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Institute of medicine (US) Vaccine security Committee; Stratton KR, Howe CJ, Johnston RB Jr., editors. Adverse Events associated with Childhood Vaccines: proof Bearing top top Causality. Washington (DC): national Academies press (US); 1994.


Institute of medicine (US) Vaccine safety Committee; Stratton KR, Howe CJ, Johnston RB Jr., editors.


The causative certified dealer of tetanus, Clostridium tetani, is a gram-positive, spore-forming anaerobic bacillus. C. Tetani produces 2 exotoxins, tetanolysin and also tetanospasmin. Tetanus results from the last toxin, one of the many potent toxin on a weight basis (Wassilak and Orenstein, 1988). Tetanus toxin beginning the nervous device at peripheral nerve endings. The toxin binding to a receptor, is internalized through endocytosis, and also is transported come nerve cell bodies, primarily motoneurons, in the central nervous device (Fishman and Carrigan, 1988). Tetanus toxin appears to job-related presynaptically to affect neurotransmitter release (Bergey et al., 1987). The mode of action of tetanus toxin is comparable to that of one more well-known toxin, botulinum toxin, which is additionally produced by an anaerobic organism (Simpson, 1986). The instrument of activity of these toxins have actually not been fully elucidated.

Early studies in experimental pets demonstrated that protective neutralizing antibodies might be elicited by recurring inoculations with a minute quantity of toxin (Wassilak and also Orenstein, 1988). This antisera also could administer passive protection as soon as administered to nonimmune recipients. In 1926, Ramon and Zoeller immunized human being subjects with a toxoid ready by formaldehyde and heat treatment of the toxin. Return the protective level the antibody could not it is in assessed straight in person subjects (by difficulty with active toxin), two early workers in this ar immunized themselves v the tetanus toxoid and then tested themselves v two to three fatal sheep of tetanus toxin. They were safeguarded by their prechallenge serum levels of 0.007 and 0.01 American units of tetanus toxoid every ml (Wolters and also Dehmel, 1942). In 1950, the civilization Health company (WHO) reset the global unit (IU) to same the American unit (see the section Biologic events Following Immunization below).

Two species of tetanus toxoid are available in the united States: fluid and adsorbed. The adsorbed vaccines contain much less than 1.25 mg of aluminum and also 4 to 10 flocculation systems (Lf) that toxoid every 0.5-ml dose. (The quantity of toxoid is measure up by in vitro flocculation when toxoid is combined with a known amount of antitoxin, and also the outcomes are tape-recorded as the limit of flocculation .) The liquid preparations contain 4 to 5 Lf that toxoid. All tetanus toxoids in the United claims contain 0.02 percent formaldehyde and 0.1 percent thimerosal. Some investigators have noted an enhanced rate of severe regional reactions and abscess formation when adsorbed diphtheria toxoid or diphtheria and also tetanus toxoids because that pediatric usage (children under 7 years of age) (DT) were provided (e.g., 30 percent adsorbed versus 8 percent fluid) (Collier et al., 1979; Holden and Strang, 1965). However, others have actually not corroborated this findings and also note the adsorbed toxoids have comparable reaction rates as long as the injections are offered intramuscularly quite than subcutaneously. In addition, adsorbed toxoids sell the advantage of amplified immunogenicity (Jones et al., 1985; Relihan, 1969; Trinca, 1965; White, 1980; White et al., 1973).


Diphtheria is an acute respiratory infection resulted in by Corynebacterium diphtheriae. In a nontoxigenic form, the organism might colonize the neck of asymptomatic people or may create mild pharyngitis. However, as soon as the bacterium is infected through a bacteriophage moving the structural gene because that biosynthesis of the toxin responsible for clinical disease, classic diphtheria can result. The clinical presentation includes a fibrinous, adherent pharyngeal membrane and complications of severe systemic toxicity, myocarditis, and also peripheral neuritis. Situation fatality prices were frequently in the variety of 50 percent before the availability of antitoxin therapy. That is now known that diphtheria toxin is one of a household of A and also B toxins. The A and also B fragments of diphtheria toxin are part of a solitary polypeptide chain. Fragment A ("active") is a potent enzyme that acts intracellularly to block protein synthesis. The only well-known substrate because that fragment A is elongation variable 2, i beg your pardon is involved in catalyzing the movement of ribosomes on eukaryotic bio messenger RNA. A solitary molecule the fragment A can kill a cell. Fragment B ("binding") is responsible for the acknowledgment of receptors on mammalian cells and the translocation the fragment A into cells (Uchida, 1986). Protective person antibodies against diphtheria space directed against fragment B (Mortimer, 1988). The protective role of antisera versus the toxin was documented by Behring in the late nineteenth century (Holmes, 1940), and also the usage of diphtheria antiserum raised in equines to treat human being diphtheria was introduced a couple of years later. Energetic immunization through inactivated toxin in experimental animals was adjusted to immunization of humans.

