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PubMed1953

International standardization of diphtheria toxoids.

The present report is an analysis of results of assays of diphtheria toxoids carried out over a four-year period at the Laboratory of Hygiene, Department of National Health and Welfare, Ottawa, Canada. A single preparation, a crude monovalent diphtheria toxoid, was used as a reference standard for all types of preparation (purified, crude, or adsorbed). The results suggest that the use of such a standard is justified even though there is evidence to show that adsorbed and plain toxoids, and toxoids of different grades of purity, do not have identical immunization curves. The merits of the present International Standard for Diphtheria Toxoid, Plain, for the assay of all types of toxoid are discussed. The results suggest that this is not particularly suitable for adsorbed preparations, probably because of its flatter immunization curve. For the latter preparations, the proposed international standard for diphtheria toxoid, adsorbed, should prove more practical and useful.

Biological Assay↗

PubMed2004

Spontaneously reported adverse reactions after diphtheria-tetanus revaccination at 4-6 years of age--a comparison of two vaccines with different amounts of diphtheria toxoid.

On 1 January 1996, diphtheria-tetanus revaccination at the age of 5 years was implemented in the Danish Childhood Vaccination Programme. Initially, a combined DT vaccine containing 25 Lf diphtheria toxoid was used. Due to a high frequency of spontaneously reported adverse reactions, however, concerns were raised that the diphtheria dose was too high, and it was reduced to 6.25 Lf. This survey presents the rates of spontaneously reported adverse reactions following diphtheria-tetanus revaccinations of 4-6-year-old from 1996 to 2002. The change to the lower dose of diphtheria toxoid resulted in a remarkable reduction in the yearly rates of injection site reactions: in 1996, the rate was 180 injection site reactions per 100,000 vaccinations; from 1998 to 2002, this changed to between 12 and 24 reactions per 100,000 vaccinations. Furthermore, the rates of systemic reactions such as fever were reduced.

Child, Preschool↗

PubMed1980

Immunogenic correlation between cross-reacting material (CRM197) produced by a mutant of Corynebacterium diphtheriae and diphtheria toxoid.

The in vivo immunizing potency of diphtheria toxoid and formalin-treated corss-reacting material (CRM197, a nontoxic mutant protein) was compared in guinea pigs. Major antigenic differences between the two untreated proteins were also tested in rats. The results showed that diphtheria toxoid and CRM197 were equally effective immunogens, but only if the latter was treated with formalin in the same concentration (0.7% vol/vol) was that of the toxoid. Formalin treatment rendered the antigens more resistant to enzymatic proteolysis by trypsin in vitro.

Animals↗

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↗

PubMed1992

Selection for immune response in goats: the effect of immunization procedure on antibody response to diphtheria toxoid and human serum albumin.

The serum antibody titers to diphtheria toxoid and human serum albumin were determined in 103 goat kids from lines selected for 12 yr for high or low antibody response to diphtheria toxoid. In the 12th yr, six groups of kids were immunized with different preparations of the antigens. In all groups but one, the antigens were emulsified in Freund's incomplete adjuvant with added sonicated Mycobacterium paratuberculosis. The groups received the following treatments: Group 1 was immunized with both antigens mixed in the same syringe, Group 2 got both antigens injected separately, Group 3 got both antigens injected separately, but with a lower concentration of M. paratuberculosis, Group 4 was immunized with diphtheria toxoid only, Group 5 was immunized with human serum albumin only, and Group 6 was immunized with both antigens mixed, but without any M. paratuberculosis. The animals were immunized at 4 wk of age, and the antibody titers were determined 3 wk later by ELISA and passive hemagglutination. The mean antibody titers to both antigens were different between the selected lines (P less than .03). There was no effect of separate vs combined injections of antigens. However, there were indications of antigen suppression or competition between the antigens. Animals receiving only one antigen seemed to mount a higher antibody response to that antigen than did animals immunized with two antigens.

Animals↗

PubMed2001

Calibration of replacement international standard and European Pharmacopoeia Biological Reference Preparation for Diphtheria Toxoid, Adsorbed.

