Diphtheria Toxoid

Diphtheria is an acute upper respiratory illness caused by Corynebacterium diphtheriae. C. diphtheriae is a minimally invasive gram-positive bacillus that is resistant to environmental change and whose virulence is mostly confined to the secretion of an exotoxin that inhibits protein synthesis in mammalian cells (MacGregor, 2010). C. diphtheriae is spread through direct contact with infected respiratory secretions and cutaneous lesions (MacGregor, 2010).

Following an incubation period of 1 to 5 days, diphtheria presents most commonly as local invasion of the respiratory tract including the back of the mouth and upper pharynx (Vitek and Wharton, 2008). Early symptoms may include low-grade fever (less than 101.3°F), malaise, and sore throat (Vitek and Wharton, 2008). Approximately 24 hours after disease onset, small patches of exudate are visible, and within 2 to 3 days a glossy, white membrane covers one or both tonsils and other oral structures including the tonsillar pillars, uvula, soft palate, oropharynx, and nasopharynx (Vitek and Wharton, 2008). The magnitude of the membrane is an indication of disease severity. Localized disease is often mild; however, the involvement of posterior structures like the soft palate and periglottal areas generally suggests the development of more substantial disease (Vitek and Wharton, 2008). In such cases, local lymph node enlargement also occurs due to swelling and inflammation, and the individual may present with a “bulk neck” appearance (Vitek and Wharton, 2008).

While diphtheria in the respiratory tract is the most common manifestation, aural, conjunctival, cutaneous, and vaginal diphtheria can also occur and taken together account for approximately 2 percent of diphtheria cases (Vitek and Wharton, 2008).

The obvious consequences of diphtheria are manifested in the complications that arise from the presence and subsequent shedding of the membrane. In severe cases, the membrane may extend into the tracheo-bronchial tree causing pneumonia and expiratory respiratory obstruction and membrane aspiration (Vitek and Wharton, 2008). Other complications are caused by the effect of the absorbed diphtheria toxin on organs and organ systems proportional to the severity of the disease (Vitek and Wharton, 2008). Evidence of myocarditis has been found in up to 66 percent of patients with 10 to 25 percent developing clinically significant cardiac dysfunction (MacGregor, 2010). Neuropathy occurs rarely in mild disease but occurs in up to 75 percent of patients with severe diphtheria (MacGregor, 2010). Hypotension, pneumonia, and renal failure are also common in severe cases, while encephalitis and cerebral infarction has been described in rare cases (MacGregor, 2010). Death occurs most frequently within 3 to 4 days from disease onset and is most often caused by asphyxia or myocarditis (MacGregor, 2010).

Immunization with diphtheria toxoid has dramatically altered the epidemiology of diphtheria in the United States and data obtained from the 1988–1994 National Health and Nutrition Examination Survey (NHANES) III serosurvey indicated that 80 percent of persons age 12 to 19 years were immune to diphtheria (McQuillan et al., 2002).

The first vaccine against diphtheria was developed in the early 1800s and was widely used in the United States as early as 1914 (Vitek and Wharton, 2008). The vaccine consisted of a toxin-antitoxin formulation and was found to be 85 percent effective in preventing diphtheria (Vitek and Wharton, 2008). In the 1920s, Ramon found that by treating the toxin with formalin and creating the toxoid, the toxicity of the preparation could be reduced while maintaining the immunogenic properties (Vitek and Wharton, 2008). In 1926, Glenny and his associates discovered that alum-precipitated toxoid was even more effective, and by the mid-1940s diphtheria toxoid was being combined with tetanus toxoid and whole-cell pertussis vaccine to create the diphtheria-tetanus-pertussis (DTP) vaccine (Vitek and Wharton, 2008). Soon after, the DTP combination vaccine was adsorbed onto an aluminum salt and researchers noted the enhanced immunogenicity of the diphtheria and tetanus toxoid in the presence of pertussis vaccine and the aluminum salt (Vitek and Wharton, 2008).

Tetanus Toxoid

Unique among the vaccine-preventable diseases, tetanus is not transmissible from person to person (Wassilak et al., 2008). The disease is caused by the gram-positive spore forming bacillus Clostridium tetani, which is widespread throughout the environment, particularly in the soil (Wassilak et al., 2008). C. tetani spores are introduced into the body through direct contact with compromised tissues, where they germinate and produce a plasmid-encoded exotoxin that binds to gangliosides at the myoneural junction of skeletal muscle and on neuronal membranes in the spinal cord, blocking inhibitory impulses to motor neurons (AAP, 2009; Wassilak et al., 2008). “The action of tetanus toxin on the brain and sympathetic nervous system is less well documented” (AAP, 2009).

The incubation period for tetanus can range from 1 day to several months but generally lasts 3 to 21 days (Weinstein, 1973). Shorter incubation periods are associated with more severe disease, while incubation periods of 10 or more days generally result in milder disease (Adams, 1968; Bruce, 1920; Garcia-Palmieri and Ramirez, 1957; LaForce et al., 1969).

There are three clinical descriptions of C. tetani infection: generalized, localized, and cephalic. Generalized tetanus occurs in more than 80 percent of all tetanus cases (Wassilak et al., 2008). Trismus (lockjaw) caused by spasm of the facial muscles is the most common manifestation of generalized tetanus (Newton-John, 1984; Pratt, 1945; Weinstein, 1973). Trismus may be followed by muscle spasms in other parts of the body including the neck, back, and abdomen (Wassilak et al., 2008). Tetanospasm, also known as generalized tonic tetanic seizure-like activity, is a sudden contraction of all the muscle groups and can occur in the presence of mild external stimuli such as sudden noise (Wassilak et al., 2008). In addition to these spasms, those with severe tetanus are at risk of developing severe autonomic nervous system abnormalities including diaphoresis, high or low blood pressure, flushing, and cardiac complications (Hollow and Clarke, 1975; Kanarek et al., 1973; Kerr et al., 1968). Tetanus neonatorum is the most common manifestation of generalized tetanus and occurs when the bacterium infects the umbilical stump (Wassilak et al., 2008). Typically manifesting 3 to 14 days after birth, tetanus neonatorum begins with excessive crying and decreased sucking capability, and is followed by trismus, difficulty swallowing, and tetanic spasm (Wassilak et al., 2008). Infants who survive this disease may experience neurologic damage and may also develop intellectual and behavioral abnormalities (Anlar et al., 1989; Barlow et al., 2001; Okan et al., 1997; Teknetzi et al., 1983). Localized tetanus is rare in humans and involves muscle spasms confined to areas. These spasms may last several months before subsiding or developing to generalized tetanus (Millard, 1954). Cephalic tetanus is associated with lesions on the head or face in line with the facial nerve and orbits (Weinstein, 1973). Considered a form of localized tetanus, incubation is complete in 1 to 2 days after the initial insult, which is most often a head wound (Weinstein, 1973).

Following the widespread use of tetanus toxoid–containing vaccines, tetanus infections have become an uncommon occurrence in the United States. In 1947, the incidence of reported cases was 0.39 per 100,000 in the United States (Wassilak et al., 2008). This number dropped dramatically, and from 1998 to 2000, the average incidence was approximately 0.16 cases per 1,000,000 representing a 96 percent decrease in the incidence rate (CDC, 2003).

Tetanus infections peak in midsummer and are more common in warm, damp climates. This is likely due to soil conditions and increased exposure to spores as well as increased injuries that occur during the summer months (Axnick and Alexander, 1957; Bytchenko, 1966; Heath et al., 1964; LaForce et al., 1969).