Early in the background of immunization versus diphtheria, active toxin and also antitoxin (prepared in horses) to be administered together a mixture. In number of reports, fatalities caused by the toxic results of inadequately neutralized diphtheria toxin emerged in children given this mixtures (Dittmann, 1981b; Wilson, 1967). Complying with the advent of toxin neutralization through chemical way (formalin), one report the incomplete detoxification appeared. In Kyoto, Japan, in 1948, 68 of 606 kids died following inoculation through a formalin-detoxified vaccine. Complimentary toxin to be detected in one batch the the vaccine (Dittmann, 1981b). Right now licensed toxoids developed in the United says are now prepared and also tested by steps specified in the password of federal Regulations, and also no cases of toxin-related condition have been reported because 1948.

Because of the severity of clinical diphtheria and the early recognition that defense was safe induced by immunization v diphtheria toxoid, controlled clinical trials of the efficacy the diphtheria toxoid were never performed. Beforehand in the history of immunization versus diphtheria, Schick (1913) introduced a check that associated with security immunity, for this reason making it possible to research both naturally acquired and also toxoid-induced immunity. This test consists of the intradermal injection of a small amount that purified toxin. In nonimmune people who lack circulating antitoxin, a red, contempt hemorrhagic area appears at the injection site within 48 hours. People with protective levels of antitoxin antibody (>0.01 U/ml) have no regional reaction. Top top the basis of the correlation of a an adverse Schick test through protective immunity and a correlation between an unfavorable Schick test results and also a serum antitoxin titer that 0.01 come 0.02 U/ml, one or both of this tests have actually been provided to measure the efficacy that diphtheria immunization protocols the utilize assorted doses and management schedules.

In the united States, youngsters receive vaccines follow to schedules determined by the American Academy the Pediatrics and also the Advisory Committee ~ above Immunization Practices. These groups recommend the diphtheria and tetanus toxoids and also pertussis vaccine (DPT) be offered at eras 2, 4, and also 6 months, in between ages 15 and 18 months, and between ages 4 and 6 years. The acellular pertussis-containing (DTaP) preparation can be substituted because that DPT for the fourth and fifth doses. Diphtheria and also tetanus toxoids for pediatric usage (DT) have to be supplied in kids younger than period 7 years in who DPT is contraindicated. Tetanus and diphtheria toxoids because that adult use (Td) need to be offered in individuals older than age 7 years. They have to be administered every 10 years adhering to the last DPT or DT vaccination.


Following one injection the tetanus toxoid, the recipient creates neutralizing antitoxin that stop the impacts of toxin on the nervous system. Antibody level are now reported in comparison v an international standard collection by the who as global units every milliliter, and also it is generally agreed that a level of 0.01 IU/ml or better is safety (Wassilak and Orenstein, 1988). Protective level of antibody are accomplished in many children and also adults after 2 doses the tetanus toxoid provided 4 or an ext weeks apart, although kids under 1 year of period may need three doses of tetanus toxoid (Barkin et al., 1984, 1985a). However, protective levels are reasonably short-lived, an especially in infants and also older adults, and also thus, a reinforcing (booster) dose is given 6 come 12 month after the primary series of immunizations. Adhering to this booster, long-term immunity generally exceeding 10 years develops (Peebles et al., 1969).

