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PubMed1988

An endosomal model for acid triggering of diphtheria toxin translocation.

An endosomal model system was developed for studying the effects of pH on vesicle-entrapped diphtheria toxin. The "endosomes" were prepared from dioleoylphosphatidylcholine (1 mg), diphtheria toxin (0.25 mg), and lysozyme (2.25 mg) in water at pH 8.4. The method used for preparing large unilamellar vesicles was adapted from the procedure of Shew and Deamer (Shew, R. L., and Deamer, D. W. (1985) Biochim. Biophys. Acta 816, 1-8). Efficiencies of trapping (typically 45-75%) and separation from untrapped proteins (typically 95-100%) were assessed by fluorescamine assays conducted before and after column chromatography and in the presence and absence of Tergitol Nonidet P-40. Intramembranous photolabeling revealed that diphtheria toxin inserts into the vesicle bilayer when the pH is dropped to 4; surface labeling revealed that the same treatment leads to exposure of diphtheria toxin at the trans surface of the vesicles. Release of toxin to the solution was not detected under the experimental conditions employed (i.e. with nicked or unnicked toxin, +/- exogenous trypsin, pH 4 or 8.4). Preliminary results indicate that this model system will be a valuable tool for elucidating the pathway by which the ADP ribosyltransferase domain of diphtheria toxin gains access to the cytoplasmic compartment of cells after endosomal uptake.

ADP Ribose Transferases↗
PubMed1988

Polyspecific human and murine antibodies to diphtheria and tetanus toxoids and phospholipids.

Human-human hybridomas produced from lymphocytes of normal individuals yielded seven clones producing monoclonal antibody reacting with tetanus toxoid. Three of these antibodies cross-reacted with diphtheria toxoid. These three and two others also reacted with cardiolipin and two with other phospholipids. One of the seven antibodies reacted with tetanus and diphtheria toxoids, cardiolipin and single-stranded DNA. All seven antibodies were IgM. To examine further this unusual cross-reactivity serum antibodies from patients with SLE and healthy individuals were affinity-purified to yield diphtheria toxoid antibodies. Six out of nine of these anti-diphtheria preparations contained IgG antibodies which cross-reacted with tetanus toxoid and two of these also reacted with cardiolipin; four preparations cross-reacted with DNA. Anti-cardiolipin and anti-DNA cross-reactivity were found in preparations from both normal and SLE sera. Similar cross-reactivities were demonstrated using four mouse monoclonal IgM antibodies raised against phospholipids. All four of these antibodies reacted with both cardiolipin and tetanus toxoid and two also reacted with diphtheria toxoid and DNA. Using a thiocyanate elution procedure, it was shown that the cross-reactivity of the monoclonal antibodies was not related to their relative affinities. The results clearly indicate that cross-reactive epitopes occur on routinely used toxoid vaccines and self antigens. Antibodies which bind to these cross-reactive epitopes are common and are not restricted in isotype, affinity or species of origin.

Animals↗
PubMed1979

Receptor-mediated transport of the hybrid protein ricin-diphtheria toxin fragment A with subsequent ADP-ribosylation of intracellular elongation factor II.

A hybrid protein of ricin and the enzymatically active fragment A of diphtheria toxin (toxin A) has been synthesized and purified. The diphtheria toxin A fragment of the hybrid protein is shown to enter the cytosol compartment of HeLa cells, its presence assayed by the fall of intracellular elongation factor II (EF-2) and the rise of ADP-ribosylated EF-2. Hybrid entrance to HeLa cells is blocked by lactose which blocks receptor-mediated entry of ricin but not by NH4Cl which blocks the transport of diphtheria toxin. It is concluded that the diphtheria toxin fragment A moiety of the hybrid enters the cell cytosol via the ricin receptor-mediated transport system. The kinetics of intracellular ADP-ribosylation of EF-2 by diphtheria toxin have also been studied. Ribosylation is preceded by a toxin dose-dependent lag period. The data suggest that the time constant responsible for the lag period is in the transport step. Models consistent with these data are discussed.

Adenosine Diphosphate Ribose↗
PubMed1983

[Improvement of the preliminary classification of Corynebacterium diphtheriae v. gravis].

