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PubMed1976

A comparison of the evolution of transmitted IgG immunoglobulin and diphtheria antitoxin titers in the newborn.

The evolution of the titers of transmitted IgG and diphtheria antitoxin was studied in 20 neonates during the first 2 months of life (6 serum samples for each). A rapid fall of the passive IgG titer was observed during the first weeks: as a rule the higher the initial titer the greater the fall. After the 15th day the rate of decline slows down. The evolution of the titer of transmitted maternal diphtheria antitoxin depends also on the initial level, and if it is low it can remain more or less constant for a long time. The initial level of passive IgG does not influence the drop in diphtheria antitoxin titre and vice versa. Therefore, the evolution of total IgG and diphtheria antitoxin levels appear not to be interdependent.

Age Factors↗
PubMedDate not supplied

The immunogenicity and safety of a new combined diphtheria, tetanus and poliomyelitis booster vaccine (Td-eIPV).

In view of the continuing risk of contracting tetanus, diphtheria and poliomyelitis, and the well-documented decline in immunity with time, the need for booster vaccinations is substantial. The immunogenicity and safety of a new combined booster vaccine against tetanus, diphtheria and poliomyelitis (REVAXIS) developed by Pasteur Mérieux Connaught (Lyon, France) were evaluated in four clinical studies. This vaccine (Td-eIPV) combines an adsorbed tetanus toxoid and low-dose diphtheria toxoid vaccine (Td) with an enhanced, inactivated polio vaccine against poliovirus types 1, 2 and 3 (eIPV). In 256 healthy young adults, a single dose of Td-eIPV was shown to be immunogenic, eliciting antibody levels considered protective against disease for each vaccine component in > or = 99.6% of the subjects. In 112 healthy older subjects (> 40 years of age), two doses of Td-eIPV elicited seroprotective levels of antibodies in 94% of the subjects for diphtheria, and in all subjects for tetanus and poliovirus types 1, 2 and 3. Safety data from all 368 subjects, as well as 31 phase I volunteers and 1,742 subjects included in a safety study, reveal that the vaccine is safe. Most reactions were predictable, temporary and mild. There was no evidence that the vaccine was associated with any clinically serious event or modification of clinical laboratory parameters. The data reviewed here show that Td-eIPV is immunogenic and safe when administered as a booster vaccination in healthy adults of all ages.

Adult↗
PubMed1999

Diphtheria toxin forms pores of different sizes depending on its concentration in membranes: probable relationship to oligomerization.

Diphtheria toxin forms pores in biological and model membranes upon exposure to low pH. These pores may play a critical role in the translocation of the A chain of the toxin into the cytoplasm. The effect of protein concentration on diphtheria toxin pore formation in model membrane systems was assayed by using a new fluorescence quenching method. In this method, the movement of Cascade Blue labeled dextrans of various sizes across membranes is detected by antibodies which quench Cascade Blue fluorescence. It was found that at low pH the toxin makes pores in phosphatidylcholine/phosphatidylglycerol vesicles with a size that depends on protein concentration. At the lowest toxin concentrations only the entrapped free fluorophore (MW 538) could be released from model membranes. At intermediate toxin concentrations, a 3 kD dextran could be released. At the highest toxin concentration, a 10 kD dextran could be released, but not a 70 kD dextran. Similar pore properties were found using vesicles lacking phosphatidylglycerol or containing 30% cholesterol. However, larger pores formed at lower protein concentrations in the presence of cholesterol. The dependence of pore size on toxin concentration suggests that toxin oligomerization regulates pore size. This behavior may explain some of the conflicting data on the size of the pores formed by diphtheria toxin. The formation of oligomers by membrane-inserted toxin is consistent with the results of chemical crosslinking and measurements of the self-quenching of rhodamine-labeled toxin. Based on these experiments we propose diphtheria toxin forms oligomers with a variable stoichiometry, and that pore size depends on the oligomerization state. Reasons why oligomerization could assist proper membrane insertion of the toxin and other proteins that convert from soluble to membrane-inserted states are discussed.

Dimerization↗
PubMed1998

Bacteriological properties of a sucrose-fermenting Corynebacterium diphtheriae strain isolated from a case of endocarditis.

