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PubMed2000

Diphtheria toxoid vaccine effectiveness: A case-control study in Russia.

Prior to the completion of this and other studies, low effectiveness of diphtheria toxoid-containing vaccine was suspected to be a major contributing factor to the diphtheria epidemic that began in the Russian Federation in 1990. A vaccine effectiveness study was done in Moscow by enrolling physician-diagnosed cases and 10 control subjects per case. Controls were matched to cases by age (+/-3 months) and clinic registration. Vaccination history was abstracted from a standardized form for case-patients and from clinic vaccination records for control subjects. Two hundred seventeen case-patients and 2169 matched controls were included in the study. Most controls (92%) had received three or more doses of a diphtheria toxoid vaccine, compared with 72% of case-patients. The vaccine effectiveness for three or more doses was 97% (95% confidence interval: 94.3-98.4). Low vaccine effectiveness was not a contributing factor to the diphtheria epidemic in the Russian Federation. To control and prevent diphtheria epidemics, it is necessary to achieve and maintain high vaccination coverage with three or more doses of diphtheria toxoid among adults and children.

Adolescent↗
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↗
PubMed1976

[Booster vaccination with a diphtheria-tetanus vaccine for dermo-jet with low diphtheria toxoid content].

Indications are provided on how the organization of polyvaccinations against tuberculosis, poliomyelitis and diphtheria-tetanus in school collectivities can be rationalized. 19 persons aged 19-20 years were vaccinated intradermally with 1.5 Lf diphtheria toxoid and 15 Lf tetanus toxoid (contained in 0.1 ml) by means of a single injection with a jet injector (Dermo-Jet). In cases which had not previously been immunized, vaccination with the toxoid doses employed did not induce detectable antitoxin titers. In all cases which had previously been immunized the antitoxin titers after the booster injection were at least 400 times higher than the protection threshold for diphtheria and 1700 times higher than the protection threshold for tetanus. This was also the case in preimmunized cases which had no detectable antitoxin titer before the vaccination. The increase in antitoxin titer was inversely proportional to the prevaccinal titer in the manner of a logarithmic exponential function. It may be concluded from these results that the benefit of a booster vaccination is particularly high in poorly immunized persons whereas it is clearly limited in cases showing a high prevaccinal titer. The well tolerated intradermal vaccination with the jet injector (Dermo-Jet) can be considered as equivalent to the subcutaneous technic. From the point of view of organization (time consumption, problems of sterilization) this method is much preferable to intramuscular or subcutaneous vaccination.

Adult↗
PubMed1991

A comparative trial of the reactogenicity and immunogenicity of Takeda acellular pertussis vaccine combined with tetanus and diphtheria toxoids. Outcome in 3- to 8-month-old infants, 9- to 23-month-old infants and children, and 24- to 30-month-old children.

The reactogenicity and immunogenicity of the Takeda acellular pertussis vaccine combined with tetanus and diphtheria toxoids were compared in 139 infants aged 3 to 8 months, 60 infants and children aged 9 to 23 months, and 99 children aged 24 to 30 months. Good antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), and agglutinogens occurred in all age groups after both the third and fourth doses. After the fourth (booster) dose, the mean antibody values in initially seronegative infants vaccinated at 3 to 8 months of age were as follows: anti-PT, 67.8 enzyme-linked immunosorbent assay units (EU) per milliliter; anti-FHA, 149.5 EU/mL; the agglutinin titer was 125.6. The values in initially seronegative children vaccinated at 24 to 30 months of age were as follows: anti-PT, 92.9 EU/mL; anti-FHA, 251.7 EU/mL; the agglutinin titer was 275.8. Reactions following immunization were minimal. Except for drowsiness after the first dose in infants, there were no clinically significant differences in reactions between infants and older children. The findings in this study coupled with the recent demonstration of efficacy of this vaccine in 2-year-old children supports the recent Japanese recommendation to lower the age of immunization with acellular pertussis vaccine combined with tetanus and diphtheria toxoids to 3 months.

Anorexia↗
PubMed1984

Antigen-specific proliferative human T cell clones with specificity for diphtheria toxoid: genetic and molecular restriction by class II antigens.

