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PubMedDate not supplied

Prevalence of diphtheria carriers in a population with disappearing clinical diphtheria.

Ten years ago the incidence of diphtheria was relatively high in Greece and a survey of school children had revealed a carrier prevalence of non-toxigenic Corynebacterium diphtheriae of 3,4%. A similar survey undertaken now has revealed that the disease seems to be disappearing. Among 895 school children (6-13 years-old) in seven primary schools of different socioeconomic levels, only seven were carriers of non-toxigenic C. diphtheriae strains, corresponding to a prevalence of 0.8%. Toxigenic strains were not found. All carriers were pupils of the same school, and the carrier state was more frequent during the first three school years. All the carriers were found in a school serving a socioeconomically deprived area. A statistically significant association was found between the prevalence of C. diphtheriae and of other non-pathogenic Corynebacteria.

Adolescent↗
PubMed1999

Reactogenicity and immunogenicity of reduced antigen content diphtheria-tetanus-acellular pertussis vaccines as a booster in 4-7-year-old children primed with diphtheria-tetanus-whole cell pertussis vaccine before 2 years of age.

BACKGROUND: The recent introduction of acellular pertussis vaccines (Pa) offers the possibility of booster doses in older children and adults. This can be conveniently accomplished by combining acellular pertussis antigens with diphtheria and tetanus toxoids. However the optimal dosage for the booster injection has not yet been determined. OBJECTIVE: To compare the reactogenicity and immunogenicity of diphtheria-tetanus-acellular pertussis vaccines (DTPa) with lower antigen contents to a licensed DTPa vaccine when given at 4-7 years of age as a booster to DTPw-primed children. METHODS: Two hundred and twenty-six children primed with four doses of DTPw before 2 years of age were enrolled and allocated to three groups to receive one dose of either DTPa (Infanrix, SmithKline Beecham, Biologicals), a reduced antigen formulation of this vaccine (dtpa, SmithKline Beecham Biologicals), or an experimental low dose formulation (dtpa-exp; d and t, Michigan Biologic Products Institute). Reactogenicity was assessed using diary cards for 15 days. Immunogenicity was determined as antibody responses against the vaccine components in pre- and 1 month postvaccination sera. RESULTS: Of the 225 children who completed the study, 60.0-66.7% reported symptoms, with no significant differences in rates between groups. Local, systemic and unsolicited symptoms occurred with similar frequencies in all three groups, the vast majority (> 90%) being considered as mild or moderate. No serious adverse events related to vaccination were reported. After vaccination, all subjects displayed seroprotective concentrations against diphtheria and tetanus, and 98.7-100% had antibodies against the three pertussis component antigens. The group receiving the reduced dose of the licensed vaccine showed antibody concentrations comparable to those of the full dose group. However, the group receiving the experimental low dose formulation had statistically significantly lower antibody concentrations against both diphtheria and tetanus toxoids compared with the two other groups, as well as significantly lower anti FHA antibody concentrations. CONCLUSIONS: Reducing the antigen content of dtpa had no deleterious effect on the immunogenicity of the vaccine when given as a fifth dose at 4-7 years of age in DTPw-primed children. The reactogenicity profile of both the reduced antigen dtpa vaccines and DTPa were acceptable, the vast majority of local and systemic reactions being considered as mild to moderate, with no vaccine-related serious adverse events reported. The use of lower antigen content dtpa vaccine as a booster in children aged 4-7 is safe and immunogenic.

Antibodies, Bacterial↗
PubMed1995

Structures of the apo- and the metal ion-activated forms of the diphtheria tox repressor from Corynebacterium diphtheriae.

The diphtheria tox repressor (DtxR) of Corynebacterium diphtheriae plays a critical role in the regulation of diphtheria toxin expression and the control of other iron-sensitive genes. The crystal structures of apo-DtxR and of the metal ion-activated form of the repressor have been solved and used to identify motifs involved in DNA and metal ion binding. Residues involved in binding of the activated repressor to the diphtheria tox operator, glutamine 43, arginine 47, and arginine 50, were located and confirmed by site-directed mutagenesis. Previous biochemical and genetic data can be explained in terms of these structures. Conformational differences between apo- and Ni-DtxR are discussed with regard to the mechanism of action of this repressor.

Amino Acid Sequence↗
PubMed1992

Construction of a diphtheria toxin A fragment-C180 peptide fusion protein which elicits a neutralizing antibody response against diphtheria toxin and pertussis toxin.

