Diphtheria toxoid vaccine effectiveness: A case-control study in Russia

Prior to the completion of this and other studies, low effectiveness of diphtheria toxoid-containing vaccine was suspected to be a major contributing factor to the diphtheria epidemic that began in the Russian Federation in 1990. A vaccine effectiveness study was done in Moscow by enrolling physician-diagnosed cases and 10 control subjects per case. Controls were matched to cases by age (+/-3 months) and clinic registration. Vaccination history was abstracted from a standardized form for case-patients and from clinic vaccination records for control subjects. Two hundred seventeen case-patients and 2169 matched controls were included in the study. Most controls (92%) had received three or more doses of a diphtheria toxoid vaccine, compared with 72% of case-patients. The vaccine effectiveness for three or more doses was 97% (95% confidence interval: 94.3-98.4). Low vaccine effectiveness was not a contributing factor to the diphtheria epidemic in the Russian Federation. To control and prevent diphtheria epidemics, it is necessary to achieve and maintain high vaccination coverage with three or more doses of diphtheria toxoid among adults and children.     

Seroimmunity to diphtheria and tetanus among mother-infant pairs; the role of maternal immunity on infant immune response to diphtheria-tetanus vaccination

BACKGROUND: This study was designed to determine the levels of immunity against diphtheria and tetanus in 110 mothers with/without diphtheria-tetanus toxoid (dT) vaccination during pregnancy and their two-month-old infants before diphtheria-tetanus-pertussis (DTP) immunisation, and also to assess the influence of pre-vaccination passive immunity on the infants' immune response to three doses of DTP vaccination. SUBJECTS AND METHODS: Sera from 110 mother-infant pairs before DTP vaccination and from 69 infants after receipt of three doses of DTP vaccine were tested to measure antidiphtheria-antitetanus toxin IgG levels, using a commercial enzyme immunoassay. History of dT toxoid vaccination of mothers at pregnancy was recorded. RESULTS: 20% of mothers did not receive dT vaccine. Among these 22 unvaccinated mothers, one (5%) and six (27%) were serologically susceptible to tetanus and diphtheria respectively. The mean concentrations of antibody titers were lower in unvaccinated than in vaccinated mothers: diphtheria 0.78 (0.30) IU/mL vs 0.31 (0.20), and tetanus 1.95 (1.20) IU/mL vs 0.51 (0.45), vaccinated mother vs unvaccinated. All infants (100%) acquired immunity against both infections after receipt of three doses of DTP vaccine. Pre-vaccination passive immunity did not influence the infants' immune response to vaccination: diphtheria 0.95 (0.40) vs 0.89 (0.25), and tetanus 2.30 (1.0) vs 2.30 (0.70), from passive immune infants before vaccination vs those without, respectively. CONCLUSION: This study showed that diphtheria-tetanus toxoid components of DTP vaccine were highly immunogenic and maternal passive immunity did not affect the infants' immune response to DTP vaccination. Since there is a 23% missed opportunity for dT immunisation, efforts must be made to increase the coverage rate of this highly immunogenic vaccine in order to sustain protection against diphtheria and tetanus in mothers and their infants..     

Epidemic diphtheria in the Kyrgyz Republic, 1994-1998

The Kyrgyz Republic experienced a widespread diphtheria epidemic during 1994-1998. National diphtheria surveillance and vaccination coverage information were used to describe the course of the epidemic. The epidemic began in August 1994, reached a peak in 1995 with 704 cases (incidence rate: 15.4/100,000 population) and 30 deaths, and declined to an incidence rate of 4.0/100,000 during the first 8 months of 1998. Age-specific incidence was highest in 1995 among persons 15-19 and 20-29 years old. Three rounds of mass vaccination with tetanus and diphtheria toxoids for adult use (Td) were conducted; reported coverage was 69% in 1995 and >95% in 1996 and 1997. Reported routine vaccination coverage with three doses of diphtheria toxoid by age 12 months increased from 62% in 1989 to 98% in 1997. Mass vaccination of the adult population with Td and improvements in childhood vaccination coverage played a major role in controlling the epidemic.     