Human T lymphocyte clones (TLC) specific for diphtheria toxoid (DT) were isolated from a DR6/7 individual by cloning in soft agar in vivo sensitized T lymphocytes. We report here the isolation and characterization of 3 of these clones by studying: (a) the kinetic of activation, (b) the surface phenotypes, (c) the fine specificity for one of the 2 DT chains and (d) the genetic restriction of the proliferative response by the haplotype DR7. Moreover, blocking studies of the proliferative response to DT by various immunochemically characterized anti-HLA-DR monoclonal antibodies indicate that, on the DR7 molecule, more than one Ia determinant may participate in the clonal DT proliferative response. By using human TLC of a defined specificity and well-characterized anti-DR monoclonal antibodies, such studies may help to define the functional repertoire of Ia molecules in man.

Clone Cells↗
PubMed1988

The reduction of animal usage by the application of indirect haemagglutination in the potency testing of diphtheria toxoid in combined vaccines.

Eight Adsorbed Diphtheria-Tetanus vaccines and 13 Diphtheria-Tetanus-Pertussis vaccines made by four different manufacturers were tested for the potency of the diphtheria components in guinea-pigs by the method of British Pharmacopoeia (1973). Two-hundred-and-ten guinea-pig sera consisting of ten sera related to each vaccine sample thus obtained were titrated for diphtheria antitoxin by indirect haemagglutination (IHA) and the conventional toxin neutralization (TN) tests. Statistical analysis of the results showed a good correlation between the titres obtained with the two tests. The potencies of the diphtheria components of various vaccines calculated from the antitoxin content of the respective guinea-pig sera titrated by the IHA test correlated significantly with the potencies obtained from the antitoxin content titrated by the routinely used TN test. The use of IHA in place of the TN test thus offers as an alternative that permits a reduction in animal usage.

Animal Testing Alternatives↗
PubMed2006

Intranasal vaccination with SfbI or M protein-derived peptides conjugated to diphtheria toxoid confers protective immunity against a lethal challenge with Streptococcus pyogenes.

We investigated whether intranasal immunisation with diphtheria toxoid (DT) conjugated polypeptides encompassing T and B cell epitopes of the SfbI protein (FNBR) or a conformational-constrained B cell epitope of the M1 protein (J8) was able to confer protection against lethal mucosal challenge with a heterologous Streptococcus pyogenes strain. To this end, BALB/c mice were immunised with the conjugates. Strong antigen-specific antibody responses were observed in both serum and mucosal secretions. Vaccinated mice were challenged 10 days after the last boost by the intranasal route. Animals receiving FNBR-DT co-administered with either the cholera toxin B subunit (CTB) or the TLR 2/6 agonist MALP-2 were efficiently protected against the virulent S. pyogenes strain (90% and 70% survival, respectively), whereas those immunised with J8-DT plus either CTB or MALP-2 showed intermediate levels of protection (60% and 40%, respectively). The obtained results indicate that in our experimental animal model peptide-based conjugate vaccines represent a valid alternative to protect against streptococcal infection.

Adjuvants, Immunologic↗
PubMed1990

Serum antibody response in adult volunteers elicited by injection of Streptococcus pneumoniae type 12F polysaccharide alone or conjugated to diphtheria toxoid.

Conjugates of an uronic acid-containing capsular polysaccharide (CP), pneumococcous type 12F (Pn12F) bound to diphtheria toxoid (DT), were studied for safety and immunogenicity in adult volunteers. In mice, these conjugates, prepared with the same lot of DT and Pn12F-40234-006, a homogenous CP of high molecular weight, or Pn12-812408, a polydisperse CP with lower-molecular-weight material, were more immunogenic than the Pn12F alone and had T-cell dependent properties (A. Fattom, W. F. Vann, S.C. Szu, A. Sutton, X. Li, B. Bryla, G. Schiffman, J. B. Robbins, and R. Schneerson, Infect. Immun. 56:2292-2298, 1988). Adult volunteers, randomized into three groups, were injected either with one of these two conjugates or with Pnu-Imune, the 23 valent pneumococcus vaccine containing 25 micrograms of Pn12F as one of its components. Volunteers were injected two times, 4 weeks apart, with the Pn12F-DT conjugates and once with the Pnu-Imune. Side reactions following injection of the conjugates of Pnu-Imune were mild and short-lived. At 4 weeks and at 7 months after the first injection, higher levels of Pn12F antibodies were found in the volunteers injected with the conjugates than in the Pnu-Imune group (P less than 0.001). The conjugate prepared with the higher-molecular-weight Pn12F elicited higher levels of antibodies than the conjugate prepared with a lower-molecular-weight Pn12F preparation (P = 0.05). Both conjugates elicited about a 13-fold rise in DT antibodies.