A genetically engineered gene fusion was constructed which encoded a nontoxic derivative of the A fragment of diphtheria toxin joined to the C180 peptide of the S1 subunit of pertussis toxin. The product of this gene fusion, termed the DTA-C180 protein, was purified from the periplasm of Escherichia coli to approximately 80% purity. The DTA-C180 protein possessed an apparent molecular weight of 43,000 by reduced sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The DTA-C180 protein was cleaved into two tryptic peptides, which migrated with apparent molecular weights of approximately 22,000. One tryptic peptide reacted with diphtheria antitoxin, while the other tryptic peptide reacted with anti-C180 peptide immunoglobulin G. The DTA-C180 protein did not inhibit protein synthesis or stimulate clustering morphology in Chinese hamster ovary cells. The DTA-C180 protein elicited an immune response, in guinea pigs, against both the DTA and C180 peptide components of the fusion protein, with alum being a more efficient adjuvant than Freund's adjuvant for eliciting neutralization titers. Neutralization titers elicited by DTA-C180 protein were weaker than those elicited by diphtheria toxoid and pertussis toxin 9K/129G, a genetically engineered double mutant of pertussis toxin. Three doses of DTA-C180 protein yielded a neutralization titer of 1/750 against pertussis toxin in Chinese hamster ovary cells and a neutralization titer of 1/50 against diphtheria toxin in Vero cells. This is the first report of a protein derived from a recombinant S1 subunit that elicits a neutralizing titer against pertussis toxin.

Adenosine Diphosphate Ribose↗
PubMed1966

Phage typing of Corynebacterium diphtheriae. Incidence of C. diphtheriae phage types in different countries.

Simultaneously with the development of vaccines against diphtheria, the authors and their colleagues have studied the biological properties of the causative agent, Corynebacterium diphtheriae, and its role in the development of epidemics. This study has been made possible by the development of a lysotyping scheme for the bacterium, covering all three biotypes-gravis, intermedius and mitis. On the basis of this scheme it was possible to lysotype 73% of the 8694 strains of C. diphtheriae isolated in Romania between 1956 and 1966-99% of the gravis strains, 39% of the intermedius and 19% of the mitis; in all, 19 lysotypes were distinguished.To check the applicability of the lysotyping scheme on an international scale, 395 strains of C. diphtheriae were obtained from the reference laboratories in 14 countries in four continents. It was possible to lysotype 62% of the strains, including 93% of the gravis type. Details are given of the geographical distribution of the different lysotypes; two lysotypes not isolated in Romania were encountered among the foreign strains and will be incorporated into the scheme as the 20th and 21st lysotypes.There is a need to extend the number of intermedius- and mitis-type phages to enable more of these types of strain to be distinguished.

Bacteriophage Typing↗
PubMed1980

[Tonsils in diphtheria and the Corynebacterium diphtheriae carrier state].

Investigations of 16 archive autopsy observations of diphtheria of the fauces confirmed bacteriologically revealed that Corynebacteria diphtheriae multiplied mainly on the surface of the mucous membrane. Fibrinous inflammation on the tonsillar surface is most typical for this agent. In all cases with manifestations of acute inflammation the lesion was caused by C. diphtheriae in combination with other bacteria, most frequently streptococci. The latter were harboured deep in the tonsills and caused there an inflammatory process with characteristic lesions. Examinations of the tonsills removed from 72 C. diphtheriae carriers showed that longterm persistence of the bacteria in the tonsills was primarily due to the specific structure of the cryptae, particularly great branchiness and depth contributing to the retention of the content. Long-term carrier state leads to a statistically significant increase of the degree of their plasmatization as compared with the control group. This occurs in parallel with changes in the general responsiveness of the host.

Autopsy↗
PubMed1954

Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. IV. Differences between human precipitating and non-precipitating skin-sensitizing diphtheria antitoxin as shown by electrophoresis.

Electrophoresis on a starch-supporting medium was used to fractionate sera containing human diphtheria antitoxin of the following varieties (a) precipitating antitoxin, (b) non-precipitating skin-sensitizing antitoxin, and (c) mixtures containing precipitating and skin-sensitizing antitoxins. Aliquots of the protein fractions thus separated were tested for activity using the rabbit toxin neutralization test, precipitin techniques, and passive transfer tests in human skin. Non-precipitating, skin-sensitizing diphtheria antitoxin migrated largely as a fast moving gamma (gamma(1)) globulin. Passive transfer studies of isolated antitoxic fractions showed that they were as potent as whole serum in the ability to cause immediate wheal reactions. These fractions were not precipitable using appropriate quantities of purified toxoid. Precipitating diphtheria antitoxin migrated largely as a slow moving gamma (gamma(2)) globulin. Isolated antitoxic fractions of appropriate strength obtained from representative sera were precipitable by toxin and were unable to cause immediate wheal reactions upon toxoid challenge in human recipients. Mixtures of skin-sensitizing and precipitating antitoxins were separable by the technique of starch electrophoresis. The individual components removed from mixtures by this method retained the properties by which they could be characterized in whole serum.

