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PubMedDate not supplied

Safety and immunogenicity of a new equine tetanus immunoglobulin associated with tetanus-diphtheria vaccine.

In a single-center double-blind, randomized trial in West Africa, we evaluated the safety and immunogenicity of a new pasteurized, pepsin-digested equine tetanus immunoglobulin (heat-treated equine tetanus immunoglobulin [HT-ETIG]) in the post-exposure prophylaxis of tetanus compared with the reference product, equine tetanus immunoglobulin (ETIG). A total of 134 adults presenting to Garoua Hospital, Cameroon with a tetanus-prone wound were randomized to receive a 3,000 international units (IU) intramuscular injection (deltoid) of either HT-ETIG or ETIG, simultaneously with a tetanus-diphtheria vaccine. No serious adverse reactions were reported. The incidences of local and systemic reactions were similar in the two groups. Repeated measures of equine tetanus-antibody levels measured from Day 0 to Day 28 showed that titers were significantly higher in the HT-ETIG group (P = 0.017). At Day 7, a higher percentage of subjects in the HT-ETIG group had equine antibody levels > or = 0.1 IU/ml (80.4% versus 37.9%; P < 0.0001). No cases of tetanus occurred during the follow-up, attesting to the efficacy of the combined prophylactic treatment.

Adolescent↗
PubMed1997

Immunization of mice with poliovirus replicons expressing the C-fragment of tetanus toxin protects against lethal challenge with tetanus toxin.

In this study, we describe the construction of poliovirus genomes or "replicons" which contain the C fragment gene of tetanus toxin substituted for the poliovirus P1 capsid. Upon transfection of replicon RNA into cells, we immunoprecipitated a protein corresponding to the C-fragment of tetanus toxin using tetanus-specific antibodies. Using a recombinant vaccinia virus expressing poliovirus P1 capsid protein (VV-P1) to provide P1 protein, the replicon RNA was encapsidated; stocks of the replicons were generated by passage with VV-P1. The immunogenicity of the replicons was determined by immunization of transgenic mice which are susceptible to poliovirus. A serum antibody response to poliovirus and tetanus toxoid was detected in all of the immunized mice. Protection against a lethal dose of tetanus toxin generally correlated with the levels of serum anti-tetanus antibodies. To address whether pre-existing antibodies to poliovirus limit the effectiveness of the replicon as a vaccine vector, mice were first immunized with the inactivated poliovirus vaccine followed by immunization with the replicons expressing C-fragment protein. Anti-tetanus antibodies were detected in these mice after a single administration of the replicon; these antibodies conferred protection upon challenge with tetanus toxin. These results demonstrate the potential use of poliovirus replicons encoding foreign proteins to induce a protective antibody response, even in the presence of pre-existing antibodies to poliovirus.

Animals↗
PubMed1998

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.

Adrenal Glands↗
PubMed1976

Affinity chromatography of tetanus toxin, tetanus toxoid, and botulinum A toxin on synaptosomes, and differentiation of their acceptors.

125I-labelled tetanus toxin and 125I-labelled botulinum A neurotoxin are known to be specifically bound to brain synapotosomes. In order to discriminate between active toxin and inactive admixtures present in the starting material or arising during iodination, synaptosome columns were prepared using bromacetylcellulose and/or kieselgur (Celite) as carriers. Both types of columns absorb the toxins from low ionic strength medium and release them if the pH and ionic strength are raised. Botulinum toxin was eluted with lower ionic strength than tetanus toxin, and could be freed from nontoxic admixtures. Analysis by affinity chromatography disclosed partially toxoided tetanus toxin in both labelled and unlabelled toxin samples. High concentrations of formaldehyde (0.5%) destroyed both toxicity and affinity to the synaptosomes of tetanus toxin. Low concentrations of formaldehyde (0.05%) yielded a derivative of low toxicity which was still however less firmly, bound to synaptosomes. Tetanus and botulinum toxin differ by their acceptors. Whereas unlabelled botulinum toxin is unable to compete with labelled tetanus toxin, unlabelled tetanus toxin slightly competes with botulinum toxin. Both labelled toxins display anomalous binding behavior in that they cannot be displaced completely even with a large excess of unlabelled toxin.

