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PubMedDate not supplied

[Specificity of antibodies to diphtheria toxin subunits in children with various forms of diphtheria infections].

In order to study the specificity of serum antibodies to separate subunits of diphtheria toxin, SDS-electrophoresis of diphtheria toxin preliminary disintegrated on the subunits via trypsin treatment was performed, followed by immunoblotting assay. 86 blood serum samples of children with diphtheria carriers of toxigenic and non-toxigenic strains of Corynebacterium diphtheriae as well as children with other infectious diseases similar to diphtheria in their clinical manifestation, and healthy ones immunized with DTP-vaccine were tested. A special computer program was written and applied for results processing and assumption. The data obtained showed that there were particular differences in frequency of predominating the antibodies to one or another subunit of diphtheria toxin among various groups of the children. We consider that the different specificity of antibodies of sick children and children-carriers is capable to predetermine the different course of infectious process.

Antibodies, Bacterial↗
PubMedDate not supplied

[Persistence of circulation of Corynebacterium diphtheriae non-toxigenic strains and low prevalence of carriers in a sample of children vaccinated against diphtheria].

This study was carried out with the aim to investigate the presence of carriers of diphtheria bacillus in a sample of 1970 healthy children, 6-14 years aged, residing in eight Italian towns. Three non-toxigenic strains of Corynebacterium diphtheriae biotype mitis were isolated from as many healthy children. Molecular characterization by ribotyping showed close genetic relation of two of the wild strains with the C7(b) reference strain whereas one of the wild strains showed close genetic relation with two collection strains isolated in the same geographic area (Emilia-Romagna) from diphtheria patients in the seventy years. This supports the hypothesis of the persistence of some non toxigenic C. diphtheriae strains derived from ancient endemic strains under the selective pressure of mass immunization against diphtheria. The persistence of carriers of diphtheria bacilli, although non toxigenic, suggests that high levels of immunity must be maintained, not only in children, but also in adults by booster vaccination.

Adolescent↗
PubMed1996

Immunity to diphtheria in women of childbearing age in Delhi in 1994: evidence of continued Corynebacterium diphtheriae circulation.

Blood samples from 171 full-term pregnant women (aged 18-38 years) of middle socioeconomic status from Delhi were tested for diphtheria antitoxins by indirect hemagglutination (IHA) test. History of primary immunization/clinical diphtheria during childhood was not ascertainable, but none had been revaccinated against diphtheria at any time. About 94% women had very high antitoxin titers (> or = 0.125 IU/ ml); none had antitoxin titer less than 0.015 IU/ml, the minimum protective level. The titers were uniformly high in all age groups. However, women having 2 or more children had significantly higher antitoxin titers than those having no or one child (p < 0.01). The results from this study and historical data on diphtheria in Delhi are compatible with continued transmission of C. diphtheriae in recent times in Delhi which is of sufficient magnitude to boost the antitoxin levels in adults, especially mothers having two or more children. The study highlights the need of increasing the immunization coverage with DPT among children to reduce the transmission of Corynebacterium diphtheriae.

Adolescent↗
PubMed2004

Prediction of DtxR regulon: identification of binding sites and operons controlled by Diphtheria toxin repressor in Corynebacterium diphtheriae.

BACKGROUND: The diphtheria toxin repressor, DtxR, of Corynebacterium diphtheriae has been shown to be an iron-activated transcription regulator that controls not only the expression of diphtheria toxin but also of iron uptake genes. This study aims to identify putative binding sites and operons controlled by DtxR to understand the role of DtxR in patho-physiology of Corynebacterium diphtheriae. RESULT: Positional Shannon relative entropy method was used to build the DtxR-binding site recognition profile and the later was used to identify putative regulatory sites of DtxR within C. diphtheriae genome. In addition, DtxR-regulated operons were also identified taking into account the predicted DtxR regulatory sites and genome annotation. Few of the predicted motifs were experimentally validated by electrophoretic mobility shift assay. The analysis identifies motifs upstream to the novel iron-regulated genes that code for Formamidopyrimidine-DNA glycosylase (FpG), an enzyme involved in DNA-repair and starvation inducible DNA-binding protein (Dps) which is involved in iron storage and oxidative stress defense. In addition, we have found the DtxR motifs upstream to the genes that code for sortase which catalyzes anchoring of host-interacting proteins to the cell wall of pathogenic bacteria and the proteins of secretory system which could be involved in translocation of various iron-regulated virulence factors including diphtheria toxin. CONCLUSIONS: We have used an in silico approach to identify the putative binding sites and genes controlled by DtxR in Corynebacterium diphtheriae. Our analysis shows that DtxR could provide a molecular link between Fe+2-induced Fenton's reaction and protection of DNA from oxidative damage. DtxR-regulated Dps prevents lethal combination of Fe+2 and H2O2 and also protects DNA by nonspecific DNA-binding. In addition DtxR could play an important role in host interaction and virulence by regulating the levels of sortase, a potential vaccine candidate and proteins of secretory system.