In this study the previously published preliminary scheme for the subdivision of toxigenic and nontoxigenic Corynebacterium diphtheriae, classified with cultivar gravis, is made more precise. 3 groups remain in this scheme: I, II and III; each of them contains toxigenic C. diphtheriae (subgroup a) and nontoxigenic precursors of C. diphtheriae (subgroup b). For the first time nontoxigenic analogs of C. diphtheriae, phagovar OPQSTg, have been introduced into group I and newly discovered toxigenic C. diphtheriae, phagovar K, with their nontoxigenic precursors converted by phages 5 tox+, 6 tox+ and W tox+ have been introduced into group III. Group IV has been provisionally excluded from the scheme because this group comprises a small number of strains (3 strains). This classification can already be used in research practice for a finer differentiation of strains classified with cultivar gravis and for correct epidemic orientation.

Bacteriophage Typing↗
PubMed1981

Proof for the lack of diphtheria toxin in culture filtrates of Corynebacterium ulcerans strain ATCC 9015.

Extensive efforts to identify the diphtheria toxin in culture filtrates of C. ulcerans strain ATCC 9015 was unsuccessful. The culture filtrates did contain a component (called D-antigen) which formed a precipitin line with commercial diphtheria antitoxin. This component was purified by immunosorbent techniques using immobilized preparations of diphtheria antitoxin. It was shown, that D-antigen has a molecular weight of 84000, is not toxic for guinea-pigs, and has nothing in common with purified diphtheria toxin when tested in gel-diffusion tests. The lack of diphtheria toxin in form of its fragments in culture filtrates concentrated 20-fold was proved by the highly sensitive and specific viroimmunoassay.

Animals↗
PubMed1981

Characterization of hybrid molecules containing fragment A from diphtheria toxin linked to concanavalin A or the binding subunit of ricin toxin.

Earlier we described the synthesis of a toxic, disulfide-linked conjugate between Fragment A from diphtheria toxin (DTA) and the lectin concanavalin A (Con A). Here we report further characterization of this Con A-SS-DTA conjugate and of a nontoxic conjugate containing DTA linked through a disulfide bridge to the binding subunit of ricin toxin, RTB. The Con A-SS-DTA conjugate preparation was heterogeneous, and contained both divalent and tetravalent forms of Con A linked to DTA. The divalent form of the conjugate, which lacked hemagglutination activity, was as toxic as the tetravalent form for 3T3 cells. Consistent with this result, Con A-SS-DTA analogs prepared with the chemically modified dimeric derivatives of Con A, succinyl-Con A and acetyl-Con A, were as toxic as DTA disulfide linked to tetravalent Con A. Two analogs of Con A-SS-DTA containing nonreducible intermolecular linkages between DTA and Con A were at least 1000-fold less toxic than Con A-SS-DTA, although they were indistinguishable from unmodified Con A in binding to 3T3 cells. This suggests that reduction of the disulfide bridge between Con A and DTA may be necessary for conjugate toxicity. Con A-SS-DTA was equally toxic for a variety of cell lines varying in sensitivity to diphtheria toxin, including Vero, CHO, HeLa, and 3T3. The conjugate was also toxic for a diphtheria toxin-resistant variant of V79 cells (V79 Dtxr-3) that has lower affinity than wild type cells for diphtheria toxin. Chloroquine, colchicine, cytochalasin B, and ammonium chloride had no effect on Con A-SS-DTA toxicity for Vero cells, although ammonium chloride and chloroquine inhibited diphtheria toxin action.

Animals↗
PubMed1995

Diphtheria epidemic--New Independent States of the former Soviet Union, 1990-1994.

Although diphtheria was controlled for approximately 30 years after the institution of childhood vaccination with diphtheria toxoid in the late 1950s, epidemic diphtheria has reemerged in the New Independent States (NIS) of the former Soviet Union (1,2) (Figures 1 and 2). The epidemic began in 1990 in the Russian Federation and spread to Ukraine in 1991 and, during 1993-1994, to 12 of the 13 remaining NIS. In most affected countries, the incidence rate of reported diphtheria has increased twofold to 10-fold each year. This report summarizes data provided to the World Health Organization (WHO) about diphtheria in the NIS during 1989-1994.*

Adolescent↗
PubMed1994

[Non-toxic Corynebacterium diphtheriae septicemia with endocarditis in an earlier healthy adult. First case and review of the literature].