Affinity Labels↗
PubMed1982

Serum levels of antibody to toxoid during tetanus and after specific immunization of patients with tetanus.

Levels of serum antibody to toxoid in patients with tetanus who were immunized with toxoid differed from those in immunized healthy persons in two respects. (1) Base-line levels preceding immunization were higher among patients with tetanus than among young or elderly healthy person, even though the patients with tetanus were evaluated before specific serotherapy. This observation suggests the occurrence of immunostimulation, whether specific or not, by disease during the incubation period. (2) No significant increase in levels of antibody to toxoid was detected among patients with tetanus from the first to the last evaluable serum sample, whereas a significant increase was observed among healthy persons. Specific immunosuppression induced by tetanus toxoid or serotherapy could account for this ineffectiveness of immunization among patients with tetanus, although nonspecific immunosuppression induced by prolonged and severe illness cannot be excluded. Among healthy persons, active immunization is less effective in elderly persons than in young persons [2]. However, age cannot, by itself, account for the type of antibody production observed in patients with tetanus.

Adult↗
PubMed1997

Safety and immunogenicity of a combined pentavalent diphtheria, tetanus, acellular pertussis, inactivated poliovirus and Haemophilus influenzae type b-tetanus conjugate vaccine in infants, compared with a whole cell pertussis pentavalent vaccine.

BACKGROUND: We compared the safety and immunogenicity of two combined diphtheria-tetanus-pertussis-inactivated poliovirus vaccines containing either acellular (Pa, SmithKline Beecham Biologicals) or whole cell (Pw, Pasteur Merieux Connaught) pertussis components, mixed with a Haemophilus influenzae type b polysaccharide polyribosylribitol phosphate-tetanus conjugate vaccine in an open, randomized study in healthy infants. DESIGN: The combined vaccines were given at 2, 4, 6 and 12 months of age, and serum samples were obtained at ages 2, 6, 7, 12 and 13 months. Adverse events were obtained by diary cards. RESULTS: The Pa group (n = 101) had a clearly lower incidence of both local and systemic adverse events than the Pw group (n = 100). Immunogenicity was comparable for the diphtheria and tetanus components, but significantly superior for pertussis toxin, filamentous hemagglutinin, pertactin and polioviruses 1, 2 and 3 in the Pa group. Both groups had an appropriate response with regard to H. influenzae type b polysaccharide polyribosylribitol phosphate, but the dynamics of the response were significantly different: geometric mean concentrations (micrograms per ml) after the second, third and booster doses were 1.27, 5.06 and 23.12 in the Pa group and 2.72, 6.66 and 13.59 in the Pw group, respectively (P = 0.0002 after second dose; P = 0.0005 after booster). CONCLUSION: The presently studied diphtheria, tetanus, acellular pertussis-H. influenzae b vaccine conjugated to tetanus toxoid combination was at least as immunogenic as the diphtheria, tetanus, whole cell pertussis-H. influenzae b vaccine conjugated to tetanus toxoid combination, with a significantly better safety profile. This is of obvious importance in countries where inactivated poliovirus vaccine is part of the routine infant immunization programs.

Antibodies, Bacterial↗
PubMed2002

Tetanus toxoid coverage as an indicator of serological protection against neonatal tetanus.

