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Infanrix

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Infanrix

Infanrix

CLINICAL PHARMACOLOGY

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 Immunization with diphtheria toxoid does not, however, eliminate carriage of C. diphtheriae in the pharynx or nares or on the skin.2

Efficacy of diphtheria toxoid used in INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) was determined on the basis of immunogenicity studies. A VERO cell toxin neutralizing test confirmed the ability of infant sera (N = 45), obtained one month after a 3-dose primary series, to neutralize diphtheria toxin. Levels of diphtheria antitoxin ≥ 0.01 IU/mL were achieved in 100% of the sera tested.

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

Efficacy of tetanus toxoid used in INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) was determined on the basis of immunogenicity studies. An in vivo mouse neutralization assay confirmed the ability of infant sera (N = 45), obtained one month after a 3-dose primary series, to neutralize tetanus toxin. Levels of tetanus antitoxin ≥ 0.01 IU/mL were achieved in 100% of the sera tested.

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 (diphtheria and tetanus toxoids and acellular pertussis) 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 (diphtheria and tetanus toxoids and acellular pertussis) when administered at 2, 4, and 6 months of age.6 A total of 15,601 infants were immunized with 1 of 2 Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) vaccines, a US-licensed whole-cell Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (DTwP) vaccine, or with DT vaccine alone. The mean length of follow-up was 17 months (mean age 24 months), beginning 30 days after the third dose of vaccine. The population used in the primary analysis of the efficacy of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) included 4,481 infants vaccinated with INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) and 1,470 DT vaccinees. After 3 doses, the absolute protective efficacy of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) 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 respect to type and duration of cough, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) was calculated to be 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. Vaccine efficacy after 3 doses and with no booster dose in the second year of life was assessed in 2 subsequent follow-up periods. A follow-up period from 24 months to a mean age of 33 months was conducted in a partially unblinded cohort (children who received DT were offered pertussis vaccine and those who declined were retained in the study cohort). During this period, the efficacy of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) against WHO-defined pertussis was 78% (95% CI: 62% to 87%).8 During the third follow-up period which was conducted in an unblinded manner among children from 3 to 6 years of age, the efficacy of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) against WHO-defined pertussis was 86% (95% CI: 79% to 91%). Thus, protection against pertussis in children administered 3 doses of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) in infancy was sustained to 6 years of age.9

A prospective efficacy trial was also conducted in Germany employing a household contact study design.7 In preparation for this study, 3 doses of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) were administered at 3, 4, and 5 months of age to more than 22,000 children living in 6 areas of Germany in a safety and immunogenicity study. Infants who did not participate in the safety and immunogenicity study could have received a DTwP vaccine or DT vaccine. Index cases were identified by spontaneous presentation to a physician. Households with at least one other member (i.e., besides index case) aged 6 through 47 months were enrolled. Household contacts of index cases were monitored for incidence of pertussis by a physician who was blinded to the vaccination status of the household. Calculation of vaccine efficacy was based on attack rates of pertussis in household contacts classified by vaccination status. Of the 173 household contacts who had not received a pertussis vaccine, 96 developed WHO-defined pertussis, as compared to 7 of 112 contacts vaccinated with INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) . The protective efficacy of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) was calculated to be 89% (95% CI: 77% to 95%), with no indication of waning of protection up until the time of the booster vaccination. The average age of infants vaccinated with INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) at the end of follow-up in this trial was 13 months (range 6 to 25 months). 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 (diphtheria and tetanus toxoids and acellular pertussis) 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%). The corresponding efficacy rates of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) against ≥ 14 days of any cough or paroxysmal cough were 73% (95% CI: 59% to 82%) and 84% (95% CI: 71% to 91%), respectively.

Immune Response to INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) Administered as a 3-Dose Primary Series

The immune responses to each of the 3 pertussis antigens contained in INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) were evaluated in sera obtained 1 month after the third dose of vaccine in each of 3 studies (schedule of administration: 2, 4, and 6 months of age in the Italian efficacy study and one US study; 3, 4, and 5 months of age in the German efficacy study). One month after the third dose of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) , the response rates to each pertussis antigen were similar in all 3 studies. Thus, although a serologic correlate of protection for pertussis has not been established, the antibody responses to these 3 pertussis antigens (PT, FHA, and pertactin) in a US population were similar to those achieved in 2 populations in which efficacy of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) was demonstrated.

Immune Response to Concomitantly Administered Vaccines

In a clinical trial in the United States, INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) was given concomitantly, at separate sites, with hepatitis B vaccine, Haemophilus influenzae type b vaccine (Hib), and poliovirus vaccine live oral (OPV), at 2, 4, and 6 months of age. One month after the third dose of hepatitis B vaccine given simultaneously with INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) , 100% of infants demonstrated anti-HBs antibodies ≥ 10 mIU/mL (N = 64). Ninety percent of infants who received Hib simultaneously with INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) achieved anti-PRP antibodies ≥ 1 mcg/mL (N = 72), and 96% to 100% of infants who received OPV simultaneously with INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) showed protective neutralizing antibody to poliovirus Types 1, 2, and 3 (N = 60-61).10

In the Italian efficacy trial, 92% of infants received hepatitis B vaccine with the first and second dose of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) . Ninety-four percent of infants received OPV with the first and second dose of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) .6

No immunogenicity data are available for concurrent administration of INFANRIX (diphtheria and tetanus toxoids and acellular pertussis) with pneumococcal conjugate vaccine, inactivated poliovirus vaccine (IPV), measles, mumps, and rubella vaccine (MMR), or varicella vaccine.

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, Wassilak SGF, et al. Persistence of protection through 33 months of age provided by immunization in infancy with two three-component acellular pertussis vaccines. Vaccine 1998;13(13):1270-1275.

9. 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.

10. Blatter M, Reisinger K, Pichichero M, et al. Immunogenicity of diphtheria-tetanus-acellular pertussis (DT-tricomponent Pa), hepatitis B (HB) and Haemophilus influenzae type b (Hib) vaccines administered concomitantly at separate sites along with oral poliovirus vaccine (OPV) in infants. In: Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 15-18, 1996; New Orleans, LA. Abstract G102.

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

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