July 2, 2016
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Pediarix

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Pediarix




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.2

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.3,4 A level > 0.1 IU/mL is considered protective.5

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 established serological correlate of protection for pertussis.

Hepatitis B

Infection with hepatitis B virus can have serious consequences including acute massive hepatic necrosis and chronic active hepatitis. Chronically infected persons are at increased risk for cirrhosis and hepatocellular carcinoma.

Antibody concentrations ≥ 10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B virus infection.6

Poliomyelitis

Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Poliovirus neutralizing antibodies confer protection against poliomyelitis disease.7

Clinical Studies

The efficacy of PEDIARIX is based on the immunogenicity of the individual antigens compared to licensed vaccines. Serological correlates of protection exist for the diphtheria, tetanus, hepatitis B, and poliovirus components. The efficacy of the pertussis component, which does not have a well established correlate of protection, was determined in clinical trials of INFANRIX.

Efficacy Of INFANRIX

Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies.

A double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy, sponsored by the National Institutes of Health (NIH), assessed the absolute protective efficacy of INFANRIX when administered at 2, 4, and 6 months of age. The population used in the primary analysis of the efficacy of INFANRIX included 4,481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. After 3 doses, the absolute protective efficacy of INFANRIX against WHO-defined typical pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was 84% (95% CI: 76%, 89%). 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 was 71% (95% CI: 60%, 78%) against > 7 days of any cough and 73% (95% CI: 63%, 80%) against ≥ 14 days of any cough. A longer unblinded follow-up period showed that after 3 doses and with no booster dose in the second year of life, the efficacy of INFANRIX against WHO-defined pertussis was 86% (95% CI: 79%, 91%) among children followed to 6 years of age. For details see INFANRIX prescribing information.

A prospective efficacy trial was also conducted in Germany employing a household contact study design. In this study, the protective efficacy of INFANRIX administered to infants at 3, 4, and 5 months of age, against WHO-defined pertussis was 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.

Immunological Evaluation Of PEDIARIX

In a US multicenter study, infants were randomized to 1 of 3 groups: (1) a combination vaccine group that received PEDIARIX concomitantly with Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US) and US-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.); (2) a separate vaccine group that received US-licensed INFANRIX, ENGERIX-B, and IPV (Sanofi Pasteur SA) concomitantly with the same Hib and pneumococcal conjugate vaccines; and (3) a staggered vaccine group that received PEDIARIX concomitantly with the same Hib conjugate vaccine but with the same pneumococcal conjugate vaccine administered 2 weeks later. The schedule of administration was 2, 4, and 6 months of age. Infants either did not receive a dose of hepatitis B vaccine prior to enrollment or were permitted to receive one dose of hepatitis B vaccine administered at least 30 days prior to enrollment. For the separate vaccine group, ENGERIX-B was not administered at 4 months of age to subjects who received a dose of hepatitis B vaccine prior to enrollment. Among subjects in all 3 vaccine groups combined, 84% were white, 7% were Hispanic, 6% were black, 0.7% were Oriental, and 2.4% were of other racial/ethnic groups.

The immune responses to the pertussis (PT, FHA, and pertactin), diphtheria, tetanus, poliovirus, and hepatitis B antigens were evaluated in sera obtained one month (range 20 to 60 days) after the third dose of PEDIARIX or INFANRIX. Geometric mean antibody concentrations (GMCs) adjusted for pre-vaccination values for PT, FHA, and pertactin and the seroprotection rates for diphtheria, tetanus, and the polioviruses among subjects who received PEDIARIX in the combination vaccine group were shown to be non-inferior to those achieved following separately administered vaccines (Table 3).

Because of differences in the hepatitis B vaccination schedule among subjects in the study, no clinical limit for non-inferiority was pre-defined for the hepatitis B immune response. However, in a previous US study, non-inferiority of PEDIARIX relative to separately administered INFANRIX, ENGERIX-B, and an oral poliovirus vaccine, with respect to the hepatitis B immune response was demonstrated.

