Diphtheria and Tetanus Toxoids and
Acellular Pertussis Vaccine Adsorbed (Certiva™)

DESCRIPTION
Certiva™ (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) is a sterile combination of diphtheria, tetanus, and pertussis toxoids (one pertussis antigen, inactivated pertussis toxin), adsorbed onto aluminum hydroxide.¹ It is intended for intramuscular injection only. After shaking, Certiva™ is a homogeneous white suspension.

The pertussis toxin (PT) is isolated from Phase 1 Bordetella pertussis grown in modified Stainer-Scholte medium. After purification by affinity chromatography, which includes the use of fetuin, a bovine serum protein, as an affinity ligand, PT is detoxified using hydrogen peroxide.

Diphtheria toxin is derived from Corynebacterium diphtheriae grown in Stainer's Diphtheria Culture Medium, containing casein hydrolysate, and is purified by fractional precipitation with ammonium sulfate. Tetanus toxin is derived from Clostridium tetani grown in modified Mueller and Miller Medium, containing casein hydrolysate, and is purified by precipitation with ammonium sulfate.2 The purified diphtheria and tetanus toxins are detoxified using formaldehyde.

Each antigen is individually adsorbed onto aluminum hydroxide.² Each 0.5 ml dose of vaccine is formulated to contain 15 Lf diphtheria toxoid, 6 Lf tetanus toxoid, 40 mcg pertussis toxoid, 0.5 mg aluminum as aluminum hydroxide, and is preserved with 0.01% thimerosal (mercury derivative). The product may contain residual fetuin. The residual free formaldehyde content by assay is less than or equal to 10 ppm. The diphtheria and tetanus toxoids each induce not less than 2 units of antitoxin per ml in the guinea pig potency test. The potency of the pertussis toxoid is evaluated by measurement of antibody titers to pertussis toxin in immunized mice using an ELISA. Diphtheria and tetanus toxoid bulks for further manufacturing use are produced by Statens Seruminstitut, Copenhagen, Denmark. The pertussis toxoid is manufactured by North American Vaccine, Inc., Beltsville, Maryland. Final formulation and release of Certiva™ are conducted by North American Vaccine, Inc.

CLINICAL PHARMACOLOGY
Immunization against diphtheria, tetanus and pertussis, using a conventional whole-cell pertussis DTP vaccine (Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed) has been routine practice during infancy and childhood in the United States since the late 1940s. Widespread immunization in the United States has played a major role in dramatically reducing the incidence of cases and deaths from each of these diseases.³

Diphtheria
Diphtheria is a disease resulting from infection of the respiratory tract or skin with Corynebacterium diphtheriae. The disease can be localized to the site of infection or can be associated with systemic toxicity, which may include myocarditis and neuritis and is caused by diphtheria exotoxin, an extracellular protein metabolite of toxigenic strains of C. diphtheriae. Humans are the only known reservoir for C. diphtheriae. More than 200,000 cases of diphtheria, primarily among children, were reported in the United States in 1921, before the general use of diphtheria toxoid vaccine.³ Approximately 5-10% of cases were fatal; the highest case-fatality rates were in the very young and the elderly. Immunization programs with diphtheria toxoid introduced in the 1940's had a significant impact on the epidemi-ology of the disease. Only 24 cases of respiratory diphtheria were reported in the United States from 1980 to 1989, and 15 cases from 1990 to 1994; however, the case-fatality rate has remained constant at about 5-10%.^3,4 Although diphtheria is currently a rare disease in the United States, the disease has remained endemic in many developing countries and recent outbreaks have occurred in areas of the former Soviet Union.⁵

A complete vaccination series with diphtheria toxoid substantially reduces the risk and severity of disease, and protection is thought to last for at least 10 years.³ Serum antitoxin concentrations of at least 0.01 antitoxin units per ml are generally regarded as protective.^6,7 Vaccination does not eliminate carriage of C. diphtheriae from the pharynx, nose, or skin.³ Efficacy of the diphtheria toxoid used in Certiva™ 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.⁷ In a clinical study with Certiva™, 99.7% of 299 U.S. infants had protective titers to diphtheria toxin (>0.01 antitoxin units per ml) in sera obtained one month after the third dose; vaccination at 2, 4, and 6 months of age.

Tetanus
Tetanus is a disease characterized by neuromuscular dysfunction resulting from the effects of a potent exotoxin elaborated by Clostridium tetani, a microorganism which is commonly found in the outdoor environment (usually soil). Persons with the disease exhibit muscular rigidity and spasms that can either be localized or generalized, depending on host factors and the site of inoculation. With the routine use of tetanus toxoid, the occurrence of tetanus in the United States has decreased markedly, from 560 reported cases in 1947 to an average of 57 cases reported annually from 1985-1994. ^3,4 Tetanus in the United States is primarily a disease of older adults. Of 99 cases with complete information reported to the Centers for Disease Control and Prevention during 1987-1988, 68% were >50 years of age, only 6 were less than 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.⁸

Spores of C. tetani are ubiquitous. Serologic tests indicate that naturally acquired immunity to tetanus toxin does not occur in the United States. Thus, universal primary immunization with subsequent maintenance of adequate antitoxin levels by means of timed boosters is needed to protect all age groups.³ Tetanus toxoid is a highly effective antigen, and a completed primary series generally induces protective levels of at least 0.01 antitoxin units per ml, a level which has been reported to be protective.⁷ It is thought that protection persists for at least 10 years.^3,9 Efficacy of the tetanus toxoid in Certiva™ 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.⁷ In a clinical study with Certiva™, 100% of 299 U.S. infants had a protective level of tetanus toxoid (>0.01 antitoxin units per ml) in sera obtained one month after the third dose; vaccination at 2, 4, and 6 months of age.

