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     

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.     

Humoral immunity to diphtheria and tetanus in pregnant women and newborn infants

Pregnant and parturient women have been examined in different regions of the USSR: Moscow, the Turkmen SSR, the Azerbaijan SSR and the Uzbek SSR. Altogether 720 placental sera and 522 funic sera have been checked for the presence of antibodies to diphtheria and tetanus toxoids in the passive hemagglutination test. Considerable groups of women with the insufficient level of immunity to diphtheria (40-66%) and tetanus (42.1-58.8%) have been revealed in different republics. Among women over 70 years the percentage of persons with the absence of antibodies or having low antibody titers has proved to be even higher. The comparative analysis of antibody titers has shown a correlation between antibody titers in mothers and newborn infants in 83.6% of cases for diphtheria toxoid and in 72.9% of cases for tetanus toxoid. These data show that among parturient women and newborn infants large groups remain unprotected against diphtheria and tetanus, which indicates the necessity of correcting the immune status of women of the productive age.     

The immunological efficacy of one, two and three inoculations against diphtheria in adults

The outbreak of diphtheria in the Republic of Belarus developed in the presence of a sharp deficiency of immunity among the population aged 35 years and over. In connection with a higher initial immunity level resulting from vaccination made in one injection the minimum antibody level (> or = 0.01 I.U./ml) was found in 79.7% of the examinees among the population under 35 years. For the age group of 35-60 years vaccination in one and two injections proved to be insufficiently effective (the minimum protective antibody titer was found, respectively, in 64.3% and 63.3% of the vaccinees). To achieve the full protection of this group of the population, vaccination in three injections was necessary; after that the minimum protective antibody titer was found in 90.7%, the protective antibody titer (0.1 I.U./ml) was found in 53.5% and the highly protective antibody titer (1.0 I.U./ml) was found in 11.6% of the examinees. The low level of highly protected persons among vaccinees receiving three injections was due to a low dose of diphtheria toxoid (2 Lf) in adsorbed DT-m vaccine with reduced antigen content.     

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.     

The level of postvaccinal immunity to diphtheria, tetanus and poliomyelitis in relation to the number of inoculations]

The work was aimed at the comparative study of the intensity of immunity to diphtheria, tetanus and poliomyelitis, depending on the number of injections of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine and poliomyelitis vaccine, for the purpose of finding out the possibility of reducing the antigenic load given to children without diminishing the intensity of immunity. To determine the level of immunity to diphtheria and tetanus, 1900 children under school age were serologically studied by the micromethod in the passive hemagglutination test. The intensity of immunity to poliomyelitis virus was studied in 333 children by means of the neutralization test. The immunogenic properties of the diphtheria component of adsorbed DPT vaccine were found to be less pronounced than those of the tetanus component of the vaccine, which made it impossible to reduce the antigenic load by decreasing the number of vaccinations against diphtheria. The results of the study of postvaccinal immunity to poliomyelitis suggest that during the first and second year of life the course of vaccination against poliomyelitis may be reduced to 3 injections.     

Evaluation of the immunological effectiveness of the planned vaccinal prophylaxis of diphtheria and tetanus in Sverdlovsk and Sverdlovsk Province

The level and intensity of antitoxic immunity to diphtheria and tetanus in children and adolescents were determined. The presence of tetanus antitoxin in titers exceeding the protective level in 96.3-98.5% of the examined children and adolescents is indicative of a high actual coverage by immunization. Protective titers against diphtheria were lower. There was no essential difference in the levels of protection in children immunized according to the vaccination schedule and in those immunized with some deviations from this schedule. A considerable part of newborns and children aged 3 months had antibodies to diphtheria and tetanus antitoxins. After the third booster immunization changes in antidiphtheria immunity characteristics occurred only in 2.5% of the vaccines and no changes in antitetanus immunity characteristics were observed.     