Table 3: Antibody Responses Following PEDIARIX as Compared to Separate Concomitant Administration of INFANRIX, ENGERIX-B, and IPV (One Montha After Administration of Dose 3) in Infants Vaccinated at 2, 4, and 6 Months of Age When Administered

PEDIARIX, Hib Vaccine,& PCV7
(N = 154-168)
INFANRIX, ENGERIX-B, IPV,Hib Vaccine, & PCV7
(N = 141-155)
Anti-Diphtheria Toxoid
  % ≥ 0.1 IU/mLb 99.4 98.7
Anti-Tetanus Toxoid
  % ≥ 0.1 IU/mLb 100 98.1
Anti-PT
  % VRc 98.7 95.1
  GMCb 48.1 28.6
Anti-FHA
  % VRc 98.7 96.5
  GMCb 111.9 97.6
Anti-Pertactin
  % VRc 91.7 95.1
  GMCb 95.3 80.6
Anti-Polio 1
  % ≥ 1:8b,d 100 100
Anti-Polio 2
  % ≥ 1:8b,d 100 100
Anti-Polio 3
  % ≥ 1:8b,d 100 100
(N = 114-128) (N = 111-121)
Anti-HBsAge
  % ≥ 10 mIU/mLf 97.7 99.2
  GMC (mIU/mL)f 1032.1 614.5
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Assay methods used: ELISA for anti-diphtheria, anti-tetanus, anti-PT, anti-FHA, anti-pertactin, and anti-HBsAg; micro-neutralization for anti-polio (1, 2, and 3).
VR = vaccine response: In initially seronegative infants, appearance of antibodies (concentration ≥ 5 EL.U./mL); in initially seropositive infants, at least maintenance of pre-vaccination concentration.
GMC = geometric mean antibody concentration. GMCs are adjusted for pre-vaccination levels.
a One month blood sampling, range 20 to 60 days.
b Seroprotection rate or GMC for PEDIARIX not inferior to separately administered vaccines [upper limit of 90% CI on GMC ratio (separate vaccine group/combination vaccine group) < 1.5 for anti-PT, anti-FHA, and anti-pertactin, and upper limit of 95% CI for the difference in seroprotection rates (separate vaccine group minus combination vaccine group) < 10% for diphtheria and tetanus and < 5% for the 3 polioviruses]. GMCs are adjusted for pre­vaccination levels.
c The upper limit of 95% CI for differences in vaccine response rates (separate vaccine group minus combination group) was 0.31, 1.52, and 9.46 for PT, FHA, and pertactin, respectively. No clinical limit defined for non-inferiority. d Poliovirus neutralizing antibody titer.
e Subjects who received a previous dose of hepatitis B vaccine were excluded from the analysis of hepatitis B seroprotection rates and GMCs presented in the table.
f No clinical limit defined for non-inferiority.

Concomitant Vaccine Administration

In a US multicenter study [see Clinical Studies ], there was no evidence for interference with the immune responses to PEDIARIX when administered concomitantly with 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) relative to 2 weeks prior.

Anti-PRP (Hib polyribosyl-ribitol-phosphate) seroprotection rates and GMCs of pneumococcal antibodies one month (range 20 to 60 days) after the third dose of vaccines for the combination vaccine group and the separate vaccine group from the US multicenter study [see Clinical Studies], are presented in Table 4.

Table 4: Anti-PRP Seroprotection Rates and GMCs (mcg/mL) of Pneumococcal Antibodies One Montha Following the Third Dose of Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7) Administered Concomitantly With PEDIARIX or With

PEDIARIX, Hib Vaccine, & PCV7
(N = 161-168)
INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
(N = 146-156)
% (95% CI) % (95% CI)
Anti-PRP 
   ≥ 0.15 mcg/mL 100 (97.8, 100) 99.4 (96.5, 100)
Anti-PRP
   ≥ 1.0 mcg/mL 95.8 (91.6, 98.3) 91.0 (85.3, 95.0)
GMC (95% CI) GMC (95% CI)
Pneumococcal Serotype
4 1.7 (1.5, 2.0) 2.1 (1.8, 2.4)
6B 0.8 (0.7, 1.0) 0.7 (0.5, 0.9)
9V 1.6 (1.4, 1.8) 1.6 (1.4, 1.9)
14 4.7 (4.0, 5.4) 6.3 (5.4, 7.4)
18C 2.6 (2.3, 3.0) 3.0 (2.5, 3.5)
19F 1.1 (1.0, 1.3) 1.1 (0.9, 1.2)
23F 1.5 (1.2, 1.8) 1.8 (1.5, 2.3)
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Assay method used: ELISA for anti-PRP and 7 pneumococcal serotypes.
GMC = geometric mean antibody concentration.
a One month blood sampling, range 20 to 60 days.

REFERENCES

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

3. 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.

4. 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.

5. 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.

6. Ambrosch F, Frisch-Niggemeyer W, Kremsner P, et al. Persistence of vaccine-induced antibodies to hepatitis B surface antigen and the need for booster vaccination in adult subjects. Postgrad Med J 1987;63(Suppl. 2): 129-135.

7. 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: 11/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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