A comparative evaluation of the immunological efficacy of ADPT vaccine and ADT-M anatoxin in the immunization of children against diphtheria and tetanus

Comparative study of the immunological effectiveness of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine and adsorbed diphtheria-tetanus toxoid with reduced antigen content (adsorbed DT toxoid R) in the immunization of children, carried out in accordance with the vaccination schedule, was made. Immune response to the injection of adsorbed DPT vaccine was higher than after immunization with adsorbed DT toxoid R, as evidenced by antibody titers. It was probably due to differences in the number of injections constituting the course of immunization: it consisted of 3 injections and 1 booster injection for adsorbed DPT vaccine and 2 injections and 1 booster injection for adsorbed DT toxoid R. Immunization with adsorbed DPT vaccine produced immunity which was retained for a longer period. These results are indicative of the expediency of the primary immunization of children with adsorbed DT toxoid R introduced in three injections in order to ensure more stable and prolonged postvaccinal (mainly antidiphtheria) immunity.     

Comparative study of the immunoglobulins and specific antibodies in the blood of rabbits immunized with ADTP vaccine and ADT-anatoxin with normal and reduced antigen contents

Adsorbed DPT vaccine and adsorbed DT toxoids with normal and reduced antigen content were used for the immunization of rabbits. The levels of IgM and IgG and the dynamics of antibodies to diphtheria and tetanus toxins and to Bordetella pertussis in the blood sera of the animals were studied in the postvaccinal period (on days 15 and 34). This study revealed that the reduction of the antigen content of adsorbed DT toxoid to 5 Lf of diphtheria toxoid and 5 binding units of tetanus toxoid did not decrease the capacity of the preparation for increasing the levels of IgG and IgM, antibodies to diphtheria and tetanus toxins in the sera of the rabbits. The reduced content of these toxoids in adsorbed DPT vaccine did not affect its capacity for inducing the enhanced synthesis of IgG, antibodies to diphtheria and tetanus toxins, while the production of IgM and IgA remained unchanged. At the same time an increase in the titers of antibodies to B. pertussis in the animals was less pronounced than that observed after the injection of commercial adsorbed DPT vaccine. Additional investigations are necessary in order to establish the protective potency of the pertussis component in adsorbed DPT vaccine with the reduced content of toxoids and to find out the optimum antigenic composition for this preparation.     

Whole-cell Bordetella pertussis vaccine component modulates the mouse immune response to an unrelated soluble antigen

Several factors are involved in the selective activation of Th1 or Th2 cells, such as different physical characteristics of antigens and the type of antigen-presenting cells involved in the immune response, among others. To study the influence of a particulate antigen on Th1/Th2 cell differentiation during the immune response to another antigen, we analysed the immune response to tetanus toxoid (soluble antigen) in BALB/c mice immunized with one of the three following vaccines: tetanus and diphtheria toxoids (DT), or DT associated with whole-cell Bordetella pertussis or its soluble antigens (DTPw and DTPa, respectively). Similar total antibody levels were observed for all vaccines. DT vaccine showed a higher IgG1/IgG2a ratio than the similar values observed for DTPw and DTPa vaccines. DT- and DTPa-primed spleen cells showed a Th2 (IL-5) profile while a Th1/Th2 (IFN gamma, IL-5) profile was observed for DTPw. IL-6 was only produced by DTPw-primed cells. Besides, IL-12 levels induced by DTPw were three times higher than the ones induced by both DT and DTPa. Our findings indicate that whole-cell B. pertussis priming modifies the tetanus immune response from Th2 to Th1/Th2 type probably via inflammatory mechanisms. In addition, in the light of conflicting reports regarding the mechanisms of protection induced by DTP vaccines, we studied the pertussis immune response. Only DTPw immunization generated memory T cells capable of proliferating with B. pertussis as an in vitro stimulus. Results might indicate that these cells may not play a key role in protecting against B. pertussis when the host is vaccinated with DTPa.     

Reactogenicity of fluid compared with adsorbed diphtheria-pertussis-tetanus vaccine.