Although described by the ancient Egyptians and Greeks, the origin of tetanus disease was not described until 1884 when Carle and Rattone showed that tetanus symptoms could be induced in rabbits when inoculated with pustular fluid from a fatal case of human tetanus (Wassilak et al., 2008). In the late 1800s, C. tetani spores were shown to survive heating and germinate in anaerobic environments, and the repeated inoculation with small quantities of toxin led to antibody production that was able to neutralize the effects of tetanus toxin (Wassilak et al., 2008). In 1924, the tetanus toxoid created by chemically inactivating the tetanus toxin was shown to induce active immunity to tetanus disease prior to exposure to the pathogen (Wassilak et al., 2008).

Currently, commercial tetanus toxoid is produced by culturing C. tet-ani in liquid medium and transforming the purified toxin with 40 percent formaldehyde at 37°C (Wassilak et al., 2008). In the United States, tetanus toxoid vaccines are available as a single tetanus toxoid vaccine (TT) (Sanofi Pasteur) and in combination with diphtheria toxoid as DT/Td, acellular pertussis as DTaP/Tdap, and as DTaP with other antigens such as Haemophilus influenzae B (HiB) conjugate (Wassilak et al., 2008).

Pertussis Antigen

Pertussis (whooping cough) is an upper respiratory infection caused by Bordetella pertussis, a gram-negative, pleomorphic bacillus that attaches to cells lining the respiratory tract (Edwards and Decker, 2008). B. pertussis is not a particularly invasive bacterium and typically does not penetrate sub-mucosal cells or the bloodstream, although toxins secreted by the bacteria may produce systemic effects (Edwards and Decker, 2008).

The incubation period lasts 7 to 10 days, and pertussis disease is transmitted by large respiratory droplets (Waters and Halperin, 2010). B. pertussis infections range from asymptomatic to severe. Symptomatic disease is characterized by three phases: catarrhal, paroxysmal, and convalescent (Gordon and Hood, 1951). The catarrhal phase lasts 1–2 weeks; symptoms of this phase may include nasal discharge, eye redness, and frequent coughing and sneezing (Gordon and Hood, 1951; Waters and Halperin, 2010). The paroxysmal phase is characterized by periods of intense coughing (paroxysms) that may lead to choking, vomiting, and an inspiratory whoop (Gordon and Hood, 1951; Waters and Halperin, 2010). This phase may last 2–6 weeks, as does the convalescent phase during which the symptoms decline. Fever is rare in pertussis infection and usually results from a secondary infection or co-infection (Gordon and Hood, 1951; Waters and Halperin, 2010).

According to Cortese and her colleagues (2008), apnea and respiratory arrest was the most common complication of pertussis followed by pneumonia and gastroesophageal reflux. Pneumonia is the most common complication in hospitalized patients (Cortese et al., 2008). Encephalopathy is a rare complication and occurs most often in younger patients (Waters and Halperin, 2010). B. pertussis antibodies have been found in the cerebrospinal fluid (CSF) of patients with pertussis encephalopathy (Grant et al., 1998). Other complications include seizures, ataxia, aphasia, blindness, deafness, subconjunctival hemorrhages, syncope, and rib fractures (Waters and Halperin, 2010). Pertussis is most serious in infants less than 12 months of age, and the risk of death is highest among infants less than 6 months old (Cortese et al., 2008; Tanaka et al., 2003; Vincent et al., 1991; Vitek et al., 2003).

B. pertussis was first isolated and grown in culture by Jules Bordet and Octave Genou in 1906, and the first whole-cell pertussis vaccines were licensed in the United States in 1914 (Edwards and Decker, 2008). These vaccines were suspensions of killed bacteria and were improved upon by Kendrick and her colleagues before being combined with diphtheria and tetanus toxoids to produce DTP vaccine (Edwards and Decker, 2008). Owing to the reactogenicity of whole-cell vaccines, alternative vaccines were sought, and the first acellular vaccine was developed in Japan (Edwards and Decker, 2008). These vaccines were composed of purified filamentous hemagglutin (FHA) and leukocytosispromoting factor hemagglutin (Sato et al., 1984) and were widely used in Japan starting in 1981. In 1996, acellular pertussis vaccines were licensed in the United States. Currently, the acellular pertussis vaccine is only available in combination with diphtheria and tetanus in the United States.

Diphtheria Toxoid–, Tetanus Toxoid–, and Pertussis Antigen–Containing Vaccines

Vaccines to prevent diphtheria, tetanus, and pertussis are available in various formulations and are given in 0.5 mL doses (see Table 10-1). The four most common combination vaccines are DTaP, Tdap, DT, and Td. Of these vaccines, two (DTaP and DT) are given to children younger than 7 years of age, and two (Tdap and Td) are given to individuals 7 years or older.¹ The Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians recommend that children routinely receive a five-dose series of vaccine against diphtheria, tetanus, and pertussis before age 7 years. ACIP recommends that the first four doses be administered at ages 2, 4, 6, and 15–18 months and the fifth dose at age 4–6 years (CDC, 1997).

TABLE 10-1

Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis–Containing Vaccines Licensed and Available in the United States.

Because the immunity provided by childhood diphtheria, tetanus, and pertussis-Containing vaccines is not lifelong, booster vaccinations are needed to maintain disease immunity. These booster vaccinations of either Td or Tdap, which in 2006 was recommended by the ACIP as a single-dose booster for those who previously had not been vaccinated with Tdap, are given every 10 years or after a tetanus exposure under certain circumstances (CDC, 2008).

According to the National Immunization Survey from 2005 through 2009 more than 95 percent of children age 19 to 35 months had received at least three doses of the DTP, DT, or DTaP vaccine and approximately 85 percent had received four doses (CDC, 2010b). In 2009, the National Immunization Survey estimated that 76.2 percent of adolescents between 13 and 17 years of age had received at least one dose of the Td or Tdap vaccines (CDC, 2010a).

One of the challenges the committee faced in assessing the safety of diphtheria toxoid–, tetanus toxoid–, and acellular pertussis–containing vaccines is that these particular antigens are often combined with other antigens in a number of different formulations (see Table 10-1). This variety at times made comparisons difficult. The committee was not charged with reviewing the evidence regarding whole cell pertussis vaccine. When the committee uses the phrase “diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine,” it is limiting the assessment to these antigens.

Epidemiologic Evidence

The committee reviewed nine studies to evaluate the risk of encephalitis or encephalopathy after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. Seven studies (Geier and Geier, 2004; Gold et al., 1999; Isomura, 1991; Kuno-Sakai and Kimura, 2004; Rosenthal et al., 1996; Stetler et al., 1985; Zielinski and Rosinska, 2008) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

The two remaining controlled studies (Greco, 1985; Yih et al., 2009) contributed to the weight of epidemiologic evidence and are described below.

