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Certiva

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Certiva

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 diphtheriue. 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. diphtheriue. 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 1940s had a significant impact on the epidemiology 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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM was determined on the basis of immunogenicity studies, with a comparison to a serological correlate of protection (³ 0.01 antitoxin units per ml) established by the Panel on Review of Bacterial Vaccines and Toxoids.7In a clinical study with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, 99.7% of 299 U. S. infants had protective titers to diphtheria toxin (³ 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 Chlostridium 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 ³50 years of age, 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.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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM was determined on the basis of immunogenicity studies with a comparison to a serological correlate of protection (³ 0.01 antitoxin units per ml) established by the Panel on Review of Bacterial Vaccines and Toxoids.7 In a clinical study with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, 100% of 299 U. S. infants had a protective level of tetanus toxoid (³0.01 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 Boraktella 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 1940s, 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.l3

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 diierent components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- 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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU was conducted in Göteborg, Sweden, where pertussis is endemic and pertussis immunization had been stopped in 1979. Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU contains the same amount of pertussis toxoid (40 mcg) per dose as Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, but contains more diphtheria toxoid (25 Lf vs. 15 Lf) and more tetanus toxoid (7 Lf vs. 6 Lf) per dose than Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM. A total of 3,450 healthy infants from 96 Child Health Centers were randomized to receive Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- 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 ³7 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 ³7 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 ³21 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 PHA-IgG) was identified in 72 (4.3%) of 1,682 Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- 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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM- EU group and 10.17 in the DT group. Starting one month after the third dose, the protective efficacy of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - 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 Cettiva TM - EU recipients, 25 cases in 1,717 DT recipients).l5

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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU during the main observation period was 63% (95% CI: 52% to 71%) against ³21 days of any cough and 54% (95% CI: 43% to 64%) against ³7 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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - 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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU recipients and 50 of 63 DT recipients were identified with a secondary case of pertussis (defined as paroxysmal cough for ³21 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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) m-EU in preventing WHO-defined pextussis after household exposure was 73% (95% CI: 57% to 86%) based on comparing the proportion of exposed subjects who were identified with pettussis 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 (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - 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 proof 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.

TABLE 1.

POSITIVE PERTUSSIS CULTURES IN THE WEBORG REGION OF SWEDEN (1989-1997)

 

Before Pertussis Immunization*

Period of Mass Immunization with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM-EU and Pertussis Toxoid

Year

1989- 1990

1990- 1991

1991- 1992

1992- 1993

1993- 1994

1994- 1995

1995- 1996

1996- 1997

1997-

Month                  
July

61

78

55

52

90

67

104

14

3

August

44

92

55

72

100

96

100

37

6

September

54

70

56

73

86

70

75

18

11

October

84

130

60

82

99

78

93

8

7

November

97

105

61

66

126

96

100

8

3

December

76

62

35

66

88

118

53

8

0

January

76

121

58

78

138

113

48

9

 
February

59

102

40

72

86

55

30

1

 
March

60

81

37

81

75

50

28

2

 
April

51

73

18

92

50

85

15

1

 
May

73

64

41

69

88

69

22

1

 
June

47

46

59

92

55

63

8

1

 
Total Positive

782

1024

575

895

1081

960

676

108

30

Total Cultures

3150

3801

2934

3608

4272

4105

2809

784

299


*National recommendation for routine pediatric pertussis vaccination reinstituted January 1996

Immune Response to Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM: In a study of Swedish infants comparing Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM to Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU, serum antibody levels to PT after three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM administered at 2, 4, and 6 months of age (n=116) were significantly higher than those after two doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU administered at 3 and 5 months of age (n=103), but were significantly lower than those observed after three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU administered at 3, 5, and 12 months of age (n=101).15 The antibody response to PT after a fourth dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - administered at 15 months of age (n=114) was similar to that after the third dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM -EU at 12 months of age (n=101). 15 In a study of U. S. infants, serum antibody titers to PT following four doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - administered at 2, 4, 6, and 15-21 months of age (n=89) were similar to those achieved following three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU administered at 3, 5, and 12 months of age [subset of Swedish children from the efficacy trial (n=232)].15 While a serologic correlate of protection for pertussis has not been established, the antibody response to PT in U.S. infants after doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM at 2, 4, 6, and 15-21 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after three doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - EU at 3,5, and 12 months of age.

Immune Response To Simultaneously Administered Vaccines: In a clinical study conducted in the United States, infants received Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM - at 2, 4, and 6 months of age, and at each time point, the majority were simultaneously immunized with Haemophilus infruenzue type b conjugate vaccine (HibTITER, 96-99%), polio vaccine live oral (OPV) (83-97%), and hepatitis B vaccine (18-80%). Immune responses to these simultaneously administered vaccines were evaluated in a subset. After a third dose of OPV, 95-96% of infants had protective neutralizing antibody to poliovirus types 1 and 3 (n=219).l5

After the third dose of HibTITER, 61% of infants achieved anti-PRP antibody levels ³1 mcg/ml (n=249), compared to 73% of infants (n=77) who received HibTITER simultaneously with whole-cell DTP in the same study; these rates (61% vs. 73%) are not significantly different (p=0.078), but the study design lacked statistical power (80%) to rule out a difference of 15% (a=5%). After two doses of hepatitis B vaccine administered concurrently with Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM, 99% had anti-HBsAg titers ³10 MIU/ml (n=101) 15; the total number of hepatitis B vaccine doses received by these infants is unknown because the number of doses received prior to entry into the study at 2 months of age was not recorded.

One-hundred thirty-three (133) infants who received 3 doses of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM in the above study received a fourth dose of Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM at 15-21 months of age and were simultaneously immunized with measles, mumps, and rubella (MMR) vaccine and HibTITER. Anti-PRP antibody levels ³1.0 mcg/ml were achieved in 100% of subjects (n=84); antibodies to measles, mumps, and rubella were detected in 91-95% of subjects (n=55). 15

In another study of 221 children who received Certiva (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) TM at 4 to 6 years of age, 89% and 16% simultaneously received polio, and measles, mumps, and rubella vaccination, respectively. Antibodies to measles, mumps and rubella were detected in 100% of tested subjects (n=32) and neutralization titers to polio types 1, 2, and 3 were achieved in 99% of tested subjects (n=105; 102 with OPV and 3 with inactivated polio vaccine). 15

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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