Shortly after the introduction of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine in British Columbia the frequency of reports of reactions to the vaccine increased. As the reasons for the increase were not clear a study was carried out in five health units to compare the reactions to adsorbed DPT vaccine manufactured by Wyeth Ltd. and Connaught Laboratories Ltd. and fluid DPT vaccines manufactured by Connaught, all the vaccines being injected in the anterolateral thigh. From the responses on 1619 questionnaires that the parents of vaccinated children had completed it was found that the relative risk of a reaction was higher with the fluid than with the adsorbed Connaught vaccine (1.7 for redness and 1.8 for swelling on the day of vaccination but 1.0 for drowsiness and 1.3 for persistent crying). The size and duration of local redness and swelling were also greater with the fluid than with the adsorbed Connaught vaccines. The results with the Wyeth and Connaught vaccine were very similar. Only 10% of the parents said that there had been no reaction; 9% said that the reaction was severe, and 6% said that it was completely unacceptable. The overall frequency of local reactions was 86.1%.     

The immunization of children with combined diphtheria and tetanus vaccine in Sweden

Two groups derived from 97 children three-four months of age were vaccinated with diphtheria and tetanus vaccines containing either a routinely prepared diphtheria toxoid or a more purified preparation. Two injections were given with an interval of one month and a third injection was given one year after the first. Prior to the third injection no child was without protection against diphtheria, i.e. had an antitoxin titre less than 0.01 IU ml-1. After the third injection 95 and 94% of the children vaccinated with the routinely and more purified diphtheria toxoids, respectively, had diphtheria antitoxin titres greater than 1 IU ml-1 (estimated to provide protection for at least ten years). Systemic reactions such as fever and malaise occurred in five children. Local reactions greater than 10 cm were observed in three children and reactions greater than 5 but less than or equal to 10 cm were seen in 14% of the children. The routinely prepared combined diphtheria and tetanus vaccine, DT, produced very good immunity against diphtheria with moderate side effects. The use of a more purified diphtheria toxoid in the combined vaccine produced the same immunity and side effects.     

Reactions after pertussis vaccine: a manufacturer's experiences and difficulties since 1964

Pertussis vaccines vary in quality, safety, and efficacy according to the production strains of Bordetella pertussis, the method of manufacture, and quality control procedures. It is therefore not justifiable to combine information on the incidence, nature, and severity of reactions after all manufacturers'' pertussis vaccines as if they were a single product. Attempts were made to collect information on all suspected cases of severe reactions that occurred after administration of about 15 million doses of Wellcome pertussis vaccines in the United Kingdom and Northern Ireland from 1964 to mid-1977. Altogether six deaths, six neurological reactions with sequelae, and 17 convulsions without sequelae were reported, but some were clearly not attributable to the vaccine, while, in other cases, the available information was inadequate for assessing the role of vaccination. Neurological disorders, similar to those reported in a few children after pertussis vaccination, occur unexpectedly in apparently healthy infants at the recommended age for immunisation, so chance association between vaccination and these events can be expected in some children. The Joint Committee on Vaccination and Immunisation has made several recommendations aimed at reducing severe reactions after pertussis vaccination. These include replacing plain vaccine with aluminium-adsorbed vaccine, but there is no clear evidence that the aluminium-adsorbed vaccine produces fewer reactions than the plain.There are difficulties enough in deciding the cause of events that occur after vaccination, since these reactions often occur naturally in children of vaccination age. The task is made even harder by the assumption that various manufacturers'' vaccines are the same and the lack of information available to manufacturers about cases in which their vaccine has been implicated. Information on vaccines administered is entered on immunisation records cards; it should be used and referred to if reactions occur.     

Simultaneous Immunization with B.C.G., Diphtheria-tetanus,and Oral Poliomyelitis Vaccines in Children Aged 13-14

The simultaneous administration of B.C.G. vaccine, diphtheria-tetanus toxoid aluminium hydroxide adsorbed vaccine, and oral poliovaccine was studied in 628 children aged 13-14 years between 1966 and 1969 in Newham, London. The efficacy of these vaccines was unaffected by administering them at the same time; routine simultaneous administration is considered justified when organizational difficulties prevent the attainment of high immunization rates with the vaccines given separately. No adverse reactions to B.C.G. or oral poliomyelitis vaccines took place, but 8% of children had moderately severe local reactions after diphtheria-tetanus aluminium hydroxide adsorbed vaccine, which were attributed to diphtheria toxoid.Serological studies showed the need for immunization against diphtheria, tetanus, and poliomyelitis at 13-14 years of age. Because of the adverse reactions to diphtheria toxoid, however, simultaneous administration of tetanus toxoid aluminium hydroxide adsorbed, oral poliomyelitis, and B.C.G. vaccines only is recommended at present.An “adult type” diphtheria-tetanus toxoid might overcome the problem of reactions, though in two to three years'' time most children aged 13-14 years will have received diphtheria-tetanus-pertussis vaccine in infancy and reinforcement might then be accomplished by a small intradermal dose of the currently available fluid diphtheria-tetanus vaccine.Continued serological studies of diphtheria and tetanus antitoxins and polio antibody are necessary to determine the future need for reinforcement of immunity; such studies should become an essential part of the surveillance of the community immunization programme.     

