Specific prevention of diphtheria in adults in foci of this infection

The studies demonstrated the immunological and epidemiological effectiveness of a single injection of adsorbed diphtheria-tetanus toxoid with reduced antigen content for adults: intense antidiphtheria immunity in 92.3% of the vaccinees 1-3 months and in 94.5% of the vaccinees 1 year after the injection. This immunity remained sufficiently intense for 3 years (the term of observation). The geometric mean of antitoxic titers was 0.84 I. U./ml. The highest intensity of immunity appearing after the injection was observed in persons aged 18-20 years who showed the highest antitoxic titers (exceeding 0.5 I. U./ml) in 100% of cases, the lowest intensity was registered in the age group of 30-39 years; in 14.2% of these vaccinees antitoxic titers were below the protective level. In other age groups (40-49 years, 50 years and over) the intensity of immunity was high. The geometric mean of the titers of diphtheria antitoxin were 1.2 I. U./ml and 2.1 I. U./ml respectively. In none of the foci under study the spread of the manifest forms of the disease was observed.     

Transplacental antibodies. Part II: Maternal antibodies against the toxins of C. diphtheriae and C. tetani

Examinations of 297 sera for diphtheria antitoxin and 160 sera for tetanus antitoxin were carried out in 1981. All sera were obtained from the cord blood of mothers between 15 and 34 years of age. The mothers were divided into four age groups each of which was further subdivided into the primipara and multipara subgroups. The aim was to assess the age-specific variations in response to active immunization against diphtheria and tetanus. The protective level of diphtheria antitoxin (at least 0.01 I.U./ml) was recorded in the serum of 96.3% of examinees and the rates of seropositivity were found to fall with increasing age. The protective level of tetanus antitoxin (at least 0.1 I.U./ml) was found in the serum of 95.2% of mothers. The serologic response encountered in groups of older mothers was a clear-cut demonstration that the country-wide mass immunization against tetanus carried out between 1974 and 1975 was highly effective and fully justified. The variations in the diphtheria and tetanus antitoxin levels found in the primipara and multipara subgroups were not statistically significant.     

The coagglutination reaction for detecting diphtheria toxin

High-titer antidiphtheria antitoxic rabbit serum has been obtained, and on the basis of this serum a coagglutinating diagnosticum has been developed. The sensitivity of the test has been found to depend on the content of antitoxic antibodies in the serum and on its purity. Diagnostica prepared from native serum containing 500 I. U./ml (a titer of 1:51, 200 in the passive hemagglutination test) permit the detection of 0.02-0.03 Lf/ml of diphtheria toxin. A decrease in antibody titer to 5-25 I. U./ml leads to a drop in sensitivity to 0.2-2 Lf/ml. The use of LgG fraction and pure antibodies increases the sensitivity of the test to 0.002-0.003 Lf/ml. The possibility of detecting toxin in Corynebacterium diphtheriae strains is shown.     

Long-Term Protection against Diphtheria in the Netherlands after 50 Years of Vaccination: Results from a Seroepidemiological Study

Background and Aims

To evaluate the National Immunisation Programme (NIP) a population-based cross-sectional seroepidemiological study was performed in the Netherlands. We assessed diphtheria antitoxin levels in the general Dutch population and in low vaccination coverage (LVC) areas where a relatively high proportion of orthodox Protestants live who decline vaccination based on religious grounds. Results were compared with a nationwide seroepidemiological study performed 11 years earlier.

Methods

In 2006/2007 a national serum bank was established. Blood samples were tested for diphtheria antitoxin IgG concentrations using a multiplex immunoassay for 6383 participants from the national sample (NS) and 1518 participants from LVC municipalities. A cut-off above 0.01 international units per ml (IU/ml) was used as minimum protective level.

Results

In the NS 91% of the population had antibody levels above 0.01 IU/ml compared to 88% in the 1995/1996 serosurvey (p<0.05). On average, 82% (vs. 78% in the 1995/1996 serosurvey, p<0.05) of individuals from the NS born before introduction of diphtheria vaccination in the NIP and 46% (vs. 37% in the 1995/1996 serosurvey, p = 0.11) of orthodox Protestants living in LVC areas had antibody levels above 0.01 IU/ml. Linear regression analysis among fully immunized individuals (six vaccinations) without evidence of revaccination indicated a continuous decline in antibodies in both serosurveys, but geometric mean antibodies remained well above 0.01 IU/ml in all age groups.

