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Pediarix

Pediarix

CLINICAL PHARMACOLOGY

The efficacy of PEDIARIX (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) is based on the immunogenicity of the individual antigens compared to licensed vaccines. The efficacy of the pertussis component, which does not have a well established correlate of protection, was determined in clinical trials of INFANRIX. The efficacy of the HBsAg was determined in clinical studies of ENGERIX-B. Serological correlates of protection exist for the diphtheria, tetanus, hepatitis B, and poliovirus components.

Diphtheria

Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Diphtheria in the United States has been controlled through the use of diphtheria toxoid-containing vaccines. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. Following adequate immunization with diphtheria toxoid, protection persists for at least 10 years. 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 Levels of 1.0 IU/mL are associated with long-term protection.1 Immunization with diphtheria toxoid does not, however, eliminate carriage of C. diphtheriae in the pharynx or nares or on the skin.2

Tetanus

Tetanus is a condition manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by C. tetani. Spores of C. tetani are ubiquitous. Naturally acquired immunity to tetanus toxin does not occur. Thus, universal primary immunization and timed booster doses to maintain adequate tetanus antitoxin levels are necessary to protect all age groups.2 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 to 0.2 IU/mL has been considered as protective.5 Following immunization, protection persists for at least 10 years.2

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. 

Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies.6,7 

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.6 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% to 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% to 78%) against > 7 days of any cough and 73% (95% CI: 63% to 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% to 91%) among children followed to 6 years of age.8 For details see INFANRIX prescribing information. 

A prospective efficacy trial was also conducted in Germany employing a household contact study design.7 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% to 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% to 78%) and against ≥ 7 days of paroxysmal cough was 81% (95% CI: 68% to 89%). For details see INFANRIX prescribing information.

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. According to the Centers for Disease Control and Prevention (CDC), hepatitis B vaccine is recognized as an anti-cancer vaccine because it can prevent primary liver cancer.9 In a Taiwanese study, the institution of universal childhood immunization against hepatitis B virus has been shown to decrease the incidence of hepatocellular carcinoma among children.10 In a Korean study in adult males, vaccination against the hepatitis B virus has been shown to decrease the incidence and risk of developing hepatocellular carcinoma in adults.11 

Modes of transmission of hepatitis B virus include sexual contact with an infected person, percutaneous or mucosal exposure to infectious blood, and perinatal exposure to an infected mother. Antibody concentrations ≥ 10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B.12 

Protective efficacy with ENGERIX-B has been demonstrated in a clinical trial in neonates at high risk of hepatitis B infection.13,14 Fifty-eight neonates born of mothers who were both HBsAg- and HBeAg-positive were given ENGERIX-B (10 mcg at 0, 1, and 2 months) without concomitant hepatitis B immune globulin. Two infants became chronic carriers in the 12-month follow-up period after initial inoculation. Assuming an expected carrier rate of 70%, the protective efficacy against the chronic carrier state during the first 12 months of life was 95%.

Poliomyelitis

Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Whereas poliovirus infections are usually asymptomatic or cause nonspecific symptoms, up to 2% of infected persons have central nervous system involvement and develop paralytic disease.15 

Poliomyelitis in the United States has been controlled through the use of poliovirus vaccines.  IPV induces the production of neutralizing antibodies against each poliovirus serotype; these neutralizing antibodies are recognized as conferring protection against poliomyelitis disease.16

Immune Response to PEDIARIX (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine)

In a US multicenter study, infants were randomized to 1 of 3 groups: (1) a combination vaccine group that received PEDIARIX (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) coadministered with US-licensed 7-valent pneumococcal and Hib conjugate vaccines [Wyeth Pharmaceuticals Inc.]; (2) a separate vaccine group that received US-licensed INFANRIX, ENGERIX-B, and IPV [Sanofi Pasteur SA] coadministered with the same pneumococcal and Hib conjugate vaccines; and (3) a staggered vaccine group that received PEDIARIX (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) coadministered 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% 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 (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) 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 (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) in the combination vaccine group were shown to be non-inferior to those achieved following separately administered vaccines (see Table 1). There was no evidence for interference with the immune responses to PEDIARIX (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) when 7-valent pneumococcal conjugate vaccine was concomitantly administered. 

