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PubMed1994

A randomized controlled trial of two acellular pertussis-diphtheria-tetanus vaccines in primary immunization in Ghana: antibody responses and adverse reactions.

Two acellular pertussis vaccines combined with diphtheria and tetanus toxoids (APDT vaccines) were compared with a whole cell PDT (WCPDT) vaccine in primary immunization in Ghana. One is a liquid vaccine which is used for general immunization in Japan and the other is a freeze-dried vaccine newly developed as a heat-stable vaccine. Eighty-nine infants were recruited in the study. Sixty-eight who completed three doses of the immunization were assessed for immunological responses. Twenty-one dropped out because of sickness or moving from the study area. A total of 242 vaccinations in 89 infants were followed up for adverse reactions. Geometric mean titres (GMTs) to filamentous haemagglutinin in the two APDT vaccinees were significantly higher than in the WCPDT recipients. GMTs to pertussis toxin, diphtheria and tetanus toxoids were not significantly different among the three groups. Seropositive rates to pertussis antigens, tetanus and diphtheria toxoids were 94.4 to 100% in the two APDT vaccines. Systemic reactions within 7 days of inoculation were similarly low in the three groups, but significantly fewer infants had local reactions after either of the two APDT vaccines than after the WCPDT vaccine.

Antibodies, Bacterial↗
PubMed2005

Infections with Corynebacterium diphtheriae: six years' experience at an inner London teaching hospital.

Recently, a preponderance of non-toxigenic strains of Corynebacterium diphtheriae has been reported, as has the broadening spectrum of disease caused by these strains. This study presents data on 85 isolates of C. diphtheriae over a six year period (1998-2003). Eighty were non-toxigenic isolates from patients with sore throat, and five (one toxigenic) were from cutaneous ulcers in travellers returning from endemic areas. When examined in relation to denominator data provided by the Health Protection Agency (HPA) for the whole of England and Wales, 1998-2002, 75% of all notifications of C. diphtheriae for England and Wales originated from the laboratories at University College London Hospitals (UCLH). In some years (1999 and 2001) 95-100% of isolates came from UCLH. We believe that national data do not reflect true incidence, as universal screening for these organisms is not routine policy in many laboratories. The results presented suggest the need for increased clinical and laboratory awareness of this important pathogen.

Adolescent↗
PubMed1970

Studies on the mode of action of diphtheria toxin. III. Effect on subcellular components of protein synthesis from the tissues of intoxicated guinea pigs and rats.

The effect of diphtheria toxin on subcellular components of protein synthesis was determined. Polyribosomes prepared from intoxicated guinea pigs functioned normally in an in vitro assay system, while the activity of soluble enzymes (transferases) from toxin-treated animals was significantly reduced. At high toxin dosages, this reduction was widespread, but when levels of toxin comparable to those which might be generated in a natural infection were given, inhibition of soluble enzyme activity was found only in extracts from heart and skeletal muscle. Possible nonspecific inhibition in the assay system due to interference by free toxin or by a serum component was eliminated. Since it was possible to demonstrate reactivation of soluble enzyme activity with nicotinamide and toxin, it was suggested that diphtheria toxin acts in the intact sensitive animal in a manner analogous to its action in tissue culture or in cell-free systems. It was hypothesized that the lethal biochemical lesion of the toxin in sensitive animals was the inactivation of transferase enzymes, principally in the heart. It was also suggested that the lethal lesion induced in diphtheria-sensitive and resistant species may not be identical.

Amino Acids↗
PubMed1998

Penicillin vs. erythromycin in the treatment of diphtheria.

