Duration of protective immunity conferred by maternal tetanus toxoid immunization: further evidence from Matlab, Bangladesh

OBJECTIVES: Although maternal tetanus immunization has been shown to be highly effective in the prevention of neonatal tetanus, unresolved questions remain concerning the required minimum number of doses and the resulting duration of effective immunity. This study examined the duration of effective immunity against neonatal tetanus provided by maternal tetanus immunization. METHODS: A randomized, double-blind cholera vaccine trial of 41,571 children and nonpregnant adult women carried out in 1974 in the Matlab comparison area of rural Bangladesh provided a unique opportunity to address dose and immunity issues. RESULTS: Children of women who received either 1 or 2 injections of tetanus toxoid experienced 4- to 14-day mortality levels consistently lower than those of children of unimmunized mothers. Analysis of neonatal-tetanus-related mortality showed that 2 injections of tetanus toxoid provided significant protection for subsequent durations of up to 12 or 13 years. CONCLUSIONS: The data demonstrate that a limited-dose regimen of maternal tetanus toxoid provides significant and extended protection against the risk of neonatal tetanus death.     

Zoonoses in Vojvodina. I. Epidemiologic characteristics of tetanus in Vojvodina

Epidemiologic characteristics of tetanus in Voivodina were analyzed on the basis of reported cases of sickness or death, during the period from 1962 to 1991, and epidemiologic investigation on 35 sick persons suffering from tetanus during the last 5 years. By compulsory immunization against tetanus this disease is practically eliminated at the age when one is protected by immunity vaccine. Abandoning domiciliary childbirth neonatorum tetanus has been eliminated. Today tetanus occurs sporadically as a result of small, naive injuries, mostly in nonimmunized elderly people. Considering number of the sick, in 6.1% it happens to persons older than 60 years of age. Tetanus remains a health problem because of its high lethality, which is statistically significantly higher in older patients. On the basis of gathered results it is realistic to expect that applying compulsory immunization against tetanus to older people in 10 year intervals will not eliminate this disease, but it will significantly reduce lethality which is still about 25% in Voivodina.     

Single - dose immunization of human subjects against tetanus

A study was performed on human subjects to assess the effectiveness of single-dose immunization with 20 CU (1 ml) of adsorbed tetanus toxoid followed by revaccination with 10 CU (0.5 ml) 1 year later. Out of 1187 students, only those were selected for observation whose blood serum did not contain tetanus antitoxin (titre less than 0.001 IU/ml); this group counted 283 students. After administering the 20 CU (1 ml) of toxoid the antitoxin titre was repeatedly checked on days 10--15 and persons whose titre had risen to over 0.01 IU/ml were excluded from observation. The remaining 109 persons were tested for the antitoxin level 1 year later and revaccinated with 10 CU of tetanus toxoid. After 10--15 days their postrevaccination titre was determined. The single-dose immunization with 20 CU of tetanus toxoid in human subjects not given tetanus antigen previously was accompanied by a gradul rise in the antitoxin titre up to the protective level and its maintenance for 1 year (observation time) until revaccination. Revaccination with 10 CU of toxoid provided in 10--15 days a multiple (100--197fold) increase of the antitoxin titre, many times exceeding the protective level. The usefulness of transition to the shortened immunization scheme for tetanus prophylaxis of the adult population is discussed.     

Direct administration and utilization of [1-13C]glucose by fetal brain and liver tissues under normal and ischemic conditions: 1H, 31P, and 13C NMR studies

The acute and delayed effects of anoxia on synaptic transmission and long-term potentiation (LTP) were examined in the CA1 region of rat hippocampal slices. Oxygen deprivation for 20 minutes completely but reversibly depressed excitatory postsynaptic potentials mediated by both N-methyl-D-aspartate receptors (NMDAR) and non-NMDAR. Although LTP was reliably produced by a single tetanus delivered 30 minutes after reoxygenation, LTP could not be induced when a tetanus was delivered 70 to 100 minutes after reoxygenation. A tetanus delivered 100 minutes after reoxygenation produced lasting synaptic enhancement when 100 mumol/L D,L-amino-phosphonovaleric acid (APV), a competitive NMDAR antagonist, was administered during the period of oxygen deprivation. The delayed effects of oxygen deprivation were not blocked when APV was administered after oxygen deprivation. Similarly, the delayed effects on LTP induction were overcome by inhibitors of nitric oxide synthase when the nitric oxide synthase inhibitors were administered during anoxia, but not when administered after oxygen deprivation. These results suggest that untimely activation of NMDAR and nitric oxide release during anoxia produce delayed inhibition of LTP induction and may be involved in the memory defects that occur subsequent to cerebral hypoxia.     