Minor neighborhood reactions (pain, erythema, ede of less than 1 cm) take place within 48 hours complying with 1-80 percent of immunizations with tetanus toxoid (Collier et al., 1979; Jones et al., 1985; White, 1980). The reaction price varies v the dose and form of toxoid, the variety of prior sheep of toxoid received, and the method of injection. Severe reactions (>8 centimeter of erythema or induration) room much less common and are frequently accompanied by a sore, puffy arm and systemic manifestations such as fever and malaise. Significant reactions occur much an ext frequently with bigger doses of toxoid (McComb and Levine, 1961; Schneider, 1964), and in numerous studies, serious reactions have actually been found to correlate with high antibody levels before immunization (Collier et al., 1979; Facktor et al., 1973; Korger et al., 1986; Levine and also Edsall, 1981; Levine et al., 1961; McComb and also Levine, 1961; Relihan, 1969; White et al., 1973). Before the acknowledgment of the lengthy duration the immunity, frequent booster doses offered after minor wounds or together prophylaxis for manufacturing facility employees or children attending summer camps caused high level of antibody.

The correlation in between severe neighborhood reactions and also high antibody levels prior to immunization strongly argues that this reactions might be resulted in by immune complicated formation in between antibodies and antigen. In the case of severe local reactions, this is classified together an Arthus reaction, in which immune complexes kind locally in the wall surfaces of little arteries (Edsall et al., 1967; Eisen et al., 1963; Facktor et al., 1973). In rarely cases, it is feasible that the immune complexes may kind in the circulation, deposit in tissues, and also activate complement. This would an outcome in the clinical syndrome the serum sickness. This patients may build glomerulonephritis, arthritis, and also vasculitis. However, part investigators have actually been unable to confirm a regular correlation between much more severe neighborhood reactions and high antibody levels (Holden and Strang, 1965; Jones et al., 1985; White et al., 1973), and thus, that is likely that other determinants such together toxoid variables, adjuvants, dose, and host factors may additionally play a function in the advance of severe regional reactions.

Routine immunization with tetanus toxoid also induces a moving immune response, and also intradermal skin testing with tetanus toxoid commonly is used as a display screen for anergy (Gordon et al., 1983; Grabenstein, 1990; Steele et al., 1976). The absence of a delayed-type hypersensitivity an answer does not suggest a lack of safety immunity, and also conversely, a positive an answer does not appear to correlate through clinically important hypersensitivity reactions to the toxoid (Eisen et al., 1963; Facktor et al., 1973; Gold, 1941; Vellayappan and Lee, 1976).


In the preimmunization era, many world acquired immune to diphtheria (and a an unfavorable Schick test) maybe by asymptomatic colonization. Also, protective immunity to be observed in young infants, most most likely on the communication of the visibility of transplacentally got antibody (Schick, 1913).

Diphtheria toxoid adsorbed through aluminum hydroxide or phosphate was shown to be an ext immunogenic and also to develop fewer local reactions than liquid toxoid. The minimum schedule for kids was discovered to be three doses, with the very first two sheep spaced through 1-2 months and also the third dose offered 6-12 months later. Booster doses were discovered to it is in necessary, specifically in nations where extensive immunization markedly decreased the opportunity for asymptomatic colonization (Bjorkholm et al., 1986; Christenson and Bottiger, 1986; James et al., 1951; Karzon and Edwards, 1988; Rappouli et al., 1988). To keep protective level of antitoxin antibody versus diphtheria, recall immunization is said in older children and adults at 10-year intervals.

Early researches of the immune an answer to immunization against diphtheria revealed that some immune people responded come a Schick check with instant hypersensitivity reaction (wheal and erythema in ~ minutes) or delayed-type hypersensitivity reactions the were maximal at 24-72 hrs (Zingher and Park, 1923). One important consequence of this monitoring was that interpretation of a "positive" Schick reaction come toxin required a regulate test through purified toxoid. Another implication was the pseudoreactions might predict clinically relevant hypersensitivity to further immunization v diphtheria toxoid (Pappenheimer, 1984). However, no all investigators found a high level of correlation between Schick test results and also adverse reactions (Settergren et al., 1986), and routine trial and error prior to immunization is impractical. Pappenheimer et al. (1950) demonstrated the a far-reaching proportion of the delayed-type hypersensitivity reactions in formerly immunized topics were versus the contaminants in the rudely toxoid quite than against the highly purified diphtheria toxin. The role of bacterial cellular fountain in disadvantage reactions has been confirmed by Relyveld and also colleagues (1979, 1980).

