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PubMed1991

Immunity and immunization of children against tetanus in sweden.

Tetanus antitoxin titres were determined in sera of 457 children, 6-, 10- and 16- year-old. Primary vaccination against tetanus had been given as 3 doses of DPT or DT vaccine at intervals of 4-6 weeks beginning in the 2nd or 3rd month of life. A booster dose is offered to schoolchildren at 8-10 years of age. As boosters, the children were given 0.1, 0.25 or 0.5 ml of diphtheria/tetanus toxoid (DT) containing 7.5 Lf/ml tetanus toxoid. The antitoxin titres against tetanus were much higher than those against diphtheria found in previous studies. Blood samples tested from 68 children, 5-year-old, who had been given basic immunization according to a spaced time schedule showed that 97% of the children had levels greater than 0.1 IU/ml. Prior to booster injection of the 6-year-old children, 1% lacked protective titre levels (greater than or equal to 0.01 IU/ml). 53% had antitoxin titre levels of greater than or equal to 0.01 - less than 0.1 IU/ml and 46% had levels of 0.1 IU/ml. The corresponding figures for the 10-year-old were 6, 65 and 29%, and for the 16-year-old 2, 7 and 91% respectively. After a booster injection high antitoxin levels were seen in all children. 95% had levels greater than 1 IU/ml irrespective of vaccine dose.

Adolescent↗
PubMed1991

Neonatal tetanus despite protective serum antitoxin concentration.

Using the ELISA technique to estimate serum antibodies against tetanus toxin, seven neonates with clinical tetanus were found to have antibody levels 4-13 times higher than the presumed minimum protective level of 0.01 IU/ml. All but one of their mothers had been vaccinated with tetanus toxoid in pregnancy. In two other neonates, whose mothers had received multiple booster doses of toxoid during pregnancy, the anti-toxin concentrations were 100- and 400-times the presumed protective level. Therefore the toxin dose may overwhelm the pre-existing anti-toxin level and produce disease. Furthermore, multiple booster injections of tetanus toxoid may not only enhance serum anti-toxin titres, but could also lead to an ineffective immune response.

Enzyme-Linked Immunosorbent Assay↗
PubMed1992

Clinical reactions and immunogenicity of the BIKEN acellular diphtheria and tetanus toxoids and pertussis vaccine in 4- through 6-year-old US children.

OBJECTIVE--To compare the immunogenicity and reactogenicity of a two-component acellular pertussis vaccine with a whole-cell diphtheria and tetanus toxoids and pertussis vaccine (W-DTP) when administered as a booster to children 4 through 6 years of age. DESIGN--This was a randomized, double-blind study. SETTING--Children in this study were from three general pediatric practices (two were private, one was university-affiliated). PARTICIPANTS--Three hundred and sixteen 4- through 6-year-old children who had received four previous W-DTP immunizations at the recommended times were studied. SELECTION PROCEDURES AND INTERVENTIONS--Children were randomly assigned in a 1:3 ratio to receive either W-DTP or one of three lots of acellular diphtheria and tetanus toxoids and pertussis vaccine (A-DTP). The A-DTPs contained 3.75 micrograms each of lymphocytosis promoting factor and filamentous hemagglutinin protein nitrogen per 0.5 mL and the same concentrations of diphtheria and tetanus toxoids as W-DTP. Serum samples were obtained on the day of immunization and 4 to 6 weeks later. Adverse reactions were recorded by parents at 6, 24, 48, and 72 hours. MEASUREMENTS AND RESULTS--An indirect enzyme-linked immunosorbent assay (ELISA) method determined IgG antibody response to lymphocytosis promoting factor, filamentous hemagglutinin, and tetanus toxoid; a CHO cell assay measured neutralizing antibodies to pertussis toxin; and serum neutralization on VERO cells assayed diphtheria antitoxin. One month after booster doses were administered, the geometric mean antibody levels for A-DTP vs W-DTP were IgG filamentous hemagglutinin, 362 vs 104 ELISA U/mL; IgG lymphocytosis promoting factor, 408 vs 81 ELISA U/mL; CHO cell, 210 vs 107; diphtheria, 21.7 vs 12.1 U/mL; and tetanus, 2.86 vs 2.04 Eq/mL. Following immunization with A-DTP, local and systemic adverse experiences were 30% to 50% and 20% to 30% fewer, respectively, as compared with W-DTP. CONCLUSIONS--The BIKEN A-DTP vaccine used in this study demonstrates enhanced immunogenicity to lymphocytosis promoting factor, filamentous hemagglutinin, and other measured antigens and less reactogenicity compared with licensed W-DTP [corrected].

