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Daptacel (Diphtheria Toxoid / Tetanus Toxoid / Acellular Pertussis Vaccine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

DAPTACEL® , Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, for intramuscular use, manufactured by Aventis Pasteur Limited, is a sterile suspension of pertussis antigens and diphtheria and tetanus toxoids adsorbed on aluminum phosphate in a sterile isotonic sodium chloride solution. After shaking, the vaccine is a white homogeneous cloudy suspension. Each dose of DAPTACEL® contains the following active ingredients:

   pertussis toxoid                                                10 µg

   filamentous hemagglutinin (FHA)                        5 µg

   pertactin (PRN)                                                 3 µg

   fimbriae types 2 and 3                                        5 µg

   diphtheria toxoid                                              15 Lf

   tetanus toxoid                                                    5 Lf

Other ingredients per dose include 3.3 mg (0.6% v/v) 2-phenoxyethanol as the preservative, 0.33 mg of aluminum as the adjuvant, </=0.1 mg residual formaldehyde and <50 ng residual glutaraldehyde.

The acellular pertussis vaccine components are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium1 modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. The fimbriae types 2 and 3 are extracted from the bacterial cells and the pertussis toxin, FHA and PRN are prepared from the supernatant. These proteins are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. Pertussis toxin is inactivated with glutaraldehyde and FHA is treated with formaldehyde. The individual antigens are adsorbed separately onto aluminum phosphate.

Corynebacterium diphtheriae is grown in modified Mueller's growth medium.2 After ammonium sulfate fractionation, the diphtheria toxin is detoxified with formalin and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion.3 Tetanus toxin is detoxified with formalin and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

The adsorbed diphtheria, tetanus and acellular pertussis components are combined in a sterile isotonic sodium chloride solution containing 2-phenoxyethanol as preservative.

Both diphtheria and tetanus toxoids induce at least 2 units of antitoxin per mL in the guinea pig potency test. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized mice to pertussis toxin, FHA, PRN and fimbriae types 2 and 3 measured by enzyme-linked immunosorbent assay (ELISA).

CLINICAL PHARMACOLOGY

Simultaneous immunization of infants and children against diphtheria, tetanus and pertussis with conventional whole-cell pertussis DTP vaccine (Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed - For Pediatric Use) has been a routine practice in the US since the late 1940s. This has played a major role in markedly reducing disease and deaths from these infections. 4 DTaP (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) vaccines were first available for use in infants in the US in 1996 and have been routinely recommended for all doses of the vaccination series for infants and children <7 years of age since 1997. 5

DIPHTHERIA

Corynebacterium diphtheriae may cause both localized and generalized disease. The systemic intoxication is caused by diphtheria exotoxin, an extracellular protein of toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibody to diphtheria toxin.

Both toxigenic and nontoxigenic strains of C. diphtheriae can cause disease but only strains that produce diphtheria toxin cause severe manifestations such as myocarditis and neuritis. Diphtheria is a serious disease, with the highest case-fatality rates among infants and the elderly. 4,6

Prior to the widespread use of diphtheria toxoid in the late 1940s, diphtheria disease was common in the US. More than 200,000 cases, primarily among children, were reported in 1921. Approximately 5%-10% of cases were fatal; the highest case-fatality rates were in the very young and the elderly. More recently, reported cases of diphtheria of all types declined from 306 in 1975 to 59 in 1979; most were cutaneous diphtheria reported from a single state. After 1979, cutaneous diphtheria was no longer reportable. 4 From 1980 through 2000, only 50 cases of diphtheria were reported in the US. During the period 1980-1996, six fatal cases of diphtheria were reported. Only 1 case of diphtheria was reported each year in 1998-2000 with no fatalities. 7 Of 40 reported cases with known age in 1982-1998, 63% were in persons >/=20 years of age. Most cases have occurred in unimmunized or inadequately immunized persons. Although diphtheria disease is rare in the US, it appears that C. diphtheriae continues to circulate in areas of the country with previously endemic diphtheria.8

Diphtheria continues to occur in other parts of the world. A major epidemic of diphtheria occurred in the newly Independent States of the former Soviet Union beginning in 1990. This epidemic resulted in approximately 150,000 cases and 5,000 deaths during the years 1990-1997. 9 This outbreak is believed to be due to several factors, including a lack of routine immunization of adults in these countries. 10

Complete immunization significantly reduces the risk of developing diphtheria and immunized persons who develop disease have milder illness. Following adequate immunization with diphtheria toxoid, protection is thought to last for at least 10 years. Immunization does not, however, eliminate carriage of C. diphtheriae in the pharynx, nose or on the skin.4

TETANUS

Tetanus manifests systemic toxicity primarily by neuromuscular dysfunction caused by a potent exotoxin elaborated by Clostridium tetani.