Corynebacterium diphtheriae septicaemia is rarely encountered, usually in very particular situations: children with severe congenital heart disease or after heart surgery. Rare cases have been reported in immunodepressed adults or drug addicts. We observed a case in a formerly healthy 41-year-old woman who was hospitalized for fever unresponsive to bacampicillin. In this patient, no portal of entry could be identified; there was no history of past surgery nor drug abuse. The patient was not immunodepressed and HIV serology was negative. The last anti-diphtheria vaccination had been given at the age of 12 years. Corynebacterium diphtheriae var. metis was identified on five blood cultures. The in vitro Elek test revealed that the strain was non-toxic. Echocardiography did not show any signs until the fourth examination performed 1 month after onset of fever and 15 days after initiating effective adapted antibiotic treatment with amoxicillin-clavanic acid. Mitral vegetations with grade 2 regurgitation completely regressed after 5 weeks of treatment. After 5 months of follow-up, the patient is in good health and no mitral damage has been observed. This is to our knowledge the first case report of Corynebacterium diphtheriae in a formerly healthy adult. In the literature 12 other cases in adults all concerned immunodepressed subjects or drug abusers. The question is raised as to whether Corynebacterium diphtheriae is undergoing mutation. The germ could persist as a commensal host and explain a certain number of the recent observations in drug abusers and immunodepressed patients.

Adult↗
PubMed1996

Diphtheria outbreak--Saraburi Province, Thailand, 1994.

Following the introduction of diphtheria toxoid in Thailand in 1978 and the acceleration of vaccination efforts by the Expanded Program on Immunization (EPI), the incidence of diphtheria in Thailand decreased substantially. A total of 1021 diphtheria cases were reported nationwide in 1984, compared with 25 cases in 1993. However, on July 19, 1994, a cluster of cases of diphtheria was reported in Saraburi province (1994 population: 565,067) to the Division of Epidemiology (DOE), Thailand Ministry of Public Health; no cases had been reported during the previous year in Saraburi. This report summarizes the outbreak investigation by the DOE, which identified 18 cases during April-August 1994 and identified carriage rates of Corynebacterium diphtheriae of 4% and 8% among household contacts and school contacts, respectively.

Adolescent↗
PubMed1997

Respiratory diphtheria caused by Corynebacterium ulcerans--Terre Haute, Indiana, 1996.

Diphtheria is a potentially severe illness; among unvaccinated persons, the case-fatality rate may be 5%-10%, even with appropriate treatment. During 1990-1995, approximately 4000 deaths resulted from the ongoing diphtheria epidemic in the former Soviet Union. In the United States, respiratory diphtheria is rare: during 1980-1995, only 41 cases were reported. Serologic studies in the 1970s and 1980s indicated that 20%-60% of U.S. adults aged > or = 20 years lacked immunity to diphtheria. This report describes a recent case of respiratory diphtheria caused by a toxin-producing strain of Corynebacterium ulcerans. The case occurred in a resident of Indiana, and an investigation by public health authorities indicated that acquisition of the organism occurred locally in the state.

Corynebacterium↗
PubMed1997

[The return of diphtheria in Europe. Is the French population protected?].

Following the generalized vaccination of children, the European countries achieved the elimination of diphtheria. However the huge epidemic which rages since 1990 in the New Independent States of ex-URSS, culminating in 1994-1995 (with respectively 47,802 and 50,412 notified cases), has showed that diphtheria could be still threatening. A serosurvey was carried out in France on 1,025 adult patients attending the emergency wards of three hospitals, located in different parts of this country. This study showed the insufficient immunity of adults, for lack of a routine programme for revaccination: only half of them have antibodies assuring their protection. The antitoxic immunity decreases according to age. This decline is more marked in women than in men, most of them being reimmunized during the military service. These data confirm the alarming results of similar serosurveys performed in others industrialized countries. The present risk of importing diphtheria in these countries requires a strengthening of clinical and bacteriological surveillance of all cases of infections attributable to C. diphtheriae, and could justify a revaccination programme for adult population, including a regular booster, at 10 year-interval, of a reduced dose of diphtheria toxoid (d), and/or using the combined toxoid Td in the wounded, instead of tetanus toxoid alone.

Adolescent↗
PubMed1978

Diphtheria corneal ulcers.