Serological response to tetanus toxoid: a field study in Pondicherry, India

To study the serological response to various doses of tetanus toxoid given to pregnant women, 320 samples of blood obtained from 173 pregnant women were analysed using the indirect haemagglutination technique. Two doses of toxoid were necessary to achieve protective titres in women who were previously unimmunized. The antibody levels appeared to persist for up to 4 years. During a subsequent pregnancy, a single booster dose of toxoid was sufficient to raise the titres adequately for protection. These findings are in accordance with the immunization programme followed for prophylaxis against tetanus among pregnant women.     

Adverse events after school leavers received combined tetanus and low dose diphtheria vaccine

Since October 1994, children in the United Kingdom have been offered tetanus vaccine combined with a low dose of diphtheria vaccine (Td) at the age of 15 to 18 years. It is recommended that schoolchildren who have already received a booster of tetanus vaccine at the time of an injury should be given low dose diphtheria vaccine alone. When this vaccine is not available, however, it is recommended that Td vaccine should be given to all children. This study was performed to compare the frequency of adverse events after Td vaccine in 15 year old children with and without a history of an additional tetanus booster in the preceding 10 years. Two hundred and sixty-five children were followed up-52 pupils (20%) with a history of an additional tetanus booster, 157 (59%) with no such history, and 56 (21%) whose history was unclear. Mild local reactions were common and occurred more commonly in children with a history of an additional tetanus booster. Twenty-three pupils (44%) who had received an additional tetanus booster had swelling over 2 cm diameter at the injection site, compared with only 39 (25%) of those with no such history (p < 0.013). Systemic symptoms were equally unusual in both groups. Only three children experienced symptoms attributed to vaccine that were severe enough for them to miss school or attend a doctor; and none of these had received an additional tetanus booster. We conclude that, in the absence of a supply of low dose diphtheria vaccine, offering Td vaccine to children with a history of additional tetanus booster is an acceptable policy.     

Beta-amino-thiols inhibit the zinc metallopeptidase activity of tetanus toxin light chain

Tetanus neurotoxin is a 150-kDa protein produced by Clostridium tetani, which causes the lethal spastic paralytic syndromes of tetanus by blocking inhibitory neurotransmitter release at central synapses. The toxin light chain (50 kDa) has a zinc endopeptidase activity specific for synaptobrevin, an essential component of the neuroexocytosis apparatus. Previous unsuccessful attempts to block the proteolytic activity of this neurotoxin with well-known inhibitors of other zinc proteases led us to study the design of specific inhibitors as a possible drug therapy to prevent the progressive evolution of tetanus following infection. Starting from the synaptobrevin sequence at the level of the cleavage site by tetanus neurotoxin (Gln76-Phe77), a thiol analogue of glutamine demonstrated inhibitory activities in the millimolar range. A structure-activity relationship performed with this compound led us to determine the requirement for the correct positioning of the thiol group, the primary amino group, and a carboxamide or sulfonamide group on the side chain. This resulted in the design of a beta-amino-(4-sulfamoylphenyl)glycine-thiol, the first significantly efficient inhibitor of tetanus neurotoxin with a Ki value of 35 +/- 5 microM.     

Products of anaerobic phloroglucinol degradation by Coprococcus sp. Pe15

Haemodynamic variables were compared in control dogs, dogs with local tetanus toxicity and dogs with generalised tetanus toxicity. The results showed an increase in the inotropic and chronotropic activation of the heart in both groups of tetanus dogs, but there was no significant change in the mean systemic blood pressure and the common carotid occlusion reflex was unchanged. Spontaneous fluctuations in the systemic blood pressure were observed in some dogs with tetanus, and occurred more often in those with generalised tetanus. The modification of these fluctuations by beta-adrenergic blockade and diazepam, suggest that they are of autonomic neural origin. It is suggested that these changes in the cardiovascular system are the results of neurophysiological and biochemical changes in the sympathetic nervous system, which have been reported to occur in tetanus.     

