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PubMed2000

Immunogenicity and safety of a trivalent tetanus, low dose diphtheria, inactivated poliomyelitis booster compared with a standard tetanus, low dose diphtheria booster at six to nine years of age. Munich Vaccine Study Group.

OBJECTIVE: To compare the immunogenicity and safety of a trivalent tetanus-diphtheria (low toxoid content)-inactivated poliomyelitis vaccine, Td-IPV (Revaxis; Pasteur Merièux), with a tetanus-diphtheria (low toxoid content) vaccine, Td (Td-Impfstoff Mérieux; Pasteur Merièux), when administered as a booster to children age 6 to 9 years. METHODS: A group of 301 children were randomized and vaccinated with Td-IPV (n = 150) or Td (n = 151) in this open, controlled, multicenter trial. Serum specimens were obtained before and 28 days after vaccination. Safety was assessed for up to 28 days postvaccination by parental diary cards. Solicited local and systemic reactions were recorded for 7 days after vaccination. RESULTS: Seroprotection (enzyme-linked immunosorbent assay titer, > or =0.10 IU/ml) against tetanus and diphtheria was induced by either Td-IPV or Td in all subjects. Tetanus and diphtheria geometric mean titer were higher after Td (34.0 and 5.74 IU/ml) than after Td-IPV (15.9 and 4.38 IU/ml). All subjects boosted with Td-IPV were seroprotected against each type of poliovirus (neutralizing antibody titer, > or =5/dilution). The most frequently reported solicited local and systemic symptoms were pain triggered by movement of the arm (54% vs. 39.1%) and headache (17.3% vs. 7.3%), after Td-IPV and Td, respectively. All other events were similar between the two groups. Reactions were generally mild and all were temporary. CONCLUSIONS: A booster dose of Td-IPV induced in all children seroprotection against tetanus, diphtheria and poliomyelitis. The overall safety profile of the two vaccines was acceptable.

Child↗
PubMed1994

Oral immunization against diphtheria and tetanus infections by fluid diphtheria and tetanus toxoids.

Purified diphtheria toxoid incorporated in egg yolk and mixed with a medicinal plant seed was used to orally immunize rabbits against diphtheria infection. Animals were partially immunized against a lethal diphtheria toxin challenge. The immunity was complete when gastric enzyme juices were inhibited before oral vaccination by aprotinin, a natural protease inhibitor. Rabbits and monkeys were orally immunized against both diphtheria and tetanus in the same way by pre-treatment with aprotinin. Adult volunteers receiving protease inhibitor before administration of oral toxoids have shown a significant rise in specific circulating antitoxins.

Adjuvants, Immunologic↗
PubMed1957

Delayed hypersensitivity. I. Induction of hypersensitivity to diphtheria toxin in guinea pigs by infection with Corynebacterium diphtheriae.

Guinea pigs infected by intradermal injection of living toxigenic diphtheria bacilli and protected by horse antitoxic globulin, given either before or after infection, develop delayed hypersensitivity of the tuberculin type to diphtherial proteins. The highest degree of hypersensitivity is specifically directed against diphtheria toxin (or toxoid) itself, although smaller delayed skin reactions may be evoked in sensitized animals by other diphtherial proteins common to both toxigenic and non-toxigenic strains. Animals sensitized to diphtheria toxin by infection with a toxigenic strain in this way react positively to the Schick test and their serum usually contains no detectable antitoxin 2 to 3 weeks after the initial infection. Animals infected with living non-toxigenic diphtheria bacilli become sensitized to proteins common to both toxigenic and non-toxigenic strains but do not show sensitivity to toxin. The observations suggest that a minute amount of toxoid, or of toxin comparable to that which might be liberated during infection, might induce the hypersensitive state if injected in the form of a complex with excess antitoxin. This prediction is verified by the results reported in the following paper (23).

Animals↗
PubMed2002

Immunochromatographic strip test for rapid detection of diphtheria toxin: description and multicenter evaluation in areas of low and high prevalence of diphtheria.