Conclusions

The NIP provides long-term protection against diphtheria, although antibody levels decline after vaccination. As a result of natural waning immunity, a substantial proportion of individuals born before introduction of diphtheria vaccination in the NIP lack adequate levels of diphtheria antibodies. Susceptibility due to lack of vaccination is highest among strictly orthodox Protestants. The potential risk of spread of diphtheria within the geographically clustered orthodox Protestant community after introduction in the Netherlands has not disappeared, despite national long-term high vaccination coverage.     

Immunity to diphtheria and tetanus in some of the administrative territories of the RSFSR

The article deals with the state of immunity to diphtheria and tetanus among the adult population in some administrative regions of the RSFSR. Of the children and adults covered by the survey, 91.3-96.7% were found to have protective antibody titers against diphtheria and 98.7-100%, against tetanus. An essential drop in the level of immunity to diphtheria in persons over 18 years of age was revealed: 71.7% of them were nonimmune, which correlated with the high morbidity rate among these persons. At the same time the percentage of adults nonimmune to tetanus was considerably lower than that of adults nonimmune to diphtheria, reaching only 27.1%. The state of immunity to tetanus in adults was found to depend on the seasons.     

A long-term follow-up study on the efficacy of further attenuated live measles vaccine, Biken CAM vaccine

Antibody persistence was measured in 39 children in an open community 12-13 years after immunization against measles with further attenuated live vaccine, Biken CAM. Serum samples of the children taken every two or three years after vaccination had higher, lower, or the same HI antibody titers as those in samples taken 6 weeks after vaccination. These differences reflected a decrease in the titer in some children and subclinical natural reinfection in others. However, all the children still retained detectable antibody in 12 or 13 years after vaccination, indicating long-term persistence of immunity after immunization with Biken CAM vaccine. For evaluation of the protective efficacy of the vaccine, matched controls were studied during the same period. Serological examination revealed that 97.5% of the controls were infected with measles and contracted the disease. In contrast, none of the vaccinees developed clinical infection after close contact with measles patients.     

Enhancement of antitoxic immunity in newborn infants by peroral administration of donor antistaphylococcal immunoglobulin

The possibility of enhancing specific immunity by the oral administration of homologous antistaphylococcal immunoglobulin in a dose of 50 I. U./kg b. w. before the first feeding was shown in 75 newborn infants with a high risk of staphylococcal infection. 24 hours after the first administration of Ig the titer of staphylococcal anti-alpha toxin in the blood rose from 0.68 +/- 0.05 I. U./ml to 2.9 +/- 0.14 I. U/ml, on day 7 this titer persisted at the level of 2.86 +/- 0.12 I. U./ml, and 3 months later the titer was 1.5 +/- 0.05 I. U./ml. No side effects were observed. In the reference group (50 infants) antitoxic titers remained low. No suppurative-septic diseases were observed in the test group within 3 months, while in the controls, focal forms of staphylococcal infection (12 cases) and sepsis (1 case) were registered.     

Recall Responses to Tetanus and Diphtheria Vaccination Are Frequently Insufficient in Elderly Persons

Demographic changes and a more active life-style in older age have contributed to an increasing public awareness of the need for lifelong vaccination. Currently many older persons have been vaccinated against selected pathogens during childhood but lack regular booster immunizations. The impact of regular vaccinations when started late in life was analyzed in an open, explorative trial by evaluating the immune response against tetanus and diphtheria in healthy older individuals. 252 persons aged above 60 years received a booster vaccination against tetanus, diphtheria, pertussis and polio and a subcohort (n=87) was recruited to receive a second booster vaccination against tetanus, diphtheria and pertussis 5 years later. The percentage of unprotected individuals at the time of enrollment differed substantially for tetanus (12%) and diphtheria (65%). Despite protective antibody concentrations 4 weeks after the first vaccination in almost all vaccinees, antibodies had again dropped below protective levels in 10% (tetanus) and 45% (diphtheria) of the cohort after 5 years. Protection was restored in almost all vaccinees after the second vaccination. No correlation between tetanus- and diphtheria-specific responses was observed, and antibody concentrations were not associated with age-related changes in the T cell repertoire, inflammatory parameters, or CMV-seropositivity suggesting that there was no general biological “non-responder type.” Post-vaccination antibody concentrations depended on pre-existing plasma cells and B cell memory as indicated by a strong positive relationship between post-vaccination antibodies and pre-vaccination antibodies as well as antibody-secreting cells. In contrast, antigen-specific T cell responses were not or only weakly associated with antibody concentrations. In conclusion, our findings demonstrate that single shot vaccinations against tetanus and/or diphtheria do not lead to long-lasting immunity in many elderly persons despite administration at relatively short intervals. Sufficient antigen-specific B cell memory B generated by adequate priming and consecutive booster vaccinations and/or exposure is a prerequisite for long-term protection.