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 reported) and can cause severe disease, particularly among the very young.³ 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, respectively, in the early 1940's, to annual reported incidences of 1.6, 2.6, and 1.8 cases per 100,000 population in 1992, 1993, and 1994, respectively, and estimated annual incidences of 2.0 and 2.4 cases per 100,000 population for 1995 and 1996, respectively.^10,11 Precise epidemiologic data do not exist because 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% had seizures, 0.9% had encephalopathy, and 0.6% died.¹² Older children and adults, in whom classic signs are often absent, may go undiagnosed and may serve as reservoirs of disease.¹³

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. The role of different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. Certiva™-EU, which contains one pertussis antigen, pertussis toxoid, has been shown to be effective in preventing World Health Organization (WHO)-defined pertussis after three doses of vaccine administered at 3, 5, and 12 months of age.

Efficacy
Between 1991-1994, a double-blind, randomized, placebo-controlled efficacy trial of Certiva™-EU was conducted in Göteborg, Sweden, where pertussis is endemic and pertussis immunization had been stopped in 1979. Certiva™-EU contains the same amount of pertussis toxoid (40 mcg) per dose as Certiva™, but contains more diphtheria toxoid (25 Lf vs. 15 Lf) and more tetanus toxoid (7 Lf vs. 6 Lf) per dose than Certiva™. A total of 3,450 healthy infants from 96 Child Health Centers were randomized to receive Certiva™-EU (n=1,724) or Statens Seruminstitut Diphtheria and Tetanus Toxoids Adsorbed Vaccine (DT) (n=1,726) at 3, 5, and 12 months of age.^14,15 Cases of pertussis were identified by obtaining nasopharyngeal cultures for B. pertussis and acute and convalescent serum samples in all subjects and family members with coughing episodes lasting > 7 days. Duration of cough and severity of symptoms were determined by telephone interview and/or office visit at approximately 4 weeks and again at 60 days after report of cough lasting > 7 days.

The main observation period started 30 days after the third dose of vaccine and lasted a mean of 17 months. During this period, WHO-defined pertussis (paroxysmal cough for > 21 days with one or more of the following: positive culture, positive culture in a family member, or a significant rise in serum PT-IgG or FHA-IgG) was identified in 72 (4.3%) of 1,682 Certiva™-EU recipients and 240 (14.3%) of 1,676 DT recipients.^14,15,16 Case rates per 100 person-years of follow-up were 2.89 in the Certiva™-EU group and 10.17 in the DT group. Starting one month after the third dose, the protective efficacy of Certiva™-EU against WHO-defined pertussis was 72% (95% CI: 62% to 78%). Protective efficacy against WHO-defined pertussis for the period starting 30 days after the second dose of vaccine up until administration of the third dose was 60% (95% CI: 13% to 83%) (10 cases in 1,708 Certiva™-EU recipients, 25 cases in 1,717 DT recipients).¹⁵

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 Certiva™-EU during the main observation period was 63% (95% CI: 52% to 71%) against > 21 days of any cough and 54% (95% CI: 43% to 64%) against > 7 days of any cough.¹⁴ After the main observation period, follow-up was continued for an additional 6 month period during which the study was unblinded. During this period the efficacy of Certiva™-EU remained high against WHO-defined pertussis at 77% (95% CI: 65% to 85%) in children whose median age was then 36.5 months.^15,17

Protective efficacy was also estimated in vaccine recipients who had household exposure to WHO-defined pertussis during the main observation period. Nineteen (19) of 88 Certiva™-EU recipients and 50 of 63 DT recipients were identified with a secondary case of pertussis (defined as paroxysmal cough for > 21 days with infection confirmed by culture and/or serologic testing and with an onset between 6-60 days after onset in the primary case). The protective efficacy of Certiva™-EU in preventing WHO-defined pertussis after household exposure was 73% (95% CI: 57% to 86%) based on comparing the proportion of exposed subjects who were identified with pertussis in each vaccine group.^15,18

Effectiveness
An epidemiologic, open-label, Mass Vaccination Project was initiated in June 1995 in the Göteborg region of Sweden to study the safety and effectiveness of Certiva™-EU and pertussis toxoid vaccines in infants and children. Effectiveness was determined by regional surveillance of pertussis cultures. Nasopharyngeal cultures were obtained from coughing individuals of all ages with suspected pertussis at the discretion of their treating physician. Cultures were analyzed by the single regional reference laboratory (Department of Clinical Bacteriology, Sahlgrenska Hospital, Göteborg, Sweden) as part of an established surveillance system from which pertussis culture data have been generated and reported since 1976. Table 1 depicts the monthly positive pertussis cultures collected from July 1989 through December 1997 (two and one half years into the project). Between 1989 and 1994 (the period before initiation of the Mass Vaccination Project), the yearly number of positive pertussis cultures varied, ranging from 575 out of 2,934 total cultures to 1,081 out of 4,272 total cultures. By the second year of the Mass Vaccination Project (July 1996 - June 1997), a total of 108 out of 784 cultures were positive for pertussis, the majority from children not participating in the Project with the remainder from children having received at least 1 dose of vaccine. During the next 6 months (July 1997 - December 1997), 30 cultures out of a total of 299 were pertussis positive, the majority from children not participating in the Project.

 

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