An immunochromatographic strip (ICS) test was developed for the detection of diphtheria toxin by using an equine polyclonal antibody as the capture antibody and colloidal gold-labeled monoclonal antibodies specific for fragment A of the diphtheria toxin molecule as the detection antibody. The ICS test has been fully optimized for the detection of toxin from bacterial cultures; the limit of detection was approximately 0.5 ng of diphtheria toxin per ml within 10 min. In a comparative study with 915 pure clinical isolates of Corynebacterium spp., the results of the ICS test were in complete agreement with those of the conventional Elek test. The ICS test was also evaluated for its ability to detect toxigenicity from clinical specimens (throat swabs) in two field studies conducted within areas of the former USSR where diphtheria is epidemic. Eight hundred fifty throat swabs were examined by conventional culture and by use of directly inoculated broth cultures for the ICS test. The results showed 99% concordance (848 of 850 specimens), and the sensitivity and specificity of the ICS test were 98% (95% confidence interval, 91 to 99%) and 99% (95% confidence interval, 99 to 100%), respectively.

Antibodies, Bacterial↗
PubMed2005

Human clinical isolates of Corynebacterium diphtheriae and Corynebacterium ulcerans collected in Canada from 1999 to 2003 but not fitting reporting criteria for cases of diphtheria.

A 5-year collection of Corynebacterium diphtheriae and Corynebacterium ulcerans human clinical isolates yielded nine isolates from blood cultures of patients with invasive infections, stressing the importance of C. diphtheriae as a serious blood-borne pathogen. Seven percent of C. diphtheriae and 100% of C. ulcerans isolates produced diphtheria toxin, demonstrating that toxigenic corynebacteria continue to circulate.

Bacteremia↗
PubMed1993

[Diphtheria--isolation of an endemic Corynebacterium diphtheriae strain in Southern Lower Saxony].

After decades of only limited epidemiological and clinical importance diphtheria (especially of the upper respiratory tract) is regaining increasing interest of public health officials, as recent case reports in national and international publications clearly demonstrate. In March 1993 we observed a case of tracheobronchial Corynebacterium diphtheriae mitis infection in a 66-year old man from the South of Lower Saxony with clinical presentation of mucopurolent exacerbation of chronic bronchitis. The C. diphtheriae mitis strain was identified by microbiological and biochemical tests; however, its expression of toxin remains scientifically controversial. Investigations by the local public health officer suggest an endemic strain of C. diphtheriae. In this paper case report and results of investigations by the local public health officer are described in detail, stressing the need for widespread preventive inoculation not only in the younger but especially in the elderly population.

Aged↗
PubMed2004

Recombinant cholera toxin B subunit (rCTB) as a mucosal adjuvant enhances induction of diphtheria and tetanus antitoxin antibodies in mice by intranasal administration with diphtheria-pertussis-tetanus (DPT) combination vaccine.

Recombinant cholera toxin B subunit (rCTB) which is produced by Bacillus brevis carrying pNU212-CTB acts as a mucosal adjuvant capable of enhancing host immune responses specific to unrelated, mucosally co-administered vaccine antigens. When mice were administered intranasally with diphtheria-pertussis-tetanus (DPT) combination vaccine consisting of diphtheria toxoid (DTd), tetanus toxoid (TTd), pertussis toxoid (PTd), and formalin-treated filamentous hemagglutinin (fFHA), the presence of rCTB elevated constantly high values of DTd- and TTd-specific serum ELISA IgG antibody titres, and protective levels of diphtheria and tetanus toxin-neutralizing antibodies but the absence of rCTB did not. Moreover, the addition of rCTB protected all mice against tetanic symptoms and deaths. DPT combination vaccine raised high levels of serum anti-PT IgG antibody titres regardless of rCTB and protected mice from Bordetella pertussis challenge. These results suggest that co-administration of rCTB as an adjuvant is necessary for induction of diphtheria and tetanus antitoxin antibodies on the occasion of intranasal administration of DPT combination vaccine.

Adjuvants, Immunologic↗
PubMed2000

A mucosal vaccine against diphtheria: formulation of cross reacting material (CRM(197)) of diphtheria toxin with chitosan enhances local and systemic antibody and Th2 responses following nasal delivery.