Comparative quantitation for the protein content of diphtheria and tetanus toxoids by DC protein assay and Kjeldahl method.

DPT, a combination vaccine against diphtheria, tetanus and pertussis is available since many years and still continued in the national immunisation schedule of many countries. Although highly potent, reactions to DPT vaccine are well known, mainly attributed to the factors like Pertussis component, aluminum adjuvant and lower purity of tetanus and diphtheria toxoids. The latter most important aspect has become a matter of concern, specially for the preparation of next generation combination vaccines with more number of antigens in combination with DPT.Purity of toxoid is expressed as Lf (Limes flocculation) per mg of protein nitrogen. The Kjeldahl method (KM) of protein nitrogen estimation suggested by WHO and British Pharmacopoeia is time consuming and less specific. Need has been felt to explore an alternative method which is quick and more specific for toxoid protein determination. DC (detergent compatible) protein assay, an improved Lowry's method, has been found to be much more advantageous than Kjeldahl method.     

In vitro induction of a diphtheria toxoid specific antibody response in human peripheral blood lymphocytes cultivated in the presence of diphtheria toxoid

In comparison with the presently used potency test for diphtheria vaccine, in vitro examination of the immunogenicity of the vaccine would have great advantages. For this reason in vitro induction of diphtheria toxoid specific antibody synthesis in human peripheral blood lymphocytes cultivated in the presence of diphtheria toxoid was investigated. The results showed that a dose dependent synthesis of diphtheria antibody was induced by adsorbed diphtheria toxoid and combined vaccines containing the diphtheria toxoid component. Plain diphtheria toxoid appeared to be less immunogenic in comparison with adsorbed toxoid. There is some indication that the pertussis component had a stimulating effect on the diphtheria antibody synthesis. In conclusion, these results are promising for in vitro examination of the immunogenicity of diphtheria vaccines. The model will be validated for the routine control of diphtheria vaccine.     

Limited controlled trial of the reactogenic properties of ADTP vaccines containing stab cultures as the pertussis component

The reactogenic properties of adsorbed DPT vaccine containing Bordetella pertussis cultures, grown by submerged cultivation, as the pertussis component were studied. The study revealed that the vaccine was low-reactogenic: no severe postvaccinal reactions were recorded in immunized children. The frequency and intensity of febrile and local reactions in children immunized with adsorbed DPT vaccine under trial and the commercial preparation commonly used in the USSR were identical, but considerably less pronounced than in children immunized with foreign vaccines having similar composition.     

The characteristics of the development of immunity with a primary immunization complex using adsorbed DTP vaccine

The intensity of immunity, depending on immune response variants characterized by the definite composition of the T and B lymphocyte subpopulation in peripheral blood, was studied in 70 practically healthy young children after the primary complex of immunization with adsorbed DPT vaccine. The most stable immune reaction was shown to appear in children with the hyperergic and normoergic variants of immune response to diphtheria and tetanus toxoids, while the reaction to pertussis antigen was essentially weaker both after the second vaccination and after the first revaccination. In children with the hypoergic variant of immune response to all components of adsorbed DPT vaccine the resulting immune reaction was 2.5-3 times weaker than in children of other groups.     

Evaluation of the reactogenicity and immunogenic potency of combined vaccine "Bubo-Kok" in the immunization of children against diphtheria, tetanus, pertussis and viral hepatitis B

Combined vaccine "Bubo-Kok" is characterized by safety and high immunological activity. The number of postvaccinal reactions in children aged 1 and 2 years, immunized with vaccine "Bubo-Kok", was not statistically different from those in groups of children immunized with adsorbed DPT vaccine, as well with such vaccine in combination with vaccine against hepatitis B. After the completion of the primary course of immunization 100% of children had protective antibody titers against diphtheria, tetanus and hepatitis B. Antibody titers against pertussis, equal to or exceeding protective titers, were found in more than 70% of immunized children. The immunogenic potency of vaccine "Bubo-Kok" with respect to all its components was not inferior to that of adsorbed DPT vaccine and vaccine against hepatitis B, when introduced simultaneously in different areas of the body. Vaccine "Bubo-Kok" successfully passed state trials and was recommended for registration.     

