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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↗

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↗

The secondary structure and aggregation of lyophilized tetanus toxoid.

Tetanus toxoid (TT), the vaccine for tetanus, is an important protein antigen and candidate for sustained release from polymeric matrices. During administration from the latter, the solid (e.g., lyophilized) protein will be exposed to elevated levels of temperature and moisture, conditions which trigger its aggregation. To examine the connection between this aggregation and the structure of the TT molecule in the solid state, Fourier-transform infrared (FTIR) spectroscopy was employed to determine the secondary structure of TT in the presence of various excipients. We found that excipient-free TT undergoes a significant alteration (mostly reversible) in the secondary structure during lyophilization. Specifically, more than half the total alpha-helix content was lost with a concomitant increase in beta-sheet structure. The extent of structural alterations in the presence of 1:5 (g:g protein) NaCl, sorbitol, or poly-(ethylene glycol), did not correlate with stability conferred towards moisture-induced aggregation. These results suggest that the degree of retention of the native protein structure in the dry state is not a general predictor of stability for the "wetted" solid within polymer controlled-release vehicles.

Excipients↗

Cytokine synthesis analyzed at the single-cell level before and after revaccination with tetanus toxoid.

Tetanus toxoid (TT) is a potent immunogen which evokes strong antibody responses after immunization. Here, TT was used as a model antigen to study the production of cytokines at the single-cell level during the in vitro immune response to a specific recall antigen. Peripheral blood mononuclear cells were obtained from healthy volunteers before and 9 weeks after TT vaccination and were cultured with antigen in vitro. The kinetics of cytokine synthesis as well as frequencies of cytokine-producing cells were determined at the single-cell level by immunofluorescent intracellular staining of the cytokine protein. The phenotype of the producer cells was revealed by concomitant staining of surface markers. Two patterns of cytokine synthesis were induced by TT: (i) T lymphocytes expressed a number of lymphokines (interleukin (IL)-2, IL-3, IL-4, IL-10, interferon (IFN)-gamma and tumor necrosis factor (TNF)-beta), each with distinct kinetics of synthesis. This cytokine expression was strictly dependent on the previous exposure of the donor to TT and positively correlated with the level of tetanus immunity, as judged by TT-specific Ab levels in plasma as well as lymphoproliferation. Cells producing IL-2, IFN-gamma and particularly TNF-beta dominated this in vitro response. After 96-120 h in culture, 1.0-1.3% of the cells produced TNF-beta, i.e. frequencies at least tenfold higher than for any of the other lymphokines assayed. The addition of IL-2 to the cultures caused a fourfold increase and a kinetics shift in the production of TNF-beta, which peaked already at 24 h. Exogenously added IL-2 also caused a five- to tenfold increase in the number of IL-2 and IFN-gamma producers but no apparent change in the kinetics of intracellular lymphokine appearance. (ii) The cytokines IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha were produced by monocytes. This inflammatory monokine response was independent of the TT-specific immune status of the donors, characterized by a rapid onset and was transient.

Adult↗

Effect of transplacentally acquired tetanus antibodies on the antibody responses to Haemophilus influenzae type b-tetanus toxoid conjugate and tetanus toxoid vaccines in Filipino infants.

BACKGROUND: Pregnant women in developing countries are vaccinated with tetanus toxoid (TT) to prevent neonatal tetanus. In populations in which the maternal TT-vaccination program is efficiently implemented, responses of the infant to TT and TT-conjugated vaccines such as Haemophilus influenzae type b (Hib) capsular polysaccaride (PS) TT-conjugate (Hib-TT) vaccine may be depressed. OBJECTIVES: To study the influence of transplacentally acquired anti-TT antibodies on responses to TT vaccination and to Hib-TT vaccine. METHODS: One hundred ninety-four healthy Filipino infants received three doses of a Hib conjugate (either Hib-TT, PRP-OMP or HbOC) with diphtheria-tetanus-pertussis vaccine (DTP) given simultaneously but in a separate syringe at the age of 6, 10 and 14 weeks (primary series). In addition 54 of the study children received a booster dose of Hib-TT at 9 months simultaneously with the measles vaccine. RESULTS: Transplacentally acquired anti-TT did not interfere with the anti-Hib PS antibody (anti-Hib PS) response to any of the conjugates. The transplacentally acquired anti-TT was not significantly associated with the concentration of anti-Hib PS either before or after the booster dose of Hib-TT. High concentrations (> or =1 IU/ml) of transplacentally acquired anti-TT inhibited the infants' anti-TT responses. CONCLUSIONS: High concentration of transplacentally acquired anti-TT did not depress anti-Hib PS responses to the Hib-TT vaccine. On the other hand the high anti-TT concentrations somewhat depressed the anti-TT responses of the infants. However, the anti-TT concentrations attained were in the protective range in all study children after either the primary series (DTP + Hib-TT) or the booster dose of Hib-TT.