We report here the characterisation of a preparation of diphtheria toxoid, adsorbed, and its calibration by twenty laboratories in fourteen countries in terms of the Second International Standard (I.S.) for Diphtheria Toxoid, Adsorbed, coded sample A (DIXA) using the established World Health Organisation (WHO)/European Pharmacopoeia (Ph Eur) challenge methods. The replacement standard preparation was found to have a unitage of 160 IU/ampoule on the basis of its calibration by in vivo bioassay. Stability was assessed within the collaborative study, and as part of candidate characterisation. Results suggest that the replacement standard will have satisfactory stability. This study also provided an opportunity to investigate serology as alternative to in vivo bioassay for potency testing of diphtheria vaccines. Six laboratories participated by performing serology according to in-house protocol. The calibration of the replacement standard in a mouse Vero cell assay gave a significantly higher results than in the established WHO/Ph Eur methods. Based on the results of this study and with the agreement of participants, the candidate standard was established as the Third International Standard for Diphtheria Toxoid, Adsorbed (coded 98/560) by the WHO Expert Committee of Biological Standardization in October 1999. The same preparation was also established as the second Ph Eur Biological Reference Preparation (Ph Eur BRP, batch no. 3) by the Steering Committee of the Biological Standardisation Programme of the European Directorate for the Quality of Medicines and approved by the European Pharmacopoeia Commission.

Adsorption↗

PubMed2000

How many doses of diphtheria toxoid are required for protection in adults? Results of a case-control study among 40- to 49-year-old adults in the Russian Federation.

During the Russian diphtheria epidemic of the 1990s, adults had an unexpectedly high rate of disease. A retrospective, matched case-control study was done to measure the effectiveness of one, two, or three or more doses of diphtheria toxoid against diphtheria among 40- to 49-year-old Russians. Thirty-nine diphtheria case-patients and 117 controls were studied. Previous vaccinations were included if one dose was received within the previous 10 years. Five cases (13%) and 33 controls (28%) had received three or more doses of vaccine. The matched odds ratio was 0.3 (95% confidence interval, 0.1-0.9) for three or more doses compared with no doses, which was a vaccine effectiveness of 70% (95% confidence interval, 10-90). A trend existed toward milder disease with increasing doses (chi2 test for trend, P=.02). The results suggest that Russian adults, who were unlikely to have acquired immunity to diphtheria through immunization or natural infection, required at least three doses of diphtheria toxoid for reliable protection against disease.

Adult↗

PubMed1981

Circulating antitoxin in rabbits after ingestion of diphtheria toxoid.

Immune responses following antigen ingestion vary from stimulation to suppression depending on animal species, antigen, and experimental protocol. Young adult rabbits were given either 0.02% diphtheria toxoid or 0.1% bovine serum albumin in drinking water for 10-day periods, a protocol previously found to immunize human infants fed bovine serum albumin. Specific serum antibody was detected by radioimmunoassay in 10 of 13 rabbits fed diphtheria toxoid for 10 days and 11 of 13 rabbits fed bovine serum albumin. Response to oral diphtheria toxoid in some animals was equal to that after an injection of alum-precipitated diphtheria and tetanus toxoids. All rabbits fed a second course of either antigen showed an enhanced, rapid rise in antibody concentration. Avidity of the antibody also increased markedly, suggesting that priming and memory had been established during the first feeding. Similar anamnestic responses occurred in animals given a parenteral challenge after ingesting antigen. One month after administration of diphtheria toxoid, no significant difference in serum antibody levels was present between unfed animals challenged with diphtheria-tetanus toxoids and although avidity of the antitoxin was higher in fed animals. Antibody activity could be detected only in the immunoglobulin G serum fractions with either antigen. These responses suggest that oral immunization protocols using protein antigens can be adapted for use against toxins causing disease.

Administration, Oral↗

PubMed2003

Frequent nasal administrations of recombinant cholera toxin B subunit (rCTB)-containing tetanus and diphtheria toxoid vaccines induced antigen-specific serum and mucosal immune responses in the presence of anti-rCTB antibodies.