Tetanus toxoid stimulation of the hypothalamic-pituitary-adrenal axis correlates inversely with the increase in tetanus toxoid antibody titers

In humans, endotoxin activates the hypothalamic-pituitary-adrenal (HPA) axis, and the resulting increase in cortisol modulates the immune response. There is little information on the HPA axis response to other antigens. We examined the effect of the protein antigen tetanus toxoid on HPA axis activity in 10 healthy, premenopausal women (aged 28.6 +/- 2.6 yr). Subjects received im injections of placebo and tetanus toxoid at 1600 h on consecutive days. Blood samples for ACTH and cortisol were obtained every half-hour from--1 to 6 h and at 8, 12, and 16 h after each injection. Compared to placebo, tetanus toxoid administration stimulated significant increases in plasma ACTH and serum cortisol, with the maximum cortisol increase of 1.6-fold occurring 4.5 h after drug administration. Urinary free cortisol increased 1.8-fold in the 8 h after tetanus toxoid administration compared to that after placebo administration. Additionally, there was a significant inverse correlation (r = 0.87; P < 0.005) between the tetanus toxoid-induced increase in serum cortisol and the increase in tetanus antibody levels measured 1 month postvaccination. Thus, administration of the protein antigen tetanus toxoid activated the HPA axis in healthy, premenopausal women. This activation of the HPA axis correlated inversely with the antibody response to tetanus toxoid.     

Effects of electrically induced fatigue on the twitch and tetanus of paralyzed soleus muscle in humans

We analyzed the twitch and summated torque (tetanus) during repetitive activation and recovery of the human soleus muscle in individuals with spinal cord injury. Thirteen individuals with complete paralysis (9 chronic, 4 acute) had the tibial nerve activated every 1,500 ms with a 20-Hz train (7 stimuli) for 300 ms and a single pulse at 1,100 ms. The stimulation protocol lasted 3 min and included 120 twitches and 120 tetani. Minimal changes were found for the acute group. The chronic group showed a significant reduction in the torque and a significant slowing of the contractile speeds of both the twitch and tetanus. The decrease in the peak twitch torque was significantly greater than the decrease in the peak tetanus torque early during the fatigue protocol for the chronic group. The twitch time to peak and half relaxation time were prolonged during fatigue, which was associated with improved fusion of the tetanus torque. At the end of the fatigue protocol, the decrease in the peak twitch torque was not significantly different from the decrease in the peak tetanus torque. After 5 min of rest, the contractile speeds recovered causing the tetanus to become unfused, but the tetanus torque became less depressed than the twitch torque. The differential responses for the twitch and the tetanus suggest an interplay between optimal fusion created from contractile speed slowing and excitation contraction coupling compromise. These issues make the optimal design of functional electrical stimulation systems a formidable task.     

Medullary actions of tetanus toxin. An electrophysiological study in man

Brain-stem reflexes have been studied in four patients with generalized tetanus. Inhibitory cutaneous reflexes were abolished or severely depressed. The same held true, to a lesser degree, for excitatory cutaneous reflexes with long polysynaptic pathways. Proprioceptive reflexes behaved variably. The observations are discussed in regard to the possible sources of enhanced motoneuronal activity in tetanus. It is concluded that, besides depression of inhibitory synapses on motoneurons, interneuronal damage may contribute to the tetanus symptomatology.     

Tetanus of immunized children

Five children aged five to 15 years contracted tetanus in Finland between 1969 and 1985, together with 101 adults. Four of the five had been adequately immunized against tetanus. The clinical picture of tetanus was mild or moderate, and none of the children needed respirator treatment. Epilepsy, meningitis and psychogenic symptoms were considered in the differential diagnosis. The course of tetanus in immunized patients is atypical and often benign, but the diagnosis is problematic--in contrast to affected children in developing countries, whose populations are not adequately immunized and where neonatal tetanus is common and often fatal.     