An atypical sucrose-fermenting Corynebacterium diphtheriae strain was isolated from three blood cultures of a 14-year-old girl presented to a university teaching hospital in Rio de Janeiro, Brazil. She had mitral endocarditis that proved to be fatal despite intensive antibiotic therapy. Blood cultures showed a fluorescent Gram-positive, aerobic, coryneform-like bacillus presenting pyrazinamidase and CAMP reaction negative. The isolate was identified as a toxigenic strain of C. diphtheriae var. mitis by both Elek and radial immunodiffusion (RID) tests. The invasive C. diphtheriae sucrose-fermenting biotype strain adhered to glass surfaces and expressed pronounced hemagglutinating activity (titer 8), a property common among the nonfermenting biotype strains. Laboratories should be alert to the possibility of the isolation of C. diphtheriae with a positive sucrose fermentation test, especially when nontoxigenic strains are isolated from uncommon anatomic sites.

Adolescent↗
PubMed2005

Conditional ablation of mature olfactory sensory neurons mediated by diphtheria toxin receptor.

The vertebrate olfactory epithelium provides an excellent model system to study the regulatory mechanisms of neurogenesis and neuronal differentiation due to its unique ability to generate new sensory neurons throughout life. The replacement of olfactory sensory neurons is stimulated when damage occurs in the olfactory epithelium. In this study, transgenic mice, with a transgene containing human diphtheria toxin receptor under the control of the olfactory marker protein promoter (OMP-DTR), were generated in which the mature olfactory sensory neurons could be specifically ablated when exposed to diphtheria toxin. Following diphtheria toxin induced neuronal ablation, we observed increased numbers of newly generated growth associated protein 43 (GAP43)-positive immature olfactory sensory neurons. OMP-positive neurons were continuously produced from the newly generated GAP43-positive cells. The expression of the signal transduction components adenylyl cyclase type III and the G-protein alpha subunit G(alpha olf) was sensitive to diphtheria toxin exposure and their levels decreased dramatically preceding the disappearance of the OMP-positive sensory neurons. These data validate the hypothesis that OMP-DTR mice can be used as a tool to ablate the mature olfactory sensory neurons in a controlled fashion and to study the regulatory mechanisms of the neuronal replacement.

Adenylyl Cyclases↗
PubMed1981

The effect of diphtheria toxin on the cellular uptake and efflux of L-carnitine. Evidence for a protective effect of prednisolone.

Diphtheria toxin added to the incubation medium reduced the rate of uptake and increased the efflux of L-[3H]carnitine in an established cell line from human heart (CCL 27, Girardi human heart cells). This resulted in a decrease in the level of intracellular carnitine to about 55% of control after exposure to 10(-8) mol/l diphtheria toxin for 24 h. As expected, a decrease in protein synthesis was found to be caused by the toxin, and this inhibition seemed to a large extent to antedate the alterations in the transport processes. Measurement of the kinetic parameters for the mechanism of uptake of L-[3H]carnitine revealed a reduction in V with unaltered Km after exposure to the toxin. We therefore suggest that diphtheria toxin imposes its effect on carnitine transport by inhibiting the synthesis of carriers. Prednisolone in the medium along with the toxin opposed its effect both on the uptake and efflux mechanism, but not on the inhibition of protein synthesis. Still, the decline in the intracellular level of carnitine was prevented by the corticoid hormone. Such a decline, accompanied by accumulation of triacyglycerols, occurs during the course of a diphtheric myocarditis. It is possible that prednisolone, by counteracting the effects of diphtheria toxin on the carnitine transport processes, could be beneficial in the treatment of this condition.

Biological Transport, Active↗
PubMed1987

Mutant with diphtheria toxin receptor and acidification function but defective in entry of toxin.

A mutant of Chinese hamster ovary cells, GE1, that is highly resistant to diphtheria toxin was isolated. The mutant contains 50% ADP-ribosylatable elongation factor 2, but its protein synthesis was not inhibited by the toxin even at concentrations above 100 micrograms/ml. 125I-labeled diphtheria toxin was associated with GE1 cells as well as with the parent cells but did not block protein synthesis of GE1 cells even when the cells were exposed to low pH in the presence or absence of NH4Cl. The infections of GE1 cells and the parent cells by vesicular stomatitis virus were similar. GE1 cells were cross-resistant to Pseudomonas aeruginosa exotoxin A and so were about 1000 times more resistant to this toxin than the parent cells. Hybrids of GE1 cells and the parent cells or mutant cells lacking a functional receptor were more sensitive to diphtheria toxin than GE1 cells. These results suggest that entry of diphtheria toxin into cells requires a cellular factor(s) in addition to those involved in receptor function and acidification of endosomes and that GE1 cells do not express this cellular factor. This character is recessive in GE1 cells.