Bacterial Proteins↗
PubMed1994

Suitability of the Vero cell method for titration of diphtheria antitoxin in the United States potency test for diphtheria toxoid.

The in vitro Vero cell method for titration of diphtheria antitoxin in immunized guinea pig sera was standardized to obtain comparable results to the in vivo toxin neutralization (TN) test in guinea pigs used to test potency of adsorbed diphtheria toxoid according to the United States Minimum Requirements. In the Vero cell method, the antitoxin titers of the guinea pig sera, obtained 4 weeks after immunization, were markedly dependent on the toxin dose level used in the assay. A toxin dose level termed the Lcd/1 dose (limit of cytopathic dose at 1 IU/ml) for Vero cell method gave comparable estimates of antitoxin activity to the in vivo TN method performed at L+/1 dose of toxin. The Lcd/1 toxin dose level for the Vero cell method is defined as the minimum concentration of diphtheria toxin required to produce a cytopathic effect on Vero cells in 4 days when the solution of diphtheria toxin is mixed with an equal volume of standard diphtheria antitoxin whose concentration is 1 IU/ml. When lower dose levels of toxin were used in the Vero cell assay (Lcd/10 to Lcd/1000), the concentrations of antitoxin in 4 weeks guinea pig sera were 2 to 11.7 times lower than with the Lcd/1 dose level and similarly lower than those measured by the in vivo TN test at L+/1 level. In contrast, the concentration of antitoxin measured in sera from guinea pigs who have been boosted with diphtheria toxoid increased approximately two-fold with the Lcd/1000 dose level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Fatal respiratory tract diphtheria apparently caused by nontoxigenic strains of Corynebacterium diphtheriae.

A major diphtheria epidemic affecting the whole population of St. Petersburg started in 1990. During the period of 1991 to 1995, 4600 patients with clinical respiratory tract diphtheria were treated in Botkin's Hospital. From 112 (2.4%) of these patients only a nontoxigenic strain of Corynebacterium diphtheriae was isolated. Three patients with this strain who were suffering from clinical disease consistent with classical toxic diphtheria died. All had myocarditis, two had asphyxia due to membrane formation in the lower respiratory tract, and one had severe polyneuritis. In two patients the causative agent was of the biotype mitis and in the third intermedius, whereas the prevailing epidemic strain was of the biotype gravis. As the clinical presentation of the disease in the three patients who died was typical of toxic diphtheria, it is considered likely that the immunodiffusion test for toxin production in vitro may fail to detect strains of Corynebacterium diphtheriae producing toxin in vivo.

Aged↗
PubMed1990

Coordinate regulation of siderophore and diphtheria toxin production by iron in Corynebacterium diphtheriae.

Iron is an environmental signal which regulates the coordinate expression of genes associated with virulence in many pathogenic bacteria. In response to iron-deprivation, lysogenic Corynebacterium diphtheriae C7 (beta) synthesizes and secretes diphtheria toxin and siderophore and induces a high-affinity iron uptake system. Diphtheria toxin is encoded by beta phage, but genes for siderophore production are encoded on the bacterial chromosome. Diphtheria toxin and siderophore production were shown to be coordinately induced during late logarithmic phase growth of wild-type C7(beta) in iron-limited medium. C. diphtheriae mutant C7hm723 produced siderophore and toxin constitutively under low-iron and high-iron conditions, but in mutants HC1, HC3, HC4, and HC5 their synthesis was partially repressed under high-iron conditions. The phenotypes of HC1, HC3, HC4, and HC5 are consistent with their severe defects in iron uptake, but the phenotype of C7hm723 is more likely to be explained by inactivation of the repressor for the iron regulon of C. diphtheriae.

Cetrimonium↗
PubMed1975

Skin infections and the epidemiology of diphtheria: acquisition and persistence of C diphtheriae infections.

