Simultaneous immunization against diphtheria, tetanus and pertussis during infancy and childhood using a conventional whole-cell DTP vaccine has been a routine practice in the United States since the late 1940s. It has played a major role in markedly reducing the incidence of, and deaths from, each of these diseases.

Diphtheria

Diphtheria is primarily a localized and generalized intoxication caused by diphtheria toxin, an extracellular protein metabolite of toxigenic strains of Corynebacterium diphtheriae. While the incidence of diphtheria in the United States has decreased from over 200,000 cases reported in 1921,¹ before the general use of diphtheria toxoid, to only 30 cases of respiratory diphtheria reported from 1983 to 1993,² the ratio of fatalities to attack rate has remained constant at about 5% to 10%. The highest case fatality rates are in the very young and in the elderly. Diphtheria remains a serious disease in some areas of the world as evidenced by the recent outbreak in the former Soviet Union.³ Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. Following adequate immunization with diphtheria toxoid, it is thought that protection lasts for at least 10 years.¹ Serum antitoxin levels of at least 0.01 antitoxin units per mL are generally regarded as protective.⁴ This significantly reduces both the risk of developing diphtheria and the severity of clinical illness. Immunization with diphtheria toxoid does not, however, eliminate carriage of C. diphtheriae in the pharynx or nose or on the skin.¹ Efficacy of the diphtheria toxoid used in Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) was determined on the basis of immunogenicity studies, with a comparison to a serological correlate of protection (0.01 antitoxin units/mL) established by the Panel on Review of Bacterial Vaccines and Toxoids.⁴ A Vero cell toxin neutralizing test confirmed the ability of infant sera (N=45), obtained 1 month after the primary course, to neutralize diphtheria toxin. Protective titers (≥ 0.01 antitoxin units/mL of serum) were achieved in 100% of the sera tested.

Tetanus

Tetanus is an intoxication manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by Clostridium tetani. The incidence of tetanus in the United States has dropped dramatically with the routine use of tetanus toxoid to a record low of 45 cases in 1992.² Tetanus in the U.S. is primarily a disease of older adults. Of 99 tetanus patients with complete information reported to the Centers for Disease Control and Prevention during 1987 and 1988, 68% were ≥ 50 years of age, while only 6 were <20 years of age. No cases of neonatal tetanus were reported. Overall, the case-fatality rate was 21%. The disease continues to occur almost exclusively among persons who are unvaccinated or inadequately vaccinated or whose vaccination histories are unknown or uncertain.⁵ Spores of C. tetani are ubiquitous. Serological tests indicate that naturally acquired immunity to tetanus toxin does not occur in the U.S. Thus, universal primary immunization with tetanus toxoid, with subsequent maintenance of adequate antitoxin levels by means of timed boosters, is necessary to protect all age groups.¹ Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. Tetanus toxoid is a highly effective antigen and a completed primary series generally induces serum antitoxin levels of at least 0.01 antitoxin units per mL, a level which has been reported to be protective.⁴ It is thought that protection persists for at least 10 years.¹ Efficacy of the tetanus toxoid used in Infanrix was determined on the basis of immunogenicity studies with a comparison to a serological correlate of protection (0.01 antitoxin units per mL) established by the Panel on Review of Bacterial Vaccines and Toxoids.⁴ An in vivo mouse toxin neutralizing test confirmed the ability of infant sera (N=45), obtained 1 month after the primary course, to neutralize tetanus toxin. Protective titers (≥ 0.01 antitoxin units/mL of serum) were achieved in 100% of the sera tested.

Pertussis

Pertussis (whooping cough) is a disease of the respiratory tract caused by Bordetella pertussis. Pertussis is highly communicable (attack rates in unimmunized household contacts of up to 90% have been reported⁶) and can cause severe disease, particularly among the very young.¹ Since immunization against pertussis became widespread, the number of reported cases and associated mortality in the United States have declined from an average annual incidence and mortality of 150 cases and 6 deaths per 100,000 population, respectively, in the early 1940s, to annual reported incidences of 1.6, 2.6 and 1.8 cases per 100,000 population in 1992, 1993 and 1994, respectively.^2,7 Precise epidemiologic data do not exist, since bacteriological confirmation of pertussis can be obtained in less than half of the suspected cases. Most reported illness from B. pertussis occurs in infants and young children in whom complications can be severe. From 1980 to 1989, of 10,749 pertussis cases reported nationally in infants less than 1 year of age, 69% were hospitalized, 22% had pneumonia, 3.0% had seizures, 0.9% had encephalopathy and 0.6% died.⁸ Older children and adults, in whom classic signs are often absent, may go undiagnosed and may serve as reservoirs of disease.⁹ Routine vaccination with whole-cell DTP vaccine has significantly reduced pertussis-related morbidity and mortality. However, concerns regarding reactogenicity of whole-cell DTP vaccine have spurred development of safer pertussis vaccines with high efficacy. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood.