An adult with cutaneous diphtheria was admitted with bilateral purulent conjunctivitis and a perforated eye with most of the cornea absent due to Corynebacterium diphtheriae. At the time of admission of grayish patch of corneal epithelium was noted in the other eye, and in the next 24 hours there developed a large corneal perforation with dissolution of much of the cornea. Involvement of the external eye in diphtheria is rare but it is usually associated with cutaneous forms of the disease. Cutaneous diphtheria has been prominent in several recent outbreaks in the United States. Prompt recognition, early antibiotic treatment, and neutralization of the toxin with antitoxin are required for successful therapy.

Cephalexin↗
PubMed1992

Determination of neutralizing antibodies and specific immunoglobulin isotype levels in infants after vaccination against diphtheria.

Serum samples were obtained from 44 infants vaccinated against diphtheria at the ages of 3, 5 and 12 months with an aluminium-adsorbed diphtheria-tetanus toxoid vaccine containing 15 Lf units of diphtheria toxoid. Toxin-neutralizing antibodies (antitoxin) were measured by the Vero cell assay and IgG, IgM and IgA antibodies against diphtheria toxoid by enzyme-linked immunosorbent assay. A neutralizing antibody titer of 10 corresponded to 0.01 IU/ml, the level considered necessary for short-term protection. Geometric mean neutralizing antibody titers at 3, 5, 6, 12, 13 and 30 months were 28, 21, 173, 61, 1076 and 61. All children had titers of greater than or equal to 10 (greater than or equal to 0.01 IU/ml) between 6 and 30 months of age. At 30 months only 48% had titers of greater than or equal to 100 (greater than or equal to 0.01 IU/ml), the level considered necessary for long-term protection. Geometric mean IgG antibody levels were 13, 36, 216, 64, 649 and 57. IgG antibodies significantly correlated with neutralizing titers and predicted neutralizing antibodies above or below 10 and 100 with an accuracy of 96 and 82%, respectively. IgG antibodies could not, however, be used to predict individual neutralizing antibody titers with great accuracy. IgM antibodies were only detected after the third vaccination. IgA antibodies were not detected in any serum sample from ten infants tested. In conclusion, the Swedish vaccination schedule results in protective antibody levels in infants until at least 30 months of age. The decline of the antibody titers indicates a need for further studies to establish the duration of protection.

Animals↗
PubMed1991

Immunity to diphtheria in the 3-19 year age group in Italy.

In Italy, immunization with diphtheria toxoid has been compulsory for all newborns since 1939. The last two clinical cases of diphtheria were reported in 1987. During the period 1987-1989, immunity against diphtheria was assessed by neutralization test in a random sample of 1740 healthy subjects 3-19 years old, from five geographical areas of Italy. Of the total population, 76.5% showed antibody levels considered to be protective (greater than or equal to 0.1 IU ml-1), 17.2% had a relative degree of protection (0.01-0.09 IU ml-1), and 6.3% lacked immunity (less than 0.01 IU ml-1). The percentage of unprotected subjects increased from 6.1% in the age group of 3-5 years to 11.4% in the age group of 18-19 years (p less than 0.01). A smaller proportion of males (5.3%) than of females (7.2%) was unprotected, but this difference was not statistically significant. Subjects residing in the south and the islands were more likely to be unprotected than those residing in the north (7.4 versus 4.1%, p less than 0.01). No association was found between lack of protective antibodies and family size (odds ratio 1.35, confidence interval 95% = 0.77-2.36). However, paternal education of less than 12 years was associated with a higher prevalence of non-responders. In order to maintain a high degree of immunity in the adult population, a routine adult booster dose of diphtheria toxoid is advisable.

Antibodies, Bacterial↗
PubMed2004

Oral vaccination against diphtheria using polyacryl starch microparticles as adjuvant.

Oral vaccination offers the advantage of eliciting both a mucosal and a systemic immune response. This study investigated the use of polyacryl starch microparticles as adjuvant for oral vaccination against diphtheria. Diphtheria toxin or cross-reacting material (CRM197) were covalently conjugated to the microparticles and fed to mice by oral gavage. Investigation of formaldehyde treatment as a means of either detoxifying (diphtheria toxin) or stabilising (CRM197) these formulations were also made. We show that all our formulations given orally or parenterally to mice induced a strong systemic immune response. Only formulations given orally induced a mucosal IgA-response. Furthermore, our formulations given parenterally or orally induced a strong diphtheria toxin-neutralising antibody response.