Greco (1985) conducted a case-control study in children (3 to 48 months of age) admitted to the Santobono Hospital in Campania, Italy, from January 1980 through February 1983. The cases were identified from the hospital intensive care unit register. Patients were included as an encephalopathy case if they were admitted to the intensive care unit for the following diagnoses, which were obtained from medical records: Reye's syndrome, coma due to unknown causes, convulsions due to unknown causes, death due to unknown causes, or stupor due to unknown causes. Two hospital controls were matched to each case on age (within 6 months), sex, and date of admission (within 30 days), and had confirmed diagnoses different from the cases. Two residence controls from the national birth register were matched to each case on age (within 1 month), sex, and place of residence (by zone or by town), and were alive during the time cases were hospitalized. A total of 45 cases, 90 matched hospital controls, and 90 matched residence controls were included in the analysis. Vaccination histories for the cases and controls were obtained from an extensive search of the national immunization register. During the 1 month preceding the hospital admission, 64 percent, 10 percent, and 13 percent of the cases, hospital controls, and residence controls received a diphtheria and tetanus toxoids vaccine, respectively. Oral polio vaccine was given at the same time as the diphtheria and tetanus toxoids vaccine in 51 percent of the cases and 28 percent of the controls; however, the authors did not explicitly state that other vaccinations were not also given. The odds ratio for encephalopathy within 1 month of the administration of diphtheria and tetanus toxoids vaccine compared to the hospital controls was 291.9 (95% CI, 53.3–1,596.9) and compared to the residence controls was 22.5 (95% CI, 8.2–62.1). The authors observed an increased risk but concluded that the study design was insufficient to infer a causal relationship between the administration of diphtheria and tetanus toxoids vaccine and encephalopathy.

Yih et al. (2009) conducted a cohort study in patients (10 to 64 years of age) enrolled in seven managed care organizations (MCOs) participating in the Vaccine Safety Datalink (VSD) from August 2005 through May 2008. The study investigated the occurrence of adverse events (reported from outpatient, inpatient, and emergency department visits) following Tdap vaccination. The exposed group included approximately 660,000 patients that received a Tdap vaccination. Diagnoses of encephalopathy, encephalitis, and meningitis were obtained from the medical records and included in the analysis if they occurred within 42 days of vaccination. The disease incidence following Tdap vaccination was compared to the disease incidence 1 to 42 days after Td vaccination in a historical VSD comparison population; this could have introduced bias if coding practices or background disease incidences differed in the two cohorts. The comparison group included approximately 890,000 patients that received a Td vaccine from 2000 through 2004. The observed number of encephalopathy– encephalitis–meningitis events in the Tdap cohort (34 events) was less than the historical Td cohort (40.33 events), which resulted in a relative risk of 0.84 (confidence interval not provided). The authors concluded that the risk of encephalopathy–encephalitis–meningitis following Tdap vaccination is not significantly higher than the risk following Td vaccination, which only provides information on the safety of the acellular pertussis antigen component.

Mechanistic Evidence

The committee identified five publications reporting encephalitis or encephalopathy after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. Four publications did not provide evidence beyond temporality (Casella et al., 2007; Ehrengut, 1986; Pollock and Morris, 1983; Sivertsen and Christensen, 1996). In addition, two of the publications also reported the administration of additional vaccines making it difficult to determine which, if any, vaccine could have been the precipitating event (Casella et al., 2007; Ehrengut, 1986). Furthermore, Ehrengut (1986) reported that one patient was sick 1 week prior to vaccination. These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Schwarz and colleagues (1988) described a 21-year-old man presenting with headache, clouding of consciousness, and tremors 7 days after administration of a tetanus toxoid vaccine and tetanus antitoxin while receiving treatment for contusions and lacerations of the elbow. Two days later the patient was unresponsive to pain and comatose. Physical examination revealed negative pupillary and corneal reflexes, divergent gaze, inadequate spontaneous respiration, spontaneous extensor posturing, and signs of meningismus. The patient recovered upon treatment with dexamethasone, amidopyrine, gentamycin, mezlocillin, and immunoglobulin. Two and one half years later the patient was administered a tetanus toxoid vaccine while receiving treatment for open injuries on the limbs. Eight days after vaccination the patient presented with signs of acute midbrain syndrome, similar to the first episode. The patient recovered upon similar treatment received during the first episode. Prior to the first episode the patient had received seven vaccinations against tetanus toxoid without incident.

Causality Conclusion

Conclusion 10.1: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and encephalitis.

Conclusion 10.2: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and encephalopathy.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of infantile spasms after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens in combination. This one controlled study (Goodman et al., 1998) contributed to the weight of epidemiologic evidence and is described below.

Goodman et al. (1998) conducted a case-control study in children (2 to 35 months of age) enrolled in the National Childhood Encephalopathy Study (NCES) in England, Scotland, and Wales from 1976 through 1979. A monthly postal questionnaire was sent to participating pediatricians, neurosurgeons, and infectious disease physicians in order to identify patients hospitalized for acute neurological illnesses. A total of 262 children hospitalized and diagnosed with infantile spasms during the study period had sufficient clinical records for the analysis. Two controls were matched to each case on age, gender, and area of residence; however, the study did not specify further how the controls were selected. The notifying physician provided the patient's clinical history, and information on past immunizations was obtained from local sources (not defined). The analysis compared the frequency of DT immunizations 28 days prior to the date of seizure onset (case reference date) to the date for which the control was exactly the same age as the case at the date of first seizure (control reference date). The odds ratio for infantile spasms within 28 days of DT vaccination was 0.83 (95% CI, 0.45–1.49). The analysis suggested that DT vaccination was more likely to occur during the 0–6 days prior to seizure onset (OR, 1.43; 95% CI, 0.49–3.95) than any other period within the 28 days; however, the odds ratio was not statistically significant. The authors concluded that DT immunization is not associated with the onset of infantile spasms observed in the cases.

Mechanistic Evidence

The committee identified two publications reporting infantile spasms after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. The publications did not provide evidence beyond temporality (Pollock and Morris, 1983; Schmitt et al., 1996). The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.3: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and infantile spasms.

Epidemiologic Evidence

The committee reviewed 14 studies to evaluate the risk of seizures after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. Ten studies (DuVernoy and Braun, 2000; Geier and Geier, 2001, 2002, 2004; Gold et al., 1999; Kuno-Sakai and Kimura, 2004; Le Saux et al., 2003; Rosenthal et al., 1996; Stetler et al., 1985; Zielinski and Rosinska, 2008) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study (Crovari et al., 1984) had very serious methodological limitations that precluded its inclusion in this assessment. The case-control study from Crovari et al. (1984) provided inadequate information on how cases were ascertained and inappropriately combined coma and seizure symptoms.

The three remaining controlled studies (Andrews et al., 2007; Huang et al., 2010; Yih et al., 2009) contributed to the weight of epidemiologic evidence and are described below.

Andrews et al. (2007) conducted a self-controlled case-series study in children (28 days to 17 years of age) diagnosed with seizures from November 1999 through September 2003 in the United Kingdom. The cases were identified using diagnostic codes for seizures located in the hospital administrative data from the London and South East regions. The hospital data were linked to vaccination information in the child-health databases from the same regions. The study participants were divided into three age groups: 28–365 days (infants), 1 year of age (toddlers), and 2–17 years of age (children). Cases were excluded from the analysis if they received a vaccination outside the recommended age range; during this period, DT and Td vaccines were recommended for the children aged 2 to 17 years. Three risk periods were defined as 0–3 days, 4–7 days, and 8–14 days after vaccination, and were compared to the background risk of seizures among the study participants (excluding the 7-day period before vaccination). A total of 788 participants from the 2–17-year age group reported 862 seizures during the study period. The relative risk of seizures within 0–3 days of DT or Td vaccine administration was 2.87 (95% CI, 0.70–11.75), within 4–7 days was 1.13 (95% CI, 0.14–8.94), within 8–14 days was 0.60 (95% CI, 0.07–4.80), and within 0–14 days was 1.33 (95% CI, 0.44–4.00). The authors found no increased risk of seizures following DT or Td vaccination among the 2–17 year age group, but they noted the confidence intervals were wide.

