliomyelitis disease.5

Clinical Studies

Immunological Evaluation

In a US multicenter study (Study 048), 4,209 children were randomized in a 3:1 ratio to receive either KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) or INFANRIX and IPV (Sanofi Pasteur SA) administered concomitantly at separate sites. Subjects also received MMR vaccine (Merck & Co., Inc.) administered concomitantly at a separate site. Subjects were children 4 through 6 years of age who previously received 4 doses of INFANRIX, 3 doses of IPV, and 1 dose of MMR vaccine. Among subjects in both vaccine groups combined, 49.6% were female; 45.6% of subjects were White, 18.8% Hispanic, 13.6% Asian, 7.0% Black, and 15.0% were of other racial/ethnic groups.

Levels of antibodies to the diphtheria, tetanus, pertussis (PT, FHA, and pertactin), and poliovirus antigens were measured in sera obtained immediately prior to vaccination and 1 month (range 31 to 48 days) after vaccination (Table 2). The co-primary immunogenicity endpoints were anti-diphtheria toxoid, anti-tetanus toxoid, anti-PT, anti-FHA, and anti-pertactin booster responses, and anti-poliovirus Type 1, Type 2, and Type 3 geometric mean antibody titers (GMTs) 1 month after vaccination. KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) was shown to be non-inferior to INFANRIX and IPV administered separately, in terms of booster responses to DTaP antigens and post­vaccination GMTs for anti-poliovirus antibodies (Table 2).

Table 2. Pre-vaccination Antibody Levels and Post-vaccination* Antibody Responses Following KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) Compared With Separate Concomitant Administration of INFANRIX and IPV in Children 4 to 6 Years of Age When Coadministered With MMR Vaccine (Study 048) (ATP Cohort for Immunogenicity)

  KINRIX INFANRIX + IPV
  N = 787-851 N = 237-262
Anti-Diphtheria Toxoid
  Pre-vaccination % ≥ 0.1 IU/mL (95% CI) 87.7 (85.3, 89.9) 85.5 (80.6, 89.5)
  Post-vaccination % ≥ 0.1 IU/mL (95% CI) 100 (99.6, 100) 100 (98.6, 100)
  % Booster Response (95% CI) 99.5 (98.8, 99.9)§ 100 (98.6, 100)
Anti-Tetanus Toxoid
  Pre-vaccination % ≥ 0.1 IU/mL (95% CI) 87.8 (85.4, 90.0) 88.2 (83.6, 91.8)
  Post-vaccination % ≥ 0.1 IU/mL (95% CI) 100 (99.6, 100) 100 (98.6, 100)
  % Booster Response (95% CI) 96.7 (95.2, 97.8)§ 93.9 (90.2, 96.5)
Anti-PT
  % Booster Response (95% CI)|| 92.2 (90.2, 94.0)§ 92.6 (88.7, 95.5)
Anti-FHA
  % Booster Response (95% CI)|| 95.4 (93.7, 96.7)§ 96.2 (93.1, 98.1)
Anti-Pertactin
  % Booster Response (95% CI)|| 97.8 (96.5, 98.6)§ 96.9 (94.1, 98.7)
Anti-Poliovirus 1
  Pre-vaccination % ≥ 1:8 (95% CI) 88.3 (85.9, 90.4) 85.1 (80.1, 89.2)
  Post-vaccination % ≥ 1:8 (95% CI) 99.9 (99.3, 100) 100 (98.5, 100)
  Post-vaccination GMT (95% CI) 2,127 (1,976, 2,290) 1,685 (1,475, 1,925)
Anti-Poliovirus 2
  Pre-vaccination % ≥ 1:8 (95% CI) 91.8 (89.7, 93.6) 87.0 (82.3, 90.8)
  Post-vaccination % ≥ 1:8 (95% CI) 100 (99.6, 100) 100 (98.5, 100)
  Post-vaccination GMT (95% CI) 2,265 (2,114, 2,427) 1,818 (1,606, 2,057)
Anti-Poliovirus 3
  Pre-vaccination % ≥ 1:8 (95% CI) 84.7 (82.0, 87.0) 85.0 (80.1, 89.1)
  Post-vaccination % ≥ 1:8 (95% CI) 100 (99.5, 100) 100 (98.5, 100)
  Post-vaccination GMT (95% CI) 3,588 (3,345, 3,849) 3,365 (2,961, 3,824)
IPV manufactured by Sanofi Pasteur SA. MMR vaccine manufactured by Merck & Co., Inc.
ATP = according-to-protocol; CI = Confidence Interval; GMT = geometric mean antibody titer
N = number of subjects with available results.
*One month blood sampling, range 31 to 48 days.
Seroprotection defined as anti-diphtheria toxoid and anti-tetanus toxoid antibody concentrations ≥ 0.1 IU/mL by ELISA and as anti-poliovirus Type 1, Type 2, and Type 3 antibody titer ≥ 1:8 by micro-neutralization assay for poliovirus.
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.
§KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) was non-inferior to INFANRIX + IPV based on booster response rates (upper limit of two-sided 95% CI on the difference of INFANRIX + IPV minus KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) ≤ 10%).
|| Booster response: In subjects with pre-vaccination < 5 EL.U./mL, post-vaccination concentration ≥ 20 EL.U./mL. In subjects with pre-vaccination ≥ 5 EL.U./mL and < 20 EL.U./mL, an increase of at least 4 times the pre-vaccination concentration. In subjects with pre-vaccination ≥ 20 EL.U./mL, an increase of at least 2 times the pre-vaccination concentration.
KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) was non-inferior to INFANRIX + IPV based on post-vaccination anti-poliovirus antibody GMTs adjusted for baseline titer (upper limit of two-sided 95% CI for the GMT ratio [INFANRIX + IPV:KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) ] ≤ 1.5).

Concomitant Vaccine Administration

In a US study (Study 047), among recipients of DTaP-IPV (same formulation as KINRIX (diptheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) but also containing 2-phenoxyethanol) and the second dose of MMR vaccine (Merck & Co., Inc.) who had pre-vaccination sera tested for antibodies to measles, mumps, and rubella (N = 175-181), 99% of subjects were seropositive for antibodies to measles, mumps, and rubella prior to vaccination.

REFERENCES

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

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. Department of Health and Human Services, Food and Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review; Proposed rule. Federal Register December 13, 1985;50(240):51002-51117.

4. Centers for Disease Control and Prevention. General Recommendations on Immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-15):1-48.

5. Sutter RW, Pallansch MA, Sawyer LA, et al. Defining surrogate serologic tests with respect to predicting protective vaccine efficacy: Poliovirus vaccination. In: Williams JC, Goldenthal KL, Burns DL, Lewis Jr BP, eds. Combined vaccines and simultaneous administration. Current issues and perspectives. New York, NY: The New York Academy of Sciences; 1995:289-299.

Last reviewed on RxList: 7/23/2008
This monograph has been modified to include the generic and brand name in many instances.

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