Tetanus toxoid has been in use for several decades in tetanus immunisations. It is recommended for all infants 6 to 8 weeks of age and older, all children, and all adults. Immunisation against tetanus consists first of a series of either 3 or 4 injections, depending on the type of Tetanus toxoid used. Booster injections are recommended every 10 years for the rest of one’s life. An emergency booster is also administered following a deep puncture or wound that is unclean or hard to clean, in particular if it has been more than 5 years since the last booster.
Tetanus toxoid may be delivered alone, as part of diptheria and tetanus vaccination (DT), or most commonly, as part of DTP vaccine (diphtheria, tetanus and pertussis), which is in the normal vaccination calendar in childhood.
No allergens from this substance have yet been fully characterised. Tetanus toxin is a potent neurotoxin of molecular weight 150 kDa, produced by the anaerobic bacterium Clostridium tetani (1). In 4 children who developed immediate urticaria after Tetanus toxoid vaccine, IgE and IgG antibodies recognised 2 proteins derived from Tetanus toxoid, of 150 and 50 kDa, corresponding respectively to the intracellular form and to a chain of the extracellular form of the Tetanus neurotoxin (2).
Adverse reactions to Tetanus toxoid (TT) vaccine are mostly mild and limited to the injection site. These include pain and tenderness, erythema and oedema, marked swelling, and, uncommonly, abscess formation. Actual IgE-mediated reactions are rare, occurring in approximately 0.001% (1/million) of individuals receiving this vaccine (2-6).
Malaise, transient fever, pain, hypotension, nausea and arthralgia may develop in some patients after the injection. Arthus-type hypersensitivity reactions, characterised by severe local reactions (generally starting 2 to 8 hours after an injection) have been reported, particularly in persons who have received multiple prior boosters (7).
A retrospective review of 740 charts of patients with a history of adverse reaction to Tetanus toxoid immunisation found that the most common reactions, by history, were local oedema and tenderness (33%), fever (15%), and anaphylactoid responses (33%). Three patients who had a vesicular eruption at the immunisation site were found to have delayed hypersensitivity to mercury. Thirty percent of the patients had received Tetanus toxoid within 1 year and 55% within 5 years of evaluation (8).
Four cases of IgE-mediated reactions to Tetanus toxoid vaccine were described, and indicate the variability of the response (9). Two hours after receiving a Tetanus toxoid booster, a 38-year-old man developed a severe but localised reaction consisting of erythema, swelling, pain, and induration, which spontaneously remitted within 10 days. A second subject was an atopic 19-year-old man, who as a child had experienced local erythema and oedema a few minutes after the first administration of the combined diphtheria and Tetanus toxoid vaccine (DT); he was also reported to have experienced, a few hours after his second DT booster a year later, generalised urticaria, facial angioedema, and fever. His most recent, adult DT booster resulted in painful local erythematous induration and fever, which required corticosteroid therapy. A third patient, a 6-year-old boy, developed local painful oedema a few hours after receiving a DT booster. Forty-eight hours later, he experienced a progressive systemic reaction consisting of skin erythema and pruritus, generalised urticaria, facial angioedema, scotoma, and fever, which remitted after oral corticosteroids. Finally, a 35-year-old woman experienced erythema and pruriginous oedema at the injection site 3 weeks after receiving a Tetanus toxoid booster. Two months later, a further dose of tetanus vaccine was administered; local painful oedema appeared within 24 hours, progressively extending to the whole arm and eyelids. All these subjects were shown to have serum-specific IgE to Tetanus toxoid. Subjects 3 and 4 also exhibited skin-specific IgE positive to Tetanus toxoid. The authors commented that the clinical significance of specific IgE to TT is unclear, since tetanus vaccine may induce specific IgE antibodies even in subjects who do not experience adverse effects after immunisation (9).
Four children who developed immediate urticaria after Tetanus toxoid vaccine, both after the vaccine and after a booster 5 years later, were described. All 4 children were shown to be skin-specific IgE-positive to Tetanus toxoid, but negative to thimerosal and aluminum phosphate; 3 developed a reaction after intramuscular provocation using increasing doses of Tetanus toxoid vaccine; and 1 refused to be tested. After 5 years the IgG antibodies were still high in all cases, but the Tetanus toxoid-specific IgE had decreased by 50% (2).
As suggested above, the manufacturing process of Tetanus toxoid may result in the presence of a number of other substances that play a role in immune-mediated reactions, such as Tetanus toxoid antigens, thimerosal or aluminum phosphate antimicrobials (2); there may be inadvertent exposure to Latex, as the stopper to the vial may contain dry Natural latex rubber. Aluminum hydroxide, like thimerosal an organic mercurial compound used as a preservative in Tetanus toxoid vaccine, may be sensitising and cause delayed hypersensitivity reactions (9).
For example, an 18-month-old boy had had 2 episodes of generalised eczema starting within 24 hours of routine administration of DPT vaccine. The patch test to 2-phenoxyethanol was positive. This substance is an antimicrobial effective against a broad spectrum of micro-organisms, particularly Pseudomonas aeuginosa, and is used in products such as vaccines, although thimerosal may be more commonly used (10).
A 38-year-old woman, who was sensitised to Horse albumin, experienced a severe anaphylactic reaction when injected with Horse anti-Tetanus toxoid serum. A skin prick test with pure antiserum and intradermal tests with a 1/1000 dilution of Horse anti-Tetanus toxoid serum were positive. Serum-specific IgE was undetectable for the Horse allergen Equ c1, but tests were highly positive for Horse, Cat and Dog serum albumins. The authors conclude the anaphylaxis was a result of allergy to Horse serum albumin (11).