In an open-label, randomized trial, 44 Vietnamese children with diphtheria were given penicillin therapy (intramuscular benzylpenicillin, 50,000 U/[kg.d] for 5 days and then oral penicillin, 50 mg/[kg.d] for 5 days), and 42 were given erythromycin therapy (50 mg/[kg.d] orally for 10 days). There were no differences in times to membrane clearance or bacteriologic clearance, but median times to fever clearance were 27 hours (95% confidence interval [CI], 19-30; range, 0-124 hours) for penicillin recipients and 46 hours (95% CI, 34-54; range, 0-148 hours) for erythromycin recipients (P = .0004). In the penicillin group, acute treatment failed for one patient, and one patient relapsed. Three patients in the penicillin group developed diphtheritic myocarditis as evidenced by abnormal electrocardiograms. Erythromycin did not cause prolongation of the QT interval corrected for heart rate. Cultures of specimens from 15 patients (17.4%) were positive for toxigenic Corynebacterium diphtheriae. All isolates were susceptible to penicillin, but for isolates (27%), all of which were from patients who received penicillin treatment, were resistant to erythromycin (minimum inhibitory concentrations, > 64 mg/L). Penicillin is recommended as first-line treatment for diphtheria in Vietnam.

Adolescent↗
PubMed1998

An outbreak of nontoxigenic Corynebacterium diphtheriae infection: single bacterial clone causing invasive infection among Swiss drug users.

From 1990 to 1996, a total of 65 patients from whom Corynebacterium diphtheriae had been isolated were reported to the Swiss Federal Office of Public Health. A retrospective review of medical and microbiological records as well as results of ribotyping of available isolates was performed. Twenty-seven patients had acquired their infection without evidence of use of illicit drugs, mostly as a skin infection imported from subtropical areas (20 patients); 38 isolations were associated with intravenous drug use (IVDU) (skin, 15; respiratory tract, 10; blood, 13). Endocarditis was documented in nine patients with bloodstream infection, four of whom died. There were two additional deaths due to overwhelming sepsis. The same ribotype of nontoxigenic C. diphtheriae was found in 31 of the 32 examined isolates associated with IVDU. All non-IVDU isolates had different ribotypes. Among Swiss drug users, a single clone of nontoxigenic C. diphtheriae was found over a period of several years with a high potential to cause severe invasive infection.

Bacteremia↗
PubMed1999

Experience with diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine in Japan.

In Japan, the morbidity rate for pertussis per 100,000 population was 147.6 in 1950 when whole cell pertussis vaccine was introduced but dropped to 0.2 in 1972 when routine immunization with a combined vaccine consisting of diphtheria toxoid, tetanus toxoid, and whole cell pertussis had been widely accepted. Thereafter, adverse reactions to the whole cell pertussis vaccine became a social problem and lowered the acceptance of the vaccine. As a result, the morbidity rate increased to 11.3 in 1979. Introduction of the safer yet efficacious acellular pertussis vaccine, consisting of mainly pertussis toxoid and filamentous hemagglutinin, into the routine childhood vaccination in combination with diphtheria and tetanus toxoids in 1981 increased the acceptance rate. The lowest morbidity rate, 0.1, was achieved in 1993. During the next 16 years, almost all cases were in unvaccinated or incompletely vaccinated persons. Regardless of whether whole cell or acellular pertussis vaccine was used, > 90% of the reported pertussis cases were in children < 10 years of age until 1990. However, since 1991, the rate of pertussis in young adults 20-44 years of age has been clearly increasing. To control pertussis, booster vaccination with diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine in adults should be considered.

Adult↗
PubMed1998

Humoral immune response to tetanus-diphtheria vaccine given during extended use of chloroquine or primaquine malaria chemoprophylaxis.

Immune suppression resulting from prolonged chemoprophylaxis and potential drug-vaccine interaction were investigated within the context of a randomized placebo-controlled trial that compared daily primaquine or weekly chloroquine administration for malaria prevention. After 11 months of prophylaxis, adult male subjects received a tetanus-diphtheria (Td) vaccination. Prophylaxis continued 4 weeks longer. Anti-tetanus and anti-diphtheria antibody levels were measured by ELISA at baseline and at 1, 3, 7, and 14 months after Td vaccination. All groups were comparable at baseline. Immunization triggered significant increases in anti-tetanus and anti-diphtheria IgG levels over each group's pre-Td baseline levels and those of an unvaccinated control group. Geometric mean anti-tetanus titers (GMTs) in the primaquine group were significantly higher than those of the placebo group at 1, 3, and 14 months. Anti-tetanus GMTs in placebo and chloroquine groups declined over 14 months to levels comparable to those of unvaccinated controls, but levels in the primaquine group remained significantly higher than in controls.