Antibodies↗
PubMed1999

Evidence of efficacy of the Lederle/Takeda acellular pertussis component diphtheria and tetanus toxoids and pertussis vaccine but not the Lederle whole-cell component diphtheria and tetanus toxoids and pertussis vaccine against Bordetella parapertussis infection.

A subanalysis of a recent cohort efficacy trial of a pertussis vaccine was performed to determine its efficacy against cough illnesses due to Bordetella parapertussis infections. Infants received four doses of either the Lederle/Takeda acellular pertussis component diphtheria and tetanus toxoids and pertussis (DTaP) vaccine or the Lederle whole-cell component diphtheria and tetanus toxoids and pertussis (DTP) vaccine at 3, 4.5, 6, and 15-18 months of age; controls received three doses of diphtheria and tetanus toxoids (DT) vaccine only. All subjects were prospectively followed for cough illnesses of > or = 7 days' duration; cases of B. parapertussis infection were confirmed by positive culture, household contact, or serology. Seventy-six cough illnesses due to B. parapertussis were identified; 24 occurred in 929 DTaP recipients, 37 in 937 DTP recipients, and 15 in 321 DT recipients, resulting in an efficacy of 50% for DTaP vaccine (95% CI [confidence interval], 5% to 74%) and 21% for DTP vaccine (95% CI, -45% to 56%). The data in the present analysis suggest that the Lederle/Takeda DTaP vaccine but not the Lederle whole-cell component DTP vaccine has efficacy against B. parapertussis infection.

Bordetella Infections↗
PubMedDate not supplied

Primary immunization with diphtheria-tetanus toxoids vaccine and diphtheria-tetanus toxoids-pertussis vaccine adsorbed: comparison of schedules.

In a double blind study patients were randomly divided into two groups. All patients received an initial immunization with diphtheria-tetanus toxoids-pertussis (DTP) vaccine at 2 months of age. One population received diphtheria-tetanus toxoids (DT pediatric) vaccine at the time of the second immunization at 4 months of age and DTP vaccine at 6 months (DTP-DT-DTP). In a second group DTP vaccine was administered as the second immunization and DT (pediatric) vaccine was given at the 6-month visit (DTP-DTP-DT). There was a significantly increased incidence and severity of adverse reactions associated with DTP vaccine when contrasted with responses observed after DT vaccine; differences were apparent whether the vaccine was administered as the second or the third immunization. All patients had serologic evidence of protection to diphtheria and tetanus following completion of either primary series. The geometric mean titer of pertussis agglutinins was similar in the two study groups 2 months after the second DTP immunization but was significantly higher in the DTP-DT-DTP group at 1 to 2 months after the completion of the primary immunization series (P less than 0.01). Both groups, however, were significantly lower than the comparable geometric mean titer measured after a series of three DTP inoculations (7.51, log2) (P less than 0.01). This study supports the recommendation that three immunizations of DTP be administered in the first year of life.

Adsorption↗
PubMed1986

Revaccination of adults against diphtheria. I: Responses and reactions to different doses of diphtheria toxoid in 30-70-year-old persons with low serum antitoxin levels.

Studies of diphtheria antitoxin levels in serum from adult populations have indicated high frequencies of unprotected subjects. Serum from 351 randomly selected Danes between 30 and 70 years old has been assessed for antitoxin concentration; 123 persons among these, who had low antibody levels, received one vaccination with 2 Lf, 5 Lf or 12 Lf diphtheria toxoid. Side-reactions were recorded, and antibody levels were studied 4 weeks later. Antitoxin concentration following vaccination increased markedly to above protective level in 83% of those vaccinated. Of subjects, who could document a complete primary vaccination series, only one receiving 2 Lf 31 years after primary vaccination did not attain protective antitoxin level. Minor local reactions only were recorded among subjects who did not respond serologically to vaccination. Frequencies of more pronounced reactions experienced by serologically responding subjects depended on dose and were 15%, 14% and 23% respectively. It was concluded that a single vaccination of the present adult Danish population will induce protective antibody levels so frequently that the effect of herd immunity will secure against epidemics if future diphtheria outbreaks are experienced. To secure individual protection, vaccination history and/or serological assessments have to be explored in order to decide whether a single vaccination is sufficient.