Challenges of traction in critical care: a case study

PROBLEM/CONDITIONS: Despite widespread availability of a safe and effective vaccine against tetanus, 124 cases of the disease were reported during 1995-1997. Only 13% of patients reported having received a primary series of tetanus toxoid (TT) before disease onset. Of patients with known illness outcome, the case-fatality ratio was 11%. REPORTING PERIOD COVERED: 1995-1997. DESCRIPTION OF SYSTEM: Physician-diagnosed cases of tetanus are reported by state and local health departments to CDC's National Notifiable Diseases Surveillance System. In addition, since 1965, supplemental clinical and epidemiologic information for cases has been provided to CDC's National Immunization Program. RESULTS: From 1995 through 1997, a total of 124 cases of tetanus were reported from 33 states and the District of Columbia, accounting for an average annual incidence of 0.15 cases per 1,000,000 population. Sixty percent of patients were aged 20-59 years; 35% were aged > or =60 years; and 5% were aged <20 years, including one case of neonatal tetanus. For adults aged > or =60 years, the increased risk for tetanus was nearly sevenfold that for persons aged 5-19 years and twofold that for persons aged 20-59 years. The case-fatality ratio varied from 2.3% for persons aged 20-39 years to 16% for persons aged 40-59 years and to 18% for persons aged > or =60 years. Only 13% of patients reported having received a primary series of TT before disease onset. Previous vaccination status was directly related to severity of disease, with the case-fatality ratio ranging from 6% for patients who had received one to two doses to 15% for patients who were unvaccinated. No deaths occurred among the 16 patients who previously had received three or more doses. Tetanus occurred following an acute injury in 77% of patients, but only 41% sought medical care for their injury. All patients who sought care were eligible for TT as part of wound prophylaxis, but only 39% received it. Tetanus in injecting-drug users (IDUs) with no known acute injury comprised 11% of all cases, compared with 3.6% during 1991-1994. None of the IDU-associated tetanus cases occurred among persons who were known to have been vaccinated. Sixty-nine percent of IDU-associated tetanus cases were reported from California, and 77% of these cases occurred in heroin users. INTERPRETATION: Tetanus remains a severe disease that primarily affects unvaccinated or inadequately vaccinated persons. Adults aged > or =60 years continue to be at highest risk for tetanus and for severe disease. However, the overall incidence of tetanus has decreased slightly since the late 1980s and early 1990s, from 0.20 to 0.15, a result primarily of a decreased incidence among persons aged > or =60 and <20 years. ACTIONS TAKEN: Tetanus is preventable through both routine vaccination and appropriate wound management. In addition to decennial booster doses of diphtheria and tetanus toxoids during adult life, the Advisory Committee on Immunization Practices (ACIP) recommends vaccination visits for adolescents at age 11-12 years and for adults at age 50 years to enable health-care providers to review vaccination histories and administer any needed vaccine. Every contact with the health-care system, particularly among older adults and IDUs, should be used to review and update vaccination status as needed.     

Epitope repertoire of human CD4+ T cells on tetanus toxin: identification of immunodominant sequence segments

Sequence regions of tetanus toxin-forming CD4+ cell epitopes in 8 HLA-disparate subjects were identified. Overlapping synthetic peptides corresponding to the complete tetanus toxin sequence were used to test, in a proliferation assay, unselected blood CD4+ cells or CD4+ cell lines propagated by stimulation with tetanus toxoid. The CD4+ cell lines recognized most peptides recognized by the blood CD4+ cells and they recognized additional peptides. Their responses were stronger than those of unselected blood CD4+ cells. Two peptides were recognized by all subjects: one largely overlapped a tetanus toxin sequence region previously identified as a "universal" T cell epitope. Thirteen other peptides elicited a CD4+ cell response in 6 or 7 of the 8 subjects, and another 10 elicited responses in 5 subjects.     

Tetanus in a 67-year-old man

A fatal case of generalized tetanus in a 67-year-old man is presented. The incubation period following finger damage was short, and the diagnosis was confirmed by the isolation of Clostridium tetani. Subsequently, a partial surgical amputation of the infected finger during the clinically active stage of the disease did not remove all the infecting organisms. Although convincing evidence of any previous active immunization was lacking, no form of tetanus antitoxin was given at the time of injury. This case illustrates the potential dangers of unfamiliarity with tetanus owing to its low incidence in developed countries.     