Adult↗
PubMedDate not supplied

Selective primary health care: strategies for control of disease in the developing world. XVII. Pertussis and diphtheria.

Pertussis and diphtheria, bacterial infections responsible for significant childhood morbidity and mortality in the developing world, are potentially controllable by mass immunization. The incidence of pertussis has been dramatically reduced in many areas of the world over the past 25 years by the use of pertussis vaccine. The massive increase in incidence of clinical pertussis in Great Britain and other European nations occurring after publicity about vaccine reactogenicity precipitated a marked decrease in vaccine acceptance has documented the efficacy of the vaccine and the necessity of continued immunization. The issue of potential toxicity is, nevertheless, being addressed with the development of a cell-free, component pertussis vaccine. The use of diphtheria toxoid, directed at protecting recipients against the systemic effects of diphtheria toxin, has resulted in excellent control of the disease in the United States and elsewhere. Certainly the use of these two vaccines on a mass scale is the preferred approach to worldwide control, if not eradication, of these infectious diseases.

Adolescent↗
PubMed2003

The complete genome sequence and analysis of Corynebacterium diphtheriae NCTC13129.

Corynebacterium diphtheriae is a Gram-positive, non-spore forming, non-motile, pleomorphic rod belonging to the genus Corynebacterium and the actinomycete group of organisms. The organism produces a potent bacteriophage-encoded protein exotoxin, diphtheria toxin (DT), which causes the symptoms of diphtheria. This potentially fatal infectious disease is controlled in many developed countries by an effective immunisation programme. However, the disease has made a dramatic return in recent years, in particular within the Eastern European region. The largest, and still on-going, outbreak since the advent of mass immunisation started within Russia and the newly independent states of the former Soviet Union in the 1990s. We have sequenced the genome of a UK clinical isolate (biotype gravis strain NCTC13129), representative of the clone responsible for this outbreak. The genome consists of a single circular chromosome of 2 488 635 bp, with no plasmids. It provides evidence that recent acquisition of pathogenicity factors goes beyond the toxin itself, and includes iron-uptake systems, adhesins and fimbrial proteins. This is in contrast to Corynebacterium's nearest sequenced pathogenic relative, Mycobacterium tuberculosis, where there is little evidence of recent horizontal DNA acquisition. The genome itself shows an unusually extreme large-scale compositional bias, being noticeably higher in G+C near the origin than at the terminus.

Aged↗
PubMed1995

Local massage after vaccination enhances the immunogenicity of diphtheria-tetanus-pertussis vaccine.

The effect of local massage on adverse reactions and immunogenicity of diphtheria-tetanus-pertussis vaccine was investigated. After diphtheria-tetanus-pertussis vaccination 327 infants were either massaged or not, and adverse reactions were evaluated. Local pain and fever were more frequent in the massage group. The extra febrile episodes from massage were mild (38-39 degrees C). For evaluation of the antibody responses, 124 infants were recruited into massage or nonmassage cohorts and antibody production was measured at 2, 6, 7, 18 and 19 months of age, respectively. Subjects in the massage group developed significantly higher antibodies against filamentous hemagglutinin at 6 and 7 months of age, pertussis toxin at 6, 7, 18 and 19 months of age, pertussis agglutinogen at 18 and 19 months of age and those in the nonmassage group. Local massage after diphtheria-tetanus-pertussis vaccination was associated with better immunogenicity and more adverse reactions, including low grade fever and local pain, which were mild and not particularly disturbing.

Antibodies, Bacterial↗
PubMed1997

Vaccine antigen interactions after a combination diphtheria-tetanus toxoid-acellular pertussis/purified capsular polysaccharide of Haemophilus influenzae type b-tetanus toxoid vaccine in two-, four- and six-month-old infants.