Low seroprevalance of diphtheria,tetanus and pertussis in ambulatory adult patients: the need for lifelong vaccination

BackgroundTetanus, diphtheria, pertussis and measles are vaccine preventable diseases that have been reported to cause morbidity and mortality in adult population in the recent years. We aimed to document the seropositivity rates and vaccination indication for these four vaccine preventable diseases among adult and elderly patients who were seen as outpatients in a university hospital.MethodsBlood samples for tetanus, diphtheria, pertussis and measles antibodies were obtained. Results were evaluated with regards to protection levels and booster vaccine indications according to the cut-off values.ResultsA total of 1367 patients consented for the study and 1303 blood samples were available for analysis at the end of the study. The antibody levels against measles conferred protection in 98% of patients. However, 65% of the patients had no protection for diphtheria, 69% had no protection for tetanus and 90% of the patients had no protection for pertussis. Only 1.3% of the study population had seropositivity against three of the diseases—Tdap booster was indicated in 98.7%. Multivariable logistic regression showed that tetanus protection decreased with increasing age. Having a chronic disease was associated with a lower rate of protective antibodies for pertussis.ConclusionsWe demonstrated very low rates of protection against three of the vaccine preventable diseases of childhood—diphtheria, pertussis and tetanus. Booster vaccinations are required in adult life in accordance with national and international adult vaccination guidelines. The concept of “lifelong vaccination” should be implemented and every encounter with the patient should be regarded as a chance for catch-up.     

Immune response to diphtheria booster vaccine in the Baltic states

A study was done to measure baseline levels of immunity to diphtheria and antibody responses to different doses of diphtheria vaccine in study participants in the three Baltic states. Diphtheria booster vaccines containing either 3 (Estonia and Lithuania), 6 (Latvia), or 12 (Latvia) limit of flocculation units of diphtheria toxoid were administered to 2315 adults. Diphtheria antibody levels were tested before and 1-2 months after vaccination. Before vaccination, 40% of the participants in Estonia, 32% in Lithuania, and 38% in Latvia had antibody levels <0.01 IU/mL, the level for minimum protection. After vaccination, 79% of the participants in Estonia, 83% in Lithuania, and 81% in Latvia had antibody levels >0. 1 IU/mL, the minimum level for full protection. However, in each of the countries, about one-third of the 40- to 49-year-old participants would have benefited from additional doses of vaccine. There was not a significantly different antibody response among persons receiving the three different doses. Age and the level of prevaccination immunity had a modifying effect on the response to vaccination; however, sex did not.     

Investigation of immunity level against diphtheria and reinforcement of immunity by booster vaccination for infection control staff in Okayama prefecture

The prevalence of immunity against diphtheria among Okayama local government staff members involved in diphtheria infection control was measured. Diphtheria booster vaccination was administered to staff members with low antitoxin levels (<0.1 IU/ml) in order to reinforce of immunity. Ninety-one (36.7%) of 248 staff members, 20-69 years of age, had fully protective antitoxin levels (> or =0.1 IU/ml), and the remaining 157 (63.3%) showed levels of <0.1 IU/ml. The rate of full protection was higher in females (44.9%) than in males (22.8%) and was also higher in the diphtheria-pertussis mixed vaccine (born in 1958-1967) and diphtheria-pertussis-tetanus mixed vaccine (born in 1968-) (58.3-61.0%) groups than in diphtheria vaccine (born in 1948-1957) and non-vaccinated (born until 1947) (7.4-18.9%) groups. Though antitoxin levels of 13 (68.4%) out of 19 staff members given booster vaccinations increased to 0.1 IU/ml, 50% of these individuals then showed levels of <0.1 IU/ml after 3 years. Most of the staff members with antitoxin levels of > or =0.1 IU/ml in the non-booster vaccination group maintained their immunity levels for 2-4 years, independent of their history of vaccination. To ensure that staff members of the local government have fully protective antitoxin levels against diphtheria, periodical confirmation of antitoxin levels and booster vaccination should both be systematically carried out.     