The study by Yih et al. (2009) was described in detail in the section on encephalitis or encephalopathy. This cohort study compared the incidence of seizures after Tdap vaccine to a historical Td comparison population. The observed number of seizures in the Tdap cohort (34 events) was less than the historical Td cohort (40.35 events), which resulted in a relative risk of 0.84 (confidence interval not provided). The authors concluded that the risk of seizures following Tdap vaccination is not significantly higher than the risk following Td vaccination, which only provides information on the safety of the acellular pertussis antigen component.

Huang et al. (2010) conducted a retrospective cohort study in children (6 weeks to 23 months of age) enrolled in seven MCOs participating in the VSD from 1997 through 2006. Children with seizure diagnoses were identified using the International Classification of Diseases, 9th revision (ICD-9) codes for seizures, seizures in newborn, simple febrile seizures, complex febrile seizures, other seizures, epilepsy, and myoclonus. The events were limited to inpatient and emergency department visits, which could miss seizures that only required a physician visit. Vaccination information was obtained from the MCOs' automated immunization tracking systems. The participant follow-up began at 6 weeks of age and continued until 23 months of age, disenrollment from the MCO, death, or December 31, 2006, whichever occurred first. A total of 433,654 children were included in the analysis and received 1,343,067 doses of DTaP vaccine during the study period. The exposed person-time period was defined as 0 to 3 days after DTaP vaccination and the remaining observed person-time was classified as unexposed. The risk-interval cohort analysis compared all exposed person-time to unexposed person-time, adjusted for multiple factors (MCO, gender, calendar year, season, age, and receipt of MMR or MMRV within 8–14 days). The case-crossover analysis, which only included children with seizure diagnoses, matched each patient's exposed period with the unexposed period for the same patient and adjusted for multiple factors (calendar year, season, age, and receipt of MMR or MMRV within 8–14 days). The adjusted relative risk of seizures within 0–3 days of DTaP vaccination across all doses was 0.87 (95% CI, 0.72–1.05) for the risk-interval analysis and 0.91 (95% CI, 0.75–1.10) for the case-crossover analysis. The authors concluded that DTaP administration is not associated with a significantly increased risk of seizures within 0 to 3 days of vaccination. Stratifying by dose and postvaccination risk interval did not change the association, which remained nonsignificant.

Weight of Epidemiologic Evidence

Only one study (Huang et al., 2010) examined the association of DTaP vaccination and seizures; this study found no association. The study by Andrews et al. (2007) found no association of seizures with DT or Td vaccine in children ≥ 2 years of age, but since the confidence intervals were wide it was not able to rule out a clinically relevant association. The paper by Yih et al. (2009) found no increased risk of seizures after Tdap vaccination compared to historical data on this adverse event after Td vaccination, which only provided information on the safety of the acellular pertussis antigen component. Although the studies were consistent in failing to find an association between forms of DTaP vaccine and seizures, a true association may have been missed if only well children were selected for vaccination, thus at reduced risk of fever from background infections. See Table 10-2 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 10-2

Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis–Containing Vaccines and Seizures.

The committee has limited confidence in the epidemiologic evidence, based on three studies that lacked validity and precision, to assess an association between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and seizures.

Mechanistic Evidence

The committee identified 20 publications reporting the development of seizures after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination. Cizewska and colleagues (1981) reported electroencephalogram changes after administration of a diphtheria and tetanus toxoid vaccine but did not report any seizures. The remaining publications did not provide evidence beyond temporality (Berkovic et al., 2006; Decker and Edwards, 1996; Decker et al., 1995; Greco et al., 1996; Hamidon and Raymond, 2003; Herini et al., 2010; Knuf et al., 2006; McIntosh et al., 2010; Miyake et al., 2001; Netterlid et al., 2009; Pollock and Morris, 1983; Pollock et al., 1984; Preziosi et al., 1997; Ramsay et al., 1994; Satoh and Watanabe, 1997; Schmitt et al., 1996; Stehr et al., 1998; Uberall et al., 1997; Zimmerman and Pellitieri, 1994). In addition, two publications reported patients either ill at the time of vaccination or an infection diagnosed the day after vaccination (Knuf et al., 2006; Satoh and Watanabe, 1997). The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.4: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and seizures.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of ataxia after the administration of DTaP vaccine. This one study (Geier and Geier, 2004) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Mechanistic Evidence

The committee identified one publication reporting the development of ataxia after the administration of DTaP vaccine. Kubota and Takahashi (2008) did not provide evidence of causality beyond a temporal relationship of 2 days between vaccine administration and development of cerebellar symptoms leading to a diagnosis of acute cerebellar ataxia. The publication did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.5: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and ataxia.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of autism after the administration of DTaP vaccine. This one study (Geier and Geier, 2004) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of autism after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.6: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and autism.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of acute disseminated encephalomyelitis (ADEM) after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee identified five publications of ADEM developing after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens alone or in combination. Four publications did not provide evidence beyond temporality, one of which was deemed too short based on the possible mechanisms involved (Abdul-Ghaffar and Achar, 1994; Bolukbasi and Ozmenoglu, 1999; Hamidon and Raymond, 2003; Rogalewski et al., 2007). In addition, Rogalewski et al. (2007) reported the administration of vaccines against hepatitis B, hepatitis A, and poliovirus in addition to diphtheria and tetanus toxoids, making it difficult to determine which vaccine, if any, could have been the precipitating event. These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Lopez-Pison and colleagues (2004) described a 14-year-old girl diagnosed with ADEM 7 to 20 days after receiving a tetanus toxoid vaccine. Eight years prior the patient developed neurological symptoms 15 days after receiving a diphtheria toxoid, tetanus toxoid, whole cell pertussis vaccine, and an oral polio vaccine.

Causality Conclusion

Conclusion 10.7: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and ADEM.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of transverse myelitis after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee identified four publications reporting the development of transverse myelitis after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. The publications did not provide evidence beyond temporality (Cizman et al., 2005; Riel-Romero, 2006; Whittle and Robertson, 1977; Zanoni et al., 2002). In addition, three publications reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event (Cizman et al., 2005; Whittle and Robertson, 1977; Zanoni et al., 2002). Furthermore, Cizman and colleagues (2005) reported that one patient had a concomitant infection with Epstein-Barr virus. The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.8: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and transverse myelitis.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of optic neuritis after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens alone or in combination. This one controlled study (DeStefano et al., 2003) was included in the weight of epidemiologic evidence and is described below.

DeStefano et al. (2003) conducted a case-control study to evaluate the association between tetanus toxoid vaccination and optic neuritis using data from three health maintenance organizations (HMOs) participating in the VSD. The optic neuritis analysis included 108 cases and 228 controls. The cases had a documented physician's diagnosis from 1995 through 1999, and were matched to controls from the HMO on date of birth (within 1 year) and sex. The authors evaluated the date of disease onset using data described in the medical record or reported in the telephone interview. The immunization status was obtained from vaccination records, medical records, and telephone interviews. The study had high rates of self-reported vaccinations from outside the HMO system (38 percent of cases and 30 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with tetanus toxoid or combined tetanus toxoid and diphtheria (Td) before optic neuritis diagnosis was 0.6 (95% CI, 0.4–1.1). The authors concluded that tetanus toxoid vaccination does not appear to be associated with an increased risk of optic neuritis in adults.