The problems of high prices of major local and also systemic reactions (fever, malaise, myalgia, headaches, and also chills) listed in previously studies v diphtheria toxoid in older children and adults have actually been alleviated through (1) the use of enhanced methods for purifying toxins, (2) palliation of the sheep of toxoid (<2 Lf of diphtheria toxoid in Td versus 10-20 Lf in DPT and 10-12 Lf in DT), and (3) the use of adsorbed vaccine (Edsall et al., 1954; Levine et al., 1961; Myers et al., 1982; Smith, 1969). By this approach, the rates of disadvantage reactions related to hypersensitivity have actually been very low (Middaugh, 1979; Mortimer et al., 1986; Myers et al., 1982; Sheffield et al., 1978). Mild regional reactions (tenderness and also swelling at the injection site) developed in 16 come 27 percent that vaccinees. Erythema, significant swelling, or systemic symptoms occurred in fewer than 2 percent that individuals.

Clinical Description

Encephalopathy has actually been supplied in the literary works to characterize a constellation the signs and symptoms reflecting a generalized disturbance in brain function often involving alterations in actions or state the consciousness, convulsions, headache, and focal neurologic deficit. The annual incidence the encephalitis for the years 1950 to 1981 in Olmsted County, Minnesota was 7.4 every 100,000 (Beghi et al., 1984; Nicolosi et al., 1986). The incidence in kids less 보다 1 year of age was 22.5, in children in between 1 and also 4 year of period it to be 15.2, and in children in between 5 and also 9 years of period it was 30.2 per 100,000. Other estimates of encephalopathy for children less than age 2 years were somewhat reduced than those reported by Beghi et al. (1984) and Nicolosi et al. (1986). Other estimates for annual incidence variety from 5 per 100,000 youngsters younger than age 2 years (Walker et al., 1988) to 10 every 100,000 kids younger than age 2 years (Gale et al., 1990). Because that a an ext complete conversation of encephalopathy, check out Chapter 3.

History of suspected Association

Diphtheria toxin reasons a toxicity peripheral neuropathy in around 20 percent of instances (Mortimer, 1988), yet diphtheria toxin has not been uncovered to be associated with main nervous system (CNS) condition such as encephalopathy. Tetanus is a neurologic an illness characterized by severe reduced motor neuron hyperexcitability through consequent muscle spasms developed by the potent neurotoxin tetanospasmin (Wassilak and Orenstein, 1988).

Diphtheria and tetanus toxoids are normally given with each other as Td in adults and as DT or DPT (a mix that includes vaccine directed versus pertussis) in children. DT and Td differ since of the lower concentration the diphtheria toxoid in the ready for adults. Monovalent diphtheria and monovalent tetanus toxoids are likewise available. Pertussis together a clinical disease has lengthy been known to cause encephalopathy, as debated in information by the institute of medicine (1991). The opportunity that immunization versus pertussis was responsible for significant adverse neurologic occasions leading come encephalopathy was raised as at an early stage as 1933, with pertains to continuing to be reported with the present. Several big epidemiologic researches were designed to research the association between DPT and also acute neurologic occasions in children. From those studies, information concerning DT was additionally obtained since of the absence of universal acceptance the DPT. The national Childhood Encephalopathy study (Alderslade et al., 1981) and the north West Thames research (Pollock and Morris, 1983) provide some information on encephalopathy and also DT. Additionally, 2 case-control studies in Italy (Crovari et al., 1984; Greco, 1985) were carried out to inspection a clinical observation that encephalopathy in several kids was temporally concerned DT immunization.

Biologic Plausibility

Although tetanus toxin have the right to reach the CNS, it is not clearly associated with encephalopathy. The neurologic sequelae that tetanus have been described. Symptoms experienced by patient after restore from tetanus encompass irritability, sleep disturbances, myoclonus, lessened libido, postural hypotension, and abnormalities top top electroencephalograms (Illis and also Taylor, 1971). The symptom disappeared within 2 year of recovery from tetanus. These to be attributed through the writer as second to the action of tetanus toxin on inhibitory synapse in the CNS. The neurologic results of diphtheria are generally peripheral neuropathy.