Antibodies, Bacterial↗

Use of diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine as a five-dose series. Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP).

Four vaccines containing diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) are currently licensed in the United States for use among infants and young children. As of October 2000, two products, ACEL-IMUNE (a product of Lederle Laboratories) and Tripedia (Aventis Pasteur, Inc.) were licensed for the five-dose DTaP vaccination series. Two other vaccines, Infanrix (SmithKline Beecham Biologicals) and Certiva (North American Vaccine, Inc.) are licensed for the first four doses of the vaccination series, beginning with the primary series at ages 2, 4, and 6 months, and for completing the DTaP series among children who began the series with diphtheria and tetanus toxoids and whole-cell pertussis vaccine. This report supplements the statement from CDC's Advisory Committee on Immunization Practices regarding use of acellular pertussis vaccines and summarizes data regarding reactogenicity of acellular pertussis vaccines when administered as the fourth and fifth consecutive doses. Increases in the frequency and magnitude of local reactions at the injection site with increasing dose number have occurred for all currently licensed DTaP vaccines. Extensive swelling of the injected limb, sometimes involving the entire thigh or upper arm, after receipt of the fourth and fifth doses of DTaP vaccines has been demonstrated for multiple products from different manufacturers. Because data are insufficient regarding the safety, immunogenicity, and efficacy of using DTaP vaccines from different manufacturers in a mixed sequence, ACIP continues to recommend that, whenever feasible, the same brand of DTaP vaccine be used for all doses in the vaccination series. When the vaccine provider does not know or does not have available the type of DTaP vaccine previously administered, any of the licensed DTaP vaccines can be used to complete the vaccine series.

Child↗

Can Haemophilus influenzae type b-tetanus toxoid conjugate vaccine be combined with diphtheria toxoid-pertussis vaccine-tetanus toxoid?

OBJECTIVE: To assess the side effects and immune responses after three serial doses of PRP-T vaccine (a Haemophilus influenzae type b [Hib]-tetanus toxoid conjugate vaccine) given concurrently or mixed with adsorbed DPT vaccine (diphtheria toxoid-pertussis vaccine-tetanus toxoid). DESIGN: Multicentre randomized controlled trial. SETTING: Four public health units in western Canada. PARTICIPANTS: Healthy infants 8 to 15 weeks old at entry who were able to receive routine primary vaccinations. Of 444 infants enrolled, 433 (98%) completed the study. INTERVENTIONS: All infants received PRP-T and DPT vaccines at 2, 4 and 6 months of age: half received them mixed in one injection and the others as separate, bilateral injections. MAIN OUTCOME MEASURES: Side-effects 24 and 48 hours after each dose and serologic responses to each vaccine component. RESULTS: Follow-up was obtained after all 1312 vaccinations. Fever was infrequent in the two treatment groups. Local adverse effects of the PRP-T vaccine were infrequent and mild (e.g., redness was noted in 5.9% of cases and the area of redness was more than 2.5 cm in diameter in 0.8%). The incidence rate of local effects of the DPT-containing vaccines was the same in the two groups except for tenderness, which was more frequent in the group given the mixed vaccine (26.6% v. 17.9%, p < 0.001). Serologic data were available for 97% of the subjects. After the three doses 98.1% of the subjects had a PRP antibody level of 0.15 micrograms/mL or more, and 87.9% had a level of 1.0 micrograms/mL or more, both levels compatible with protection against Hib. Responses to PRP-T were comparable between the treatment groups as were responses to the diphtheria and tetanus toxoids. Pertussis agglutinin titres were reduced after administration of one of two PRP-T lots mixed with DPT vaccine, but responses to four other pertussis antigens were not impaired. CONCLUSION: PRP-T vaccine is well tolerated and immunogenic. Combined PRP-T and DPT vaccines performed satisfactorily and may be the preferred method of administration.