Mechanistic Evidence

The committee identified one publication reporting the development of optic neuritis after the administration of vaccines containing tetanus toxoid antigens. The publication did not provide evidence beyond temporality (Quast et al., 1979). The publication did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.9: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and optic neuritis.

Epidemiologic Evidence

The committee reviewed five studies to evaluate the risk of onset (date of first symptom) of multiple sclerosis (MS) in adults after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens alone or in combination. Three controlled studies (Kurtzke et al., 1997; Lauer and Firnhaber, 1990; Pekmezovic et al., 2004) had very serious methodological limitations that precluded their inclusion in this assessment. Kurtzke et al. (1997) enrolled controls (family members or neighbors of the cases) that could have introduced selection bias, and the vaccination information provided in the self-report questionnaire was not validated. The control group used in the study by Lauer et al. (1990) was flawed, and the authors may have selected a group at greater or lesser likelihood to receive the vaccine. The case-control study from Pekmezovic et al. (2004) used an inadequate control group that included patients diagnosed with other various neurological disorders.

The two remaining controlled studies (DeStefano et al., 2003; Hernan et al., 2004) were included in the weight of epidemiologic evidence and are described below.

The study by DeStefano et al. (2003) was described in detail in the section on optic neuritis. This case-control study evaluated the association between tetanus toxoid vaccination and MS or optic neuritis using data from three HMOs participating in the VSD. The MS analysis included 332 cases and 722 controls. Although there is a large number of cases and controls, the study had high rates of self-reported vaccinations from outside the HMO system (38 percent of cases and 30 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with tetanus toxoid or Td before MS onset was 0.6 (95% CI, 0.4–0.8). The authors found tetanus toxoid vaccination to be associated with a significant decreased risk of MS onset in adults.

Hernan et al. (2004) used the General Practice Research Database (GPRD) to perform a nested case-control study. Cases with a confirmed MS diagnosis from 1993 through 2000, and a minimum of 3 years follow-up in the database, were selected and matched with controls on age (within 1 year), sex, general practice, and date of joining the practice (within 1 year). The study included 163 cases and 1,604 controls. The date of first symptom of MS and tetanus toxoid vaccination status were identified in the medical record. The rates of vaccination were very low among the cases and controls (11.7 percent and 17.4 percent, respectively), which raised the possibility that subjects selected for vaccination were importantly different. The odds ratio for MS onset within 3 years of immunization against tetanus toxoid was 0.6 (95% CI, 0.4–1.0). The authors concluded that tetanus toxoid vaccination does not appear to be associated with an increased risk of MS onset in adults.

Weight of Epidemiologic Evidence

Neither of the two case-control studies considered in the assessment of the epidemiologic evidence found an association between tetanus toxoid vaccine and onset of MS in adults. However, there are some concerns about the study design and analyses. DeStefano et al. (2003) did not define a specific exposure time and had no short-term assessment in their primary analysis. The authors performed secondary analyses considering the timing of the tetanus toxoid vaccination (< 1 year, 1–5 years, and > 5 years) relative to the MS onset, which showed no significant association, but they did not state how they handled the timing of vaccination for those who had more than one tetanus toxoid vaccine before the onset of MS or when tetanus toxoid was given in combination with other vaccines. Hernan et al. (2004) considered a fixed exposure time of 3 years within the onset of MS but did not present results on any subanalysis considering the timing of the tetanus toxoid vaccination. In addition, the rates of vaccination were very low among the cases and controls. Given these study limitations and the small number of studies, the committee has limited confidence in the overall evidence. See Table 10-3 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 10-3

Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis–Containing Vaccines and MS Onset in Adults.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision, to assess an association between diphtheria toxoid or tetanus toxoid vaccine and onset of MS in adults.

The epidemiologic evidence is insufficient or absent to assess an association between acellular pertussis vaccine and onset of MS in adults.

Mechanistic Evidence

The committee identified one publication reporting the onset of MS in adults after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens alone or in combination. The publication did not provide evidence beyond temporality (Rogalewski et al., 2007). In addition, the patient was vaccinated against hepatitis B, hepatitis A, and poliovirus concomitantly, making it difficult to determine which, if any, vaccine could have been the precipitating event. In addition, the committee identified two publications that studied whether the antibodies against tetanus toxoid and diphtheria toxoid are predictive of the development of MS (Massa et al., 2009; Salmi et al., 1981). The publications found no difference between the level of antibodies against tetanus toxoid and diphtheria toxoid between MS cases and matched controls. The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.10: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and onset of MS in adults.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of relapse of MS (date of third demyelinating episode) in adults after the administration of vaccines containing tetanus toxoid antigens. This one controlled study (Confavreux et al., 2001) contributed to the weight of epidemiologic evidence and is described below.

Confavreux et al. (2001) conducted a case-crossover study in adults attending neurology centers affiliated with the European Database for Multiple Sclerosis. The study included 643 adults with definite or probable MS diagnosis and at least one relapse of symptoms that occurred from 1993 through 1997. The relapse was confirmed during outpatient visits or during hospitalizations at the neurology centers. The immunization status was obtained from telephone questionnaires and confirmed with vaccination records or written confirmation from the physician. Vaccinations were confirmed for 260 participants, not confirmed for 57, and 326 reported receiving no vaccinations during the study period. Tetanus toxoid vaccinations were given alone or in combination with poliovirus or diphtheria or both. The risk period was defined as any time within 2 months before the relapse, and the four control periods were outlined as 2-month intervals prior to the risk period (2 to 10 months before the relapse). The relative risk of relapse of MS within 2 months of administration of tetanus toxoid vaccine was 0.75 (95% CI 0.23–2.46). The authors concluded that tetanus toxoid vaccination does not appear to increase the risk of MS relapse in adults.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of MS relapse in adults after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.11: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, and acellular pertussis–containing vaccine and relapse of MS in adults.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of relapse of MS (date of second episode) in children after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens in combination. This one controlled study (Mikaeloff et al., 2007) contributed to the weight of epidemiologic evidence and is described below.

Mikaeloff et al. (2007) conducted a retrospective cohort study with children (younger than 16 years of age) enrolled in the French Kid Sclérose en Plaques (KIDSEP) neuropediatric dataset. The study included 356 children with a first episode of acute central nervous system (CNS) inflammatory demyelination that occurred from 1994 through 2003, of which 165 received tetanus toxoid vaccine and 191 were not vaccinated after the first episode. In all but one case, tetanus toxoid vaccination was combined with other vaccinations: tetanus toxoid, diphtheria, and polio (98 cases); tetanus toxoid, diphtheria, pertussis, and polio (45 cases); and tetanus toxoid, diphtheria, pertussis, polio, and Haemophilus influenza B (22 cases). The outcome reported was a second episode of neurological symptoms. The first episode was confirmed in the medical record, and the second episode was reported through routine clinical visits and telephone interviews until the end of 2005. The immunization status was obtained from vaccination certificates, and telephone interviews were used for six participants that did not provide certificates. The participants exposed to tetanus toxoid vaccine significantly differed from those without the vaccination. In particular, those who were vaccinated were more likely to have had infections during the month before a first episode, more frequently from low socioeconomic status families, younger at first episode, and less likely to have a first episode after 1997. The adjusted hazard ratio for relapse of MS within 3 years of tetanus toxoid vaccination was 0.99 (95% CI, 0.58–1.67). Adjusted hazard ratios were also reported for MS relapse within 3 months (HR, 0.79; 95% CI, 0.25–2.50), 6 months (HR, 1.22; 95% CI, 0.59–2.53), and 1 year (HR, 0.97; 95% CI, 0.51–1.84) of tetanus toxoid vaccination. The authors concluded that tetanus toxoid vaccination is not associated with a significant increased risk of a second episode of MS in children.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of relapse of MS in children after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.12: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and relapse of MS in children.