The development of new generation vaccines against diphtheria is dependent on the identification of antigens and routes of immunization that are capable of stimulating immune responses similar to, or greater than, those obtained with the parenterally-delivered toxoid vaccine, while reducing the adverse effects that have been associated with the traditional vaccine. In this study, we examined the cellular and humoral immune responses in mice generated after both parenteral and mucosal immunizations with cross-reacting material (CRM(197)) of diphtheria toxin. We found that both native and mildly formaldehyde-treated CRM(197) and conventional diphtheria toxoid (DT) induced mixed Th1/Th2 responses and similar levels of anti-DT serum IgG following parenteral immunization. In contrast, CRM(197) preparations were poorly immunogenic when administered intranasally in solution. However, formulation of the antigens with chitosan significantly enhanced their immunogenicity, inducing high levels of antigen-specific IgG, secretory IgA, toxin-neutralizing antibodies and T cell responses, predominately of Th2 subtype. Furthermore, intranasal immunization with CRM(197) and chitosan induced protective antibodies against the toxin in a guinea pig passive challenge model. We also found that priming parenterally with DT in alum and boosting intranasally with CRM(197) was a very effective method of immunization in mice, capable of inducing high levels of anti-DT IgG and neutralizing antibodies in the serum and secretory IgA in the respiratory tract. Our findings suggest that boosting intranasally with CRM(197) antigen may be very effective in adolescents or adults who have previously been parenterally immunized with a conventional diphtheria toxoid vaccine.

Administration, Intranasal↗
PubMed1996

Comparison of the conformation, hydrophobicity, and model membrane interactions of diphtheria toxin to those of formaldehyde-treated toxin (diphtheria toxoid): formaldehyde stabilization of the native conformation inhibits changes that allow membrane insertion.

Toxoids are inactivated protein toxins that are used in vaccines. The behavior of diphtheria toxin reacted with formaldehyde (diphtheria toxoid) was compared to that of diphtheria toxin in order to understand the nature of the changes that occur in toxoids upon protein reaction with formaldehyde. Despite the intramolecular cross-links in the toxoid, the conformations of the toxoid and the toxin were very similar in both the native and low pH-induced membrane-penetrating states as judged by fluorescence and hydrophobicity properties. However, the toxoid underwent thermal-, low-pH-, and guanidinium chloride-induced conformational changes only at more extreme conditions than needed to induce such changes in the toxin. This implies that formaldehyde modification stabilizes the native conformation relative to several conformations that involve different degrees of unfolding. The stabilization to conformational changes induced by low pH is particularly interesting because low pH induces partial unfolding of the toxin to a molten globule-like state. It was found that the toxoid only gained the ability to interact with model membrane vesicles at a lower pH than the toxin. Because low-pH-induced unfolding and membrane interaction are critical steps in the entry of diphtheria toxin into cells, the resistance of the toxoid to these changes may be linked to its lack of toxicity. The implications of these results for the construction of toxoids are discussed.

Binding Sites↗
PubMed1986

[Neural complications after diphtheria vaccination and inoculations with diphtheria toxoid-mixed vaccines. Observations on their etiopathogenesis].

In five children neural complications occurred following diphtheria immunization. In two cases, damage was related to the injection (vaccination-induced poliomyelitis), in three cases it could be traced back to a hyperergic reaction to diphtheria toxoid on the cerebral vessels. The latter complication is typical of individuals being immunized against diphtheria. Such complications are extremely rare; by no means can they question the value of active immunization against diphtheria.

Cerebrovascular Disorders↗
PubMed1990

Molecular cloning and DNA sequence analysis of a diphtheria tox iron-dependent regulatory element (dtxR) from Corynebacterium diphtheriae.

Although the structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages, the regulation of tox expression is controlled, to a large extent, by its bacterial host Corynebacterium diphtheriae. Optimal yields of tox gene products are obtained only when iron becomes the growth-rate-limiting substrate. Previous studies suggest that regulation of tox expression is mediated through an iron-binding aporepressor. To facilitate molecular cloning of the tox regulatory element from genomic libraries of C. diphtheriae, we constructed a tox promoter/operator (toxPO)-lacZ transcriptional fusion in Escherichia coli strain DH5 alpha. We report the molecular cloning and nucleic acid sequence of a diphtheria tox iron-dependent regulatory element, dtxR, and demonstrate that expression of beta-galactosidase from the toxPO-lacZ fusion is regulated by dtxR-encoded protein in an iron-sensitive manner. In addition, we show that expression of the toxPO-lacZ fusion is not affected by the E. coli iron-regulatory protein Fur and that the dtxR protein does not inhibit expression of fur-regulated outer-membrane proteins.

