Adverse Effects of Vaccines Evidence and Causality (2012) / Chapter Skim
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10 Diphtheria Toxoid, Tetanus Toxoid, and Acellular PertussisContaining Vaccines
10 Diphtheria Toxoid, Tetanus Toxoid, and Acellular PertussisContaining Vaccines
Pages 525-598
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From page 525... ...
. 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)
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From page 526... ...
. 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)
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. "The action of tetanus toxin on the brain and sympathetic nervous system is less well documented" (AAP, 2009)
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From page 528... ...
(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)
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From page 529... ...
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.
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From page 530... ...
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.
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From page 531... ...
25 mg pertussis toxin; 25 mg FHA; 8.0 mg pertactin DTaP DAPTACEL Sanofi Pasteur, Ltd 0.5 mL (single- 15 LF diphtheria toxoid; 0 6 weeks– 5 Intramuscular dose vials) 5 LF tetanus toxoid; 6 years 10 mg pertussis toxin; 5 mg FHA; 3 mg PRN; 5 mg FIM 531 continued
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From page 532... ...
25 µg pertussis toxin; 25 µg FHA; 8 µg pertactin; 10 µg HBsAg; 40 DU type 1 poliovirus; 8 DU type 2 poliovirus; 32 DU type 3 poliovirus DTaP-IPV KINRIX GlaxoSmithKline 0.5 mL (single- 25 LF diphtheria toxoid 0 4–6 years Booster Intramuscular Biologicals dose vials and 10 LF tetanus toxoid; syringes) 25 µg pertussis toxin; 25 µg FHA; 8 µg pertactin; 40 DU type 1 poliovirus; 8 DU type 2 poliovirus; 32 DU type 3 poliovirus DTaP- Pentacel Sanofi Pasteur 0.5 mL 15 LF diphtheria toxoid; 0 6 weeks– 4 Intramuscular IPV-Hib Limited (two vials: 5 LF tetanus toxoid; 4 years combination 20 µg PT; of DTaP- 20 µg FHA; IPV vaccine 3 µg PRN; and ActHIB 5 µg FIM; vaccine)
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From page 533... ...
2 LF diphtheria toxoid; years 2.5 µg PT; 5 µg FHA; 5 µg FIM; 3 µg PRN Tdap Boostrix GlaxoSmithKline 0.5 mL (single- 5 LF tetanus toxoid; 0 Booster Intramuscular ≥ 10 Biologicals dose vials and 2.5 LF diphtheria toxoid; years syringes)
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From page 534... ...
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)
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From page 535... ...
The committee has limited confidence in the epidemiologic evi dence, based on two studies that lacked validity and precision, to assess an association between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and encephalitis or encephalopathy.
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From page 536... ...
Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence. Schwarz and colleagues (1988)
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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. INFANTILE SPASMS 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.
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From page 538... ...
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)
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From page 539... ...
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.
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From page 540... ...
. 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.
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The committee has limited confidence in the epidemiologic evi dence, 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.
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From page 542... ...
days after RR of seizures within vaccination 8–14 days of DT or Td vaccination: 0.60 (95% CI, 0.07–4.80) Yih Diagnostic Seven Ages Cohort with 660,000 Relative risk of seizures in None Serious et al.
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Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.
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From page 544... ...
The committee assesses the mechanistic evidence regarding an as sociation between acellular pertussis vaccine and seizures as weak based on knowledge about the natural infection. The committee assesses the mechanistic evidence regarding an as sociation between diphtheria toxoid or tetanus toxoid vaccine and seizures as lacking.
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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. AUTISM Epidemiologic Evidence The committee reviewed one study to evaluate the risk of autism after the administration of DTaP vaccine.
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From page 546... ...
after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination. Weight of Epidemiologic Evidence The epidemiologic evidence is insufficient or absent to assess an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccines and ADEM.
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From page 547... ...
Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of ADEM; however, the publications did not provide evidence linking these mechanisms to diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine. The committee assesses the mechanistic evidence regarding an as sociation between tetanus toxoid vaccine and ADEM as weak based on one case.
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From page 548... ...
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)
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From page 549... ...
Weight of Epidemiologic Evidence The committee has limited confidence in the epidemiologic evi dence, based on one study that lacked validity and precision, to assess an association between diphtheria toxoid or tetanus toxoid vaccine and optic neuritis. The epidemiologic evidence is insufficient or absent to assess an association between acellular pertussis vaccine and optic neuritis.
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The committee assesses the mechanistic evidence regarding an as sociation between the diphtheria toxoid–, tetanus toxoid–, or acel lular pertussis–containing vaccine and optic neuritis as lacking. 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.
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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.
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Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.
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From page 553... ...