Adult↗
PubMed1981

Diphtheria immunization in adolescents and adults with reduced doses of adsorbed diphtheria toxoid.

A study was undertaken in Schick-positive university students and schoolchildren to determine the diphtheria antitoxin response to vaccines containing a reduced dose of adsorbed diphtheria toxoid. It was found that the majority of participants, apparently previously sensitized, responded with an increase in antitoxin titre to protective levels after performance of the Schick test, or after the first dose of vaccine. A group of non-immune students required three doses of vaccine to reach adequate antitoxin levels to ensure durable immunity. Only one local reaction was observed in the group of 51 students, and this was attributed to an Arthus-type reaction involving the tetanus toxoid component of a combined adsorbed diphtheria and tetanus vaccine.

Adolescent↗
PubMed1990

Effect of different concentrations of diphtheria toxoid & aluminum phosphate on potency of diphtheria component in DPT vaccines.

An effort was made to determine the optimum concentration of diphtheria toxoid in combination with aluminum phosphate gel in DPT vaccines which may give a safe, potent and economical preparation. The effect of four different concentrations of aluminum phosphate and three different antigenic concentrations of diphtheria toxoid on potency of diphtheria component in DPT vaccine was assessed. A gradual increase in potency was seen with increase in toxoid concentration and a gradual decrease in potency with the increase in aluminum phosphate content. Vaccines made with minimum quantities of toxoid (30 Lf/ml) and aluminum phosphate (3 mg/ml) were found to be highly satisfactory. Vaccines prepared with high antigenic purity toxoid have better potency, as compared to those prepared with a relatively low antigenic purity toxoid.

Adjuvants, Immunologic↗
PubMed2000

Economic evaluation of use of diphtheria, tetanus, and acellular pertussis vaccine or diphtheria, tetanus, and whole-cell pertussis vaccine in the United States, 1997.

OBJECTIVE: To compare the economic costs and benefits associated with using either diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) or diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) in the United States in 1997. DESIGN: Standard cost-benefit analysis, from both the societal and health care system perspectives, was performed for each combination vaccine as well as for the pertussis components singly. SETTING: A simulated cohort of 4.1 million children from birth to age 15 years. MAIN OUTCOME MEASURES: Net costs (savings) and benefit-cost ratios (BCRs) RESULTS: Without a vaccination program, diphtheria, tetanus, and pertussis disease caused more than 3 million cases and more than 28,000 deaths, at a cost of $23.6 billion. From the societal perspective, net savings because of the use of DTaP and DTwP were $22.510 million and $22.623 million, respectively. The net savings from the acellular pertussis component and the whole-cell pertussis component only were $4.362 million and $4.474 million, respectively. Benefit-cost ratios for DTaP from a societal and health care system perspective were 27:1 and 9:1, respectively. Sensitivity analyses of key variables did not result in appreciable changes in results. CONCLUSIONS: Compared with no program, vaccination with DTaP or DTwP resulted in substantial savings, regardless of the perspective taken and for all sensitivity analyses conducted. Compared with DTwP, use of DTaP generated a small cost increase that might be offset by the value of other factors, such as increased confidence in pertussis vaccination resulting from reduced adverse events. Arch Pediatr Adolesc Med. 2000;154:797-803

Adolescent↗
PubMed1995

Epidemiology and molecular characterisation of toxigenic Corynebacterium diphtheriae var mitis from a case of cutaneous diphtheria in Manchester.

Diphtheria is now an uncommon disease in Britain. We describe an imported case of cutaneous diphtheria in a previously immunised adult cause by C. diphtheriae var mitis. The control measures adopted to deal with the index case and two secondary cases so as to limit further spread among household and school contacts are outlined. Molecular typing was used to study the mode of spread of the organism among contacts.

Adult↗
PubMedDate not supplied

Differences in the immunogenicity of native and formalinized cross reacting material (CRM197) of diphtheria toxin in mice and guinea pigs and their implications on the development and control of diphtheria vaccine based on CRMs.