Amino Acid Sequence↗
PubMed1992

Epidemiological features of an outbreak of diphtheria and its control with diphtheria toxoid immunization.

An outbreak of diphtheria primarily involving adults occurred in seven townships and one farm in Jiangling county, Hubei, China from September 1988 to January 1989. Of the 103 reported cases, 80 were aged over 16 years, and there were two deaths. One hundred cases were reported in Jingzhou and its surrounding townships, only three occurred in townships distant from Jingzhou. The incidence and case fatality rates were 11.54/100,000 and 1.94% respectively. Twenty-one strains of diphtheria bacillus were isolated from 68 patients. A special immunization programme using adsorbed diphtheria toxoid was conducted 1 month into the outbreak, following which the incidence declined rapidly. Five vaccinees subsequently developed diphtheria.

Adolescent↗
PubMed1988

Simultaneous administration of Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine with routine diphtheria-tetanus-pertussis and inactivated poliovirus vaccinations of childhood.

A Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) is capable of protecting infants against invasive H. influenzae diseases. Therefore it is very likely that it will be incorporated in routine vaccination schedules during the next few years. In order to test the suitability of simultaneous administration of PRP-D and other vaccines we administered it to 25 infants mixed with diphtheria-tetanus-pertussis vaccine at 3, 4 and 6 months and simultaneously, but in a separate syringe, with inactivated polio vaccine at 12 months. A comparison group of equal size received only diphtheria-tetanus-pertussis and inactivated poliovirus vaccines. The concentration of postvaccination antibodies to diphtheria toxoid was 0.411 IU/ml in the group that received PRP-D vs. 0.352 IU/ml in the comparison group, to tetanus toxoid 3.666 vs. 3.668 IU/ml and the neutralization titer to poliovirus type 1 was 370 vs. 320 units in the comparison group, to type 2 titer values were 230 vs. 270 units and to type 3, respectively, 210 vs. 290 units. Thus the seroresponse to antigens in routine vaccines was not affected by the presence of PRP-D in the vaccination schedule, and PRP-D can safely and effectively be included in the vaccination schedule of infancy.

Bacterial Vaccines↗
PubMed1991

Characterization of a defective diphtheria toxin repressor (dtxR) allele and analysis of dtxR transcription in wild-type and mutant strains of Corynebacterium diphtheriae.

The production of diphtheria toxin and siderophore by the Corynebacterium diphtheriae regulatory mutant C7(beta)hm723 is resistant to the inhibitory effects of iron, and the mutant strain is defective for function of the regulatory gene dtxR. A 2.8-kb HindIII fragment carrying the C7(beta)hm723 dtxR allele was cloned and characterized in Escherichia coli. The restriction endonuclease maps of the 2.8-kb HindIII fragment from C7(beta)hm723 and the corresponding fragment from wild-type C. diphtheriae C7 were identical. RNA dot blot analysis with total RNA isolated from wild-type C. diphtheriae C7 and C7(beta)hm723 indicated that the dtxR gene was transcribed at very low but equivalent levels in both strains and was not regulated by iron. beta-Galactosidase synthesis from a tox-lacZ translational fusion construct in E. coli in high-iron medium was not repressed by the C7(beta)hm723dtxR allele, but was strongly repressed by the wild-type dtxR gene. The 28- to 29-kDa polypeptide expressed from the mutant dtxR allele in E. coli had the same electrophoretic mobility as the wild-type dtxR gene product in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The nucleotide sequence of the coding region and the 5' upstream region of the C7(beta)hm723 dtxR allele was determined and compared with the wild-type nucleotide sequence. The dtxR allele from C7(beta)hm723 contained a single-base change located 140 nucleotides from the 5' start of the gene, which resulted in replacement of arginine in the wild-type sequence by histidine in the mutant protein. These data demonstrate that C7(beta)hm723 expresses a mutant DtxR repressor protein that is severely defective in repressor activity.