Antibodies, Bacterial↗
PubMed1992

Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc.

Tetanus and botulinum neurotoxins are the most potent toxins known. They bind to nerve cells, penetrate the cytosol and block neurotransmitter release. Comparison of their predicted amino acid sequences reveals a highly conserved segment that contains the HexxH zinc binding motif of metalloendopeptidases. The metal content of tetanus toxin was then measured and it was found that one atom of zinc is bound to the light chain of tetanus toxin. Zinc could be reversibly removed by incubation with heavy metal chelators. Zn2+ is coordinated by two histidines with no involvement in cysteines, suggesting that it plays a catalytic rather than a structural role. Bound Zn2+ was found to be essential for the tetanus toxin inhibition of neurotransmitter release in Aplysia neurons injected with the light chain. The intracellular activity of the toxin was blocked by phosphoramidon, a very specific inhibitor of zinc endopeptidases. Purified preparations of light chain showed a highly specific proteolytic activity against synaptobrevin, an integral membrane protein of small synaptic vesicles. The present findings indicate that tetanus toxin, and possibly also the botulinum neurotoxins, are metalloproteases and that they block neurotransmitter release via this protease activity.

Acetylcholine↗
PubMed2000

Safety and immune responses to attenuated Salmonella enterica serovar typhi oral live vector vaccines expressing tetanus toxin fragment C.

Attenuated Salmonella enterica serovar Typhi vaccine strain CVD 908-htrA was used as a vector to deliver fragment C of tetanus toxin as a single-dose oral tetanus vaccine candidate to elicit protective levels of serum tetanus antitoxin. Twenty-one healthy adult volunteers received doses of 1.6 x 10(7) to 8.2 x 10(9) CFU of one of two strains, CVD 908-htrA(pTETnir15) or CVD 908-htrA(pTETlpp), which contained plasmid-encoded fragment C, with sodium bicarbonate, and the safety and immune responses to serovar Typhi antigens and tetanus toxin were assessed. No volunteer had fever or positive blood cultures after vaccination, although diarrhea occurred in 3 volunteers and vomiting in 2 volunteers within 3 weeks after vaccination. Most volunteers excreted the vaccine strain in the first 72 h after vaccination. Three of nine volunteers who received 10(8) CFU or higher doses of the CVD 908-htrA(pTETlpp) construct developed rises in serum antitoxin antibodies. The serum and cellular immune responses to serovar Typhi antigens were less frequent than those previously observed in volunteers who ingested the parent strain CVD 908-htrA. This study demonstrates that fragment C of tetanus toxin delivered orally to volunteers in an S. Typhi vector can elicit protective levels of serum antitoxin.

Adolescent↗
PubMed1991

Distinct targets for tetanus and botulinum A neurotoxins within the signal transducing pathway in chromaffin cells.