A comparative evaluation of the effectiveness of methods for serological sampling examinations]

Blood serum samples of 3,448 schoolchildren of grades 1-10 in 35 schools of Dushanbe were examined in the passive hemagglutination test in 1988 and 1989. The proportion of persons unprotected against diphtheria and tetanus was estimated by common methods in different kinds of selective serologic survey: mass screening (43.4-83.0%), testing in selected groups reduced 2, 3 and 5 times, cluster sampling. The reduction of the groups to be examined (from 3,033 to 250 persons) was not accompanied by essential changes (t < 2) in the characteristics of mass immunity against diphtheria and tetanus. The cluster method was shown to be highly reliable also in the study of population immunity.     

Diphtheria and tetanus immunity among blood donors in Toronto

OBJECTIVE: To determine the diphtheria and tetanus antitoxin levels among blood donors in Toronto. DESIGN: Cross-sectional seroprevalence study. SETTING: Two fixed-site blood-donation clinics in Toronto from September to November 1994. PARTICIPANTS: Blood donors 20 years of age or older were eligible to participate; of the 781 eligible donors, 710 (90.9%) participated in the study. MAIN OUTCOME MEASURES: Diphtheria and tetanus antitoxin levels and factors associated with disease susceptibility, such as vaccination history, country of birth, age and sex. A diphtheria antitoxin level lower than 0.01 lU/mL and a tetanus antitoxin level lower than 0.15 lU/mL were considered nonprotective. RESULTS: Among the participants, 147 (20.7%) had a diphtheria antitoxin level in the nonprotective range, and 124 (17.5%) had a tetanus antitoxin level that was nonprotective. Increasing age and lack of written vaccination records were associated with susceptibility to the 2 diseases. Birth outside Canada was significantly related to tetanus susceptibility. CONCLUSION: Adults over 50 years of age who did not know their vaccination history were the least likely to be protected against diphtheria and tetanus. The greatest benefit of any immunization strategy would be gained by targeting this group.     

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.     

Alternative diphtheria, tetanus and whooping cough immunization schedule to evoke a Th2 tetanus and a Th1 pertussis immune response

In a previous study, using BALB/c mice, we found that while diphtheria (D), tetanus (T) and whooping cough (Pw, whole-cell Bordetella pertussis) immunization induces a Th1/Th2 tetanus response and memory T cells able to proliferate in response to in vitro stimulation with B. pertussis, DTPa immunization induces a Th2 tetanus immune response and no memory T cells that recognize B. pertussis as stimulus. Considering that a pro-inflammatory cytokine production is not necessary for protection against tetanus and therefore should be avoided, an alternative DTP immunization schedule with minimal Pw exposure was assessed in order to obtain a Th2 tetanus response and a Th1 pertussis response. BALB/c mice were primed with DT vaccine at day 0, with Pw vaccine at day 14 and boosted with DTPa vaccine at days 21 and 28. A control group was inoculated with saline. Antibodies against B. pertussis surface antigens, tetanus and diphtheria toxoids were produced by mice. Spleen cells stimulated in vitro with B. pertussis produced IL-6 and IFNgamma. Only IL-5 was produced by cells in response to tetanus toxoid stimulation. These results are in line with the low IgG1/IgG2a ratio for pertussis antibodies compared with those corresponding to tetanus and diphtheria. The immunization protocol presented herein succeeded in producing tetanus and pertussis immune responses of Th2 and Th1 type, respectively. In contrast to previous results obtained with DTPw immunization, no IL-12 production was observed. Our findings provide direct evidence that an immunization protocol with an interval of 14 days between DT and Pw primings, followed by DTPa boosters, can induce appropriate immune responses against DTP vaccine antigens.     

Serosurveillance of Vaccine Preventable Diseases and Hepatitis C in Healthcare Workers from Lao PDR

Background and Aims

Healthcare workers (HCW) have an increased risk of exposure to infectious diseases and are a potential source of infections for their patients. The Lao People’s Democratic Republic (Lao PDR) has no national policy regarding HCW vaccinations and routine vaccination coverage is low within the general population. This cross-sectional serostudy determines the level of exposure and risk of infection in Lao HCW against 6 vaccine preventable diseases and hepatitis C.