OBJECTIVE: A Multiple-Indicator Cluster Survey (MICS) was conducted at mid-decade in more than 60 developing countries to measure progress towards the year 2000 World Summit for Children goals. These goals included the protection of at least 90% of children against neonatal tetanus through the immunization of their mothers, as measured by tetanus toxoid (TT) coverage. In the Central African Republic (CAR), serological testing was added to the MICS to understand better the relationship between survey estimates of TT coverage and the prevalence of serological protection. METHODS: In the CAR MICS, mothers of children younger than one year of age gave verbal histories of the TT vaccinations they had received, using the MICS TT questionnaire. A subsample of mothers was tested for tetanus antitoxin, using a double-antigen enzyme-linked immunoadsorbent assay (ELISA). Seropositivity was defined as a titre of > or =0.01 IU/ml, and TT coverage was defined as the proportion of mothers protected at delivery, according to their history of TT vaccinations. FINDINGS: Among the 222 mothers in the subsample, weighted TT coverage was 74.4% (95% Confidence Interval (CI); 67.0% - 81.7%) and tetanus antitoxin seroprevalence was 88.7% (95% CI; 83.2% - 94.2%). The weighted median antitoxin titre was 0.35 IU/ml. CONCLUSIONS: Tetanus toxoid coverage in the CAR was lower than the prevalence of serological protection against neonatal tetanus. If this relationship holds for other countries, TT coverage estimates from the MICS may underestimate the extent to which the year 2000 goal for protecting children against neonatal tetanus was reached. We also showed that a high level of serological protection had been achieved in a country facing major public health challenges and resource constraints.

Central African Republic↗
PubMed1994

Severe tetanus--in spite of tetanus toxoid.

A 66-year-old man sustained an injury to his right foot while gardening. Despite receiving tetanus toxoid one hour later and adequate wound toilet, he developed severe tetanus complicated with autonomic dysfunction six days later. He died 20 days after admission. This case shows that tetanus toxoid alone may not be sufficient to prevent tetanus in wounded patients. Careful consideration must be given to the immune status of the patient and to the nature of the wound sustained. Incompletely immunised patients or patients with unknown immune status who sustain a tetanus prone wound should be protected with both tetanus toxoid and tetanus immunoglobulin.

Aged↗
PubMed1997

Safety and immunogenicity of a Haemophilus influenzae type B polysaccharide-tetanus toxoid conjugate vaccine combined with diphtheria, tetanus and pertussis vaccines in Thai infants.

A randomized, open, multicenter trial was conducted to determine the safety and immunogenicity of a Haemophilus influenzae type b polysaccharide-tetanus toxoid (PRP-T) conjugate vaccine combined with tetanus, diphtheria and pertussis (DTP) vaccine in 271 Thai infants born to mothers immunized against tetanus during pregnancy. Infants were immunized at approximately 2, 4 and 6 months of age with these vaccines. To determine if elevated levels of anti-tetanus toxin antibodies suppressed the anti-PRP antibody response, a second group of infants were immunized with PRP complexed with outer membrane proteins of Neisseria meningitidis (Pedvax HIB) in one limb at 2 and 4 months of age and DTP vaccine in the other limb at 2, 4 and 6 months of age. A third group of infants received only DTP vaccine at 2, 4 and 6 months of age. The occurrence of both local and systemic adverse reactions were comparable in all 3 groups. The geometric mean anti-tetanus antibody titer was > 1 IU/ml at baseline. Approximately 1 month after the administration of the third dose of vaccine, 98.5%, 99.3% and 9.7% of the children immunized with DTP+Pedvax HIB, DTP-PRP-T or DTP possessed > or = 0.15 microgram of anti-PRP antibody per ml. No child in the DTP group achieved > or = 1 microgram/ml while 74.2% and 89.3% did so after immunization with DTP+Pedvax HIB, or DTP-PRP-T, respectively (p < 0.05). Immune responses to diphtheria, tetanus and pertussis antigens were similar in all vaccine groups. These results demonstrate that elevated tetanus antibody titers do not diminish the anti-PRP antibody response following immunization with a PRP-T conjugate combined with DTP vaccine.