Tetanus and botulinum A neurotoxins inhibited exocytosis evoked by various secretagogues in intact and permeabilized chromaffin cells. The block of exocytosis in intact chromaffin cells due to botulinum A neurotoxin could partially be overcome by enhancing nicotine- and veratridine-induced stimulation, whereas the block due to tetanus toxin persisted under the same conditions. The receptor-mediated restoration of 3H-noradrenaline release was specific for nicotinic stimulation, because exocytosis did not occur during muscarinic stimulation. Depolarization of intact chromaffin cells with increasing concentration of K+ failed to restore exocytosis that had been blocked by either toxin. When chromaffin cells, treated with tetanus or botulinum A neurotoxins, were exposed to the Ca2(+)-ionophore A 23187 or permeabilized by staphylococcal alpha-toxin, Ca2(+)-stimulated exocytosis was also inhibited. The inhibition was unaffected by increasing concentrations of free Ca2+. Activation of proteinkinase C and of G-proteins by phorbolester and GMPPNHP, respectively, increased Ca2(+)-induced exocytosis in control cells as well as in cells treated with tetanus and botulinum A neurotoxins. The block, however, could not be relieved by these manipulations, and it could not be relieved by activating the cGMP or cAMP pathways with analoga of cyclic nucleotides, phosphodiesterases inhibitors, and forskolin either. It is concluded that nicotine and veratridine trigger a mechanism within the sequence of events leading to exocytosis that is located beyond the increase in intracellular Ca2(+)-concentration. This pathway may not be affected by botulinum A neurotoxin. The target of tetanus toxin is probably located even closer to the fusion process, i.e. beyond the step upon which botulinum A neurotoxin acts.

Adrenal Glands↗
PubMed1994

Pore formation by tetanus toxin, its chain and fragments in neuronal membranes and evaluation of the underlying motifs in the structure of the toxin molecule.

The pore-forming activity of tetanus toxin, its chains and fragments was studied on membrane patches from spinal cord neurons of fetal mice using the outside-out patch-clamp configuration. 1. The dichain tetanus toxin forms pores at pH 5, but not at pH 7.4. The elementary pore conductance is 38.4 +/- 1.1 pS and nonselective for small cations. The open probability of the pores is voltage-dependent and increases with membrane depolarisation. The pores activate at +80 mV with a time constant of about 20 ms and deactivate at -80 mV with two time constants of about 2 ms and 10 ms. Besides the elementary pore conductance, larger pore conductances which are multiples of the elementary conductance were observed. With increasing conductances, their frequency of occurrence decreases exponentially. 2. The light chain of tetanus toxin alone does not form pores in neuronal membranes at pH 5 or at pH 7.4. 3. The heavy chain of tetanus toxin forms pores at pH 5 as well as at pH 7.4. The single pore conductance increases from 35.0 +/- 1.2 pS at pH 5 to 43.2 +/- 1.8 pS at pH 7.4. The pores allow mono- and divalent cations and chloride ions to pass. Only at pH 5 do they have a voltage dependence with time constants identical to those obtained with tetanus toxin. 4. Secondary structure predictions show a high density of presumably helically organized elements in fragment beta 2 (45 kDa) of the heavy chain between residues 700-850.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Tetanus in Switzerland 1980-1989.

Tetanus cases that occurred in Switzerland between 1980 and 1989 have been reviewed with the help of three data surveillance systems: a) morbidity data from the Federal Office of Public Health (FOPH), b) mortality data from the Swiss Federal Statistical Office (SFSO), and c) data from the Association of Swiss Hospitals and Clinics (VESKA), completed by a written enquiry to clinics which did not (or only partly) participate in the VESKA system during the study period. For every case, a questionnaire was sent to the clinic to verify the diagnosis and to obtain additional information on the circumstances of occurrence. Ninety-one cases were identified. This corresponds to a yearly incidence of 1.93 per million population between 1980-84 and 0.88 for the 1985-89 period (p < 0.01). Eighty-one percent of the cases were older than 50 years of age and women were significantly more frequently affected than men. None of the cases identified had a documented primary immunization series. Data available at the FOPH and SFSO level have been compared to data obtained through the VESKA system using the Chandra Sekhar and Deming method. It is estimated that 134 tetanus cases (95% CI: 91-197) have occurred in Switzerland between 1980 and 1989, together with 28 deaths (95% CI: 27-31). Based on these estimates, FOPH appears to detect only 6-13% of tetanus cases occurring in Switzerland. By contrast, SFSO had fairly consistent data for 81-100% of tetanus associated deaths. The low rate of tetanus reported by physicians necessitates a sustained effort to increase the understanding of epidemiological surveillance by Swiss practitioners.