Epidemiologic Evidence

The committee reviewed four studies to evaluate the risk of Guillain-Barré syndrome (GBS) after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. Three studies (Kuno-Sakai and Kimura, 2004; Souayah et al., 2009; Tuttle et al., 1997) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. The one remaining study (Yih et al., 2009) lacked an unvaccinated comparison population for the GBS analysis and thus did not contribute to the epidemiologic weight of evidence.

Mechanistic Evidence

The committee identified 10 publications reporting the development of GBS after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. The publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved (Bakshi and Graves, 1997; Holliday and Bauer, 1983; Hopf Ch, 1980; Newton and Janati, 1987; Pritchard et al., 2002; Quast et al., 1979; Schessl et al., 2006; Schlenska, 1977; Talbot et al., 2010; Zimmerman and Pellitieri, 1994). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. One publication also reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event (Schessl et al., 2006). Furthermore, Schessl et al. (2006) reported that one patient had an upper respiratory infection in the 6 weeks preceding the diagnosis of GBS. The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.13: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccines and GBS.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of chronic inflammatory disseminated polyneuropathy (CIDP) after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee identified five publications reporting CIDP after the administration of vaccines containing tetanus toxoid antigens. Two publications did not provide evidence beyond temporality (Pritchard et al., 2002; Quast et al., 1979). The publications did not contribute to the weight of mechanistic evidence. Described below are three publications that merit further discussion.

Pollard and Selby (1978) reported one case of a 42-year-old man who developed limb weakness, at times associated with numbness, after receiving tetanus toxoid vaccines administered after sustaining minor trauma or lacerations of the feet on three occasions. The first, second, and third episodes developed 3 weeks, 2 weeks, and 10 days, respectively, after vaccination. The first and second episodes were separated by 9 years while the second and third episodes were separated by 5 years. The patient was subsequently diagnosed with a spontaneously relapsing remitting neuropathy and experienced episodes in association with acute viral infections.² The authors did not rule out other possible causes (e.g., viral illnesses) and did not provide evidence beyond a temporal relationship between administration of the vaccine and development of symptoms after vaccination.

Reinstein et al. (1982) described a 33-year-old man presenting with occasional numbness of the feet 8 weeks after receiving a tetanus toxoid vaccine administered upon sustaining minor trauma. The patient received two additional tetanus toxoid vaccines, after sustaining minor trauma or lacerations, 4 and 5 months after the administration of the first vaccine. The patient noted increased numbness and weakness during the 6 weeks after administration of the third vaccine.

Hughes and colleagues (1996) described a 27-year-old man presenting with a peripheral neuropathy 8 weeks after administration of a tetanus toxoid vaccine. The patient experienced two relapses after administration of tetanus toxoid vaccines 21 and 25 years after the first episode. The latency between the relapses and vaccination were not reported.

Causality Conclusion

Conclusion 10.14: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and CIDP.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of opsoclonus myoclonus syndrome (OMS) after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of OMS after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.15: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and OMS.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of Bell's palsy after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. This one controlled study (Yih et al., 2009) contributed to the weight of epidemiologic evidence and is described below.

The study by Yih et al. (2009) was described in detail in the section on encephalitis or encephalopathy. This cohort study compared the incidence of cranial nerve disorders, including Bell's palsy, after Tdap vaccine to a historical Td comparison population. The observed number of cranial nerve disorders in the Tdap cohort (126 events) was greater than the historical Td cohort (100.8 events), which resulted in a relative risk of 1.25 (confidence interval not provided). The authors concluded that the risk of cranial nerve disorders following Tdap vaccination is not significantly higher than the risk following Td vaccination, which only provides information on the safety of the acellular pertussis antigen component.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of Bell's palsy after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.16: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and Bell's palsy.

Epidemiologic Evidence

The committee reviewed eight studies to evaluate the risk of anaphylaxis after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination. These eight studies (Bohlke et al., 2003; Gold et al., 1999; Jackson et al., 2009; Jacobs et al., 1982; Korger et al., 1986; Kuno-Sakai and Kimura, 2003; Nakayama et al., 1999; Thierry-Carstensen et al., 2004) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems or lacked unvaccinated comparison populations.

Mechanistic Evidence

The committee identified 11 publications describing clinical, diagnostic, or experimental evidence of anaphylaxis after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. Two publications reported a temporal association between administration of a tetanus containing vaccine and development of symptoms, but the committee did not consider the symptoms to be definitive anaphylaxis (Bohlke et al., 2003; Chanukoglu et al., 1975). Four publications reported anaphylaxis after vaccination but did not report a time frame between vaccination and development of symptoms (Nakayama and Onoda, 2007; Peng and Jick, 2004; Pollock and Morris, 1983; Thierry-Carstensen et al., 2004). These publications did not contribute to the weight of mechanistic evidence.

Described below are five publications that contributed to the weight of mechanistic evidence.

Bhatia (1985) described a 12-year-old boy presenting with a deep wound on a lower limb. Due to a family history of allergy, a test dose of a 1:10 dilution of tetanus toxoid was administered intradermally. Within a few minutes the patient developed local pain and itching increasing to generalized urticaria, a rapid thready pulse, and severe bronchospasm.

Bilyk and Dubchik (1978) described the case of a 38-year-old patient presenting with a laceration to the right hand. Two to three minutes after receiving purified and adsorbed tetanus toxoid the patient developed dizziness, tinnitus, nausea, vomiting, erythematous skin rash, tachycardia, and breathing difficulty.

Mandal and colleagues (1980) described the case of a 21-year-old woman (case 1) presenting with restlessness, itching over the tongue initially and then the whole body, a sensation of warmth, inspiratory difficulty with rhonchi, tightness in the throat with voice change, pain in the lower back and abdomen, erythema and swelling of the face and neck, and an urticarial rash on the limbs 2 to 3 minutes after receiving the second dose of a tetanus toxoid vaccine.

Mansfield and colleagues (1986) describe two cases of anaphylaxis after exposure to a tetanus toxoid vaccine. Case 1 describes a 33-year-old woman presenting with a severe anaphylactic reaction involving wheezing, facial edema, and peripheral urticaria 5 minutes after skin prick testing to full-strength tetanus toxoid. The patient was treated with epinephrine, corticosteroids, and antihistamines. Furthermore, at the age of 4 years the patient developed an urticarial rash and fever after receiving tetanus toxoid and tetanus antitoxin. Case 2 (case 3 in the publication) describes a 23-year-old highly atopic man who collapsed after experiencing wheezing and generalized itching after skin prick testing with full-strength tetanus toxoid.

Zaloga and Chernow (1982) reported the case of a 20-year-old man presenting with dyspnea, wheezing, lightheadedness, stridor, and the loss of consciousness within minutes of receiving purified fluid tetanus toxoid. The patient recovered after treatment with two doses of epinephrine and diphenhydramine hydrochloride.