OBJECTIVE: The safety and immunogenicity of a diphtheria-tetanus toxoid-acellular pertussis vaccine (DTaP; Trepedia)/Haemophilus influenzae b polysaccharide (PRP-T; ActHib) combined vaccine (TriHibir; Pasteur Mérieux Connaught) was compared with DTaP and PRP-T given at the same visit but at separate sites in a prospective multicenter, open label trial. METHODS: Infants were randomized to four groups (three consistency lots of DTaP/PRP-T vs. one of the consistency lots given as separate vaccines); injections were administered at 2, 4 and 6 months of age. Pre-Dose 1 and post-Dose 3 sera were assayed for antibody titers against all antigens. Reactions to the vaccinations were assessed by parent questionnaire for 30 days after each injection visit. RESULTS: Four hundred eighty-five infants were enrolled; 296 evaluable infants were included in the DTaP/PRP-T group compared with 70 infants in the DTaP and PRP-T vaccine group. Infants who received the combined vaccine had higher post-Dose 3 geometric mean antibody titers to diphtheria antitoxin (P < 0.01) and pertussis filamentous hemagglutinin (P < 0.05) and lower geometric mean antibody titers to tetanus antitoxin (P < 0.05) and Haemophilus influenzae b (Hib) polysaccharide (PRP) (P < 0.05). The geometric mean anti-PRP antibody titer in the DTaP/PRP-T group was 4.3 micrograms/ml compared with 7.0 micrograms/ml in the separate vaccine group (P < 0.05), and the percentage of infants with antibody titers > or = 0.15 and 1 microgram/ml were, respectively, 95 and 86%, whereas they were 100% for both titers in the separate vaccines group. DTaP/ PRP-T vaccine given concomitantly or 1 month apart from hepatitis B vaccine and oral poliomyelitis vaccine caused no significant differences in immunogenicity or safety. The safety assessments for the DTaP/PRP-T vaccine showed no consistent differences in systemic or local injection site reactions compared with DTaP and PRP-T administered separately. CONCLUSION: Although the antibody responses to tetanus and Hib polysaccharide in the evaluated DTaP/PRP-T combined vaccine were significantly lower than those seen after separate DTaP and PRP-T administration, the combined vaccine elicited an immune response against diphtheria, tetanus, pertussis and Haemophilus influenzae b likely to confer protection.

Analysis of Variance↗
PubMed2000

Absence of a significant interaction between a Haemophilus influenzae conjugate vaccine combined with a diphtheria toxoid, tetanus toxoid and acellular pertussis vaccine in the same syringe and inactivated polio vaccine.

BACKGROUND: We compared the antibody response to Haemophilus influenzae type b capsular polysaccharide (PRP) after three doses of a diphtheria toxoid, tetanus toxoid and acellular pertussis vaccine (DTaP) combined with a PRP-tetanus conjugate (PRP-T) in infants randomized to receive oral polio vaccine (OPV) or inactivated polio vaccine (IPV). The polio vaccine was given separately at the same visit. METHODS: Three hundred fifty-six infants from pediatric practices in suburban Chicago and New Orleans were randomized into two groups. Group A received OPV at 2 and 4 months of age; Group B received IPV at 2 and 4 months of age. Both groups received DTaP/PRP-T at 2, 4 and 6 months of age and hepatitis B vaccine at 2 and 4 months of age. A serum sample was obtained before immunization (age 2 months) and 1 month after 3 doses of DTaP/PRP-T (age 7 months). Sera were assayed for antibody responses to all relevant vaccine antigens. RESULTS: No significant vaccine antigen interference was found when polio immunization was provided by IPV or OPV for anti-PRP, diphtheria, tetanus or pertussis antibodies. OPV recipients had a significantly higher mean antibody response to serotype 1 (P = 0.03) and 2 (P = 0.0001) poliovirus. CONCLUSION: Whether polio immunization was accomplished with IPV or OPV did not significantly influence the antibody responses in sera obtained at 7 months of age for anti-PRP, anti-diphtheria and anti-tetanus toxoid antibodies and antibodies to pertussis antigens, when DTaP/PRP-T was given in the primary series.

Antibodies, Bacterial↗
PubMed2005

Immunogenicity and reactogenicity of a combined adsorbed tetanus toxoid, low dose diphtheria toxoid, five component acellular pertussis and inactivated polio vaccine in six-year-old children.