Antibodies, Bacterial↗

ELISA detection of specific functional antibodies in human serum to Escherichia coli, tetanus toxoid, and diphtheria-tetanus toxoids: normal values for IgG, IgA, and IgM.

An inexpensive, easily performed enzyme-linked immunosorbent assay (ELISA) was developed to measure specific IgG, IgA, and IgM antibodies to the common antigens Escherichia coli, diphtheria-tetanus toxoid, and tetanus toxoid. Normal values were established. Classical antibody deficiency disease states were confirmed and delineated by these assays. Additionally, several instances were discovered when functional antibody levels were abnormal when the serum immunoglobulin levels were normal. The use of ELISA assays for antibodies to common antigens provides a useful technique to measure and monitor isotype responses of the humoral immune system.

Adult↗

Titration of antibodies to tetanus toxoid by agglutination of purified tetanus toxoid sensitized latex particles.

The method of sensitized latex particle agglutination which we have devised allows the selection of samples of plasma for the preparation of immunoglobulins. The population of thus selected samples is the same as is selected by the in vivo test, having a titer greater than or equeal to 6 IU/ml. The test gives a clear-cut difference between the positive and negative results and does not give any prozone phenomenon. It can be used extensively, as the batches of sensitized latex particles may be stored for quite a long time.

Adult↗

Safety and immunogenicity of Haemophilus influenzae vaccine (tetanus toxoid conjugate) administered concurrently or combined with diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine to healthy infants at two, four and six months of age.

The safety and immunogenicity of Haemophilus influenzae vaccine (tetanus toxoid conjugate (PRP-T) administered concurrently in separate sites or mixed in the same syringe with diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine were assessed in 439 infants at 2, 4 and 6 months of age. The proportions with local redness, tenderness and swelling in the separate and combined groups were 18% vs. 11% (P < 0.001), 27% vs. 24% and 15% vs. 13%, respectively. Systemic reactions occurred at similar rates in both groups. The combined vaccine induced tetanus and diphtheria antitoxin titers > or = 0.01 IU/ml in 99.5 and 99.1% of infants, pertussis agglutinin titers > or = 64 in 92.4%, anti-polyribosylribitol phosphate titers > or = 0.15 microgram/ml in 93.8% and > or = 1.0 microgram/ml in 75% and polio-neutralizing titers > or = 8 in > 98% of infants. However, antibody concentrations to PRP-T, some pertussis antigens and tetanus toxoid were significantly lower after combined than after separate injections of DPT/diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine and PRP-T. The clinical significance of these differences is not known, but the interactions observed among the components of the pentavalent vaccine may be of concern because they might influence antibody persistence until the fourth dose is administered.

Diphtheria-Tetanus-Pertussis Vaccine↗

The induction and suppression of in vitro IgG anti-tetanus toxoid antibody synthesis by human lymphocytes stimulated with tetanus toxoid in the absence of in vivo booster immunizations.