Animals↗
PubMed1987

Quantitative estimation of diphtheria and tetanus toxoids. 2. Single radial immuno-diffusion tests (Mancini) and rocket immuno-electrophoresis test in comparison with the flocculation test.

The concentration in Lf units, of an unknown diphtheria or tetanus toxoid preparation is estimated in the flocculation test relative to reference preparations of tetanus and diphtheria antitoxins, respectively. By replacing the antitoxin reference preparations with toxoid reference preparations it should be possible to use immunological methods other than the flocculation test for the quantitative estimation of toxoids in Lf units. A number of diphtheria and tetanus toxoids were tested by rocket immuno-electrophoresis and single radial immuno-diffusion (Mancini test). The concentrations of the unknown toxoids were expressed relative to a diphtheria toxoid calibrated in Lf units (DIFT) and a tetanus toxoid calibrated in Lf units (TEFT), respectively. These two toxoid preparations are regarded as candidates for establishment as international standard preparations. The results obtained in the two tests were compared with those obtained in the flocculation test. In most cases the differences between the results did not exceed 10%. It is concluded, therefore, that the rocket electrophoresis or the radial immuno-diffusion tests can be used as alternatives to the flocculation test.

Diphtheria Toxoid↗
PubMed1994

Comparative study of Lederle/Takeda acellular and Lederle whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants in Germany.

In preparation for a large efficacy trial in Germany, a pilot study was initiated in December 1990. In this study 149 infants were enrolled; with double-blind randomization 75 received Lederle/Takeda acellular pertussis component diphtheria-tetanus-pertussis vaccine (APDT) and 74 received Lederle whole-cell pertussis component diphtheria-tetanus-pertussis vaccine (DTP). The mean age at first dose was 3.5 months, and the second and third doses followed at 6-week intervals. Reactions were relatively mild with both vaccines; in general they were less frequent following APDT. The IgG antibody responses to lymphocytosis promoting factor (LPF) and fimbriae-2 were similar in both groups whereas the responses to pertactin and filamentous haemagglutinin (FHA) were greater in APDT recipients. DTP recipients had greater responses to tetanus and diphtheria toxoids. When age of first dose was examined (8-12 weeks versus 16-20 weeks), it was found that young age had a suppressive effect on antibody responses in DTP but not APDT recipients to LPF toxoid, pertactin, fimbriae-2, and tetanus and diphtheria toxoids. High values of transplacentally acquired antibody lessened the response to LPF toxoid and tetanus toxoid in DTP recipients and to tetanus toxoid in APDT vaccinees. The IgG immune response to LPF toxoid, FHA and fimbriae-2 was found to be more uniform in APDT recipients than in DTP vaccinees. An IgA antibody response to fimbriae-2 was noted in 13% of DTP recipients but in no APDT vaccinees. The broad immunogenicity and mild reactogenicity of this APDT vaccine justifies its use in the German efficacy trial.

Antibodies, Bacterial↗
PubMed2005

Diphtheria toxin translocation across cellular membranes is regulated by sphingolipids.

Diphtheria toxin is translocated across cellular membranes when receptor-bound toxin is exposed to low pH. To study the role of sphingolipids for toxin translocation, both a mutant cell line lacking the first enzyme in de novo sphingolipid synthesis, serine palmitoyltransferase, and a specific inhibitor of the same enzyme, myriocin, were used. The serine palmitoyltransferase-deficient cell line (LY-B) was found to be 10-15 times more sensitive to diphtheria toxin than the genetically complemented cell line (LY-B/cLCB1) and the wild-type cell line (CHO-K1), both when toxin translocation directly across the plasma membrane was induced by exposing cells with surface-bound toxin to low pH, and when the toxin followed its normal route via acidified endosomes into the cytosol. Toxin binding was similar in these three cell lines. Furthermore, inhibition of serine palmitoyltransferase activity by addition of myriocin sensitized the two control cell lines (LY-B/cLCB1 and CHO-K1) to diphtheria toxin, whereas, as expected, no effect was observed in cells lacking serine palmitoyltransferase (LY-B). In conclusion, diphtheria toxin translocation is facilitated by depletion of membrane sphingolipids.