Methods

1128 HCW were recruited from 3 central, 2 provincial and 8 district hospitals. Sera were tested by ELISA for the presence of antibodies and antigens to hepatitis B, hepatitis C, measles, rubella, varicella zoster, tetanus and diphtheria.

Results

Only 53.1% of the HCW had protective anti-hepatitis B surface antigen antibodies (anti-HBs) with 48.8% having anti-hepatitis B core antibodies (anti-HBc), indicating previous exposure and 8.0% were hepatitis B surface antigen carriers. 3.9% were hepatitis C seropositive. Measles and rubella antibodies were detected in 95.4% and 86.2% of the HCW, with 11.9% of females being unprotected against rubella. Antibodies against varicella zoster, tetanus and diphtheria were detected in 95%, 78.8% and 55.3%, respectively. Seroprevalence varied according to age, gender and number of children.

Conclusion

An unacceptably high proportion of Lao HCW remain susceptible to infection with hepatitis B, diphtheria, tetanus and rubella. Furthermore, a high number of healthcare workers are chronically infected with hepatitis B and C viruses. These data emphasize the need for a robust HCW vaccination policy in addition to increased awareness within this subpopulation.     

The immunization of adults against diphtheria in Sweden

Two hundred and three women who disclaimed vaccination against diphtheria were divided into four groups and injected with either 2.0 or 6.25 Lf of a routine diphtheria toxoid or of a more purified preparation. One hundred and twenty-six of these women who did not show a secondary antibody response were given a second and a third injection one month and one year, respectively, after the first injection. Prebooster (third injection) antitoxin titres of greater than or equal to 0.01 IU ml-1 (the minimum level for protection) were found in 22 and 37% of those who received 2.0 and 6.25 Lf, respectively. Postbooster titres of greater than or equal to 1.0 IU ml-1 (calculated to give a protection of at least ten years of duration) were found in 23 and 58% of those who received 2.0 and 6.25 Lf, respectively. The rate of untoward reactions was low. Fever of short duration occurred in five women. Four out of the five women received 6.25 Lf of the more purified diphtheria toxoid and one 2 Lf of the routine toxoid. Local reactions greater than 10 cm were observed in three women. All received the higher dose, 6.25 Lf of diphtheria toxoid. Local reactions greater than 5 but less than or equal to 10 cm occurred in up to 13% (6.25 Lf of diphtheria toxoid). No significant difference between the groups of women vaccinated with routine or more purified toxoid was found. It was concluded that the diphtheria toxoids in the two doses of 2 Lf and 6.25 Lf did not induce a satisfactory immune response. To induce adequate protection the dose of diphtheria vaccine needs to be the same for adults and children, i.e. 12.5 Lf.     

Immunisation of adults during an outbreak of diphtheria.

In an outbreak of infection due to Corynebacterium diphtheriae in a hospital for mentally subnormal adults sera from 211 members of staff were screened for diphtheria antitoxin titres. Of these, 79 (37%) required immunisation, and a low dose preparation (1 LfU of diphtheria and 10 LfU tetanus toxoids) was offered. Of the 64 subjects who accepted a single immunisation and were subsequently retested, seroconversion to diphtheria toxoid occurred in 45 (70%), the rate being highest in younger adults. Seroconversion to tetanus toxoid occurred in 59% of subjects. Local reactions to the single dose were reported by 29 (43%) subjects, and nine (13%) experienced moderately severe local reactions and systemic symptoms. We conclude that adults should not be vaccinated without previous screening for susceptibility to diphtheria; that neither previous immunisation nor age is reliable in predicting the need for vaccination; and that though a single booster dose of diphtheria toxoid is probably effective in adults under 45, two doses should be given to those in the older age group.     

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%).     

Evaluation of reactogenicity and immunogenicity of Bubo-M, the Russian combined vaccine for immunization of adults against diphtheria, tetanus and viral hepatitis B

Bubo-M, the first Russian associated vaccine, was found to have low reactogenicity and high immunogenic potency. The frequency of postvaccinal reactions in the group of persons immunized with Bubo-M (20%) appeared to be considerably lower than among persons who received the combined injection of adsorbed DT toxoid with reduced antigen content and vaccine against hepatitis B (47.7%). Following the course of vaccination the level of anti-HBs considerably exceeded the protective level. Immune response to the diphtheria and tetanus components of Bubo-M exceeded that observed after immunization with absorbed DT toxoid with reduced antigen content (p < 0.05).     