Vaccination via a mucosal route is a very attractive means for immunization, because both local and systemic immune responses are inducible and vaccines can be administered easily and safely from infants to elderly persons. For developing widely applicable mucosal vaccines using recombinant cholera toxin B subunit (rCTB) as a safe adjuvant, we examined whether frequent nasal administrations of rCTB-containing same and different vaccines could induce antigen-specific immune responses without induction of systemic tolerance and suppression by pre-existing anti-rCTB immunity. Ten repetitive nasal administrations to mice of tetanus toxoid (TT) + rCTB or diphtheria toxoid (DT) + rCTB raised and maintained high levels of antigen- and rCTB-specific serum IgG including high levels of tetanus/diphtheria antitoxin titres and raised nasal, salivary, lung, vaginal and fecal secreted IgA, suggesting that the regimen did not induce systemic tolerance to TT/DT and rCTB. Mice successively received repetitive five doses of TT as the first antigen and subsequent five doses of DT as the second antigen, and vice versa, raised serum IgG to the second antigen at various levels including low but sufficient protective levels of antitoxin titres and induced mucosal IgA in the lungs, the vaginas and feces, but hardly in the nasal secretions and salivas. After an interval of 22 weeks between the dosage of the first and second antigens, mice induced serum IgG to the second antigen at high levels and mucosal IgA in all sites. In conclusion, anti-TT and -DT serum and mucosal antibody responses induced by repeated intranasal immunization using rCTB adjuvant lasted for a long period, and for improving the effectivity of vaccination, different rCTB-containing vaccines should be administered at appropriate intervals.

Administration, Intranasal↗

PubMed1991

Controlled delivery of diphtheria toxoid using biodegradable poly(D,L-lactide) microcapsules.

Diphtheria toxoid, which is an important vaccine in the expanded program of immunization (EPI) in the developing countries, was microencapsulated using poly(D,L,-lactide) of 49,000 molecular weight and the in-water drying technique. The microcapsules were subjected to an in vitro antigen release study using a sensitive enzyme-linked immunosorbent assay (ELISA) developed in the laboratory. Antibody titers in immunized Balb/C mice were also determined using direct ELISA. The antibody units in the immunized group till day 75 were quite comparable to those in the group receiving conventional three-dose injection of diphtheria toxoid with calcium phosphate as an adjuvant. SEM photographs of the microcapsules during in vitro degradation demonstrated the erosion kinetics of the polymer, leading to controlled release of the antigen.

Animals↗

PubMed1989

Increased dosage of diphtheria toxoid for basic immunization of adults.

Basic immunization of adults with increased dosages of a diphtheria toxoid vaccine (2100 flocculation units (Lf)/mg) was evaluated. Three injections of 7.5 Lf or 15 Lf diphtheria toxoid were given to 243 adults who had a history of no more than one previous vaccine injection. Systemic reactions were rare in both groups. Following the first two injections, local reactions (greater than 5 cm) were observed in 6-14% of the adults. After the third injection, 35% of adults in the 15 Lf group reported a local reaction (greater than 5 cm) compared to 11% in the 7.5 Lf group (p less than 0.001). The 15 Lf dose elicited a better antitoxin response than the 7.5 Lf dose. In a seronegative subgroup including 65 vaccinees who showed no booster response to the first vaccination, 79% had a postvaccination titer of greater than or equal to 0.1 IU/ml and 28% a titer of greater than or equal to IU/ml after the third injection of 7.5 Lf. The corresponding numbers in the 15 Lf group were 94% and 44%, respectively. The study demonstrates that 7.5 Lf and 15 Lf diphtheria toxoid of high purity can safely be given to adults for basic immunization. The higher dose is more immunogenic but local reactions increase after the third injection.

Adult↗

PubMed1988

Synthesis and physicochemical and immunological characterization of pneumococcus type 12F polysaccharide-diphtheria toxoid conjugates.

A scheme for the synthesis and purification of conjugates, composed of the type 12F capsular polysaccharide of Streptococcus pneumoniae (Pn12F) and diphtheria toxoid, is described. The scheme is a modification of that described previously for the Vi capsular polysaccharide of Salmonella typhi, a linear homopolymer of N-acetylgalactoseaminouronic acid (S. C. Szu, A. L. Stone, J. D. Robbins, R. Schneerson, and J. B. Robbins, J. Exp. Med. 166:1510-1524, 1986). Pn12F is a branched-chain copolymer composed of a hexasaccharide repeating unit containing an aminouronic acid, N-acetylmannoseaminouronic acid (K. Leontein, B. Lindberg, and J. Lonngren, Can. J. Chem. 59:2081-2085, 1981). Sulfhydryl groups were introduced into Pn12F by forming an amide bond between cystamine and carboxyl groups of N-acetylmannoseaminouronic acid in the presence of a carbodiimide. The disulfide moiety of cystamine was reduced to form the cysteamine derivative of Pn12F which was, in turn, covalently bound to diphtheria toxoid by using the heterobifunctional linker N-succinimidyl-3-(2-pyridylthio)propionate. Unbound, high-molecular-weight Pn12F was removed from the conjugate by hydrophobic interaction chromatography through octyl Sepharose by using n-octyl-beta-D-glucopyranoside as the eluent. In young outbred mice, Pn12F did not elicit detectable serum antibodies. Pn12F-diphtheria toxoid, in contrast, elicited antibodies after two injections and had T-cell-dependent properties as evidenced by a response to priming and by its ability to elicit booster responses. This scheme seems applicable to the synthesis of conjugates with other capsular polysaccharides containing aminouronic acids. Clinical evaluation of Pn12F-diphtheria toxoid conjugates in healthy and in immunocompromised hosts is planned.