Evaluation of a guinea pig model to assess interference in the immunogenicity of different components of a combination vaccine comprising diphtheria, tetanus and acellular pertussis (DTaP) vaccine and haemophilus influenzae type b capsular polysaccharide conjugate vaccine.

A guinea pig model to assess the immunogenicity of a combination vaccine containing diphtheria, tetanus and acellular pertussis (DTaP) vaccine and Haemophilus influenzae type b (Hib) capsular polysaccharide conjugated to tetanus toxoid (HibT) was evaluated comparatively with the mouse immunogenicity test to study the effect of combining these antigens on the immunogenicity of various components. The immunogenicity test in mice was performed by subcutaneous injection of groups of 10 animals twice at an interval of four weeks with 1/10 of a single human dose of various formulations of combination vaccines, DTaP or HibT vaccine. The animals were bled at 4 and 6 weeks and IgG or total antibodies to various components were determined by ELISA or RIA. The guinea pig immunogenicity model included groups of animals injected subcutaneously twice at an interval of six weeks with 1.5 times the single human dose of various formulations. The animals were bled at 4, 6 and 8 weeks and serum samples were tested for antibodies to various components by ELISA, RIA and/or neutralization tests. Additionally, potency of tetanus and diphtheria components was assessed as per the US Food and Drug Administration's regulations. Aluminium phosphate (AIPO(4)) adsorbed HibT vaccine or HibT as a combination with AIPO(4)adsorbed DTaP vaccine showed significant increases in IgG antibodies to tetanus toxin in mice as well increased tetanus antitoxin levels in guinea pigs as compared to soluble HibT vaccine. In general, combining DTaP and HibT vaccines did not affect the antibody levels to tetanus and diphtheria toxoids whereas DTaP-HibT combination vaccine elicited significantly lower IgG antibodies to pertussis toxin and filamentous haemagglutinin than DTaP vaccine alone, particularly after first injection. Mice showed similar Hib antibody responses for the combination and HibT alone whereas guinea pigs consistently showed lower anamnestic responses to Hib for combination formulations than for HibT alone. Reducing the amount of HibT and/or tetanus toxoid in the combination formulations reduced this suppression of Hib antibody response in guinea pigs. Suppression of Hib antibody response in combination vaccines has also been reported from recent clinical trials. Based on the results from this study, it appears that the guinea pig model may be able to predict the human response to various components of combination vaccines.     

Antidiphtheria immunity in children after immunization with adsorbed DPT vaccine and ADPT-M toxoid

Antidiphtheria immunity in children aged 3-15 years was evaluated, depending on their age, the vaccinal preparation chosen for immunization and the immunization schedule. Adsorbed DPT vaccine was shown to have a higher immunological activity in comparison with adsorbed DT toxoid with reduced antigen content. The relationship between the tension of antidiphtheria antitoxic immunity in children and the possibility of the formation of the clinical forms of diphtheria with different severity in the patients was established. Children aged 4-6 years were considered to be a group of high risk in diphtheria morbidity, as it was among the children of this group that toxic and subtoxic forms of diphtheria were most often registered (44.9 +/- 7.1% of the examinees); in addition, a high proportion of children seronegative to this infection (26,3 +/- 2.2%) was observed in this group.     

Immune response in adult immunized with adsorbed DT-M anatoxin with reduced antigen content and Imovax-DT-adulte vaccine

The comparative study of immune response after immunization of adults with adsorbed DT toxoid with reduced antigen content and Imovax-DT-adulte vaccine, as well as the safety of these preparations, was made. The study revealed that immunization of adults with adsorbed DT toxoid having reduced antigen content, made in two injections, and the injection of Imovax-DT-dulte vaccine, as well as the successive injection of these preparations, produced the same the levels of antitetanus immunity. Antidiphtheria immunity, evaluated by the number of seroconverted to diphtheria persons following two injections immunization was similar for the two preparations, while the level of antidiphtheria antibodies was higher in persons immunized with adsorbed DT toxoid. The immune stratum index was rather high among persons aged 16-29 years. This age group exhibited the highest number of persons, seropositive to both diphtheria and tetanus. Both vaccine preparations, adsorbed DT toxoid with reduced antigen content and Imovax-DT-adulte vaccine, were found to be equally capable of inducing autoimmune reactions in the vaccinees, detected by laboratory methods.     