Antigenic components of B. pertussis believed to contribute to protective immunity include: pertussis toxin; filamentous hemagglutinin; and pertactin.^10,11 Although the role of these antigens in providing protective immunity in humans is not well understood, clinical trials which evaluated candidate acellular DTP vaccines manufactured by SmithKline Beecham Biologicals supported the efficacy of three-component Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed).^12-14 Infanrix, which contains three pertussis antigens (PT, FHA and pertactin), has been shown to be effective in preventing WHO-defined pertussis in two published clinical trials when administered as a primary series.^13,14 A double-blind, randomized, placebo-controlled (DT) 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.¹³ A total of 15,601 infants were immunized with one of two tri-component acellular DTP vaccines (containing inactivated PT, FHA and pertactin), or with a U.S.-licensed whole-cell DTP vaccine manufactured by Connaught Laboratories, Inc., or with DT vaccine alone. The mean length of follow-up was 17 months, beginning 30 days after the third dose of vaccine. The population used in the primary analysis of vaccine efficacy included 4,481 Infanrix vaccinees, 4,348 whole-cell DTP vaccinees and 1,470 DT vaccinees. After three doses, the 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%) while the efficacy of the whole-cell DTP vaccine was 36% (95% CI: 14% to 52%). 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% to 78%) against >7 days of any cough and 73% (95% CI: 63% to 80%) against ≥ 14 days of any cough. A longer follow-up of the Italian trial showed that after three doses, the absolute efficacy of Infanrix remained high against WHO-defined pertussis at 78% (95% CI: 62% to 87%) in children whose average age was then 33 months (20-39 months).¹⁵ A prospective, blinded efficacy trial was also conducted in Germany employing a household contact study design.¹⁴ In preparation for this study, three doses of Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) were administered at 3, 4 and 5 months of age to more than 22,000 children living in six areas of Germany in a large safety and immunogenicity trial. Infants who did not participate in this trial could have received whole-cell DTP vaccine (manufactured by Behringwerke A.G., Germany) or DT vaccine. Pediatricians were asked to monitor households with a first potential case (index case) of typical pertussis which was identified by spontaneous presentation to a physician. Households were enrolled in the study if there was at least one other household member (a household contact) 6 to 47 months of age. Prospective follow-up of household contacts of index cases for the incidence and progression of pertussis was performed by a separate 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 unvaccinated household contacts, 96 developed WHO-defined pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing), as compared to 7 of 112 contacts vaccinated with Infanrix and 1 of 75 contacts vaccinated with whole-cell DTP vaccine. The protective efficacy of Infanrix was calculated to be 89% (95% CI: 77% to 95%), with no indication of waning of protection up until the time of the booster. The protective efficacy of the whole-cell DTP vaccine was calculated to be 98% (95% CI: 83% to 100%). The average age of Infanrix vaccinees at the time of follow-up in this trial was 13 months (range 6-25 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% to 78%) and against ≥ 7 days of paroxysmal cough was 81% (95% CI: 68% to 89%). The corresponding efficacy rates of Infanrix 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 Administered as a Three-Dose Primary Series

The immune responses to each of the three pertussis antigens contained in Infanrix were evaluated in sera obtained 1 month after the third dose of vaccine in each of three studies (schedule of administration: 2, 4 and 6 months of age in the Italian efficacy study and one U.S. 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 three studies. Thus, although a serologic correlate of protection for pertussis has not been established, the antibody responses to these three pertussis antigens (PT, FHA and pertactin) in a U.S. population were similar to those achieved in two populations in which efficacy of Infanrix was demonstrated.

Immune Response to Simultaneously Administered Vaccines

In a small clinical trial in the United States, Infanrix was given simultaneously, 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, 100% of infants demonstrated anti-HBs antibodies ≥ 10 mIU/mL (N=64). Ninety percent of infants who received Hib simultaneously with Infanrix achieved anti-PRP antibodies ≥ 1 mcg/mL (N=72), and 96% to 100% of infants who received OPV simultaneously with Infanrix showed protective neutralizing antibody to poliovirus types 1, 2 and 3 (N=60-61).¹⁶ In the Italian efficacy trial, 92% of infants received hepatitis B vaccine with the first and second dose of Infanrix. Ninety-four percent of infants received OPV with the first and second dose of Infanrix.¹³

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