Spores of C. tetani are ubiquitous. Serological tests indicate that naturally acquired immunity to tetanus toxin does not occur in the US. Thus, universal primary immunization, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect all age groups. Tetanus toxoid is a highly effective antigen and a completed primary series generally induces protective levels of serum antitoxin that persist for 10 years or more. 4

Following routine use of tetanus toxoid in the US, the occurrence of tetanus disease decreased dramatically from 560 reported cases in 1947 to an average of 50-100 cases reported annually from the mid 1970s through the late 1990s to 35 cases in 2000. 7 The case-fatality rate has been relatively constant at approximately 30%. During the years 1982-1998, 52% of reported cases were among persons 60 years of age or older. In the mid to late 1990s, the age distribution of reported cases shifted to a younger age group, in part due to an increased number of cases among injection drug users in California. From 1995-1997, persons 20-59 years of age accounted for 60% of all cases, with persons 60 years of age or older accounting for only 35%. In the US, tetanus occurs almost exclusively among unvaccinated or inadequately vaccinated persons. 8

PERTUSSIS

Pertussis (whooping cough) is a disease of the respiratory tract caused by Bordetella pertussis. This gram-negative coccobacillus produces a variety of biologically active components. The role of the different components produced by B. pertussis in either the pathogenesis of, or immunity to, pertussis is not well understood. 6

Pertussis is highly communicable (attack rates of 90% have been reported for susceptible individuals exposed to a case in the home) 11 and can cause severe disease, particularly among young infants. Since pertussis became a nationally reportable disease in the US in 1922, the highest number of pertussis cases (approximately 260,000) was reported in 1934. Following the introduction and widespread use of whole-cell pertussis DTP vaccine among infants and children in the mid to late 1940s, pertussis incidence gradually declined, reaching a historical low of 1,010 cases reported in 1976. 12

During the 1980s and 1990s, the number of reported pertussis cases in the US has gradually increased, particularly among adolescents and adults. 12,13 Improvements in the diagnosis and reporting of pertussis in older age groups is thought to have contributed, at least in part, to the increase in reported cases. The number of cases of pertussis reported among children aged 6 months to 4 years has remained stable throughout the 1990s, suggesting that protection offered by vaccination has continued with the introduction of DTaP vaccines. 12

During 1997-2000, a total of 29,134 cases were reported, for an estimated average annual incidence rate of 2.7 per 100,000 population.12 Among 29,048 cases for whom age was known, 29% were aged < 1 year, 12% were aged 1-4 years, 10% were aged 5-9 years, 29% were aged 10-19 years and 20% were >/=20 years of age. 12 Average annual incidence rates during 1997-2000 were highest among infants aged <1 year (55.5 cases per 100,000 population) and lower in children aged 1-4 years (5.5), children aged 5-9 years (3.6), persons aged 10-19 years (5.5) and persons aged >/=20 years (0.8). 12

The severity of pertussis remains highest in infants. Of 7,203 infants <6 months of age reported as having pertussis during the period 1997-2000, 63% were hospitalized, 12% had pneumonia, 1.4% had one or more seizures, 0.2% had encephalopathy and 0.8% died. 12

Atypical infection, including nonspecific symptoms of bronchitis or upper respiratory tract infection, may occur at any age but more commonly in older children and adults, including some who were previously immunized. In these cases, pertussis may not be diagnosed because classic signs, particularly the inspiratory whoop, may be absent. Older preschool-aged and school-aged children, as well as adolescents and adults who develop pertussis, may play a role in transmission to young infants. 8

Concerns about the safety of whole-cell pertussis DTP vaccines prompted the development of less reactogenic DTaP vaccines that contain purified antigens of B. pertussis. The pertussis component of DTaP vaccines contains inactivated pertussis toxin and may contain one or more of FHA, PRN and fimbriae types 2 and 3. DTaP vaccines were first available for use in infants in the US in 1996 and have been routinely recommended by the Advisory Committee on Immunization Practices (ACIP) for all doses of the vaccination series for infants and children <7 years of age since 1997. 5

Since 1991, 7 studies conducted in Europe and Africa have evaluated the efficacy of 8 DTaP vaccines administered to infants. The vaccines, produced by different manufacturers, contained a varying number and quantity of antigens. The derivation and formulation of the individual antigens also varied among different vaccines. The studies differed in study design and 3, including the Sweden I Efficacy Trial (1992-1995), were randomized placebo-controlled clinical trials. Because of these and other differences, comparisons among studies should be made with caution. Within individual studies, however, the efficacy of acellular pertussis vaccines can be compared directly with that of a placebo control or whole-cell pertussis DTP. The efficacy of 3 doses of acellular pertussis vaccines in preventing moderate to severe pertussis disease was within the range expected for most whole-cell pertussis DTP vaccines. Point estimates of the efficacy of DTaP vaccines ranged from 59%-89%. 5

The effectiveness of pertussis vaccine among US children aged 7-18 months in 1998 and 1999 was calculated using the screening method. During this time, the National Immunization Survey reported 66% of children aged </=18 months received DTaP rather than whole-cell pertussis DTP. 12 The screening estimate of 88% reflects the effectiveness of the overall vaccination program that used approximately two thirds DTaP and one third whole-cell pertussis DTP in children aged 7-18 months. This estimate is similar to that observed in clinical trials for acellular pertussis vaccines. During 1997-2000, the incidence rates were highest among infants aged <1 year, lower in children aged 1-4 years and remained stable among children aged 5-9 years. 12