Adjuvants, Immunologic↗
PubMed2004

Immunogenicity and safety of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine as a pre-school booster in UK children.

This open, randomised controlled trial studied the immunogenicity and reactogenicity of two combined low-dose diphtheria, tetanus and acellular pertussis vaccines (Td5aP-IPV, REPEVAX, Aventis Pasteur MSD; and Td5aP, COVAXIS, Aventis Pasteur MSD + OPV, GlaxoSmithKline) in comparison with a standard dose diphtheria pre-school booster vaccine (DT2aP-IPV, TETRAVAC, Aventis Pasteur MSD) in a population of 3.5-5-year-old children administered concomitantly with measles, mumps and rubella vaccine (M-M-R II, Aventis Pasteur MSD). A linked sub-study aimed to evaluate the immunogenicity and reactogenicity of Td5aP-IPV in a population of younger children, aged 3-3.5 years. This study demonstrated non-inferiority of seroprotection rates for diphtheria and tetanus for the study vaccines and comparable immunogenicity for pertussis and polio components of the vaccines. Reactogenicity was similar for all three vaccines. The study vaccines containing low-dose diphtheria antigen (Td5aP-IPV and Td5aP + OPV) are immunogenic and have acceptable reactogenicity for use as a pre-school booster vaccine administered concomitantly with MMR.

Antitoxins↗
PubMed2005

In vitro pyrogenicity of the diphtheria, tetanus and acellular pertussis components of a trivalent vaccine.

We have earlier found that a trivalent vaccine, containing antigenic components from both Gram-positive and Gram-negative bacteria, induced secretion of the endogenous pyrogen interleukin 6 (IL-6) when added to fresh human blood in vitro. The results of the present study showed that the IL-6 secretion was induced by toxoids derived from the Gram-positive bacterium Corynebacterium diphtheriae. However, fresh whole blood from different donors reacted differently to the stimulation. The blood from some donors induced secretion of large concentrations of IL-6, while the blood from other donors induced essentially no IL-6 secretion as a response to stimulation with diphtheria toxoid or a mixture of diphtheria and tetanus toxoids. Repeated testing over several years using blood from the same donor confirmed a donor-dependency of the reaction. This donor-dependency was only found for the toxoid, since blood from all donors reacted with approximately similar IL-6 production to stimulation by endotoxin from the Gram-negative bacterium Escherichia coli, known to be mediated via the toll-like receptor (TLR) 4. Also, no donor-dependecy was found to highly purified lipoteichoic acid from the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus, known to be mediated via TLR-2 and TLR-6. The receptors involved in stimulation by diphtheria toxoid are not known, but may differ from those used by endotoxin and lipoteichoic acid.

Antibodies, Bacterial↗
PubMed1999

Induction of systemic and mucosal antibody responses in mice immunized intranasally with aluminium-non-adsorbed diphtheria toxoid together with recombinant cholera toxin B subunit as an adjuvant.

Nasal mucosal immunization is very attractive for vaccination to prevent various bacterial and viral infectious diseases because of induction of systemic and mucosal immune responses. The aim of the present study was to investigate the possibility of changing the immunization procedure of diphtheria toxoid (DT) from intramuscular or subcutaneous injection to intranasal administration. Intranasal immunization with aluminium-non-adsorbed diphtheria toxoid (nDT) together with recombinant cholera toxin B subunit (rCTB, 10 microg) induced, at a concentration of 5 Lf, high levels of serum DT-specific IgG antibody responses and high or moderate levels of the specific IgA antibody responses in all mice and only a slight level of the specific IgE antibody responses in some mice. Furthermore, sufficiently high diphtheria antitoxin titres more than 0.1 international units (IU) ml(-1) were obtained from mice which showed high levels of serum DT-specific IgG antibody responses. Under the same experimental conditions, induction of significant levels of mucosal DT-specific IgA antibody responses occurred in the nasal cavity, the lung, the saliva and vaginal secretions and the small and large intestines of all mice, although there were different titres between individual mice. Similar results were also obtained with rCTB-specific serum IgG and IgA and mucosal IgA antibody responses; serum rCTB-specific IgE antibody titres were not detected. These results show that intranasal administration of nDT with rCTB must be a very useful means for vaccination against diphtheria.

Adjuvants, Immunologic↗