Adolescent↗
PubMed1987

Safety and immunogenicity of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) in infants.

Safety and immunogenicity of a Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) was evaluated in infants seven to 14 months of age. PRP-D (80% of subjects) or saline placebo (20%) was randomly and blindly administered (two doses separated by two months). Incidence of mild reactions lasting less than 48 hr did not differ significantly between the placebo and vaccine recipients. Preimmunization levels of antibody to PRP were less than or equal to 0.15 micrograms/ml in 97% of subjects. A twofold increase in antibody concentration occurred in 88% of subjects following the first dose and in 99% following the second dose of vaccine. No change occurred in placebo recipients. Mean level of antibody and percentage of subjects with levels of antibody greater than or equal to 1 microgram/ml after vaccination increased with increasing age. Responses were related to vaccine lot but not to sex, race, or geographic location. Two doses of PRP-D in infants seven months of age and older induced antibody levels equal to or greater than levels in infants 24 months of age given the polysaccharide alone.

Antibodies, Bacterial↗
PubMed1994

Clinical comparison of the Haemophilus influenzae type B polysaccharide-diphtheria toxoid and the oligosaccharide-CRM197 protein vaccines in infancy.

OBJECTIVE: To compare two Haemophilus influenzae type B (HiB) conjugate vaccines, a polysaccharide-diphtheria toxoid conjugate (PRP-D) vaccine and an oligosaccharide-CRM197 protein conjugate (HBOC [PRP-CRM]) vaccine, in the same population. DESIGN: One hundred twenty-five thousand infants were randomized to receive the PRP-D or HBOC vaccine. Primary immunization consisted of two doses of either vaccine administered at 4 and 6 months and a booster dose was given at 14 to 18 months. Protection was assessed by recording episodes of invasive disease with HiB isolated from the blood or another normally sterile body site. SETTING: One thousand thirty-six child health care centers in Finland. PARTICIPANTS: Infants born in Finland during the 24-month period from 1987 to 1989. INTERVENTION: Each vaccine dose was injected intramuscularly in a volume of 0.5 mL. At the same time, a separate site was injected with the diphtheria and tetanus toxoids and pertussis vaccine at 4 months of age, with inactivated poliovirus vaccine at 6 months of age, and with measles-mumps-rubella vaccine at 14 to 18 months of age. MAIN RESULTS: The mean anticapsular antibody concentration 1 month after the second dose was 0.63 micrograms/mL and 4.32 micrograms/mL in the PRP-D and HBOC vaccine recipients, respectively. The booster dose resulted in a high antibody concentration: 33.3 micrograms/mL and 58.3 micrograms/mL for PRP-D and HBOC vaccine recipients, respectively. At 36 months of age, the antibody concentration declined to 2.5 micrograms/mL and 5.6 micrograms/mL for PRP-D and HBOC vaccine recipients, respectively. After two doses of the vaccine, there were five episodes (39 were expected based on historical controls) of invasive HiB disease in the PRP-D group and two episodes (35 were expected) in the HBOC group. Hence, an 87% (95% confidence limit [CL], 69, 96) protection rate in the PRP-D group and a 95% (95% CL, 76, 99) protection rate in the HBOC group were achieved. No episodes occurred after the booster dose in either group. CONCLUSIONS: Both the PRP-D and HBOC vaccines are safe and effective. A two-dose primary vaccination schedule seems appropriate, at least in circumstances prevailing in Finland and probably in other areas with similar epidemiological effects of HiB disease.