Antibodies, Bacterial↗
PubMed1987

Immunity to tetanus: tetanus antitoxin and anti-BIIb in human sera.

Immunity to tetanus was investigated in 157 individuals aged between 1 and 77 years using, for the evaluation of both tetanus antitoxin and antibody to fragment BIIb (anti-BIIb), an easily performed ELISA that gave reproducible results. Among these people 72% were protected against tetanus (tetanus antitoxin titres greater than 0.06 IU ml-1). Anti-BIIb titres greater than 0.15 U ml-1 were found in 75% of the males vs 57% of the females (P less than 0.02) with marked variations according to age. Furthermore, 13 out of 41 individuals with antitoxin titres less than 0.06 IU ml-1 (not protected against tetanus) were found to have anti-BIIb titres greater than 0.15 U ml-1. These data raise questions as to the significance and protective effect of anti-BIIb against tetanus.

Adolescent↗
PubMed1992

Reductive cleavage of tetanus toxin and botulinum neurotoxin A by the thioredoxin system from brain. Evidence for two redox isomers of tetanus toxin.

Inhibition of neurotransmitter release by tetanus toxin and botulinum neurotoxin A can be mimicked by intracellular application of the corresponding toxin light chains. The aim of this study was to determine whether the two-chain toxins are reduced by brain preparations to yield free light chains which would represent the ultimate toxins. The interchain disulfide of two-chain tetanus toxin was cleaved by rat cortex homogenate fortified with NADPH. Reduction was promoted further by addition of thioredoxin. Thioredoxin reductase was demonstrated in and purified from porcine brain cortex. The thioredoxin system which consisted of purified enzyme, thioredoxin and NADPH reduced both toxins. The resulting light chains appeared homogeneous in SDS gel electrophoresis. The complementary heavy chain of tetanus but not of botulinum toxin migrated in two bands, the faster one with the velocity of heavy chain obtained by chemical reduction. The major, slower form was converted into the faster by chemical but not by enzymatic reduction. Tetanus toxin, whether in its single-chain or two-chain version also occurred in two forms which differed by their electrophoretic mobility. The two forms of single-chain toxin were interconverted by chemical reduction or oxidation but not by the thioredoxin system. It is concluded that a) a thioredoxin system in brain tissue reduces the interchain disulfide of two-chain tetanus toxin and botulinum neurotoxin A, b) tetanus toxin but not botulinum neurotoxin A consists of two electrophoretically distinct forms which differ by the thiol-disulfide status of their heavy chains, c) the disulfide loop within the heavy chain of tetanus toxin is resistant to the thioredoxin system.

Animals↗
PubMed1997

Increased in vitro tetanus-induced production of HIV type 1 following in vivo immunization of HIV type 1-infected individuals with tetanus toxoid.

We have previously demonstrated that immunization of HIV-1-infected individuals with the common recall antigen, tetanus, induced transient increases in plasma viremia as well as an increased ability to isolate virus from CD8+ T cell-depleted peripheral blood mononuclear cells (PBMCs) under minimally stimulated culture conditions (IL-2 plus IL-4) postimmunization. In this study, HIV-1-infected individuals were immunized with tetanus toxoid and PBMCs were examined at multiple time points following immunization. Tetanus-induced production of virus was defined as an increased ability to isolate HIV-1 from CD8+ T cell-depleted PBMCs in vitro in the presence of tetanus antigen as opposed to no antigen or control antigen alone. Following immunization, in vitro tetanus-induced production of HIV-1 was observed in 8 of 13 (62%) patients compared to 2 of 13 (15%) patients prior to immunization. In four of these patients, virus could also be isolated from CD8+ T cell-depleted PBMCs in the presence of tetanus without the addition of any exogenous IL-2. Furthermore, virus could be isolated from the unfractionated PBMCs of two patients when tetanus antigen alone was added to the culture in the absence of added PHA or PHA blasts. HIV-1 was isolated predominantly from CD4+ T cells with a CD45RO+, CD25+ phenotype and was associated with a trend to elevated levels in culture supernatants of IFN-gamma, IL-6, TNF-alpha, and IL-4. These findings have important implications with regard to the role of ongoing antigen-specific immune responses in the induction of HIV-1 expression in vivo.