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)
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Weight of Epidemiologic Evidence The committee has limited confidence in the epidemiologic evi dence, based on one study that lacked validity and precision, to assess an association between tetanus toxoid vaccine and relapse of MS in adults. The epidemiologic evidence is insufficient or absent to assess an association between diphtheria toxoid or acellular pertussis vaccine and relapse of MS in adults.
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MULTIPLE SCLEROSIS RELAPSE IN CHILDREN 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.
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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. Weight of Mechanistic Evidence Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the committee did not identify literature reporting evidence of these mechanisms after administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination.
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From page 557... ...
Weight of Epidemiologic Evidence The epidemiologic evidence is insufficient or absent to assess an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccines and GBS. 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.
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From page 558... ...
after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination. Weight of Epidemiologic Evidence The epidemiologic evidence is insufficient or absent to assess an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and CIDP.
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From page 559... ...
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.
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From page 560... ...
after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination. Weight of Epidemiologic Evidence The epidemiologic evidence is insufficient or absent to assess an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and OMS.
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From page 561... ...
BELL'S PALSY 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)
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From page 562... ...
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. Weight of Mechanistic Evidence While rare, infection with Clostridium tetani or Corynebacterium diphtheria has been associated with facial nerve palsy (MacGregor, 2010; Reddy and Bleck, 2010)
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From page 563... ...
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)
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From page 564... ...
The patient recovered after treatment with two doses of epinephrine and diphenhydramine hydrochloride. Weight of Mechanistic Evidence The publications, described above, presented clinical evidence sufficient for the committee to conclude the vaccine was a contributing cause of anaphylaxis after administration of a tetanus toxoid vaccine.
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From page 565... ...
Weight of Epidemiologic Evidence The epidemiologic evidence is insufficient or absent to assess an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and chronic urticaria. 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.
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SERUM SICKNESS 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. Weight of Epidemiologic Evidence The epidemiologic evidence is insufficient or absent to assess an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and serum sickness.
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From page 567... ...
The committee assesses the mechanistic evidence regarding an as sociation between acellular pertussis vaccine and serum sickness as lacking. 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.
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From page 568... ...
The committee has limited confidence in the epidemiologic evi dence, 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.
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From page 569... ...
toxoid through nationwide arthritis arthritis arthritis vaccination campaign and diagnosis diagnosis 163 control within 10 controls recruited confirmed by after tetanus patients with years of from Psoriasis local consultant toxoid psoriasis disease onset Clinic at the rheumatologists vaccination: Dermatology 1.91 (95% Centre, Hope CI, 1.0–3.7) Hospital, Salford 569 continued
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From page 570... ...
toxoid or 6/2002 rheumatoid arthritis arthritis Controls diphtheria arthritis by a diagnosis Cases were matched 2,252 controls toxoid rheumatologist within 5 years identified at on age, vaccination of tetanus rheumatology sex, and within 5 toxoid units in Sweden residential years of vaccination: and controls were area disease onset 1.0 (95% CI, selected from the 0.8–1.2) national population register OR for rheumatoid arthritis diagnosis within 5 years of diphtheria toxoid vaccination: 1.0 (95% CI, 0.7–1.4)
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From page 571... ...
Weight of Mechanistic Evidence The symptoms described in the publications referenced above are consistent with those of arthropathy. Autoantibodies, T cells, complement activation, immune complexes, and infection may contribute to arthropathy; however, the publications did not provide evidence linking these mechanisms to diphtheria toxoid–, tetanus toxoid–, or acellular pertussis– containing vaccine.
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From page 572... ...
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)
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From page 573... ...
. The authors concluded that administration of tetanus toxoid or diphtheria toxoid vaccine does not increase the risk of type 1 diabetes in children.
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From page 574... ...
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)
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From page 575... ...
reported to years with type 1 combined diphtheria and the Swedish diabetes tetanus toxoid vaccination: Cases were Childhood 0.96 (95% CI, 0.71–1.30) enrolled in 786 Diabetes the Swedish controls OR for type 1 diabetes Register Childhood matched diagnosis any time after Diabetes on age, tetanus toxoid vaccination: Register sex, and 0.96 (95% CI, 0.70–1.31)
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From page 576... ...
school rolls OR for type 1 diabetes diagnosis any time after diphtheria toxoid vaccination using a logistic regression analysis: 1.27 (95% CI, 0.63–2.56; p = .51)
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From page 577... ...
diabetes in the VSD 1988 with type 1 after acellular pertussis diagnosis in through diabetes vaccination using Model 1: the medical 1997, ages 0.92 (95% CI, 0.53–1.57) 768 record 10 months controls OR for type 1 diabetes to 10 years matched diagnosis any time on sex, after acellular pertussis date of vaccination using Model 2: birth, 1.12 (95% CI, 0.63–1.99)
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Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.