Antibody Formation↗
PubMed1986

Studies on the combined administration of Haemophilus influenzae type B--diphtheria toxoid conjugate vaccine (PRP-D) and DTP.

The safety and immunogenicity of an Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid vaccine (PRP-D) has been evaluated when administered alone or simultaneously with other vaccines in over 1,400 2-24 month old subjects. In the first infant study, groups of subjects received either the PRP-D, PRP or placebo vaccine at 3, 5 and 7 months, one month after DPT immunization at 2, 4 and 6 months of age. In a subsequent study infants received either the PRP-D or PRP vaccine simultaneously with DPT. Safety of the PRP-D vaccine was indistinguishable from that of the PRP and placebo vaccines. In both studies, greater than 90% of the PRP-D recipients developed protective levels of antibody (greater than 0.15 microgram/ml) and the majority developed greater than 1.0 microgram/ml of anti-PRP. Following a booster dose of PRP-D at 14-18 months, simultaneously with either MMR, DPT or polio vaccine, all children in these studies developed greater than 1.0 micrograms/ml of antibody. Several other administration schedules have been evaluated in separate clinical studies. Acceptability of a combined DPT/PRP-D vaccine is currently being evaluated in experimental studies.

Antibodies, Bacterial↗
PubMed1987

Monoclonal B-cell response to diphtheria toxoid: evidence for cross-reactive epitopes.

Our previous studies on the human specific B- and T-cell responses against diphtheria toxoid (DT) had shown that the B- and T-cell antigenic determinants were mostly assembled topographic sites with large intra-molecular cross-reactivities. In order to characterize further the B-cell responses against DT, and to investigate these cross-reactivities, we have produced 54 murine monoclonal antibodies (moAbs) against the native DT. Determination of their antigenic specificity showed that 25 moAbs recognized conformational determinants on the native DT, 20 moAbs reacted against the A fragment (DTA) of the toxin, and nine moAbs reacted with at least three distinct highly purified CNBr peptides of the B fragment (DTB); some of them simultaneously recognized two or three purified CNBr peptides of DTB. As shown by cross-inhibition studies, the epitopes cross-reacting with those moAbs were distinct. Previously described sequence data indicated that these epitopes were not induced by repetitive amino-acid sequences. Finally, a cross-reactive idiotype was shared by moAbs specific for the CB1 and the CB3 peptides of DTB. Altogether, these data indicate that anti-DT moAbs are mostly directed against conformational determinants, and may cross-react with several DTB CNBr peptides.

Animals↗
PubMed1990

Antibody-secreting peripheral blood lymphocytes induced by immunization with a conjugate consisting of Streptococcus pneumoniae type 12F polysaccharide and diphtheria toxoid.

Healthy adult volunteers were injected either with one of two conjugates composed of Streptococcus pneumoniae type 12F polysaccharide (Pn12F) covalently coupled to diphtheria toxoid or with Pn12F alone (as a component of Pnu-Imune, a 23-valent pneumococcus vaccine). The conjugates induced Pn12F-specific antibody-secreting cells in peripheral blood with numbers and isotype distribution similar to those induced by Pnu-Imune, with immunoglobulin A (IgA) as the predominant isotype. The conjugates also elicited high numbers of diphtheria toxoid-specific antibody-secreting cells of the IgG class. There was no distinct booster effect, since a second dose of the conjugates induced antibody-secreting cells at significantly lower numbers than after the first dose. In contrast to the cell numbers, the conjugate vaccines induced higher increases of IgA1 Pn12F antibodies in serum than did Pnu-Imune. However, neither the conjugates nor Pnu-Imune induced a secretory antibody response. Antibody levels in serum and saliva correlated poorly with the frequency of antigen-specific antibody-secreting cells. Circulating antibody-secreting cells present 7 days postimmunization were probably not responsible for the high increase of antibodies in serum but rather represented a population of in vivo-activated B cells with the ability to disseminate the humoral response from the antigen recognition site to distant locations of antibody production.