Acquisition and persistence of C. diphtheriae infections of skin lesions and of the respiratory tract were observed in households exposed to C. diphtheriae carriers in a community experiencing a diphtheria outbreak and in households in two communities free of the disease. Acquisition of C. diphtheriae was more frequent in epidemic households, apparently due to a greater frequency of respiratory tract acquisition. Skin lesion acquisition was constant in both situations. The pattern of persistence appeared to be the same in both types of households, although skin lesion C. diphtheriae infections had a greater tendency to persist than respiratory tract infections. Acquisition occurred more frequently following exposure to a skin lesion C. diphtheriae carrier than following a respiratory carrier exposure.

Carrier State↗
PubMed1999

Diphtheria in the Republic of Georgia: use of molecular typing techniques for characterization of Corynebacterium diphtheriae strains.

Sixty-six Corynebacterium diphtheriae strains (62 of the gravis biotype and 4 of the mitis biotype) isolated during the Georgian diphtheria epidemic of 1993 to 1998 and 13 non-Georgian C. diphtheriae strains (10 Russian and 3 reference isolates) were characterized by (i) biotyping, (ii) toxigenicity testing with the Elek assay and PCR, (iii) the randomly amplified polymorphic DNA (RAPD) technique, and (iv) pulsed-field gel electrophoresis (PFGE). Fifteen selected strains were ribotyped. Six RAPD types and 15 PFGE patterns were identified among all strains examined, and 12 ribotypes were found among the 15 strains that were ribotyped. The Georgian epidemic apparently was caused by one major clonal group of C. diphtheriae (PFGE type A, ribotype R1), which was identical to the predominant epidemic strain(s) isolated during the concurrent diphtheria epidemic in Russia. A dendrogram based on the PFGE patterns revealed profound differences between the minor (nonpredominant) epidemic strains found in Georgia and Russia. The methodologies for RAPD typing, ribotyping, and PFGE typing of C. diphtheriae strains were improved to enable rapid and convenient molecular typing of the strains. The RAPD technique was adequate for biotype differentiation; however, PFGE and ribotyping were better (and equal to each other) at discriminating between epidemiologically related and unrelated isolates.

Bacterial Typing Techniques↗
PubMedDate not supplied

[Mathematical model of the infection process in diphtheria for determining the therapeutic dose of antitoxic anti-diphtheria serum].

It is known that administration of horse serum against diphtheria toxin can cause autoimmune and allergic complications. Therefore it is important for improvement of serotherapy to develop methods of prediction of disease course and quantity of diphtheria toxin and antitoxic antibodies in a serum. We have developed the mathematical model of diphtheria infection, which consists of six differential equations describing dynamics of diphtheria toxin and antitoxic antibodies in a serum, quantity of infection agent and macrophages in a site of inflammation. This mathematical model allows to predict the course of infectious process, the level of diphtheria toxin and antitoxic antibodies in the sera of people with diphtheria and to calculate the individual therapeutic dose of antitoxic serum for each patient.

Diphtheria↗
PubMed2006

Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel.

On June 10, 2005, a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) formulated for use in adults and adolescents was licensed in the United States for persons aged 11-64 years (ADACEL, manufactured by sanofi pasteur, Toronto, Ontario, Canada). Prelicensure studies demonstrated safety and efficacy, inferred through immunogenicity, against tetanus, diphtheria, and pertussis when Tdap was administered as a single booster dose to adults. To reduce pertussis morbidity among adults and maintain the standard of care for tetanus and diphtheria prevention and to reduce the transmission of pertussis to infants and in health-care settings, the Advisory Committee on Immunization Practices (ACIP) recommends that: 1) adults aged 19-64 years should receive a single dose of Tdap to replace tetanus and diphtheria toxoids vaccine (Td) for booster immunization against tetanus, diphtheria, and pertussis if they received their last dose of Td >or=10 years earlier and they have not previously received Tdap; 2) intervals shorter than 10 years since the last Td may be used for booster protection against pertussis; 3) adults who have or who anticipate having close contact with an infant aged <12 months (e.g., parents, grandparents aged <65 years, child-care providers, and health-care personnel) should receive a single dose of Tdap to reduce the risk for transmitting pertussis. An interval as short as 2 years from the last Td is suggested; shorter intervals can be used. When possible, women should receive Tdap before becoming pregnant. Women who have not previously received Tdap should receive a dose of Tdap in the immediate postpartum period; 4) health-care personnel who work in hospitals or ambulatory care settings and have direct patient contact should receive a single dose of Tdap as soon as feasible if they have not previously received Tdap. An interval as short as 2 years from the last dose of Td is recommended; shorter intervals may be used. These recommendations for use of Tdap in health-care personnel are supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC). This statement 1) reviews pertussis, tetanus and diphtheria vaccination policy in the United States; 2) describes the clinical features and epidemiology of pertussis among adults; 3) summarizes the immunogenicity, efficacy, and safety data of Tdap; and 4) presents recommendations for the use of Tdap among adults aged 19-64 years.