Acyltransferases↗
PubMed2005

Decreased sensitivity to diphtheria toxin of Vero cells cultured in serum-free medium.

Vero cell cultures are used in the quality control of Diphtheria vaccines: to estimate vaccine potency and to determine residual toxicity and reversion to toxicity. The impact of replacing foetal calf serum containing medium (SCM) by serum free media (SFM) on the sensitivity of Vero cells to Diphtheria Toxin was studied. Compared to SCM, SFM showed an eight-fold decrease in sensitivity to Diphtheria Toxin. This decrease was almost immediate, indicating that this phenomenon was not caused by a change in membrane structure or protein expression. We investigated the effect of SFM on Diphtheria Toxin in order to determine the cause of the decrease in sensitivity. Our results show that oligopeptides, which are often used in SFM as part of the replacement of foetal calf serum, are the most likely cause.

Alprostadil↗
PubMed2004

Patterns of adherence to HEp-2 cells and actin polymerisation by toxigenic Corynebacterium diphtheriae strains.

Corynebacterium diphtheriae strains displayed different degrees of attachment to HEp-2 cell monolayers with two distinct adherence patterns, termed localised (LA) and diffuse (DA). The LA phenotype predominated over the DA phenotype. The non-sucrose fermenting strains expressing DA pattern adhered mostly with high index values (> or =10bact/cell). Low adhesion index (<10bact/cell) was mainly observed among sucrose fermenting strains. The fluorescein isothiocyanate (FITC)-labelled phalloidin assay (fluorescent-actin staining test) showed positive results for microorganisms of both LA and DA phenotypes. The FITC-labelled C. diphtheriae non-fimbrial surface proteins 67-72p interacted directly with HEp-2 cell membranes. Therefore, toxigenic C. diphtheriae exhibited LA and DA adherence patterns and ability to induce actin polymerisation. The experimental evidences also pointed to 67-72p as putative adhesins of C. diphtheriae to HEp-2 cells.

Actins↗
PubMed2004

Intranasal immunization with genetically detoxified diphtheria toxin induces T cell responses in humans: enhancement of Th2 responses and toxin-neutralizing antibodies by formulation with chitosan.

We previously reported that intranasal immunization with a non-toxic mutant cross-reacting material (CRM)197 of diphtheria toxin, formulated with chitosan, generated protective neutralizing antibodies in mice and guinea pigs. Furthermore, we demonstrated that intranasal delivery of a powder formulation of the CRM197-based vaccine was well tolerated and significantly boosted antibody responses in adult volunteers. Here we report that intranasal booster immunization with CRM197 alone or with chitosan induced systemic T cell responses. We addressed for the first time the induction of T cell subtypes following intranasal vaccination in humans. Intranasal vaccination with CRM197, like parenteral immunization with a conventional diphtheria toxoid vaccine, enhanced antigen-specific IFN-gamma production. However, formulation of the nasal diphtheria vaccine with chitosan significantly augmented Th2-type responses, which correlated with protective levels of toxin-neutralizing antibodies in intranasally boosted individuals. The results suggest that vaccines capable of inducing strong Th2-type responses, such as CRM197 formulated with chitosan, have potential for the development of a protective mucosal vaccine against diphtheria in humans. Furthermore, our findings demonstrate that mucosal subunit vaccines with appropriate delivery systems have considerable potential for booster immunization of adults.

Administration, Intranasal↗
PubMed2004

Tetanus and diphtheria antibodies and response to a booster dose in Brazilian HIV-1-infected women.

Tetanus and diphtheria (Td) antibodies were studied in HIV-1-infected women during puerperium. HIV group (n=61) was compared with Control group (n=101). Twenty-one women from HIV and 13 from Control group who had antibody levels lower than 0.1 IU/mL received a booster with Td vaccine. Antibodies were assessed by double antigen ELISA. Mean tetanus and diphtheria antibody levels from HIV group were lower than those from Control group. Multiple linear regression analysis showed that tetanus and diphtheria antibody levels were decreased by HIV-1-infection, and that was independent of the reduction due to the time interval between last booster and antibody assessment. After a booster dose, both groups had an increase in mean tetanus and diphtheria antibody levels, but in Control group the levels were higher than in HIV group.

Adolescent↗
PubMed2006

Induction of protective and mucosal immunity against diphtheria by a immune stimulating complex (ISCOMS) based vaccine.