BACKGROUND: The objective of this study was to assess the immunogenicity and reactogenicity of the combined adsorbed tetanus toxoid, low dose diphtheria toxoid, 5-component acellular pertussis and inactivated polio vaccine (TdcP-IPV) as compared with a pediatric dose diphtheria formulation, combined with adsorbed tetanus toxoid and 3-component acellular pertussis (DTacP), in 6-year-old children who were immunized with 4 doses of diphtheria-tetanus-whole cell cellular pertussis (DTwcP) plus oral polio vaccine (OPV) before 2 years of age, according to the local Spanish vaccination calendar. METHODS: One hundred ninety-four healthy 6-year-old children were randomized to receive 1 dose of TdcP-IPV or 1 dose of DTacP and OPV. RESULTS: One month postvaccination, antidiphtheria and antitetanus titers were > or =0.1 IU/mL in 100% of patients in both study groups. TdcP-IPV reached 100% seroprotection rates against polio types 1, 2 and 3. In OPV recipients, these rates were 100, 100 and 96.8%, respectively. Seropositivity rates for pertussis toxin, filamentous hemagglutinin, pertactin and fimbrial components of the TdcP-IPV vaccine were 97.9, 89.6, 90.6 and 100%. The incidence of local and systemic reactions was 50.5 and 39.2% in the TdcP-IPV group and 59.4 and 38.5% in the DTacP plus OPV group, and no serious adverse events were reported. CONCLUSIONS: TdcP-IPV vaccine was shown to be immunogenic and safe when given as a booster in children 6 years of age who were primed with 4 doses of DTwcP and OPV.

Child↗
PubMed2005

A modified vaccine reduces the rate of large injection site reactions to the preschool booster dose of diphtheria-tetanus-acellular pertussis vaccine: results of a randomized, controlled trial.

BACKGROUND: Large injection site reactions commonly follow booster doses of diphtheria-tetanus-acellular pertussis (DTaP) vaccines at 4-6 years of age. A vaccine with lower diphtheria and pertussis dosage (Tdap) might be better tolerated for this dose. METHODS: We conducted a randomized, controlled, evaluator-blinded comparison of local reactions to DTaP.inactivated poliomyelitis vaccine (IPV) or Tdap booster vaccinations, in 4- to 5.5-year-old children. Reactions were assessed daily by parents and after 48 hours by study nurses. Serologic responses were measured before and 4 weeks after vaccination and examined in relation to large local reactions (>or=50 mm redness and/or swelling). RESULTS: 288 children were vaccinated, 145 with DTaP.IPV and 143 with Tdap, and after 48 hours examiners noted local redness >or= 50mm in 17.2 and 6.3%, respectively (P = 0.004). DTaP.IPV vaccinees initially experienced local pain (in 54%) which limited arm motion (in 37%), but symptoms largely resolved by 48 hours. Tdap vaccinees had fewer symptoms (pain in 20%, limited arm motion in 14%). Children with large reactions to DTaP.IPV more often than nonreactors had elevated preimmunization antibody concentrations to 1 or more of diphtheria, pertussis toxin or pertactin and elevated postimmunization antibody concentrations to all antigens except fimbriae. Booster responses to Tdap were reduced with the smaller antigen doses but were generally satisfactory. CONCLUSIONS: This preschool DTaP.IPV booster vaccination caused large local reactions in 1 in 5 children, with transient discomfort. With Tdap vaccine, such reactions were significantly fewer but not eliminated. A Tdap.IPV vaccine warrants study for routine use at 4-6 years of age.

Antibody Formation↗
PubMed1993

Analysis of diphtheria toxin repressor-operator interactions and characterization of a mutant repressor with decreased binding activity for divalent metals.