Trial Registration

EU Clinical Trials Register (EU-CTR); EudraCT number 2009-011742-26; www.clinicaltrialsregister.eu/ctr-search/trial/2009-011742-26/AT     

Quantification of plasma-derived blood coagulation factor VIII by real-time biosensor measurements

Plasma-derived blood coagulation factor VIII was analyzed in real time using biosensor technology. Monoclonal antibodies directed against the heavy and against the light chain of factor VIII were immobilized on different carboxymethyl dextran surfaces. Different factor VIII concentrations were injected over the antibody surfaces in parallel and response levels were determined from the dissociation phase at a fixed time after sample injection. Serial dilutions of plasma-derived factor VIII with known concentrations determined by a commercial FVIIIC:Ag ELISA were used as standards. A quantification limit of 0.9 I.U./ml with antibody 530p and 1.5 I.U./ml with antibody 531p was calculated. Intra-assay precision expressed as percent coefficient of variation was below 10% for concentrations above 0.6 I.U./ml. Inter-assay precision for antibody 530p was below 20% for concentrations higher than 0.6 I.U./ml. For 531p, inter-assay precision was below 10% for concentrations higher than 2 I.U./ml. A sensor chip lifetime in respect to regeneration of at least 100 cycles for both antibodies was found. The small sample requirement of 35 μl allows fast analysis of different FVIII products and the use of two monoclonal antibodies directed against two different FVIII domains provides additional information about the integrity of the FVIII molecule.     

Diphtheria-neutralizing antibody levels in healthy adults from Rio de Janeiro, Brazil

In Brazil, until 2004, the immunization policy against diphtheria involved childhood vaccination with no official routine booster dose administered after 15 years of age. This study assessed functional antibody levels against diphtheria among blood donors. A total of 140 blood samples were collected, and diphtheria antitoxin levels were evaluated by Vero cell neutralization test. The mean age of the population was 34 years old (range: 18-61 years); 37.8% females and 62.2% males. Overall, 30.7% (95%, CI: 23.4-38.7) individuals presented neutralizing antitoxin antibody titers < 0.01 IU/ml; 42.1% (95%, CI: 34.1-50.4) showed values between 0.01-0.09 IU/ml and, 27.1% (95%, CI: 20.2-34.9) had (3) 0.1 IU/ml. In the subgroup of individuals with history of diphtheria immunization during childhood (85%), a number of 28.5% showed unprotective levels of circulating neutralizing antibody (< 0.01 IU/ml). Despite the continuous progress of immunization programs directed to Brazilian population, currently healthy adults remain susceptible to diphtheria.     

Epidemiological and immunological features of tetanus under conditions of long-term planned vaccine prophylaxis

The introduction of mass immunization against tetanus has resulted in the decrease of morbidity rate (5.2 times), the leveling of morbidity rate among the urban and rural population and among males and females, though no essential effect on the seasonal distribution of tetanus morbidity has been observed. Persons over 50 years of age (housewives and pensioners) have become the main groups of risk at the post-immunization period. Mass immunization against tetanus over a period of many years has ensured the existence of a sufficient immune stratum (89.9 +/- 3.0% to 100 +/- 3.0%) and a sufficient level of antitoxic immunity (means geom equal to 6.72-9.6 I.U./ml) among children. Among adults, the proportion of persons protected from tetanus decreases in older age groups from 82.1 +/- 1.3% in persons aged 31-40 years to 22.1 +/- 2.0% in persons over 60 years. The observed differences between the coverage of the population with immunization and the proportion of persons having protective titers of tetanus antibodies require constant control of the intensity of immunity and its correction with regard to its initial level, especially in persons of older age groups.     

Diphtheria in the Maritime Territory

The results of the analysis of the present epidemiological situation in diphtheria in the Maritime Territory are presented. The data on absolute and intensive characteristics, death rate due to this infection, the vaccination status of diphtheria patients, as well as the results of the study of the level and intensity of antidiphtheria immunity in the healthy population of the territory. The study revealed that the defects of collective antidiphtheria immunity correlated with morbidity rate among adults and children. Adults aged 40-50 years and children aged 6-7 years were regarded as risk groups; among them the highest proportion of nonimmune persons and the highest diphtheria morbidity rate were registered. Stabilization achieved by the present moment was the result of the mass immunization of the adult population, ensuring the necessary coverage (92%) of vaccination in 1995.     

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.     