EFFICACY OF DAPTACEL®

PERTUSSIS

A randomized, double-blinded, placebo-controlled efficacy and safety study was conducted in Sweden from 1992-1995 (Sweden I Efficacy Trial) under the sponsorship of the National Institute of Allergy and Infectious Diseases (NIAID). A total of 9,829 infants received 1 of 4 vaccines: DAPTACEL® (n = 2,587); another investigational acellular pertussis vaccine (n = 2,566); whole-cell pertussis DTP vaccine (n = 2,102); or DT vaccine as placebo (Swedish National Bacteriological Laboratory, n = 2,574). Infants were immunized at 2, 4 and 6 months of age. The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of DAPTACEL® against pertussis after 3 doses of vaccine using the World Health Organization (WHO) case definition (>/=21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 84.9% (95% confidence interval [CI] 80.1 to 88.6). 14 The protective efficacy of DAPTACEL® against mild pertussis (>/=1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6 to 82.2). 15 Protection against pertussis by DAPTACEL® was sustained for the 2-year follow-up period.14,15

In order to assess the antibody response to the pertussis antigens of DAPTACEL® in the US population, 2 lots of DAPTACEL® , including the lot used in the Sweden I Efficacy Trial, were administered to US infants in the US Bridging Study.15 In this study, antibody responses following 3 doses of DAPTACEL® given to US children at 2, 4 and 6 months of age were compared to those from a subset of the infants enrolled in the Sweden I Efficacy Trial. Assays were performed in parallel on the available sera from the US and Swedish infants. Antibody responses to all the antigens were similar except for those to the PRN component. For both lots of DAPTACEL® , the geometric mean concentration (GMC) and percent response to PRN in US infants (Lot 006, n = 107; Lot 009, n = 108) were significantly lower after 3 doses of vaccine than in Swedish infants (n = 83). In a separate study performed in Canada (Phase II), in which children received 4 doses of DAPTACEL® at 2, 4, 6 and 17-18 months of age, antibody responses following the fourth dose (n = 275) were equivalent or higher than those seen in the Swedish infants after 3 doses. While a serologic correlate of protection for pertussis has not been established, the antibody response to all antigens in North American infants after 4 doses of DAPTACEL® at 2, 4, 6 and 17-20 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after 3 doses of DTaP at 2, 4 and 6 months of age. 15

DIPHTHERIA AND TETANUS

In a Canadian clinical study, 324 children were enrolled to receive DAPTACEL® at 2, 4, 6 and 17-18 months of age. The proportion of children with post-dose 3 diphtheria (n = 313) and tetanus (n = 313) antitoxin levels >/=0.01 IU/mL was 100% and >/=0.10 IU/mL was 85% and 100%, respectively. 15 The proportion with post-dose 4 diphtheria (n = 296) and tetanus (n = 296) antitoxin levels >/=0.10 IU/mL was 100%. 15 The efficacy of the diphtheria and tetanus toxoids used in DAPTACEL® 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. 16

In the US Bridging Study, for which data are only available following 3 doses, 99.2% (n = 261) achieved diphtheria antitoxin levels of >/=0.01 IU/mL, 80.6% (n = 261) achieved levels of >/=0.10 IU/mL and 100% (n = 260) achieved tetanus antitoxin levels of 0.01 IU/mL and 0.10 IU/mL. 15

CONCURRENTLY ADMINISTERED VACCINES

In a clinical trial conducted in the US, DAPTACEL® was given simultaneously with Haemophilus influenzae type b vaccine and with live oral poliovirus vaccine (OPV) at 2, 4 and 6 months of age according to local practices. Two hundred eighty-one infants received 3 doses of Haemophilus influenzae type b vaccine and 305 received 3 doses of OPV. Immune responses to these vaccines were evaluated in a subset of 258 children. One month after the third dose, 96.9% (n = 253) achieved anti-PRP antibody levels of at least 0.15 µg/mL, 82.7% (n = 216) achieved antibody levels of at least 1.0 µg/mL; and 100% (n = 178), had protective neutralizing antibody of >/=1:8 for poliovirus types 1 and 2 and 98.3% (n = 175) for poliovirus type 3.15

In the same study, hepatitis B vaccine (supplied by different manufacturers) was also given to children by different schedules. Hepatitis B vaccine was given concurrently with DAPTACEL® at 2 and 6 months of age to a subset of infants who received a birth dose of hepatitis B vaccine. Of infants with adequate serum available for serology testing (n = 82), 97% achieved anti-HBs antibody levels >/=10 mIU/mL post dose 3.15

No immunogenicity data are available for concurrent administration of DAPTACEL® with IPV; pneumococcal conjugate vaccine; measles, mumps and rubella vaccine (MMR) or varicella vaccine.

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