February 21, 2017
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Corynebacterium diphtheriae may cause both localized and generalized disease. Systemic intoxication is caused by diphtheria exotoxin, an extracellular protein metabolite of toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin.

At one time, diphtheria was common in the United States. More than 200,000 cases, primarily among young children, were reported in 1921. Approximately 5% to 10% of cases were fatal; the highest case-fatality ratios were recorded for the very young and the elderly. 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 a notifiable disease. From 1980 to 1989, only 24 cases of respiratory diphtheria were reported; two cases were fatal, and 18 (75%) occurred among persons 20 years of age or older. 2

Diphtheria is currently a rare disease in the United States primarily because of the high level of appropriate vaccination among children (97% of children entering school have received ³ three doses of diphtheria and tetanus toxoids and pertussis vaccine adsorbed [DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) ]) and because of an apparent reduction in the prevalence of toxigenic strains of C. diphtheriae. Most cases occur among unvaccinated or inadequately immunized persons. 2

Both toxigenic and nontoxigenic strains of C. diphtheriaecan cause disease, but only strains that produce toxin cause myocarditis and neuritis. Toxigenic strains are more often associated with severe or fatal illness in noncutaneous (respiratory or other mucosal surface) infections and are more commonly recovered in association with respiratory than from cutaneous infections. 2

A complete vaccination series substantially reduces the risk of developing diphtheria, and vaccinated persons who develop disease have milder illness. Protection lasts at least 10 years. Vaccination does not, however, eliminate carriage of C. diphtheriae in the pharynx or nose or on the skin. 2


Tetanus is an intoxication manifested primarily by neuromuscular dysfunction caused by a potent exotoxin elaborated by Clostridium tetani.

The occurrence of tetanus in the United States has decreased dramatically from 560 reported cases in 1947 to a record low of 48 reported cases in 1987. Tetanus in the United States is primarily a disease of older adults. Of 99 tetanus patients with complete information reported to the Centers for Disease Control and Prevention (CDC) during 1987 and 1988, 68% were ³50 years of age, while only six were < 20 years of age. Overall, the case-fatality rate was 21%. In 1992, 45 cases were reported of which 82% were ³50 years of age. 3 The disease continues to occur almost exclusively among persons who are unvaccinated or inadequately vaccinated or whose vaccination histories are unknown or uncertain. 2

In 4% of tetanus cases reported during 1987 and 1988, no wound or other condition could be implicated. Non-acute skin lesions, such as ulcers, or medical conditions such as abscesses were reported in 14% of cases. 2

Spores of C. tetani are ubiquitous. Serologic tests indicate that naturally acquired immunity to tetanus toxin does not occur in the United States. 2 Thus, universal primary vaccination, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect persons among all age-groups. Tetanus toxoid is a highly effective antigen, and a completed primary series generally induces protective levels of neutralizing antibodies to tetanus toxin that persist for > 10 years. 2

The potency of diphtheria and tetanus toxoids was determined on the basis of immunogenicity studies with a comparison to a serological correlate of protection (0.01 I. U./mL) established by the Panel on Review of Bacterial Vaccines & Toxoids. 4


Circulating protective levels of neutralizing antibodies to diphtheria and tetanus toxins can be induced by the administration of Diphtheria and Tetanus Toxoids Adsorbed USP (For Pediatric Use) (DT) or D.P.

A clinical study was performed in 20 children under one year of age to determine the serological responses and the adverse reactions when Connaught Laboratories, Inc. (CLI) DT was administered as a primary series of three doses. Protective levels of diphtheria and tetanus antitoxins that were equal to or greater than 0.01 I. U./mL were detected in 100% of the children following two doses of the vaccine. However, maternal antibody may have contributed to the total neutralizing antibody in some of these infants. Protective levels of antitoxin were observed in 100% of these infants following three doses of DT. No local or systemic reactions were observed in approximately half of the infants and only mild or moderate reactions were observed in the remainder of the DT study group. 5

Another clinical study to evaluate serological responses and adverse reactions of CLI DT was performed in 40 children under one year of age. One group of 20 children received 0.5 mL doses of D.P. DT, DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) at two, four and six months of age, respectively. The second group of 20 children received 0.5 mL doses of D.P. DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) , and DT, respectively, at the same ages. The immunologic protection against diphtheria and tetanus as measured by toxin neutralizing antibodies induced by DT was comparable when administered as either a second or third dose. 6 The reaction rates following CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination closely correlated with the rates observed with other commercially available whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccines. 7 The incidence of adverse reactions was significantly lower following DT administration (p < 0.05). Although the number of vaccinees was small, no persistent screaming episodes or severe neurological reactions such as seizures or encephalopathy were observed with either vaccine in this study. 6


Disease caused by Bordetella pertussis was once a major cause of infant and childhood morbidity and mortality in the United States. Pertussis (whooping cough) became a nationally notifiable disease in 1922, and reports reached a peak of 265,269 cases and 7,518 deaths in 1934. The highest number of reported pertussis deaths (9,269) occurred in 1923. The introduction and widespread use of standardized whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids (DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) ) in the late 1940s resulted in a substantial decline in pertussis disease, a decline which continued without interruption for nearly 30 years. 2

By 1970, the annual reported incidence of pertussis had been reduced by 99%. During the 1970s the annual numbers of reported cases stabilized at an average of approximately 2,300 cases each year. During the 1980s, however, the annual numbers of reported cases gradually increased from 1,730 cases in 1980 to 4,517 cases in 1989. An average of eight pertussis-associated fatalities was reported each year throughout the 1980s. 2

From 1989 to 1991, 11,446 cases of pertussis were reported for an unadjusted incidence per 100,000 population of 1.7 in 1989, 1.8 in 1990 and 1.1 in 1991. The incidence for 1992 was 1.6 per 100,000. Age specific incidence and hospitalization rates were highest in the first year of life, decreasing with increasing age. Trends of the past years suggest an increase in reported pertussis since 1976, with the peak year being 1990. 8

During the period 1989 to 1991, of 3,900 reports of hospitalization, 1,115 had developed pneumonia, seizures occurred in 157 cases, encephalopathy was reported for 12, and there were 20 pertussis attributed deaths. These events were more frequently reported in children less than 6 months of age and were generally less frequent with increasing age. 7 Of patients 3 months through 4 years of age, where vaccination status was known, 65% of 4,471 patients had not received the recommended schedule of immunization and 39% had not received any pertussis containing vaccine. 3

Among older children and adults, including those previously vaccinated, B. pertussis infection may result in symptoms of bronchitis or upper-respiratory-tract infection. Pertussis may not be associated with classic signs, especially the inspiratory whoop. Older preschool children and school-age siblings who are not fully vaccinated and who develop pertussis can be important sources of infection for infants < 1 year of age. Adults also play an important role in the transmission of pertussis to unvaccinated or incompletely vaccinated infants and young children. 2


Although DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) has been evaluated as a control vaccine in a number of clinical trials of Acellular pertussis vaccines, no formal efficacy trial was performed prior to approval. Approval was based on historical and continuing evidence of protection (surveillance) in the population at risk. It was also shown that vaccines with acceptable mouse protection potencies induced protective serum agglutinin antibody titers. 4 The pertussis component of each lot of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) is tested for potency by a mouse protection test.

In clinical trials, one dose of CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine was used to reconstitute one lyophilized single dose vial of ActHIB ® or OmniHIB with no diminution in anti-PRP response or diphtheria, tetanus and pertussis responses.

Last reviewed on RxList: 12/6/2016
This monograph has been modified to include the generic and brand name in many instances.

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