Adult↗
PubMed1995

Characterization of an iron-dependent regulatory protein (IdeR) of Mycobacterium tuberculosis as a functional homolog of the diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae.

The DtxR protein from Corynebacterium diphtheriae is an iron-dependent repressor that regulates transcription from the tox, IRP1, and IRP2 promoters. A gene from virulent Mycobacterium tuberculosis H37Rv was recently shown to encode a protein, here designated iron-dependent regulator (IdeR), that is almost 60% homologous to DtxR from C. diphtheriae. A 750-bp PCR-derived DNA fragment carrying the M. tuberculosis ideR allele was subcloned to both high- and low-copy-number vectors. In Escherichia coli, transcription from the C. diphtheriae tox, IRP1, and IRP2 promoters was strongly repressed by ideR under high-iron conditions, and ideR restored normal iron-dependent expression of the corynebacterial siderophore in the C. diphtheriae dtxR mutant C7(beta)hm723. The M. tuberculosis IdeR protein was overexpressed in E. coli and purified to near homogeneity by nickel affinity chromatography. Gel mobility shift experiments revealed that IdeR bound to a DNA fragment that carried the C. diphtheriae tox promoter/operator sequence. DNAse I footprint analysis demonstrated that IdeR, in the presence of Cd2+, Co2+, Fe2+, Mn2+, Ni2+, or Zn2+, protected an approximately 30-bp region on DNA fragments carrying the tox, IRP1, or IRP2 promoter/operator sequences. IdeR reacted very weakly in Western blots (immunoblots) with antiserum against the C. diphtheriae DtxR protein, suggesting that the immunodominant epitopes of DtxR may be located in its poorly conserved carboxyl-terminal domain.

Bacterial Proteins↗
PubMed2004

The diphtheria and pertussis components of diphtheria-tetanus toxoids-pertussis vaccine should be genetically inactivated mutant toxins.

Replacement of cellular with acellular pertussis (aP) vaccines has considerably reduced the systemic reactions observed with diphtheria-tetanus toxoids-pertussis vaccine but has not eliminated the extensive swelling (sometimes involving an entire limb) observed after the fifth injection of diphtheria-tetanus toxoids-aP (DTaP) vaccine. This local reaction, which is likely an Arthus hypersensitivity reaction caused by high levels of antibodies reacting with DTaP vaccine, could discourage its use in adults, who serve as the major reservoir of pertussis for infants. That a critical level of antibodies to pertussis toxin is both essential and sufficient to prevent infection with Bordetella pertussis is derived from data from animal and clinical studies, including data showing the similarities between the immunity induced by diphtheria and pertussis toxoids. The genetically inactivated diphtheria and pertussis mutant toxins are more immunogenic and, therefore, induce comparable levels of antitoxin at lower protein levels than do the formalin-treated native toxins. Replacement of the diphtheria and aP components with these improved antigens will reduce the amount of protein in DTaP vaccine and, most likely, the incidence and severity of local reactions in teenagers and adults.

Adult↗
PubMed2000

[Antibody levels for diphtheria, tetanus and pertussis in young adult females immunized with whole cell pertussis-diphtheria-tetanus toxoid vaccine in infancy].

Antibody levels for diphtheria, tetanus and pertussis in 84 young adult females were measured. They had been immunized with whole cell pertussis-diphtheria-tetanus toxoid (DTwP) vaccine as a routine immunization in their infancy. Their history of DTwP vaccination were confirmed in their Maternal and Child Health Handbook, which includes their immunization record. Among the 84 cases, 4 cases (4.7%) had been immunized with the first dose of DTwP, 5 cases (6.0%) with the second dose, 23 cases (27.4%) with the third dose and 52 cases (61.9%) with the fourth dose. Of the 84 cases, 89.3% had received DTwP vaccine more than the third dose. In the 15-19 years after the last DTwP vaccination, the antibody positive rate for diphtheria and tetanus (> or = 0.01 IU/ml) were 86.9% and 94.0%, respectively. On the other hand, antibody positive rate for anti-pertussis toxin (anti-PT) and anti-filamentous hemaggulutinin (anti-FHA) (> or = 10 EU/ml) were 35.7% and 55.9%, respectively. The positive rate for pertussis compared with those for diphtheria and tetanus were lower. These findings suggested that DTwP vaccination in infancy does not provide sufficient immunity for young adults against pertussis, but DTwP vaccination provides adequate immunity against diphtheria and tetanus.