Animals↗

PubMed1994

Suitability of the Vero cell method for titration of diphtheria antitoxin in the United States potency test for diphtheria toxoid.

The in vitro Vero cell method for titration of diphtheria antitoxin in immunized guinea pig sera was standardized to obtain comparable results to the in vivo toxin neutralization (TN) test in guinea pigs used to test potency of adsorbed diphtheria toxoid according to the United States Minimum Requirements. In the Vero cell method, the antitoxin titers of the guinea pig sera, obtained 4 weeks after immunization, were markedly dependent on the toxin dose level used in the assay. A toxin dose level termed the Lcd/1 dose (limit of cytopathic dose at 1 IU/ml) for Vero cell method gave comparable estimates of antitoxin activity to the in vivo TN method performed at L+/1 dose of toxin. The Lcd/1 toxin dose level for the Vero cell method is defined as the minimum concentration of diphtheria toxin required to produce a cytopathic effect on Vero cells in 4 days when the solution of diphtheria toxin is mixed with an equal volume of standard diphtheria antitoxin whose concentration is 1 IU/ml. When lower dose levels of toxin were used in the Vero cell assay (Lcd/10 to Lcd/1000), the concentrations of antitoxin in 4 weeks guinea pig sera were 2 to 11.7 times lower than with the Lcd/1 dose level and similarly lower than those measured by the in vivo TN test at L+/1 level. In contrast, the concentration of antitoxin measured in sera from guinea pigs who have been boosted with diphtheria toxoid increased approximately two-fold with the Lcd/1000 dose level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Prevalence and correlates of diphtheria toxoid antibodies in children and adults in Israel.

A seroepidemiological study was performed to evaluate immunity to diphtheria and to determine the correlates of diphtheria toxoid antibody levels among children and adults in Israel. In total, 3,185 sera from an age-stratified sample of children and adults, obtained in 2000-2001, were tested for diphtheria toxoid antibodies by an in-house double-antigen ELISA. A level of or=0.1 IU/mL (full protection or seropositivity). Seronegativity increased significantly in subjects aged >50 years, reaching levels of 9.7%, 12.6% and 18.9% in the groups aged 50-54, 55-59 and >60 years, respectively (p 0.001), with rates of basic immunity following a similar pattern. Subjects born abroad had higher seronegativity rates than those born in Israel (7.7% vs. 4.9%; p 0.019). No difference in diphtheria toxoid antibody levels was found according to other demographical variables, such as gender, Jewish or Arab ethnicity, urban or rural settlements, and the subjects' place of residence. The level of immunity to diphtheria among children and adults in Israel was satisfactory, with the exception of individuals aged >50 years. The risk of diphtheria outbreaks is low, but sporadic cases may occur among individuals lacking basic immunity against the disease.

Adolescent↗

PubMed1998

Controlled release microparticles as a single dose diphtheria toxoid vaccine: immunogenicity in small animal models.

Diphtheria toxoid (DT) was encapsulated in microparticles prepared from polylactide-co-glycolide (PLG) polymers using a solvent evaporation technique. Combinations of small and large sized microparticles with controlled release characteristics were used to immunize Sprague Dawley rats and the antibody responses were monitored for one year. For comparison, control groups of rats were immunized at 0, 1 and 2 months with DT adsorbed to alum. The antibody responses generated by the microparticles were comparable to the alum immunized control groups from 32 weeks. Microparticles with a single entrapped antigen (DT) induced better antibody responses than microparticles with two antigens entrapped simultaneously (DT + TT). Microparticles prepared from a single polymer were less effective for long term antibody induction than a combination of microparticles prepared from three different polymers. A combination vaccine consisting of antigen absorbed to alum and also entrapped in microparticles gave the best response. In an inhibition assay designed to determine the relative binding of antisera to the antigen, the sera from the microparticle and the alum immunized animals showed comparable binding. An intradermal challenge study was performed in rabbits, which showed similar levels for the alum and the microparticle immunized animals at 4, 12 and 32 weeks after immunization.