Adolescent↗
PubMed1979

Dysfunction of the sympathetic nervous system in tetanus. A study of 3 cases.

In severe cases of tetanus an overactivity of the sympathetic nervous system has been postulated because of the clinical symptoms including hypertension, fluctuating blood pressure, tachycardia, tachyarrhythmia and peripheral vasoconstriction. In the present study the involvement of the sympathetic nervous system in tetanus was investigated by serial determinations of plasma adrenaline (A) and noradrenaline (NA) in 2 patients who developed severe symptoms of tetanus and the characteristic cardiovascular disturbances. Sustained high circulating levels of NA and A could be observed indicating a prolonged overactivity of the sympathetic nervous system. In one case, the elevation of the NA level in plasma persisted until the disturbances of the motor nervous system ceased. In a third case of tetanus without cardiovascular abnormalities, the plasma NA and A only increased slightly on a few occasions. The results demonstrate that an overactivity of the sympathetic nervous system can complicate the course of severe tetanus.

Adult↗
PubMed2005

[Acute aspiration and trismus due to tetanus].

Tetanus is a worldwide health problem, causing the deaths of approximately 1,000,000 people every year. In Germany, about 15 infections are reported annually. The initial symptoms often develop in the head and neck region. As a result, some patients are referred to the otorhinolaryngologist. We report on a 83 year old female who suffered from recurrent aspiration and trismus. She had acquired a small injury on her lower leg 2 weeks earlier; protective antibody levels did not exist. The neurophysiological examination showed a result typical of tetanus. The patient received tetanus immunoglobulin, metronidazole and benzodiazepines. Due to respiratory problems, tracheotomy and ventilation became necessary. Elderly people often lack protective antibody levels against tetanus. If typical symptoms are manifest, tetanus has to be considered as a possibility. A complete history, including recent injuries and past vaccinations, should be compiled.

Acute Disease↗
PubMed1997

Management of blood pressure instability in severe tetanus: the use of clonidine.

OBJECTIVE: To evaluate the effectiveness of clonidine in the management of unstable blood pressure in severe tetanus. DESIGN: Patients with severe tetanus and blood pressure instability were treated with clonidine and the results were compared with those of other patients with severe tetanus who were not treated with clonidine. SETTING: Intensive care unit of the Chest Hospital of Athens. PATIENTS: We studied 27 patients with severe tetanus and autonomic dysfunction. INTERVENTIONS: Patients were managed according to a protocol. MEASUREMENTS AND RESULTS: Clonidine was administered until blood pressure stability was the fully restored and the dose was then gradually reduced. Five patients from the nonclonidine group and 2 from the clonidine group died. CONCLUSIONS: These results suggest that clonidine is effective in the treatment of blood pressure instability in severe tetanus.

Adrenergic alpha-Agonists↗
PubMed2002

Tetanus: continuing problem in the developing world.

Despite diligent efforts by the World Health Organization and the governments of developing world countries, tetanus persists as a global health problem. This retrospective study was undertaken to assess the outcome for victims of tetanus presenting to the Baptist Medical Centre in Ogbomoso, Nigeria and to develop better management techniques for future patients. Sixty patients (46 males, 14 females) with nonneonatal tetanus were seen over a 5-year period (1995-1999). The mean age was 26 years, and 74% were 30 years or younger. All patients were treated with antitetanus serum, antibiotics, wound débridement (when a wound was identified), and antispasmodics. No patients underwent tracheostomy or gastrostomy. The mortality rate was 44%. Factors significant for predicting mortality were age greater than 14 years, occupation as a farmer, short incubation period, short symptom duration, high degree of severity on presentation, and high temperature during hospital care. The best hope for improvement in the treatment of tetanus in our institution is more conscientious titration of antispasmodics to control spasms without causing significant respiratory depression. The only real hope for reducing the global mortality for tetanus, however, lies in renewed immunization efforts by all health care providers in developing world countries, not just community health workers.