HIV Infections↗
PubMed2006

Ultrasound examination of extensive limb swelling reactions after diphtheria-tetanus-acellular pertussis or reduced-antigen content diphtheria-tetanus-acellular pertussis immunization in preschool-aged children.

OBJECTIVE: The aim of this study was to determine the site, extent, and resolution of tissue involvement when extensive limb swelling occurred in the injected limb for children who received diphtheria-tetanus-acellular pertussis or reduced-antigen content diphtheria-tetanus-acellular pertussis vaccine at 4 to 6 years of age. METHODS: Children who had experienced an injection site reaction at 18 months of age were assigned randomly to receive an intramuscular injection of either reduced-antigen content diphtheria-tetanus-acellular pertussis vaccine or diphtheria-tetanus-acellular pertussis vaccine between 4 and 6 years of age. Children who developed extensive limb swelling were recruited for assessment by clinical examination; ultrasound studies of the affected and opposite (control) arms were performed 24 to 48 hours after immunization and 48 to 96 hours later. RESULTS: Twelve children with extensive limb swelling were enrolled in the study. Ultrasound examinations demonstrated swelling of both the subcutaneous and muscle layers of the vaccinated arm. Ultrasound assessment showed that the swelling exceeded the clinical measurements of skin redness and swelling. Subcutaneous and muscle tissues expanded to 281% and 111% of the tissue thicknesses of the control arm, respectively. Repeat ultrasound examinations after 48 to 96 hours showed considerable resolution of muscle swelling, compared with subcutaneous tissue swelling. There was no significant difference in the extent of swelling detected between children who received diphtheria-tetanus-acellular pertussis vaccine and those who received reduced-antigen content diphtheria-tetanus-acellular pertussis vaccine. CONCLUSION: Extensive limb swelling reactions after diphtheria-tetanus-acellular pertussis or reduced-antigen content booster immunizations involved swelling of subcutaneous and muscle tissues with swelling and duration more marked in subcutaneous tissue.

Antigens, Bacterial↗
PubMedDate not supplied

Pediatric diphtheria and tetanus toxoids-adsorbed vaccine: immune response to the first booster following the diphtheria and tetanus toxoids vaccine primary series.

Diphtheria and tetanus toxoids (DT) vaccine should be given to children at 2, 4 and 6 months of age when there are contraindications to the administration of pertussis vaccine. We have previously reported that such children develop protective antitoxin antibody levels to diphtheria and tetanus antigens. This follow-up study evaluates the decay in antitoxin antibody levels and the booster response elicited to DT antigen when a fourth dose is given at approximately 18 months of age. Twenty-three children receiving DT vaccine were compared to 38 receiving diphtheria and tetanus toxoids-pertussis (DTP) vaccine. The prebooster antibody titer to diphtheria and tetanus at approximately 18 months of age had declined below the recommended protective level in one child who had received DT vaccine and in three children who had received DTP. Following the 18-month booster dose of DT and DTP vaccine, all of the children had protective titers to diphtheria and tetanus toxin. These results suggest that the adjuvant effects of pertussis vaccine are not required to achieve adequate immunization to diphtheria and tetanus when currently available DT vaccine is used in early childhood.

Antibodies, Bacterial↗
PubMed2006

Reduction of the ganglioside binding activity of the tetanus toxin HC fragment destroys immunogenicity: implications for development of novel tetanus vaccines.