Animals↗

PubMed2003

Physicochemical and immunochemical techniques predict the quality of diphtheria toxoid vaccines.

The most critical step in the production of diphtheria vaccines is the inactivation of the toxin by formaldehyde. Diphtheria toxoid (DTx) is produced during this inactivation process through partly unknown, chemical modifications of the toxin. Consequently, diphtheria vaccines are difficult to characterise completely and the quality of the toxoids is routinely determined with potency and safety tests. This article describes the possibility of monitoring the quality in diphtheria vaccine production with a selection of physicochemical and immunochemical tests as an alternative to established in vivo tests. To this end, diphtheria toxin was treated with increasing formaldehyde concentrations resulting in toxoid products varying in potency and residual toxicity. Differences in the quality of the experimental toxoids were also assessed with physicochemical and immunochemical techniques. The results obtained with several of these analyses, including SDS-PAGE, primary amino group determination, fluorescence spectroscopy, circular dichroism (CD) and biosensor analysis, showed a clear correlation with the potency and safety tests. A set of criteria is proposed that a diphtheria toxoid must comply with, i.e. an apparent shift of the B-fragment on SDS-PAGE, a reduction of primary amino groups in a diphtheria molecule, an increased resistance to denaturation, an increased circular dichroism signal in the near-UV region and a reduced binding to selected monoclonal antibodies. In principle, a selected set of in vitro analyses can replace the classical in vivo tests to evaluate the quality of diphtheria toxoid vaccines, provided that the validity of these tests is demonstrated in extensive validation studies and regulatory acceptance is obtained.

Animals↗

PubMed1978

Studies on adjuvants for human prophylactics. I. Comparison of efficiencies of different adjuvants at various stages of immunization with tetanus and diphtheria toxoids.

Kinetic studies on the adjuvanticities of several substances with different modes of action were performed in guinea pigs by using tetanus and diphtheria toxoids as the antigens. When injected subcutaneously into animals, aluminium, endotoxin, pertussis vaccine and water in oil in water (w/o/w) showed very similar adjuvanticities to tetanus toxoid at the beginning stage of immunization, but the activities except that of aluminium became less significant at later stages after the primary stimulus when antitoxin was produced abundantly. Poly L-lysine and to a less extent poly A:U showed potent adjuvanticities next to that of aluminium throughout the whole immunization period. Combination of poly L-lysine with 0.03 mg aluminium showed a similar adjuvanticity to that of 0.9 mg of aluminium alone. In contrast to rather low adjuvanticities to tetanus toxoid, more distinct adjuvanticities were observed to diphtheria toxoid throughout the whole period of immunization with various substances such as aluminium, poly A:U, w/o/w and poly L-lysine but not with endotoxin.

Adjuvants, Immunologic↗

PubMed1986

Simultaneous administration of diphtheria-tetanus-pertussis-polio and hepatitis B vaccines in a simplified immunization program: immune response to diphtheria toxoid, tetanus toxoid, pertussis, and hepatitis B surface antigen.

We studied the interactions of hepatitis B vaccine with other vaccines used in the World Health Organization expanded programs of immunization. Three groups of Senegalese children were vaccinated with hepatitis B vaccine (HB) alone, diphtheria-tetanus-pertussis (DTP)-polio vaccine alone, or a combination of hepatitis B vaccine and DTP-polio vaccines simultaneously. The immune responses to HBsAg, tetanus toxoid, diphtheria toxoid, and pertussis were measured after one and two vaccinations at 6-month intervals. The immune responses to the combination of HB vaccine and DTP-polio vaccines were similar to the immune responses observed after administration of each vaccine alone. In addition, no adverse reactions were noted. These experimental trials also demonstrated that with a DTP-polio vaccine containing 30Lf of tetanus and diphtheria toxoids, two doses given at 6-month intervals are sufficient to provide a satisfactory immune response. In the case of pertussis and HB vaccines; however, a third dose is necessary.

Antibodies, Bacterial↗