Adverse reactions may also be attributable to toxoids other than Tetanus, as this forms only part of the DT vaccine (diptheria-tetanus) and the DPT vaccine (diptheria-pertussis-tetanus).
For example, an anaphylactic reaction after the administration of the fifth booster dose of DT vaccine to a 6-year-old child was described. Skin- and serum-specific IgE showed that the IgE response was directed against Tetanus and diphtheria toxoids. IgG antibodies were also detected by ELISA and immunoblotting. The Specific IgE tests and immunoblotting inhibitions showed no cross-reactivity between the 2 toxoids, indicating the presence of co-existing but non-cross-reacting IgE and IgG antibodies. This was confirmed with repeat analysis at 18 and 30 months after the episode. The study suggests that after an immediate reaction to DT, evaluation of specific IgE antibodies to both Tetanus and diphtheria toxoid should be undertaken (12).
The clinical significance of specific IgE to Tetanus toxoid is unclear, since Tetanus vaccine may induce specific IgE antibodies even in subjects who do not experience adverse effects after immunisation. For example, 50% of 538 24-month-old children developed detectable Tetanus toxoid-specific IgE antibodies in response to immunisation, but no major systemic or large local clinical reactions were reported after immunisation with TT (13).
Reaction proneness to Tetanus toxoid vaccine was reported to correlate with serum antitoxin levels. Among 104 adults with adverse reactions to TT vaccine, 97% had at least 4 times the minimal protective level of antibodies (i.e., 0.01 IU/ml), and 58% had levels higher than 5 IU/ml (14). In view of such phenomena, immediate skin test reactivity to TT does not always help to determine the mechanism of adverse reactions to the vaccine, as they may not be IgE-mediated.
In approximately 25% of subjects receiving tetanus booster immunisation, substantial serum IgE antibody levels were found. IgE response to immunisation appears to peak before the IgG response and was found to often be higher at week 1 than at week 2. The study noted that in 2 subjects who received 2 booster injections, at the time of the second injection very high serum IgE and IgG levels to Tetanus toxoid were present, but no signs of an allergic reaction were noted. A significant association with atopy-related factors was found, but many apparently non-atopic subjects developed IgE antibodies (15).
Unexpectedly long duration of the IgE response has been reported in a number of studies. A study investigated the effects of diphtheria and Tetanus toxoids 2 years after a DT booster with either an adsorbed or a nonadsorbed fluid vaccine, given at 10 years of age. Although IgE levels had declined, detectable IgE to diphtheria and Tetanus toxoids was still found in 82% and 67% of samples, respectively. The prevalence of allergic symptoms was similar in the 2 vaccination groups (16).
A number of neurological complications have been reported to be associated with vaccines containing Tetanus toxoid (17): these include cochlear lesions (18), brachial plexus neuropathies (18-19), paralysis of the radial nerve (20), paralysis of the recurrent nerve (18), accommodation paresis, Guillain-Barré syndrome (GBS), EEG disturbances with encephalopathy, and relapsing neuropathy (21).
- Niemann, H. Molecular Biology of Clostridial Neurotoxins in Sourcebook of Bacterial Protein Toxins J. E. Alouf and J.H. Freer, eds., Academic Press, 1991;303-348.
- Mayorga C, Torres MJ, Corzo JL, Alvarez J, Garcia JA, Rodriguez CA, Blanca M, Jurado A. Immediate allergy to tetanus toxoid vaccine: determination of immunoglobulin E and immunoglobulin G antibodies to allergenic proteins. Ann Allergy Asthma Immunol 2003 Feb;90(2):238-43.
- Vervloet D, Pradal M, Castelain M. Drug Allergy. ISBN 91-973440-0-1. Pharmacia & Upjohn Diagnostics 1999
- Barbaud A, Schmutz JL, Mougeolle JM. Cutaneous immunoallergic reactions caused by vaccines. (Article in French) Ann Derm Venereol 1995;122(3):129-38
- Leonar-Bellfill R, Cistero-Bahima A, Cerda-Trias MT, Olive-Perez A. Tetanus toxoid anaphylaxis. Ann Pharmacother 1991;25:870.
- Atanaskovic-Markovic M, Nestorovic B. Desensitization to diphtheria, tetanus and pertussis vaccine. [Serbian] Srp Arh Celok Lek 2003;131(11-12):427-31.
- Recommendations of the Immunization Practices Advisory Committee (ACIP). Diphtheria, Tetanus, and Pertussis: Recommendations for vaccine use and other preventive measures. MMWR 40: No. RR-10, 1991
- Sutter RW. Adverse reactions to tetanus toxoid. JAMA 1994;271(20):1629
- Bellioni Businco B, Paganelli R, Bruno G, Grossi O, Di Rienzo A, Businco L. Allergy to tetanus toxoid vaccine. Allergy 2001;56(7):701-2
- Vogt T, Landthaler M, Stolz W. Generalized eczema in an 18-month-old boy due to phenoxyethanol in DPT vaccine. Contact Dermatitis 1998 Jan;38(1):50-1.
- Demoly P, Botros HG, Rabillon J, David B, Bousquet J. Anaphylaxis to antitetanus toxoid serum. Allergy 2002;57(9):860-1