Adult↗
PubMed2004

Spontaneously reported adverse reactions after diphtheria-tetanus revaccination at 4-6 years of age--a comparison of two vaccines with different amounts of diphtheria toxoid.

On 1 January 1996, diphtheria-tetanus revaccination at the age of 5 years was implemented in the Danish Childhood Vaccination Programme. Initially, a combined DT vaccine containing 25 Lf diphtheria toxoid was used. Due to a high frequency of spontaneously reported adverse reactions, however, concerns were raised that the diphtheria dose was too high, and it was reduced to 6.25 Lf. This survey presents the rates of spontaneously reported adverse reactions following diphtheria-tetanus revaccinations of 4-6-year-old from 1996 to 2002. The change to the lower dose of diphtheria toxoid resulted in a remarkable reduction in the yearly rates of injection site reactions: in 1996, the rate was 180 injection site reactions per 100,000 vaccinations; from 1998 to 2002, this changed to between 12 and 24 reactions per 100,000 vaccinations. Furthermore, the rates of systemic reactions such as fever were reduced.

Child, Preschool↗
PubMed1985

Diphtheria toxin promoter function in Corynebacterium diphtheriae and Escherichia coli.

The expression of the diphtheria tox228 gene encoding the nontoxic, serologically related CRM228 mutant diphtheria toxin has been analyzed in Corynebacterium diphtheriae and Escherichia coli. The diphtheria toxin promoter has been used to direct the expression of beta-galactosidase in E.coli, and the efficiency of promotion has been compared to that obtained with the lac promoter. Expression in C.diphtheriae is known to be dependent on the absence of iron, and we present for the first time direct evidence that this regulation occurs at the level of transcription. The 5' end of toxin mRNA maps at the same position in C.diphtheriae and E.coli, suggesting identical sequences to be recognized by C.diphtheriae and E.coli RNA polymerase. The diphtheria toxin promoter carries at position -34 a TTGATT sequence closely related to the E.coli -35 consensus sequence and in the -14 to -8 region a set of overlapping sequences with complete or partial homology to the E.coli -10 consensus sequence.

Base Sequence↗
PubMed1987

Susceptibility to diphtheria in populations vaccinated before and after elimination of indigenous diphtheria in Denmark. A comparative study of antitoxic immunity.

The need for routine diphtheria revaccination is still controversial. Only single cases of diphtheria have been observed in Denmark since the mass vaccinations in the 1940s and the introduction of routine vaccination of infants in 1950, despite the fact that general revaccination has not been recommended. An investigation of antitoxin immunity in 1.188 probands 2-69 years of age, randomly or cluster selected, indicated that immunity in the Danish population is still above the limit generally believed to guard against diphtheria epidemics (around 70% being immune in a population). The highest frequency of susceptibility (46%) was found among females 30-39 years of age. Serum antitoxin concentrations in 529 subjects with documentation for complete primary vaccination 1-40 years previously corresponded to a continuous fall-off. Relative to time from vaccination, individuals born when diphtheria occurred frequently in Denmark had significantly higher antitoxin levels than those born later, and among children susceptibility had increased considerably as compared to observations in the 1950s. These phenomena were explained by the effect of natural immune stimulation previously. The present concept of relatively high frequencies of immune subjects also in other western countries may not be valid in the future, when the number of subjects born after the elimination of indigenous diphtheria increases. General revaccinations seem required to maintain herd immunity.

Adolescent↗
PubMed1990

Quantitative estimation of diphtheria and tetanus toxoids. 4. Toxoids as international reference materials defining Lf-units for diphtheria and tetanus toxoids.

The Lf-unit, which is used in the control of diphtheria and tetanus toxoid production and in some countries also to follow immunization of horses for production of antitoxins, has hitherto been defined by means of antitoxin preparations. A diphtheria toxoid and a tetanus toxoid preparation, both freeze-dried, were examined in an international collaborative study for their suitability to serve as reference reagents in the flocculation tests and for defining the Lf-units. It was shown that flocculation tests using the reference toxoids are very reproducible and reliable and the WHO Expert Committee on Biological Standardization established: the toxoid called DIFT as the International Reference Reagent of Diphtheria Toxoid for Flocculation Test with a defined content of 900 Lf-units of diphtheria toxoid per ampoule; and the toxoid called TEFT as the International Reference Reagent of Tetanus Toxoid for Flocculation Test with a defined content of 1000 Lf-units of diphtheria toxoid per ampoule.

Animals↗