Immunogenicity of native and formalinized cross reacting material (CRM197) of diphtheria toxin (DTx) was assessed in mice and guinea pigs. For the primary response, mice produced similar levels of diphtheria toxoid (DTxd) IgG antibodies to both native and formalinized preparations of CRM197 though the antibody levels were significantly lower than those elicited by conventional DTxd (P < 0.05). In contrast, guinea pigs showed significantly higher levels of DTxd IgG antibodies to the formalinized CRM197 preparation than the native preparation (P < 0.001) after single injection. These differences in the immunogenicity of mice and guinea pigs to native and formalinized CRM197 preparations have implications for the development and control of diphtheria or other vaccines involving the use of CRMs.

Animals↗
PubMed1975

The role of cutaneous diphtheria infections in a diphtheria epidemic.

Twenty-four people with diptheria and 48 carriers were found in an isolated, circumscribed, rural area during a one-month period. Four patients had cutaneous lesions, which were similar to those of typical impetigo, form which Corynebacterium diptheriae was isolated. These cases constituted an epidemiologic focus from which the other cases were infected. Ten of 52 classroom contacts of two patients with skin infections harbored C. diphtheriae in the pharynx, while only eight of 132 classroom contacts of eight respiratory cases were similarly infected. Respiratory carriage of C. diphtheriae in five of 12 Head start classroom contacts of another patient with cutaneous infection with C. diptheriae in the classroom situation. A tendency toward greater environmental contamination by cutaneous diphtheria than by respiratory diptheria might be related to the greater contagiousness cases.

Adolescent↗
PubMed1998

Comparative reactogenicity and immunogenicity of booster doses of diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine and diphtheria-tetanus-inactivated poliovirus vaccine in preadolescents.

BACKGROUND: The changing epidemiology of pertussis in France has emphasized the need for booster vaccinations in adolescents. Although not previously recommended because of the high reactogenicity of whole cell pertussis in children older than 2 years old, the development of less reactogenic acellular pertussis vaccines means that this recommendation may be reconsidered. OBJECTIVES: Assessment of the reactogenicity and immunogenicity of a diphtheria-tetanus-acellular pertussis-inactivated poliovirus (DTPa-IPV=Group 1) vaccine administered as the fifth dose in preadolescents in comparison with a commercial diphtheria-tetanus-inactivated poliovirus (DT-IPV) (Group 2) vaccine currently recommended for this age group. MATERIALS AND METHODS: An open, randomized study involving 115 healthy subjects ages 10 to 13 years previously vaccinated with 4 doses of diphtheria-tetanus-whole cell pertussis-IPV vaccines. Reactogenicity was assessed for 4 days postvaccination using diary cards. Immunogenicity based on antibody assays in sera taken before and 1 month postvaccination was evaluated for all vaccine antigen components. RESULTS: Both vaccines showed good tolerability, local and general reactogenicity being similar. For local reactions Group 1=88.1% and Group 2=86.8%, and for general reactions Group 1=40.7% and Group 2=47.2%. Headache was the most frequent general symptom with 27.1% for DTPa-IPV and 39.6% for DT-IPV. The incidence of fever was 5.1% with DTPa-IPV and 9.4% for DT-IPV. Good immune responses were obtained against all vaccine components. CONCLUSIONS: The inclusion of acellular pertussis did not significantly increase the reactogenicity of DTPa-IPV in comparison with the currently recommended DT-IPV vaccine when given as a fifth dose in preadolescents. To prevent recent resurgence of pertussis in France, this vaccine should be preferred as the booster dose of DTPa-IPV at 11 to 13 years of age as recently approved by the National Council of Hygiene of France.

Adolescent↗
PubMed1992

Cytotoxic activity of a recombinant chimaeric protein between Pseudomonas aeruginosa exotoxin A and Corynebacterium diphtheriae diphtheria toxin.

A segment of the exotoxin A gene of Pseudomonas aeruginosa, coding for the N-terminal end of domain I and domain II of the toxin (ETA), was genetically fused to the diphtheria toxin gene of Corynebacterium diphtheriae, coding for the N-terminal end of A fragment of diphtheria toxin (DT). The resulting hybrid protein (termed CED1) was produced in large amounts and exported to the periplasm in Escherichia coli. This chimaeric protein reacted with both anti-ETA and anti-DT antisera. Furthermore, the chimaeric protein displayed ADP-ribosylation activity and exhibited cytotoxicity to mouse 3T6 fibroblasts. These results demonstrated that the chimaeric protein is cytotoxic, and that the toxic potential of DTA can be selectively internalized and translocated via domains I and II of exotoxin A, which are thus sufficient to direct and translocate an enzymatically active heterologous polypeptide segment into the cytosol of sensitive cells.

3T3 Cells↗