The diphtheria toxin repressor (DtxR) is an Fe(2+)-activated protein with sequence-specific DNA-binding activity for the diphtheria toxin (tox) operator. Under high-iron conditions in Corynebacterium diphtheriae, DtxR represses toxin and siderophore biosynthesis as well as iron uptake. DtxR and a mutant repressor with His-47 substituted for Arg-47, designated DtxR-R47H, were purified and compared. Six different divalent cations (Cd2+, Co2+, Fe2+, Mn2+, Ni2+, and Zn2+) activated the sequence-specific DNA-binding activity of DtxR and enabled it to protect the tox operator from DNase I digestion, but Cu2+ failed to activate DtxR. Hydroxyl radical footprinting experiments indicated that DtxR binds symmetrically about the dyad axis of the tox operator. Methylation protection experiments demonstrated that DtxR binding alters the susceptibility to methylation of three G residues within the AT-rich tox operator. These findings suggest that two or more monomers of DtxR are involved in binding to the tox operator, with symmetrical DNA-protein interactions occurring at each end of the palindromic operator. In this regard, DtxR resembles several other well-characterized prokaryotic repressor proteins but differs dramatically from the Fe(2+)-activated ferric uptake repressor protein (Fur) of Escherichia coli. The concentration of Co2+ required to activate DtxR-R47H was at least 10-fold greater than that needed to activate DtxR, but the sequence-specific DNA binding of activated DtxR-R47H was indistinguishable from that of wild-type DtxR. The markedly deficient repressor activity of DtxR-R47H is consistent with a significant decrease in its binding activity for divalent cations.

Bacterial Proteins↗
PubMed1994

Iron, DtxR, and the regulation of diphtheria toxin expression.

In recent years considerable advances have been made in the understanding of the molecular basis of iron-mediated regulation of diphtheria toxin expression. The tox gene has been shown to be regulated by the heavy metal ion-activated regulatory element DtxR. In the presence of divalent heavy metal ions, DtxR becomes activated and binds to a 9 bp interrupted palindromic sequence. The consensus-binding site has been determined by both the sequence analysis of DtxR-responsive operators cloned from genomic libraries of Corynebacterium diphtheriae as well as by in vitro genetic methods using cyclic amplification of selected targets (CASTing). It is now clear that DtxR functions as a global iron-sensitive regulatory element in the control of gene expression in C. diphtheriae. In addition, the metal ion-activation domain of DtxR is being characterized by both mutational analysis and determination of the X-ray structure at 3.0 A resolution.

Bacterial Proteins↗
PubMed1998

Trans-sialidase activity for sialic acid incorporation on Corynebacterium diphtheriae.

A rapid and sensitive assay for neuraminidase using peanut lectin hemagglutination was used to study the prevalence of neuraminidase activity among sucrose-fermenting and non-sucrose-fermenting toxigenic Corynebacterium diphtheriae strains. Neuraminidase activity was found in 15 (100%) isolates regardless of biotype, hemagglutinating activity and site of isolation of bacteria. Besides expressing the neuraminidase activity that hydrolyzes sialic acid from glycoconjugates, C. diphtheriae was also capable of transferring sialic acid residues from a sialyl-lactose donor. A single molecule probably expresses both neuraminidase and trans-sialidase activity. The trans-sialidase activity was documented by observations of the interactions of bacterial cells with wheat germ agglutinin and peanut lectins. C. diphtheriae expressed a trans-sialidase activity located on the cell surface that produced asialoglycoconjugates from a sialyl donor substrate and at the same time generated bacterial sialyl derivatives of beta-Gal acceptors.

Corynebacterium diphtheriae↗
PubMed1984

Comparison of gel filtration and ammonium sulphate precipitation in the purification of diphtheria toxin and toxoid.

Crude diphtheria toxin and toxoid were subjected to purification by gel filtration and stepwise ammonium sulphate precipitation. The various fractions obtained by the purification procedures were studied by immunological methods. A high molecular weight fraction of glycoprotein nature was present in all of the crude preparations studied. The fraction was antigenically non-identical with the real toxin or toxoid and did not have its origin in the culture medium. It showed a long flocculation time when tested against equine diphtheria toxoid antiserum. The fraction could be removed from the crude preparations by gel filtration or by precipitation with 21% (w/v) ammonium sulphate. When comparing toxoids purified by each of these methods, the method of gel filtration resulted in a somewhat higher degree of purity, suggesting that this method would be more suitable than the AS precipitation method for the purification of diphtheria toxoid.

Ammonium Sulfate↗