Case-control evaluation of an adult diphtheria immunization program in Ukraine

In response to concerns about diphtheria vaccine efficacy, a case-control study was undertaken in Ukraine in 1996 to determine whether those recently immunized were indeed protected from disease, whether multiple doses were more protective, whether contact with children was related to disease, and whether there were detectable differences in protective efficacy between Western and Russian vaccines. In each of the three sites (one rural and two urban), 60 adults with laboratory-confirmed cases of diphtheria were identified from health center records along with 2 adult controls, who were matched to the case by neighborhood. Demographic and vaccination data were gathered from health center records. Using conditional logistic regression to estimate odds ratios, it was determined that cases were more likely to have had no vaccine in the year prior to the index data (odds ratio, 5.0; 95% confidence interval, 2.8-9.0), for a vaccine efficacy of 80%. Two doses gave greater protection, living with children increased disease risk, and no difference was detectable between the Russian and Western vaccines.     

Diphtheria in Latvia, 1986-1996

After nearly two decades without a diphtheria case in Latvia, the disease reappeared in 1986. From 1990 to 1996, case counts were highest among adults 40-49 years of age, school-aged children, and adolescents. Nonetheless, the average annualized incidence of disease was highest among infants and preschoolers. In August 1995, mass vaccination efforts began to provide adults 25-60 years of age with at least one dose of vaccine. By the end of the year, a 77% coverage rate was achieved, resulting in a decrease of reported diphtheria cases by 1996. From February to September 1997, special outreach efforts were focused on hard-to-reach populations; as a result, by June 1997, 55% of adults had received three doses of vaccine. While decreases in the incidence of and morbidity from diphtheria have occurred, additional efforts still need to be concentrated on improving vaccination coverage in adults and children <2 years of age and in reducing mortality from diphtheria.     

Epidemic diphtheria in Belarus, 1992-1997

In 1990, epidemic diphtheria reemerged in Russia and spread to Belarus in 1992, when 66 cases were reported. Diphtheria cases doubled each year in 1993 and 1994 and peaked in 1995, when 322 cases were reported. Intensified routine immunization of young children and mass vaccination of older children and selected groups of adults were conducted in 1995 and were followed by mass vaccination campaigns targeting all adults in 1996. By the end of 1996, full immunization of >95% of children and coverage of>87% of adults with >/=1 dose resulted in a rapid decline in diphtheria cases. In 1998, only 36 cases of diphtheria were reported. More than 70% of the 965 cases and 26 fatalities reported during 1990-1998 occurred among persons >14 years of age. High levels of immunity among the entire population are needed for rapid control of diphtheria epidemics in the vaccine era.     

Immunity against diphtheria and tetanus in the age group 30-70 years

In Denmark, childhood primary vaccination against diphtheria and tetanus has been recommended since 1950. No routine revaccinations or general vaccination of adults have been offered. In most other western countries revaccinations are recommended later in childhood. However, death still occurs from diphtheria and tetanus in countries with such vaccination programs although it is generally accepted that protective immunity can be obtained by vaccination. On this basis the immunity against diphtheria and tetanus was assessed in a random sample of 351 subjects in the age range 30-70 years. Diphtheria antitoxin titres were determined by in vitro neutralization technique using VERO cells. 26% had diphtheria antitoxin titres below protective level (0.01 international antitoxin units/ml serum). The highest number of unprotected against diphtheria was found among 30-39 year old women (68%) and 60-69 year old subjects (36%). Tetanus titres were determined by a combination of ELISA technique and an in vivo neutralization assay. 51% were unprotected against tetanus (less than 0.01 international antitoxin units/ml serum). The highest number of unprotected against tetanus was found among 60-69 year old subjects (68%) and especially among females in this age group (77%). To avoid epidemics of diphtheria in the future the immunity among adults must be raised within the coming years. Thus, revaccination must be recommended and high attendance ensured. One revaccination is sufficient only when complete primary vaccination is documented.     