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From page 579... ...
Weight of Mechanistic Evidence Autoantibodies, T cells, complement activation, and molecular mimicry may contribute to the symptoms of type 1 diabetes; however, the committee did not identify literature reporting evidence of these mechanisms after administration of vaccines containing diphtheria toxoid, tetanus toxoid, and acellular pertussis antigens alone or in combination. The committee assesses the mechanistic evidence regarding an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and type 1 diabetes as lacking.
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From page 580... ...
Autoantibodies, complement activation, molecular mimicry, and T cells may contribute to the symptoms of myocarditis; however, the publications did not provide evidence linking these mechanisms to diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine. The committee assesses the mechanistic evidence regarding an as sociation between diphtheria toxoid vaccine and myocarditis as weak based on knowledge about the natural infection.
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From page 581... ...
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. Weight of Mechanistic Evidence The committee assesses the mechanistic evidence regarding an as sociation between diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine and fibromyalgia as lacking.
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From page 582... ...
after the administration of vaccines containing diphtheria toxoid, tetanus toxoid, or acellular pertussis antigens alone or in combination.
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From page 583... ...
Weight of Mechanistic Evidence The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of ITP. Autoantibodies, complement activation, immune complexes, and T cells may contribute to the symptoms of ITP; however, the publications did not provide evidence linking these mechanisms to diphtheria toxoid–, tetanus toxoid–, or acellular pertussis–containing vaccine.
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From page 584... ...
584 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY 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. CONCLUDING SECTION Table 10-6 provides a summary of the epidemiologic assessments, mechanistic assessments, and causality conclusions for diphtheria toxoid–, tetanus toxoid–, and acellular-pertussis-containing vaccines.
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From page 585... ...
–, and Acellular Pertussis (aP) –Containing Vaccines Studies Contributing Cases Contributing Epidemiologic to the Epidemiologic Mechanistic to the Mechanistic Causality Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion DT, TT, or Encephalitis Limited 2 Weak 1 Inadequate aP containing DT, TT, or Encephalopathy Limited 2 Weak 1 Inadequate aP containing DT, TT, or Infantile Spasms Limited 1 Lacking None Inadequate aP containing (diphtheria toxoid or tetanus toxoid)
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From page 586... ...
Insufficient None (acellular pertussis) DT, TT, or Multiple Sclerosis Onset in Limited 2 Lacking None Inadequate aP containing Adults (diphtheria toxoid or tetanus toxoid)
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From page 587... ...
TT Anaphylaxis Insufficient None Strong 6 Convincingly Supports DT or aP Anaphylaxis Insufficient None Lacking None Inadequate DT, TT, or Chronic Urticaria Insufficient None Lacking None Inadequate aP containing DT, TT, or Serum Sickness Insufficient None Weak 1 Inadequate aP containing (diphtheria toxoid or tetanus toxoid Lacking None (acellular pertussis) 587 continued
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From page 588... ...
Lacking None (tetanus toxoid or acellular pertussis) DT, TT, or Fibromyalgia Insufficient None Lacking None Inadequate aP containing DT, TT, or Sudden Infant Death Insufficient None Lacking None Inadequate aP containing Syndrome DT, TT, or Immune Thrombocytopenic Insufficient None Lacking None Inadequate aP containing Purpura *
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From page 589... ...
1997. Guillain-Barré syndrome after combined tetanus diphtheria toxoid vaccination.
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From page 590... ...
1995. Comparison of 13 acellular pertussis vaccines -- adverse reactions.
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From page 591... ...
2004. An evaluation of serious neurological disorders follow ing immunization: A comparison of whole-cell pertussis and acellular pertussis vaccines.
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From page 592... ...
2009. Frequency of medically attended adverse events following tetanus and diphtheria toxoid vaccine in adolescents and young adults: A Vaccine Safety Datalink study.
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From page 593... ...
2010. Post-marketing safety evaluation of a tetanus toxoid, reduced diphtheria toxoid and 3-component acellular pertussis vaccine administered to a cohort of adolescents in a United States health maintenance organization.
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From page 594... ...
1999. A clinical analysis of gelatin allergy and determination of its causal relationship to the previous administration of gelatin containing acellular pertussis vaccine combined with diphtheria and tetanus toxoids.
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From page 595... ...
1996. The safety of acellular pertussis vaccine vs whole cell pertussis vaccine: A postmarketing assessment.
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From page 596... ...
1996. Clinical experi ence of a tricomponent acellular pertussis vaccine combined with diphtheria and tetanus toxoids for primary vaccination in 22,505 infants.
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From page 597... ...
1997. Severe adverse events in a comparative efficacy trial in Germany in infants receiving either the Lederle/Takeda acellular pertussis component DTP (DTaP)
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