Case Reports, instance Series, and Uncontrolled Observational Studies

The phibìc West Thames research by Pollock and also Morris (1983), an untreated cohort study, to be a collection of reports of every reactions to vaccines in the phibìc West Thames region of England and Wales. It was designed to intensify the reporting of major manifestations, specifically neurologic complications, ~ childhood immunization in between January 1975 and December 1981. Of 400,500 sheep of DT and oral polio vaccine (OPV) (133,500 kids completing a primary series of three doses the vaccine) and also 221,000 solitary booster sheep of DT given at institution entry, seven kids had seizures without neurologic damage and also were well at follow-up. Three kids with other neurologic problems were identified; one child (9 months old) had infantile spasms predating vaccination, one more child (9 years old) had a seizure with hemiplegia 1 day after receipt of DT yet was normal on follow-up, and another boy (7 month old) arisen hemiparesis 14 job after receipt of DT and was common on follow-up. None of these neurologic occasions was taken into consideration to it is in encephalopathic.

Because it was felt the reactions that arisen after vaccination with DT were being underreported in the an initial part that the north West Thames examine (compared through the reporting of reaction that arisen after vaccination with DPT), one alternative method of research was undertaken ~ above the basis of a hospital activity analysis that hospitals in the north West Thames an ar during 1979. Youngsters under 2 year of age were consisted of in the research if your diagnosis at the moment of discharge included a neurologic event. No manage group was used. The 18,000 kids who perfect a primary series of DT (approximately 54,000 sheep of DT to be administered), 18 youngsters had seizures (all febrile) within 28 job of DT immunization and 3 kids had some various other neurologic an illness that developed within 28 days of DT immunization. 2 of these youngsters had focal length seizures at 22 and also 24 days after DT immunization, and the various other child died of encephalopathy 28 work after DT immunization. Insufficient detail was offered to define the situation of encephalopathy.

Several clinical trials contrasted DT and also DPT (therefore, lock are taken into consideration uncontrolled cohort studies for DT), and also they showed that there to be no severe neurologic adverse events after receipt that DT. Those studies, by Cody et al. (1981) and Barkin et al. (1985b), had actually only very tiny samples the those immunized v DT (784 and 40 subjects, respectively) and also therefore carry out not carry out much extr knowledge that the adverse events following immunization through DT.

Quast and colleagues (1979) found in the records of Behringwerke (a medicine firm in the previous West Germany) a instance report that a 36-year-old woman who emerged polyneuromyeloencephalopathy 5 days after receiving her first dose the aluminum-adsorbed tetanus toxoid in 1976. The authors detailed no clinical details other 보다 the truth that she recovered completely.

Several little case collection described in the literature looked because that adverse occasions following immunization through both DPT and DT (Feery, 1982; Waight et al., 1983). Those studies verified no disadvantage neurologic occasions following receipt of DT, although the sample sizes in those two researches were tiny (335 and 221 subjects, respectively).

The following situations were report in the Vaccine Adverse event Reporting system (VAERS) between November 1990 and also July 1992: a 50-year-old male who developed syncope, visual disturbance, and hypoglycemia 1 job after receiving tetanus toxoid; a 14-year-old male who emerged encephalitis and transverse myelitis 2.5 months complying with Td administration; and a 17-year-old masculine who emerged lymphocytic meningoencephalitis 10 days complying with receipt that Td and measles-mumps-rubella vaccine (MMR).

Controlled Observational Studies

The ideal observational case-control examine that provides information about immunization through DT and also association through neurologic condition is the nationwide Childhood Encephalopathy examine (NCES) (Alderslade et al., 1981), which to be undertaken because of pertains to about possible adverse events following receipt that pertussis vaccine. That study identified youngsters aged 2-36 months that were admitted come a hospital v neurologic disease during the 3 years from July 1976 to June 1979 in England, Scotland, and also Wales. The very first 1,000 that 1,182 instances identified throughout that time were studied. For each situation there were two ""at-home"" controls matched because that age, sex, and also area that residence. No statistically significant association through DT immunization and neurologic adverse events was found in cases compared v controls. On the basis of the data in Table V.15 on page 122 that the NCES (Alderslade et al., 1981), the odds proportion (OR) is 0.92 (95 percent confidence interval , 0.64-1.30). However, as with infantile spasms, a nonsignificantly greater rate the exposure come DT to be observed in ~ the 7 days prior to the day of onset of condition in the instance patients, and a correspondingly lower rate the exposure to be observed between much more than 7 and also less than 28 days prior to onset. Because virtually one-third the the instances had lengthy febrile convulsions, the excess price of exposure to DT in ~ 7 days, if real, may merely reflect the tendency of DT vaccination to cause fever.