Booster vaccination against tetanus and diphtheria: insufficient protection against diphtheria in young and elderly adults

We have recently demonstrated that single shot vaccinations against tetanus and diphtheria do not lead to long-lasting immunity against diphtheria in elderly persons despite administration at 5 year intervals. In the present study we have immunized a group of young adults against tetanus and diphtheria to compare the pre- and 28 days post-vaccination immune responses in the young group with results of the same vaccination performed in an elderly group of a previous study. We also studied protection in both groups 5 years after vaccination. We compared antibody titers at all three time points and also analyzed the T cell responses in both age groups 5 years after vaccination.Before vaccination 9 % of the elderly persons were not protected against tetanus, and 48 % did not have protection against diphtheria. In the young group all participants were protected against tetanus, but 52 % were also unprotected against diphtheria before vaccination. 28 days after vaccination 100 % of all participants had protective antibody concentrations against tetanus and only a small percentage in each age group (<10 %) was unprotected against diphtheria. 5 years later, 100 % of both cohorts were still protected against tetanus, but 24 % of the young and 54 % of the elderly group were unprotected against diphtheria. Antibody concentrations against diphtheria measured by ELISA correlated well with their neutralizing capacity. T cell responses to tetanus and diphtheria did not differ between young and old persons. We conclude that booster vaccinations against tetanus and diphtheria according to present recommendations provide long-lasting protection only against tetanus, but not against diphtheria, independently of age. In elderly persons, the level of protection is even lower, probably due to intrinsic age-related changes within the immune system and/or insufficient vaccination earlier in life.     

Isolation and study of the properties of a polyvalent corpuscular Pseudomonas aeruginosa vaccine. An evaluation of the biological properties of a polyvalent corpuscular Pseudomonas aeruginosa vaccine

P. aeruginosa killed polyvalent corpuscular vaccine, tested in a trial on 42 volunteer donors, is safe, low reactogenic and possesses pronounced immunogenicity, as the injection of the vaccine induced a rise in the titer of antibodies to P. aeruginosa up to 1:1280 in 95% of the immunized donors. To obtain specific antibodies in the blood plasma of the donors in an amount sufficient for the protective activity of the plasma becoming manifest, it is expedient to use the vaccination schedule providing for subcutaneous injections of 0.5, 0.5 and 1.0 ml at intervals of 7 days. Intense immunity thus induced in the donors lasts for 3-4 months. The hyperimmune plasma obtained from the donors has an antibody titer of at least 1:320 and shows a 90-100% protective effect in mice infected intraperitoneally with P. aeruginosa. The preliminary results of the clinical trial of anti-P. aeruginosa plasma have demonstrated its efficiency as a part of the complex treatment of patients with purulent septic complications of P. aeruginosa etiology.     

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.     

Characteristics of the immune response to staphylococcal anatoxin in healthy persons

The immunization of young healthy males with adsorbed staphylococcal toxoid revealed the existence of two main types of postimmunization humoral response. One of them was characterized by an early (on days 7-14 after immunization) rise in the titer of antibodies with the subsequent gradual decrease of their content, while the number of circulating T-suppressors remained unchanged. The characteristic feature of the other type was a slow rise in the level of antitoxins by day 21 after immunization with the subsequent drop of their titers, preceded by a considerable increase in the number of circulating T-suppressors. The maximum antibody titer was definitely higher in the first type of response than in the second type (14.8 +/- 1.41 and 9.0 +/- 1.53 I. U./ml respectively). A single plasmapheresis procedure on day 21 after immunization produced no essential effect on the dynamics of the characteristics of cell-mediated and humoral immunity.     

Studies on live attenuated mumps vaccine. II. Follow-up study on the efficacy of Biken Vaccine.

Clinical and serological follow-ups were made on 18 children for 3 years and on another 18 children for 4 years, after immunization against mumps by attenuated mumps vaccine; Biken vaccine. To evaluate the protective efficacy of the vaccine, matched controls were studied during the same period. Serological examinations revealed that 77% of the vaccinees and 93% of the controls were infected with mumps after close contacts with mumps patients. Regular mumps was contracted by 88% of the controls, but none of the vaccinees. There was no substantial decrease in the antibody titers in unexposed vaccinees after vaccination.     

Immunity to diphtheria, six to 15 years after a basic three-dose immunization schedule

The results of a study of the immunity to diphtheria of 283 girls (9-18 years of age) vaccinated at the age of two years with three doses of vaccine, are reported. The rabbit skin test was used to determine the titre of serum diphtheria antitoxin. 55.8% of the subjects were found to be protected (titre greater than or equal to 0.1 IU/ml), 38.9% were only relatively immune (titre greater than or equal to 0.01- less than 0.01 IU/ml), and 5.3% were unprotected (titre less than 0.01 IU/ml). The antitoxin titres showed a tendency to decrease with time. Even so, 6-15 years after vaccination, the percentages of protected and partially protected subjects were still high (95%).     

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.