The antidiphtheria and antitetanus immunities of children of the Maritime Territory after the use of adsorbed DTP vaccine and adsorbed DT-m anatoxin]

The state of collective immunity to diphtheria and tetanus in children of preschool age, depending on the kind of vaccine preparation used for immunization, was studied. The immunological potency of adsorbed DPT vaccine (i.e. its capacity of forming prolonged and stable basic immunity) was shown to be higher in comparison with the potency of adsorbed DT toxoid with reduced antigen content (DT-R). The study revealed that in all groups of children the level of antitetanus immunity was higher than the level of antidiphtheria immunity, and 3 years later its decrease was less pronounced. A stricter approach to giving medical grounds for the use of low-reactive adsorbed DT-R in the immunization of children belonging to groups of risk is recommended.     

Epidemiological and immunological criteria of the effectiveness of immunization with adsorbed DPT vaccine by the old and new schedules

The study revealed that the immunization of children with adsorbed DPT vaccine from the age of 3-4 months, as compared with the immunization of children from the age of 5-6 months, did not lead to an essential increase in the coverage of children with immunization at the period under study (1970-1983) and did not affect the total level of pertussis morbidity, as well as the proportion of children aged up to 1 year in the total number of pertussis cases. Children immunized at an early age produced antibodies in titers, equivalent to the titers in older children, but their immunity against pertussis, in contrast to their immunity against diphtheria and tetanus, was retained for a shorter period. The injection of adsorbed DPT vaccine at the age of 3-4 months was accompanied by a poorly pronounced increase in the content of IgG, the predominant synthesis of IgM and the suppression of the synthesis of IgA. The shift of the start of vaccination to the age of 3-4 months has probably some immunological grounds for diphtheria and tetanus, but it is premature with respect to pertussis.     

The development of a new generation of pertussis vaccine

The results of the weight gain test on mice have shown that acellular pertussis vaccine is less toxic than the pertussis component of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine due to a lower content of endotoxin in the acellular vaccine; but the leukocytosis-promoting and histamine-sensitizing activities of JNIH-6 and adsorbed DPT vaccines are indicative of incomplete inactivation of Bordetella pertussis toxin. The content of incompletely inactivated B. pertussis toxin is practically the same in both preparations, constituting 1/100-1/200 of the calculated initial activity. For this reason, the use of the new pertussis vaccine also involves a risk of development of serious postvaccinal reactions and/or complications caused by this toxin. Search for the optimum method of inactivation of B. pertussis main toxin should be continued. As shown by the enzyme immunoassay, acellular pertussis vaccine used in the same immunizing dose as adsorbed DPT vaccine induces a more intensive immune response to hemagglutinin and B. pertussis toxin. This is due to higher residual toxicity of the corpuscular component of adsorbed DPT vaccine. Induction of antibodies to B. pertussis toxin has been shown to decrease in response to injection of acellular pertussis vaccine containing a certain residual amount of incompletely inactivated B. pertussis toxin.     

Antidiphtheria and antitetanus antitoxic immunity indices in the population of the Estonian SSR (an assessment of the effectiveness of a planned vaccine prophylaxis)]

In 1972-1974 and 1977 in the Estonian SSR children and adults were surveyed for the presence of antibodies against tetanus and diphtheria toxins (toxoids) by means of the passive hemagglutination test. The level of protection against tetanus was revealed to correspond to the proportion of child population covered by vaccination: in 1977, with 98.8% covered by vaccination, the level of protection among children aged 7 to 14 years and adolescents of 15-19 years exceeded 98%; with the increase of age (every 10-15 years) the level of protection against tetanus regularly decreased. This dynamics correlated with the existing terms of postvaccinal immunity and the epidemiological independence of tetanus as infectiion. The level of protection in child population against diphtheria in 1972-1974 and 1977 lagged behind the level of protection against tetanus and the coverage by vaccination. The diphtheria component of adsorbed DPT vaccine seemed to be unable to ensure the sufficient level and intensity of immunity under conditions of a sharply decreased risk of encounter with the infective agent. In persons aged 40 years and over the indices of immunity against diphtheria were higher than against tetanus. These indices resulted from diphtheria infection at the prevaccination period and could serve as an objective sign in following up the decrease of the process of diphtheria epidemics.     

The evaluation of the efficacy of a first course of immunization against diphtheria and tetanus in children with kidney diseases

The results of the determination of the level of antitoxic antibodies (Ab) to diphtheria and tetanus toxoids in children with glomerulonephritis and pyelonephritis are presented. The influence of the form of the disease and the kind of medicinal therapy on level of specific Ab has been studied. As shown in this study, the injection of adsorbed DT toxoid with reduced antigen content leads to the formation of the protective titers of antidiphtheria and antitetanus Ab, but a lower level than after the injection of adsorbed DPT vaccine.