Causality Conclusion

Conclusion 10.17: The evidence convincingly supports a causal relationship between tetanus toxoid vaccine and anaphylaxis.

Conclusion 10.18: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid or acellular pertussis vaccine and anaphylaxis.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of chronic urticaria after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of chronic urticaria after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.19: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and chronic uticaria.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of serum sickness after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee identified one publication reporting clinical, diagnostic, or experimental evidence of serum sickness after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens alone or in combination. Daschbach (1972) described a 7-year-old boy presenting with typical serum sickness 3 days after administration of a diphtheria and tetanus toxoid vaccine while being treated for a burn. The patient was treated with corticosteroids and antihistamines. Laboratory examination of the patient's serum revealed precipitins for tetanus but not diphtheria.

Causality Conclusion

Conclusion 10.20: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and serum sickness.

Epidemiologic Evidence

The committee reviewed three studies to evaluate the risk of arthropathy after the administration of vaccines containing diphtheria toxoid and tetanus toxoid antigens alone or in combination. One study (Stetler et al., 1985) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Two controlled studies (Bengtsson et al., 2010; Pattison et al., 2008) were included in the weight of epidemiologic evidence and are described below.

Pattison et al. (2008) conducted a case-control study in 98 patients with psoriatic arthritis and 163 psoriasis controls in the United Kingdom. The cases were identified through a nationwide campaign and confirmed by local consultant rheumatologists, whereas controls were recruited from the Psoriasis Clinic at the Dermatology Centre, Hope Hospital, Salford. A self-report questionnaire was sent to the cases and controls to assess exposures in the 10 years before disease onset; 64.9 percent of the cases and 50.0 percent of the controls responded to the questionnaire. The authors reported an increased risk of psoriatic arthritis after tetanus toxoid vaccination (OR, 1.91; 95% CI, 1.0–3.7).

Bengtsson et al. (2010) conducted a case-control study in adults living in parts of Sweden from May 1996 through June 2006. The cases were diagnosed with rheumatoid arthritis by a rheumatologist and were identified at rheumatology units in Sweden. Controls were selected from the national population register and matched to cases on age, sex, and residential area. A questionnaire was given to the cases and controls to report vaccination histories in the 5 years before disease onset. A total of 1,998 (95 percent) cases and 2,252 (81 percent) controls completed the questionnaire and were included in the analysis. The major weakness of the study was that it employed no independent verification of reported immunizations, and past studies have suggested that many people do not keep careful written records nor do they have accurate memories of past immunizations. The odds ratio for rheumatoid arthritis diagnosis within 5 years of administration of tetanus toxoid vaccine was 1.0 (95% CI, 0.8–1.2) and diphtheria vaccine was 1.0 (95% CI, 0.7–1.4). The authors concluded that tetanus toxoid or diphtheria vaccination does not increase the risk of rheumatoid arthritis. Apparently, combination vaccines with pertussis antigen were not studied.

Weight of Epidemiologic Evidence

The two studies described above had serious limitations and low precision. One study by Pattison et al. (2008) found an association with tetanus toxoid vaccine in a small subgroup—individuals with psoriasis; thus the results could not be generalized to all adults. The study by Bengtsson et al. (2010) found no association with tetanus toxoid or diphtheria vaccine, but it relied on subject self-report to determine immunization status. Also, there was no assessment of pertussis antigen exposure, which is a component of many vaccines for diphtheria and tetanus toxoid administered in the United States. The committee did not identify any controlled studies that investigated the risk of arthritis and DTaP vaccine, or the risk of arthralgia and tetanus toxoid–containing vaccines. Therefore, the weight of epidemiologic evidence has a narrow focus. See Table 10-4 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 10-4

Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis–Containing Vaccines and Arthropathy.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision, to assess an association between diphtheria toxoid or tetanus toxoid vaccine and chronic arthritis.

The epidemiologic evidence is insufficient or absent to assess an association between acellular pertussis vaccine and arthropathy.

Mechanistic Evidence

The committee identified 12 publications reporting arthropathy after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. Sidebotham and Lenton (1996) did not provide clinical, diagnostic, or experimental evidence of causality, including the latency between administration of a diphtheria and tetanus toxoid vaccine and development of joint aches after vaccination. Eleven publications did not provide evidence beyond temporality (Aksu et al., 2006; Cassidy et al., 2005; David et al., 2006; Gasparini et al., 2010; Hong et al., 2000; Jawad and Scott, 1989; Kaul et al., 2002; Pichichero et al., 2005; Pou et al., 2008; Sahin et al., 2009; Zimmerman and Pellitieri, 1994). In addition, four publications reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event (Aksu et al., 2006; Cassidy et al., 2005; Gasparini et al., 2010; Pou et al., 2008). The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.21: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and arthropathy.

Epidemiologic Evidence

The committee reviewed five studies to evaluate the risk of type 1 diabetes after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. These five controlled studies (Blom et al., 1991; DeStefano et al., 2001; Hviid et al., 2004; Klein et al., 2010; Patterson, 2000) contributed to the weight of epidemiologic evidence and are described below.

Blom et al. (1991) conducted a case-control study in diabetic children (0 to 14 years of age) enrolled in the Swedish Childhood Diabetes Register from September 1985 through August 1986. A total of 393 children with type 1 diabetes were matched to 786 controls (two controls for each case matched on age, sex, and county) from the official Swedish population register. The dates of vaccination were ascertained from questionnaires that were sent to the parents of cases and their matched controls within 4 weeks of disease diagnosis. Questionnaires were returned for 86 percent of the cases and 67 percent of the controls. There were no systematic differences in the age, sex, and county categories of those that returned the questionnaire compared to those that did not, but other factors that were not reported in the study could suggest selection bias. Self-report vaccination data were compared to vaccination records from the local child health care centers and school health units. The authors were able to validate the vaccination status of 88.5 percent and 82.1 percent of the cases and controls, respectively. Since the relative risk ratio of matched and unmatched data remained close to 1, the case and control matching was removed to avoid losing information during the analysis. The odds ratio for type 1 diabetes diagnosis any time after vaccination with combined diphtheria and tetanus toxoids vaccine is 0.96 (95% CI, 0.71–1.30), and for tetanus toxoid vaccine it is 0.96 (95% CI, 0.70–1.31). The authors concluded that combined diphtheria and tetanus toxoids vaccination, or tetanus toxoid vaccination, does not increase the risk of type 1 diabetes in children.

Patterson et al. (2000) conducted a case-control study in children (under 15 years of age) with type 1 diabetes enrolled at the seven centers participating in the European Diabetes: Aetiology of Childhood Diabetes on an Epidemiological Basis (EURODIAB ACE) Group from 1989 through 1995. Controls were selected at each center from population registers, general practitioners' lists, or school rolls, and matched to cases by age. Of the 1,028 cases and 3,044 controls invited to participate in the study, 900 (87.5 percent) and 2,302 (75.6) responded, respectively. The authors did not provide any information on the nonresponders. Vaccination data were obtained from parent interviews or questionnaires depending on the center, and were validated with official records or child health care booklets in 74 percent of the cases and 78 percent of the controls. A diagnosis date was assigned to each control based on the midpoint of the recruitment period for the corresponding diabetic child. The Mantel Haenszel approach was used to stratify the analysis by center; the odds ratio for type 1 diabetes diagnosis any time after tetanus toxoid vaccination was 1.20 (95% CI, 0.66–2.19), and any time after diphtheria toxoid vaccination it was 1.09 (95% CI, 0.62–1.93). A logistic regression analysis was used to adjust for confounding variables; the odds ratio for type 1 diabetes diagnosis any time after tetanus toxoid vaccination was 1.56 (95% CI, 0.73–3.33), and any time after diphtheria toxoid vaccination it was 1.27 (95% CI, 0.63–2.56). The authors concluded that administration of tetanus toxoid or diphtheria toxoid vaccine does not increase the risk of type 1 diabetes in children.