Adolescent↗
PubMed1981

Structure of tetanus toxin: the arrangement of papain digestion products within the heavy chain-light chain framework of extracellular toxin.

Upon digestion with papain, single chain intracellular tetanus toxin was completely converted to the extracellular form of the toxin, which consists of two disulfide-linked polypeptide chains (heavy chain and light chain of tetanus toxin). A portion of the material was degraded further by papain to yield the two major protein fragments, B and C, respectively, previously identified after digesting extracellular tetanus toxin with this enzyme. Thus it may be concluded that the order of release of these of these fragments from the intracellular toxin does not provide a clue as to their position within the original molecule. However, N-terminal analysis of the two fragments in conjunction with recent N-terminal data on tetanus toxin itself clearly indicated that fragment B of tetanus toxin contains the light chain polypeptide and the N-terminal portion of the heavy chain, whereas fragment C is derived from the C-terminal portion of the heavy chain.

Clostridium tetani↗
PubMed1992

Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis.

Tetanus toxin is a potent neurotoxin that inhibits the release of neurotransmitters from presynaptic nerve endings. The mature toxin is composed of a heavy and a light chain that are linked via a disulfide bridge. After entry of tetanus toxin into the cytoplasm, the released light chain causes block of neurotransmitter release. Recent evidence suggests that the L-chain may act as a metalloendoprotease. Here we demonstrate that blockade of neurotransmission by tetanus toxin in isolated nerve terminals is associated with a selective proteolysis of synaptobrevin, an integral membrane protein of synaptic vesicles. No other proteins appear to be affected by tetanus toxin. In addition, recombinant light chain selectively cleaves synaptobrevin when incubated with purified synaptic vesicles. Our data suggest that cleavage of synaptobrevin is the molecular mechanism of tetanus toxin action.

Animals↗
PubMed1975

Comparison between the retrograde axonal transport of nerve growth factor and tetanus toxin in motor, sensory and adrenergic neurons.

In previous studies it has been shown that nerve growth factor (NGF) is taken up with high selectivity by adrenergic and sensory nerve terminals and is transported retrogradely to the corresponding cell bodies by a colchicine sensitive mechanism 10,11,23. The present study was designed to investigate whether this retrograde transport of NGF depends on properties of the nerve terminals which are common to all the neurons or restricted to those which respond to NGF either during the whole life cycle (adrenergic neurons) or during a restricted period of embryonic development (sensory neurons). In order to investigate the retrograde transport of NGF in motor neurons we injected [125I]NGF into the musculus deltoideus and measured the side differences of accumulation of radioactivity in the spinal cord (C6-C8) from 4-48 h. At no time was there a preferential accumulation of radioactivity on the injected side. In contrast, tetanus toxin was accumulated preferentially on the injected side and an approximate rate of transport of 7.5 mm/h was calculated. Astonishingly there was also a retrograde transport of tetanus toxin in sensory and adrenergic neurons. The rate of transport was identical to that of NGF and the transport could be blocked by transection of the corresponding nerve fibers and local administration of colchicine. After unilateral injection of [125I]tetanus toxin into the forepaw or the musculus deltoideus light microscopic autoradiographs revealed heavily labeled neuronal cell bodies in the dorsal root ganglia or the ventrolateral spinal cord of the injected side. It is concluded that the retrograde transport of [125I]NGF depends on properties of the neuronal membrane which are specific for adrenergic and sensory neurons, whereas that of tetanus toxin is determined by features which are common to all, or at least to all peripheral, neurons. The fact that the rate of transport for both NGF and tetanus toxin is identical in all examined neurons, supports the hypothesis that the specificity of retrograde transport is determined by specific uptake sites in the neuronal membrane whereas the retrograde transport system is non-specific.