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 (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) relative to separately administered INFANRIX, ENGERIX-B, and an oral poliovirus vaccine, with respect to the hepatitis B immune response was demonstrated.17

Table 1: Antibody Responses Following PEDIARIX (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) 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 Coadministered With Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7)

  PEDIARIX, Hib Vaccine, & PCV7 INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
  (N = 154-168) (N = 141-155)
Anti-Diphtheria
  % ≥ 0.1 IU/mLb 99.4 98.7
Anti-Tetanus
  % = 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
  % = 1:8bd 100 100
Anti-Polio 2
  % = 1:8bd 100 100
Anti-Polio 3
  % = 1:8bd 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 and PCV7 manufactured by Wyeth Pharmaceuticals Inc. IPV manufactured by Sanofi Pasteur SA.
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 (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) 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 pre-vaccination 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 PRN, 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.

Immune Responses to Concomitantly Administered Vaccines

Anti-PRP 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 described previously are presented in Table 2.

Table 2: 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 (diphtheria, tetanus toxoids and acellular pertussis adsorbed, hepatitis b and inactivated poliovirus vaccine) or With INFANRIX, ENGERIX-B, and IPV

  PEDIARIX, Hib Vaccine, & PCV7 INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
(N = 161-168) (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 and PCV7 manufactured by Wyeth Pharmaceuticals Inc. IPV manufactured by Sanofi Pasteur SA.
GMC = Geometric mean antibody concentration.
a One month blood sampling, range 20 to 60 days.

REFERENCES

1. Wharton M and Vitek CR. Diphtheria Toxoid. In: Plotkin SA and Orenstein WA, eds. Vaccines. 4th ed. Philadelphia , PA: Saunders Press; 2004:211-228.

2. Centers for Disease Control. Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures — Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR-10):1-28.

3. Wassilak SGF, Roper MH, Murphy TV and Orenstein WA. Tetanus Toxoid. In: Plotkin SA and Orenstein WA, eds. Vaccines. 4th ed. Philadelphia , PA: Saunders Press; 2004:745-781.

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) and the American Academy of Family Physicians (AAFP). MMWR 2002;51(RR-2):1-35.

6. Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med 1996;334(6):341-348.

7. Schmitt H-J, von König CHW, Neiss A, et al. Efficacy of acellular pertussis vaccine in early childhood after household exposure. JAMA 1996;275(1):37-41.

8. Salmaso S, Mastrantonio P, Tozzi AE, et al. Sustained efficacy during the first 6 years of life of 3-component acellular pertussis vaccines administered in infancy: The Italian experience. Pediatrics 2001;108(5):E81.

9. Centers for Disease Control and Prevention. Proposed vaccine information materials for hepatitis B, Haemophilus influenza type B (Hib), varicella (chickenpox), and measles, mumps, rubella (MMR) vaccines. Federal Register September 3, 1998;63(171):47026-47031.

10. Chang MH, Chen CJ, Lai MS. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. NEngl J Med 1997;336:1855-1859.

11. Lee MS, Kim DH, Kim H, et al. Hepatitis B vaccination and reduced risk of primary liver cancer among male adults: A cohort study in Korea. IntJ Epidemiol 1998;27(2):316-319.

12. 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 MedJ 1987;63(Suppl. 2):129-135.

13. Andre FE and Safary A. Clinical experience with a yeast-derived hepatitis B vaccine. In: Zuckerman AJ, ed. Viral hepatitis and liver disease. New York, NY: Alan R Liss, Inc.; 1988:1025-1030.

14. Poovorawan Y, Sanpavat S, Pongpunlert W, et al. Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBe antigen-positive mothers. JAMA 1989;261(22):3278-3281.

15. Centers for Disease Control and Prevention. Poliomyelitis. In: Atkinson W and Wolfe C, eds. Epidemiology and prevention of vaccine-preventable diseases. 7th ed. Atlanta, GA: Public Health Foundation; 2002:71-82.

16. 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.

17. Yeh SH, Ward JI, Partridge S, et al. Safety and immunogenicity of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and polio combination vaccine in infants. Pediatr Infect Dis J 2001;20:973-980.

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

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