This report presents a new approach that by-passes booster immunizations with tetanus toxoid (TT) before in vitro studies of antibody (Ab) production. The methodology for optimal TT-induced synthesis of specific IgG anti-tetanus toxoid Ab (IgG anti-TT) by peripheral blood mononuclear cells (PBMC) from randomly selected TT immune individuals without recent booster immunizations is described. PBMC from most normal immune subjects could be repeatedly induced to produce in vitro IgG anti-TT; PBMC from subjects with high TT titers are not required for this new approach. This approach uses high cell concentrations in multiple replicate microcultures and TT washout to obtain optimal IgG anti-TT synthesis. Washed cultures produced more Ab than nonwashed cultures (p less than or equal to 0.005). The readdition of TT (2.5 to 250 ng/ml) to the culture media after washout of TT on day 4 suppressed specific Ab formation, whereas diphtheria toxoid added at comparable doses did not inhibit specific Ab formation. Suppression of antibody synthesis mediated by T cells could be induced by TT per se, and was not due to binding of synthesized Ab to TT in the latter 8 days of culture. In addition, suppression could not be induced in the first 4 days of culture by IgG anti-TT, IgG, or IgM. This approach permits the analysis of antigen-specific regulatory circuits in the steady and activated immune states, and the evaluation of in vivo and in vitro effects of biologic response modifiers on specific Ab production.

Adult↗

Comparison of the morbidity of tetanus toxoid boosters with tetanus-diphtheria toxoid boosters.

A double-blind randomized trial was performed to compare the subjective morbidity of tetanus toxoid (T) with that of tetanus-diphtheria toxoid (Td). Symptoms occurred in 46 (48%) of 93 patients who received T, and in 75 of 100 patients who received Td (chi 2 = 12.3; P less than .001). The effectiveness of immunization is clear, but with shift from use of T to Td as recommended, adherence to immunization guidelines and taking of adequate immunization histories becomes even more important.

Adult↗

Effectiveness of prenatal tetanus toxoid immunization against neonatal tetanus in a rural area in India.

BACKGROUND: Neonatal tetanus is the cause of 23 to 73% of neonatal deaths in developing countries and continues to be an important killer in many parts of India. METHODS: In this nonrandomized cohort study in a rural area in India, tetanus toxoid immunization status was recorded for 1688 pregnant women. Liveborn children were followed up for 30 days for the occurrence of neonatal tetanus. Nonimmunized and partially immunized women were asked their reasons for not receiving tetanus toxoid vaccine. RESULTS: Complete prenatal immunization with tetanus toxoid during pregnancy (two doses 1 month apart) was associated with an 88% reduction in the risk of neonatal tetanus among the newborn children [95% confidence interval (CI) 59 to 98%]. In multivariable analysis only complete immunization and the use of clean instruments for cutting the umbilical cord were independently associated with a reduction in risk of neonatal tetanus. Registration by the health care provider before 29 weeks of gestation, being 5 km or less from the vaccination facility, having two or more contacts with the health provider and having some school education were independently associated with complete immunization. CONCLUSIONS: Immunization of pregnant women with tetanus toxoid was the single most effective intervention against neonatal tetanus independent of other interventions.

Adult↗

Quantitative estimation of diphtheria and tetanus toxoids. 4. Toxoids as international reference materials defining Lf-units for diphtheria and tetanus toxoids.

The Lf-unit, which is used in the control of diphtheria and tetanus toxoid production and in some countries also to follow immunization of horses for production of antitoxins, has hitherto been defined by means of antitoxin preparations. A diphtheria toxoid and a tetanus toxoid preparation, both freeze-dried, were examined in an international collaborative study for their suitability to serve as reference reagents in the flocculation tests and for defining the Lf-units. It was shown that flocculation tests using the reference toxoids are very reproducible and reliable and the WHO Expert Committee on Biological Standardization established: the toxoid called DIFT as the International Reference Reagent of Diphtheria Toxoid for Flocculation Test with a defined content of 900 Lf-units of diphtheria toxoid per ampoule; and the toxoid called TEFT as the International Reference Reagent of Tetanus Toxoid for Flocculation Test with a defined content of 1000 Lf-units of diphtheria toxoid per ampoule.

Animals↗

Double-blind comparative trial of standard (commercial) and antibody-affinity-purified tetanus toxoid vaccines.

Tetanus toxoid purified by antibody-affinity chromatography, was compared with conventionally purified material in a double-blind trial in 205 healthy blood donors. There was neither any difference in immunogenicity as assessed by enzyme-linked immunoassay nor in side-reactions between the two vaccines. This study confirms that side-reactions to tetanus toxoid are not eliminated by purifying it.

Adolescent↗