Amino Acid Sequence↗
PubMed2003

Detection of differences in the nucleotide and amino acid sequences of diphtheria toxin from Corynebacterium diphtheriae and Corynebacterium ulcerans causing extrapharyngeal infections.

While Corynebacterium ulcerans can mimic classical diphtheria, extrapharyngeal infections are extremely rare. Sequencing of the diphtheria toxin (DT)-encoding tox gene of two C. ulcerans isolates from extrapharyngeal infections revealed differences from C. diphtheriae DT sequences, mainly in the translocation and receptor-binding domains. C. ulcerans supernatants were much less potent than supernatant from C. diphtheriae. A C. ulcerans DT-specific PCR is described below.

Adult↗
PubMed1997

Infections with Corynebacterium diphtheriae--changing epidemiology and clinical manifestations. Report of the third international meeting of the European Laboratory Working Group on Diphtheria (ELWGD), Institute Pasteur, Paris 7-8 June 1996.

A widespread epidemic of diphtheria began in 1990 in the former Soviet Union, in the context of falling immunisation rates and social disruption. Control was impeded by limited diagnostic resources in affected countries (mainly Russia) and there was a risk of spread to neighbouring countries. The European Laboratory Working Group on Diphtheria (ELWGD) was formed to assist in control of the epidemic. The ELWGD is convened by the Public Health Laboratory Service in the United Kingdom and includes 15 laboratories in Europe, one in North America (Centers for Disease Control and Prevention) and the Institute of Clinical Pathology and Medical Research, Sydney. At the group's last annual meeting in Paris, reports were presented on the progress of the epidemic, control strategies and improvements in laboratory diagnosis. The group discussed the increased carriage of, and infection with, nontoxigenic Corynebacterium diphtheriae in countries with high immunisation rates, including the United Kingdom and Australia. They also considered the possible relationship between this increase and the continued diphtheria outbreak in eastern Europe. Preliminary results of molecular typing of toxigenic and nontoxigenic isolates from many parts of the world were presented. It was agreed that further epidemiological investigation is required, using a standardised ribotyping system.

Corynebacterium diphtheriae↗
PubMed1987

[Cloning of the structural gene for diphtheria toxin from Corynebacterium diphtheriae PW8 and expression of its deletion derivative in E. coli].

The coding region of diphtheria toxin gene from Corynebacterium diphtheriae PW8 was cloned in Escherichia coli on pUC19 plasmid. 5' end of the gene was deleted. The deleted gene codes for a toxin like protein truncated for 36 N-terminal aminoacids. The modified gene was fused with 5' terminal part of the lacZ gene on pUC19 plasmid having kept the translational frame intact. The hybrid gene transcription depends on lacP promoter, Mr of the resulting toxoid is 54,000. The toxoid is devoid of ADP-ribosyltransferase activity peculiar for diphtheria toxin and thus is not toxic. The constructed version of the toxin gene can be used for production of diphtheria anatoxin which does not require to be inactivated by formalin.

Chromosome Deletion↗
PubMed2000

Immunogenicity of tetanus-diphtheria toxoids (Td) among Ukrainian adults: implications for diphtheria control in the Newly Independent States of the Former Soviet Union.

After 30 years of control, epidemic diphtheria returned to the Soviet Union in 1990. To develop control strategies, the immunogenicity of the tetanus and diphtheria toxoids (Td) vaccine was assessed. Workers who were 18-67 years old received two Td immunizations separated by 30 days. A neutralization assay determined diphtheria antitoxin (DAT) on enrollment and on days 7, 30, 60, and 425. On enrollment, 43.0% of 488 workers had DAT <0.1 IU/mL. After one dose, 88.5% had DAT >/=0.1 IU/mL, after two doses, 92.2% had >/=0.1 IU/mL and >90% of participants <30 or >/=50 years of age attained >/=1.0 IU/mL; however, only 78.4% of those who were 30-39 years old and 51.8% of those who were 40-49 years old achieved >/=1.0 IU/mL after two doses. To control the epidemic in Ukraine, one Td dose should be administered to virtually the entire population (persons 30-49 years old require three doses of Td for optimal individual protection and to maximize population immunity).

Adolescent↗