In this study, the immunogenicities of the nontoxic H(C) fragment of tetanus toxin and derivatives lacking ganglioside binding activity were compared with that of tetanus toxoid after subcutaneous immunization of mice. Wild-type H(C) (H(C)WT) protein and tetanus toxoid both elicited strong antibody responses against toxoid and H(C) antigens and provided complete protection against toxin challenge. Mutants of H(C) containing deletions essential for ganglioside binding elicited lower responses than H(C)WT. H(C)M115, containing two amino acid substitutions within the ganglioside binding site, provided reduced protection against tetanus toxin challenge compared with H(C)WT, consistent with lower anti-H(C) and anti-toxoid antibody titers. Circular-dichroism spectroscopy and intrinsic fluorescence spectroscopy showed minimal structural perturbation in H(C)M115. We conclude that the presence of the ganglioside binding site within H(C) may be essential for induction of a fully protective anti-tetanus response comparable to that induced by tetanus toxoid by subcutaneous injection.

Animals↗
PubMed2000

Elevated levels of maternal anti-tetanus toxin antibodies do not suppress the immune response to a Haemophilus influenzae type b polyribosylphosphate-tetanus toxoid conjugate vaccine.

Reported are the effects of elevated levels of anti-tetanus antibodies on the safety and immune response to a Haemophilus influenzae type b polyribosylphosphate (PRP)-tetanus toxoid conjugate (PRP-T) vaccine. A group of Thai infants (n = 177) born to women immunized against tetanus during pregnancy were vaccinated with either a combined diphtheria-tetanus-pertussis (DTP) PRP-T vaccine or DTP and a PRP-conjugate vaccine using Neisseria meningitidis group B outer-membrane proteins as a carrier (PedVax HIB). Although most infants possessed high titres (> 1 IU/ml) of anti-tetanus antibodies, the DTP-PRP-T combined vaccine engendered an excellent antibody response to all vaccine components. In both vaccine groups > 98% of infants attained anti-PRP antibody titres > or = 0.15 microgram/ml. The geometric mean anti-PRP antibody titres were 5.41 micrograms/ml and 2.1 micrograms/ml for infants immunized with three doses of PRP-T versus two doses of PedVax HIB vaccines, respectively (P < 0.005). Similarly, the proportion of infants who achieved titres > or = 1 microgram/ml was higher in the PRP-T group (87.8%) than in the group immunized with PedVax HIB (74.2%) (P = 0.036). A subgroup analysis showed that there was no significant difference in the anti-PRP antibody response for infants exhibiting either < 1 IU of anti-tetanus antibody per millilitre or > or = 1 IU/ml at baseline. These finding indicate that pre-existing anti-carrier antibody does not diminish the immune response to the PRP moiety. All infants possessed protective levels of anti-D and anti-T antibody levels after immunization.

Antibodies, Bacterial↗
PubMed1977

Tetanus toxin induced actions on spinal Renshaw cells and Ia-inhibitory interneurones during development of local tetanus in the cat.

In anaesthetized cats the activities of Renshaw cells (RCs) and Ia-inhibitory interneurones (IaINs) were recorded during the accumulation of tetanus toxin in the spinal cord following injection into the gastrocnemius muscle. The early response of the RCs increased during the period of development of local tetanus. With some cells there was a subsequent decrease in the early response in later periods of the observation time (16-44 hrs after intramuscular injection). The effects on the spontaneous activity of the RCs were in good correspondence to those on the early response. The hyperactivity of the RCs is proposed to be mediated mainly via disinhibited cholinergic gamma-motoneurones using muscarinic postsynaptic receptors. The "pause" which follows the early response and the recurrent inhibition of IaINs was not reduced during the development of local tetanus. These results indicate that the central action of tetanus toxin in local tetanus does not consist of a general loss of postsynaptic inhibition. It is suggested that tetanus toxin acts mainly on synaptic elements of the alpha- and gamma-motoneurones or on presynaptic nerve terminals in their vicinity. In later periods of disturbing influence on the cholinergic transmission at Renshaw cells seems to occur.

Animals↗