Greco (1985) carried out a case-control study in the Campania (Naples) region of Italy indigenous January 1980 to February 1983 to test the association between encephalopathy and also immunization v DT. The Italian to adjust of Health had actually received reports that explained several situations of encephalopathy in children who had actually received DT in ~ the week prior to illness, and those reports to be the incentive for the study. A situation was characterized as a patient between the ages of 3 and 48 months that was admitted come the Santobono Hospital intensive care unit throughout the study duration with one or much more of the complying with diagnoses: coma the unknown cause, Reye syndrome, convulsions of unknown cause, respiratory distress with coma from an unknown cause, and also death or stupor native an unknown cause. Forty-five patients the met the case meaning were identified, and also for each instance there were 4 matched controls: 2 hospital controls and also two residential controls. Hospital controls were matched to situations by age, sex, and date of admission; residential controls to be matched by age, sex, and also place of residence. The authors discovered that 64 percent that the situation patients had been immunized with DT throughout the month before hospitalization, vice versa, 10 percent of hospital controls and 13 percent that residence controls had been immunized with DT. The reported ORs were 40.9 (95 percent CI, 6.3-102.5) for immunization v DT within the month before hospitalization and 92.6 (95 percent CI, 35.1-244.1) within the week prior to hospitalization.

The research by Greco (1985) has many methodologic problems. An initial and foremost, the instances leading to the Italian to adjust of Health"s alert worrying the feasible association in between DT vaccination and encephalopathy served as part of the situation group for the study. Additionally, instances were selected without blinding with respect to their prior immunization status. As described in the article, many of the case patients had elevated transaminase and also ammonia levels however had regular cerebrospinal fluid (CSF) findings, saying the diagnosis of Reye syndrome. To the level that DT may have been offered to kids with concomitant influenza or other viral illnesses, the event of regional or febrile reactions may have led to treatment with aspirin and. Secondarily, the development of Reye syndrome. No details on aspirin use was given in the short article describing the study. In addition, situation DT recipients were double as most likely as control DT recipients to have actually received OPV simultaneously.

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In solution to the same reports that led to the examine by Greco (1985), an additional case-control research (Crovari et al., 1984) to be undertaken in the Luguria (Genoa) an ar of Italy to assess the association in between recent DT immunization and coma or complicated convulsions. The examine of Crovari et al. (1984) drew its instances from admissions to the intensive treatment unit, infectious condition ward, and general ward that the hospital the the Istituto G. Gaslini in Genoa in between January 1980 and also June 1983. The case patients were in between 3 and also 48 month of age and were admitted v coma, complicated convulsions of unknown etiology, or both. Children with well-known epilepsy or febrile convulsions were supposedly excluded from the case group, however the authors later state (in the results) the the bulk of patients presented v "hyperpyrexia." Twenty-nine situations were identified, and also each instance was matched with 4 controls (two inpatient and two outpatient) by sex and age because that inpatient controls and by age, sex, and residence for outpatient controls. The research did not display a statistically far-ranging association between receipt of DT and also coma or complex convulsions (matched OR, 1.6; 95 percent CI, 0.54-4.74). However, the outpatient controls were randomly selected from records of vaccinated children. This would certainly inflate exposure rates amongst the outpatient regulate group and perhaps produce a negative bias in the odds ratio. Unpublished information detailed by the authors allowed a separate (unmatched) evaluation for the cases and also inpatient controls, which revealed an unmatched OR that 2.16 (95 percent CI, 0.37-12.49). A meta-analysis combine the data from the NCES and also the cases and also inpatient controls indigenous the research of Crovari et al. (1984) returns a Mantel-Haenszel OR of 0.95 (95 percent CI, 0.68-1.34).