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Mechanism Of Action
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 is an acute toxin-mediated infectious 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 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 (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.
Diphtheria And Tetanus
Efficacy of diphtheria toxoid used in INFANRIX 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.
Efficacy of tetanus toxoid used in INFANRIX 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.
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 assessed the absolute protective efficacy of INFANRIX when administered at 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. The mean length of follow-up was 17 months, beginning 30 days after the third dose of vaccine. 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 respect to type and duration of cough, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX was calculated to be 71% (95% CI: 60, 78) against > 7 days of any cough and 73% (95% CI: 63, 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 against WHO-defined pertussis was 78% (95% CI: 62, 87). 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 against WHO-defined pertussis was 86% (95% CI: 79, 91). Thus, protection against pertussis in children administered 3 doses of INFANRIX in infancy was sustained to 6 years of age.
A prospective efficacy trial was also conducted in Germany employing a household contact study design. In preparation for this study, 3 doses of INFANRIX 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 with 7 of 112 contacts vaccinated with INFANRIX. The protective efficacy of INFANRIX was calculated to be 89% (95% CI: 77, 95), with no indication of waning of protection up until the time of the booster vaccination. The average age of infants vaccinated with INFANRIX at the end of follow-up in this trial was 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 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). The corresponding efficacy of INFANRIX against ≥ 14 days of any cough or paroxysmal cough were 73% (95% CI: 59, 82) and 84% (95% CI: 71, 91), respectively.
Pertussis Immune Response to INFANRIX Administered as a 3-Dose Primary Series
The immune responses to each of the 3 pertussis antigens contained in INFANRIX 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, 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 was demonstrated.
Immune Response To Concomitantly Administered Vaccines
In a US study, INFANRIX was given concomitantly, at separate sites, with Hib conjugate vaccine (Sanofi Pasteur SA) at 2, 4, and 6 months of age. Subjects also received ENGERIX-B and oral poliovirus vaccine (OPV). One month after the third dose of Hib conjugate vaccine, 90% of 72 infants had anti-PRP (polyribosyl-ribitol-phosphate) ≥ 1.0 mcg/mL.
In a US study, INFANRIX was given concomitantly, at separate sites, with ENGERIX-B, IPV (Sanofi Pasteur SA), pneumococcal 7-valent conjugate (PCV7), and Hib conjugate vaccines (Wyeth Pharmaceuticals Inc.) at 2, 4, and 6 months of age. Immune responses were measured in sera obtained approximately one month after the third dose of vaccines. Among 121 subjects who had not received a birth dose of hepatitis B vaccine, 99.2% had anti-HBsAg (hepatitis B surface antigen) ≥ 10 mIU/mL following the third dose of ENGERIX-B. Among 153 subjects, 100% had anti-poliovirus 1, 2, and 3, ≥ 1:8 following the third dose of IPV. Although serological correlates for protection have not been established for the pneumococcal serotypes, a threshold level of ≥ 0.3 mcg/mL was evaluated. Following the third dose of PCV7 vaccine, 91.8% to 99.4% of subjects (N = 146-156) had anti-pneumococcal polysaccharide ≥ 0.3 mcg/mL for serotypes 4, 9V, 14, 18C, 19F, and 23F, and 73.0% had a level ≥ 0.3 mcg/mL for serotype 6B.
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.
Last reviewed on RxList: 11/13/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Infanrix Information
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