There is increasing concern over the efficacy of existing vaccines for diphtheria and there is interest in the development of a mucosally active formulation which might improve local protection. Lipophilic immune stimulating complexes (ISCOMS) containing Quil A are active by both parenteral and mucosal routes and here we have established methods for incorporating palmitified diphtheria toxoid (DT) into ISCOMS. The resulting formulation was immunogenic by the subcutaneous, oral and intranasal routes, with very low doses of DT inducing systemic humoral immune responses, as well as cell mediated immunity including both gammaIFN and IL5 production. Intranasal immunisation with DT in ISCOMS also stimulated significant local antibody production in tracheal washes, as well as cellular immunity in draining lymphoid tissues and serum neutralising antibodies. Finally, subcutaneous immunisation of guinea pigs with DT in ISCOMS primed protective immunity against challenge with diphtheria holotoxin more efficiently than the equivalent doses of DT in the conventional alum vaccine. ISCOMS based vaccines may provide a novel strategy for mucosal and systemic immunisation against diphtheria.

Adjuvants, Immunologic↗
PubMed1985

Booster immunisation for diphtheria and tetanus: no evidence of need in adults.

Recommendations to give adults diphtheria and tetanus toxoid every ten years have been based on serological surveys that have shown lower antibody levels in older populations. The purpose of an immunisation programme, however, is to prevent disease and not merely to produce antibodies. In Canada, although an immunisation programme against diphtheria has been in operation for nearly sixty years, age-specific morbidity and mortality rates for diphtheria do not show an increase with age. Similarly, age-specific death rates from tetanus do not show any increase. From Canadian surveillance data, there is no evidence to suggest that people are leaving the immune pool and entering the susceptible pool. Immunisation programmes do not need to include routine administration of booster doses of diphtheria and tetanus toxoids to adults since the benefits of the procedure do not justify the risks or costs. Continuing case-surveillance will bring to light any increase in incidence of disease justifying a need for an adult programme.

Adult↗
PubMed2000

Humoral immunity against diphtheria, tetanus and poliomyelitis after antineoplastic therapy in children and adolescents--a retrospective analysis.

Serum antibodies against diphtheria- and tetanus-toxin were measured in 71 children and against poliomyelitis viruses 1-3 in 65 children and adolescents 0-18 months after cessation of antineoplastic therapy. Non or marginally protective serum titers were found in 62% of patients against diphtheria, in 18% of patients against tetanus and in 72% of patients against one or more poliomyelitis virus serotypes. Of these patients, 55%, 46% and 75% were immunized adequately according to age against diphtheria, tetanus and poliomyelitis, respectively. In 50% or more of patients a lack of protective immunity against diphtheria, tetanus and poliomyelitis was found which could not be explained by an inadequate immunization status. This suggests that other factors (e.g. influence of underlying illness, antineoplastic therapy or both on lymphocytes) might be responsible for these findings and this deserves further investigation. Measurement of serum antibodies against vaccine-preventable illnesses and consecutive booster immunizations are an essential part of long-term follow up in pediatric patients after antineoplastic therapy.

Adolescent↗
PubMed2000

Seroprevalence of diphtheria immunity among injured adults in Austria.

Over a period of 1 year a seroepidemiological study was conducted at the outpatient clinic of a trauma department. Immunity to diphtheria was determined in serum samples from 558 injured patients (205 women and 353 men, age from 18 to 70). Diphtheria-antitoxin concentrations were measured with an enzyme immunoassay and a tissue culture toxin-neutralization assay. Sero-immunity was classified as susceptibility (<0.01 IU/ml), basic protection (0.01-<0.1 IU/ml) and full protection (>/=0.1 IU/ml) against the toxic manifestations of the disease. A total of 27.1% of the subjects were susceptible to diphtheria, 26.5% had basic protection, and 46.4% were fully protected. The median antitoxin concentration reached 0.08 IU/ml (0. 0-0.29; quartiles Q25-Q75). A non linear trend toward decreasing immunity with increasing age was observed (P<0.001) and females proved less protected than males (P=0.006). The country of original immunization (Austria, Western European countries, Eastern European countries and Non European countries) had no influence on sero-immunity (P=0.49). Multiple linear regression analysis revealed that age (P<0.001) and gender (P=0.004) had a significant independent influence on diphtheria immunity level, whereas the country of original immunization was not significant (P=0.72).

Adolescent↗