DeStefano et al. (2001) conducted a case-control study in children (10 months to 10 years of age) enrolled in four HMOs participating in the VSD. A total of 252 type 1 diabetes cases and 768 matched controls were included in the analysis. The study required participants to be born in 1988 through 1997, enrolled in the HMO since birth, and continuously enrolled for the first 6 months of life. Additionally, cases had to be enrolled at least 12 months before the diabetes diagnosis except when diagnosis occurred before 12 months of age. The case index date was defined as the first date of type 1 diabetes diagnosis in the medical record; controls were assigned the same index date as their matched case. At least three controls were matched to each case on sex, date of birth (within 7 days), HMO, and length of enrollment in the HMO (up to the index date). Trained chart abstractors obtained complete vaccination histories from the medical records of the cases and controls. Acellular pertussis vaccination was introduced in the later years of the study, and only 23 percent of the cases and controls received the vaccine. The results of two conditional logistic regression models were provided: model 1 stratified by the matching variables; model 2 stratified by the matching variables and race, ethnicity, and family history of type 1 diabetes (additional variables also obtained from medical records). The odds ratio for diabetes diagnosis any time after acellular pertussis vaccination using model 1 was 0.92 (95% CI, 0.53–1.57), and using model 2 it was 1.12 (95% CI, 0.63–1.99). The authors concluded that vaccination with acellular pertussis does not increase the risk of type 1 diabetes in children.

Hviid et al. (2004) conducted a retrospective cohort study in children born from January 1990 through December 2000 and who resided in Denmark through December 2001 (end of study period). The participants were identified in the Danish Civil Registration System, and linked to information on type 1 diabetes diagnoses in the Danish National Hospital Register and vaccination data from the National Board of Health. The children were followed from birth and removed from the study at the first occurrence of an outcome of interest. The study outcomes included diagnosis of type 1 diabetes, loss to follow-up or emigration, reaching 12 years of age, and death. Vaccination status was considered a time-varying variable and was classified according to the number of doses administered (zero, one, two, or three doses of each vaccine). A total of 739,694 children were included in the study, of whom 16,421 were prematurely removed from the analysis because of loss to follow-up, emigration, or death. The rate ratio for type 1 diabetes diagnosis any time after at least one dose of combined DTaP-IPV vaccine (compared to the unvaccinated) was 0.96 (95% CI, 0.71–1.30). The study also evaluated the rate ratios of diabetes diagnosis 1, 2, 3, 4, and > 4 years after DTaP-IPV vaccination and found no significant differences. The authors concluded that DTaP-IPV vaccination does not increase the risk of type 1 diabetes in children.

Klein et al. (2010) conducted a cohort study in children (10 to 18 years of age) enrolled in the Northern California Kaiser Permanente (NCKP) Health Care Plan. Children who received a Tdap vaccination during September 2005 through December 2006 were included in the analysis and monitored for type 1 diabetes diagnoses for the 6 months following vaccination (ending in June 2007). To identify new cases of diabetes, no diagnoses could appear in the medical records during the year before vaccination. The study identified a historical NCKP comparison cohort who received a Td vaccination from June 2002 through September 2005, and was matched to the Tdap cohort on age, sex, geographic location, and season of vaccination. Each cohort included 12,509 children for a total of 25,018 study participants. The matched odds ratio for type 1 diabetes diagnosis within 6 months following Tdap vaccination (compared to type 1 diabetes within 6 months of Td vaccination) was 0.333 (95% CI, 0.006–4.151). However, only one event and three events of diabetes were observed in the Tdap and Td cohorts, respectively, which resulted in low statistical power to detect an association. The authors concluded that Tdap vaccination does not increase the risk of type 1 diabetes in children compared to Td vaccination, which only provides information on the safety of the acellular pertussis antigen component.

Weight of Epidemiologic Evidence

The five observational studies consistently report no increased risk of type 1 diabetes following vaccination with diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination; two studies had negligible limitations (Patterson et al., 2000; Hviid et al., 2004). The five studies had relatively large sample sizes and were representative of European and U.S. populations of children across a broad range of ages and varying time periods at risk of type 1 diabetes following vaccination. See Table 10-5 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 10-5

Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis–Containing Vaccines and Type 1 Diabetes.

The committee has a high degree of confidence in the epidemiologic evidence based on five studies with validity and precision to assess an association between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and type 1 diabetes; these studies consistently report a null association.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of type 1 diabetes after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.22: The evidence favors rejection of a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and type 1 diabetes.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of myocarditis after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee identified five publications reporting myocarditis developing after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. The publications did not provide evidence beyond temporality (Amsel et al., 1986; Dilber et al., 2003; Korger et al., 1986; Langsjoen and Stinson, 1965; Thanjan et al., 2007). In addition, two publications also reported the administration of additional vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event (Amsel et al., 1986; Thanjan et al., 2007). The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.23: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and myocarditis.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of fibromyalgia after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of fibromyalgia after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Causality Conclusion

Conclusion 10.24: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and fibromyalgia.

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of sudden infant death syndrome (SIDS) after the administration of DTaP vaccine. This one study (Geier and Geier, 2004) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Mechanistic Evidence

The committee identified three publications reporting SIDS after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. The publications did not provide evidence beyond temporality (Balci et al., 2007; Pollock et al., 1984; Schmitt et al., 1996). In addition, Balci and colleagues (2007) reported the administration of additional vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. Also, Schmitt et al. (1996) reported that the incidence of SIDS after administration of Infanrix was not higher than expected based on the incidence of SIDS in the general population. The publications did not contribute to the weight of mechanistic evidence.

Causality Conclusion

Conclusion 10.25: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and SIDS.

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of immune thrombocytopenic purpura (ITP) after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.

Mechanistic Evidence

The committee identified two publications reporting ITP developing after administration of DTaP vaccine. Demircioglu and colleagues (2009) did not provide evidence of causality beyond a temporal relationship of less than 1 month between administration of diphtheria, tetanus, pertussis and oral polio vaccines and development of ITP in two patients, younger than 2 years of age, diagnosed from 1995 through 2007. During the study period diphtheria, tetanus, whole cell pertussis, and DTaP vaccines were administered, and the authors did not indicate which vaccine was administered prior to the development of ITP. Furthermore, the concomitant administration of vaccines make it difficult to determine which, if any, vaccine could have been the precipitating event. Hsieh and Lin (2010) reported one case of thrombocytopenic purpura developing 88 days after administration of the second dose of a hepatitis B vaccine and the first dose of a DTaP vaccine in a 3-month-old patient. The long latency between vaccine administration and development of symptoms make it impossible to rule out other possible causes. The publications did not contribute to the mechanistic weight of evidence.

Causality Conclusion

Conclusion 10.26: The evidence is inadequate to accept or reject a causal relationship between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and ITP.