Involvement of nitric oxide and cGMP in the protective effect of neurotensin on hepatocytes

STUDY OBJECTIVE: Tetanus antibody levels have been shown to be inadequate in 50% of patients older than 65 years. Although immunization recommendations have been made for this age group, the efficacy of this intervention has not been well documented. We sought to determine the difference in tetanus antibody levels after the administration of one tetanus toxoid immunization to geriatric patients without adequate titers. METHODS: Thirty-five patients older than 65 years at a large urban comprehensive care geriatric center who were documented to have inadequate tetanus antibody titers were each given one tetanus toxoid immunization. Repeat titers were obtained at least 2 months after the immunization with the use of enzyme-linked immunosorbent assay (Bindazyme kit; the Binding Site Corporation, Birmingham, England). We considered tetanus antibody levels greater than .17 IU/mL protective. RESULTS: The mean age was 79.4 years; 30 of 35 (86%) were female. Repeat tetanus antibody titers were obtained an average of 123 days (range, 63 to 204 days) after immunization with tetanus toxoid. The mean preimmunization antibody titer was .1 IU/mL (range, .04 to .16 IU/mL). After immunization, antibody titers increased a mean of .61 IU/mL (range, -.01 to 2.23 IU/mL; 95% confidence interval, .35 to .87 IU/mL). Thirty of the 35 patients who received a single injection of tetanus toxoid (86%) developed protective titers. We found no relationship between seroconversion and age, sex, or medical history; nor did we find a relationship between antibody level and time elapsed since immunization when repeat titers were obtained. CONCLUSION: Administration of one tetanus toxoid injection affords protective immunity in many geriatric patients.     

Neutralizing antibodies in 6-year-old children after five doses of tetanus toxoid

It has recently been suggested that multiple boosters of tetanus toxoid may enhance serum antitoxin titres but may not necessarily lead to an effective immune response. Tetanus antitoxin titres by haemagglutination inhibition and mouse toxin neutralization tests were determined in sera of 64 children, 5 and 6 years old. Primary vaccination against tetanus was given as four doses of diphtheria-pertussis-tetanus (DPT) vaccine beginning in the second or third month of life, and a booster dose given to schoolchildren at 6 years of age. In our area more than 90% of children receive five doses of tetanus toxoid before their seventh birthday. The children were given 0.5 ml of DPT or DT containing 10 Lf ml-1 tetanus toxoid at each injection. The haemagglutination titres and the toxin neutralization titres were much higher in 6-year-old than in 5-year-old children. We concluded that the fifth dose is an effective booster in 6-year-old children.     

The myocardial energetic active state. I. Oxygen consumption during tetanus of cat papillary muscle

The potential role of active state maintenance as a determinant of myocardial oxygen consumption (MVO2) has not been defined. Right ventricular papillary muscles from 15 cats were studied in a polarographic myograph at 23 degrees C in a Krebs-Ringer solution containing 7.5 mM Ca2+ and 10 mM caffeine. MVO2 was determined for isometric tetani at Lmax of 1-5 seconds' duration. Increases in tetanus duration related linearly to increments in both active tension time (delta active tension) and MVO2. In order to examine the oxygen cost of active state maintenance not attributable to associated tension generation, both the same isometric and 2.5- to 10.0-second lightly preloaded isotonic tetani were produced in nine muscles. For each tetanus duration the contribution throughout the contraction of developed force (preload) to MVO2 could be subtracted from overall isotonic MV02. In the absence of the MVO2 associated with force development, the active state duration was related linearly to MVO2, with a mean active state MVO2 of 2.42 +/- 0.29 nl O2/mg dry muscle/sec of isotonic tetanus; this MVO2 is 68% of the value of 3.58 +/- 0.42 nl O2/mg dry muscle/sec that was obtained for isometric tetanus at Lmax. This study identifies active state maintenance as the major determinant of MVO2 during myocardial tetanus and, furthermore, suggests the possibility that alterations in ative state intensity and duration may be the biochemical mechanism by which other determinants of MVO2 act in a more physiological setting.     

Postoperative tetanus after gangrenous ileus

Tetanus has become an uncommon disease in developed countries. Tetanus is caused by exotoxins from the bacteria Clostridium tetani. This microbe, which is obligate anaerobe, is present in soil, and animal and human faeces. The condition usually appears after contamination of wounds. However, reports have been published of tetanus occurring after both acute and selective gastrointestinal surgery. We present a case of severe postoperative tetanus in a 57 year-old woman who underwent bowel resection after strangulation of the ileum. The patient was treated on an intensive care unit and was artificially ventilated for 64 days. Seven months later she had fully recovered. Clinical presentation, diagnosis, treatment, and complications are discussed in the report. The diagnosis of tetanus is made by clinical observation. Nowadays, lack of suspicion of this condition may cause delay in administering proper treatment. Women and older men are often inadequately immunized. Doctors should therefore examine the immunization status of these groups of patients regularly.