Animals↗
PubMed1988

Tetanus toxin binding to mouse spinal cord cells: an evaluation of the role of gangliosides in toxin internalization.

Studies on the binding of 125I-labelled tetanus toxin to mouse spinal cord cell cultures revealed two classes of toxin acceptor, one a high-affinity protease-sensitive site, the other a lower affinity protease-resistant site. The latter was shown to be sialidase-sensitive and may represent binding to gangliosides. Tetanus toxin internalization by spinal cord cells is rapid and coated pits have been implicated in the process (Parton et al. J. Neurochem., 49 (1987) 1057-1068). To investigate the role of gangliosides in the internalization process, trisialoganglioside was incorporated into the plasma membrane of Balb/c 3T3 cells which lack endogenous toxin-binding activity. 125I-labelled tetanus toxin bound specifically to ganglioside treated cells at 4 degrees C. On warming cells to 37 degrees C, a proportion of bound toxin was degraded indicating that some internalization of toxin had occurred. The mechanism of internalization was studied using tetanus toxin adsorbed to colloidal gold. At 4 degrees C, toxin-gold was concentrated in non-coated cell surface membrane invaginations. On warming cells to 37 degrees C, toxin gold was internalized via non-coated vesicles and accumulated within multivesicular bodies and lysosomes. The relative roles of coated and non-coated vesicular uptake systems in the mechanism of action of tetanus toxin are discussed.

Animals↗
PubMed1995

Tetanus toxin-induced seizures in infant rats and their effects on hippocampal excitability in adulthood.

A new experimental model of developmental epilepsy is reported. Behavioral and EEG features of seizures produced by unilateral intrahippocampal injection of tetanus toxin in postnatal day 9-11 rats, are described. Within 24-72 h of tetanus toxin injection, rat pups developed frequent and often prolonged seizures which included combinations of repetitive wet dog shakes, and wild running-jumping seizures. Intrahippocampal and cortical surface EEG recordings showed that coincident with these behaviors, electrographic seizures occurred not only in the injected hippocampus, but also in the contralateral hippocampus and bilaterally in the neocortex. Analysis of the interictal EEG revealed multiple independent spike foci. One week following tetanus toxin injection, the number of seizures markedly decreased; however, interictal spiking persisted. After injection rats were allowed to mature some were observed to have unprovoked behavioral seizures and/or epileptiform EEG activity. Mature animals were also studied using in vitro slice techniques. Recordings from hippocampal slices demonstrated spontaneous epileptiform burst discharges in the majority of rats which had tetanus toxin induced seizures as infants. These events occurred in area CA3 and consisted of interictal spikes and intracellularly recorded paroxysmal depolarization shifts (PDSs). On rarer occasions, electrographic seizures were recorded. The use of the tetanus toxin model in developing rats may facilitate a better understanding of the unique features of epileptogenesis in the developing brain and the consequences early-life seizures have on brain maturation and the genesis of epileptic conditions in later life.

Animals↗
PubMed1994

Synaptobrevin cleavage by the tetanus toxin light chain is linked to the inhibition of exocytosis in chromaffin cells.

Exocytosis of secretory granules by adrenal chromaffin cells is blocked by the tetanus toxin light chain in a zinc specific manner. Here we show that cellular synaptobrevin is almost completely degraded by the tetanus toxin light chain within 15 min. We used highly purified adrenal secretory granules to show that synaptobrevin, which can be cleaved by the tetanus toxin light chain, is localized in the vesicular membrane. Proteolysis of synaptobrevin in cells and in secretory granules is reversibly inhibited by the zinc chelating agent dipicolinic acid. Moreover, cleavage of synaptobrevin present in secretory granules by the tetanus toxin light chain is blocked by the zinc peptidase inhibitor captopril and by synaptobrevin derived peptides. Our data indicate that the tetanus toxin light chain acts as a zinc dependent protease that cleaves synaptobrevin of secretory granules, an essential component of the exocytosis machinery in adrenal chromaffin cells.

Amino Acid Sequence↗