Adolescent↗
PubMed2004

Collaborative study for the validation of serological methods for potency testing of diphtheria toxoid vaccines-part 1.

A collaborative study on the evaluation of an alternative functional assay, the Vero cell method, to the Ph. Eur. in vivo challenge procedures for potency determination of diphtheria toxoid in 6 different combined vaccines was initiated in January 2001. The study was an extension of a previous study for the validation of serological methods for potency testing of tetanus toxoid vaccines for human use. To allow interim evaluation of test results and to monitor study progress, the project was divided into three consecutive phases. The results of Phase I and II studies are presented in this report. Pre-validation (Phase I) study, performed in two laboratories, indicated that comparable diphtheria potency estimates were obtained in the Ph. Eur. direct intradermal challenge assay in guinea pigs, in Vero cell assay and in indirect ELISA for five vaccines of different potencies (range of estimates: ca. 20-200 IU/ml). The correlation coefficients between the challenge assay and the Vero cell assay corresponded to those between the challenge assay and ELISA, confirming that the antibodies play an important role in protection and that predominantly protective/neutralising antibodies are present in guinea pigs, at the time point investigated. It was observed, for Vero cell assays, that about 16-35 (9-28 in Phase II study) fold lower titre of individual serum samples were obtained when using equine, rather than guinea pig reference serum. The study also provided preliminary information that sera from the same guinea pigs may be used for potency determination of both diphtheria and tetanus toxoid components of vaccines. In Phase II, another five laboratories analysed a subset of the vaccines included in Phase I study plus an additional vaccine. Four laboratories performed the lethal challenge assay and one laboratory carried out the intradermal challenge assay. All laboratories also performed the Vero cell assay and both ELISA for diphtheria antitoxin and ELISA for tetanus antitoxin. One laboratory also performed the tetanus ToBI assay. The correlation coefficient (r) between Vero cell assay and ELISA for diphtheria antitoxin ranged from 0.76 to 0.91 in the different laboratories. The correlation between diphtheria serological assays and challenge assays were confirmed satisfactory as ca. 90 per cent of serum-estimates lead to correct prediction of mortality. All laboratories had identical rankings of the vaccines in all serological assays and in the valid challenge assays. The ranking order was identical to assumed/provided potency for the highest and the lowest vaccine. Two of the vaccines had an inversion in some assays and laboratories. As these two vaccines have almost identical potencies in all assays, these inversions are not significant. As the vaccine doses were optimised for the diphtheria component, serum anti-tetanus toxoid/toxin activities varied widely between the vaccines, making it questionable to apply a parallel line model to calculate exact potencies. However, the dose levels used showed a clear regression and good linearity in general. DTaP vaccines containing the IPV component did not always meet the present Ph. Eur. requirements in the serological assays. It should be further investigated in the Phase III study if this is a general feature of such combined vaccines. Preliminary investigations on samples from two laboratories indicate that the neutralising activity of type 1, 2 and 3 polioviruses can also be detected, in a dose-dependent way. Further studies are in progress with serum samples from other laboratories. In the light of results obtained in the first two phases, it is recommended to proceed with Phase III study to investigate reliability of the in vitro assays. In Phase III it will also be further investigated whether the serological assays for D and T components are suitable for the control of the multi-component vaccines currently marketed in Europe.

Animals↗
PubMed2003

Gene expression after vaccination of mice with formulations of diphtheria toxoid or tetanus toxoid and different adjuvants: identification of shared and vaccine-specific genes in spleen lymphocytes.

We immunized mice with four different combinations of diphtheria toxoid or tetanus toxoid with aluminum phosphate or Freund's adjuvant and studied the resulting gene expression profiles in spleen lymphocytes. Genes, which are unique for each combination or shared in several combinations, were found activated, with functions in immune response but also in other cellular processes like apoptosis or signal transduction. Using bioinformatic tools we show, that some of the genes may serve as indicators for adverse reactions, while other genes may be new immune response markers. The results also suggest that adjuvant participates in the formation of an immunological memory.

Adjuvants, Immunologic↗