Vaccination coverage in hard to reach Roma children in Slovenia

The results of the retrospective analysis of data on vaccination coverage in the preschool-aged and school-aged Roma children (436 preschool and 551 schoolchildren) in three geographical regions of Slovenia were analyzed to establish the differences concerning coverage for specific vaccinations: poliomyelitis, diphtheria, tetanus, pertussis, measles, mumps and rubella between the two generation. The data were obtained from health records, immunization records (Vaccination booklet) and National Computerized Immunization System (CEPI 2000). Vaccination coverage was calculated by comparing the number of children eligible for immunization with the number of vaccinated children. This article performs the log-rank statistical test, also known as the Mantel-Haenszel test. Log rang test is comparing survival curves for two generations. Preschool-aged Roma children showed higher vaccination coverage than the school-aged Roma generation. There was no significance difference in the generations of preschool aged and school aged Roma children fully vaccinated against poliomyelitis, diphtheria, tetanus and pertussis. Rubella vaccination was significantly lower in the school aged Roma generation. Only 33% of school aged Roma population received two doses of measles, mumps and rubella vaccine. Vaccination coverage of preschool Roma children in Slovenia against poliomyelitis, diphtheria, tetanus, pertussis and MMR (measles, mumps, rubella) were significantly lower then the national vaccination coverage for preschool aged Slovenia children. Many joint efforts will have to be made to improve the vaccination coverage in Roma communities.     

青海省2006年14岁以下儿童百日咳白喉破伤风抗体水平监测

调查青海省0~14岁健康儿童百日咳、白喉、破伤风抗体水平,抽样评价预防接种质量。在全省六州一地一市各选择1个县,对0~14岁健康儿童进行抗体检测。结果显示,百日咳、白喉、破伤风抗体阳性率分别为93.42%、94.96%和92.93%。不同地区0~14岁健康儿童百日咳、白喉和破伤风抗体阳性率虽有差别,但都达到较高的抗体水平;个别地区抗体水平低,说明青海省儿童计划免疫工作存在薄弱环节。     

Sterile Protection against Plasmodium knowlesi in Rhesus Monkeys from a Malaria Vaccine: Comparison of Heterologous Prime Boost Strategies

Using newer vaccine platforms which have been effective against malaria in rodent models, we tested five immunization regimens against Plasmodium knowlesi in rhesus monkeys. All vaccines included the same four P. knowlesi antigens: the pre-erythrocytic antigens CSP, SSP2, and erythrocytic antigens AMA1, MSP1. We used four vaccine platforms for prime or boost vaccinations: plasmids (DNA), alphavirus replicons (VRP), attenuated adenovirus serotype 5 (Ad), or attenuated poxvirus (Pox). These four platforms combined to produce five different prime/boost vaccine regimens: Pox alone, VRP/Pox, VRP/Ad, Ad/Pox, and DNA/Pox. Five rhesus monkeys were immunized with each regimen, and five Control monkeys received a mock vaccination. The time to complete vaccinations was 420 days. All monkeys were challenged twice with 100 P. knowlesi sporozoites given IV. The first challenge was given 12 days after the last vaccination, and the monkeys receiving the DNA/Pox vaccine were the best protected, with 3/5 monkeys sterilely protected and 1/5 monkeys that self-cured its parasitemia. There was no protection in monkeys that received Pox malaria vaccine alone without previous priming. The second sporozoite challenge was given 4 months after the first. All 4 monkeys that were protected in the first challenge developed malaria in the second challenge. DNA, VRP and Ad5 vaccines all primed monkeys for strong immune responses after the Pox boost. We discuss the high level but short duration of protection in this experiment and the possible benefits of the long interval between prime and boost.     

Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice

Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11–17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life.