The impaired immune response to diphtheria vaccinationin elderly chronic hemodialysis patients is related to zinc deficiency

Zinc deficiency causes abnormalities of the immuneresponse. In chronic hemodialysis therapyabnormalities in zinc metabolism as well as animpaired immune response to vaccination have beenreported. Therefore we performed a vaccination studyagainst diphtheria and hypothesized that the responseto diphtheria vaccination is related to serum zincdeficiency in hemodialysis patients. Serum zincconcentrations were assayed in 16 chronic hemodialysispatients (10 male, 6 female; mean age 65 years)without a documented vaccination history againstdiphtheria. Nine of these patients were tripleimmunized against diphtheria while seven received asingle vaccination. The response to diphtheriavaccination was measured by ELISA detecting specificantibodies to diphtheria-toxoid. Seroconversion 6 and12 months after vaccination was defined as thedoubling of antibody titers in patients 0.1IU/ml prior to vaccination or as titers %gt; 0.1 IU/mlin all other patients. Only 6/16 hemodialysispatients responded to immunization against diphtheriaby specific antibody production (> 0.1 IU/ml).Twelve months after the single injection 3/7 patientsseroconverted while six months after the triplevaccination 3/9 patients responded to immunization.This was not age-dependent, whereas in non-responderswe detected significantly decreased serum zinc levels.In contrast, responders showed similar serum zinclevels as age-matched controls. Furthermore, wemeasured a decreased 2-macroglobulinconcentration only in the responders amongst thehemodialysis patients. Protection against diphtheriaand the immune response to diphtheria vaccination inhemodialysis patients is poor. The failure to respondto active diphtheria vaccination is related to asignificantly decreased serum zinc concentration inhemodialysis patients.     

Risk factors for diphtheria: a prospective case-control study in the Republic of Georgia, 1995-1996

The large-scale resurgence of diphtheria in the former Soviet Union offered a unique opportunity to evaluate risk factors for the transmission of respiratory diphtheria; therefore, a prospective case-control study was done in the republic of Georgia. In total, 218 diphtheria cases (hospitalized between October 1995 and March 1996) and 408 matched controls participated. One hundred cases (45%) were /=15 years of age (range: <1 to 75 years). In the multivariate analyses, the following risk factors were found to be significant: lack of vaccination (matched odds ratio [mOR]=19.2), household exposure to diphtheria (mOR=7.4), exposure to skin lesions (mOR=5.8), history of eczema (mOR=3.4), fever with myalgia prior to illness (mOR=2.6), having tonsils (mOR=4.4), sharing a bed (mOR=1.9), sharing cups and glasses (mOR=2.7), and taking a bath less than once a week (mOR=2.6). These findings emphasize primary prevention through immunizations, secondary prevention following exposure to diphtheria (and to suspicious skin lesions), and adherence to strict standards of personal hygiene.     

The immunogenicity and safety of a new combined diphtheria, tetanus and poliomyelitis booster vaccine (Td-eIPV)

Summary In view of the continuing risk of contracting tetanus, diphtheria and poliomyelitis, and the well-documented decline in immunity with time, the need for booster vaccinations is substantial. The immunogenicity and safety of a new combined booster vaccine against tetanus, diphtheria and poliomyelitis (REVAXIS^™) developed by Pasteur Mérieux Connaught (Lyon, France) were evaluated in four clinical studies. This vaccine (Td-eIPV) combines an adsorbed tetanus toxoid and low-dose diphtheria toxoid vaccine (Td) with an enhanced, inactivated polio vaccine against poliovirus types 1, 2 and 3 (eIPV). In 256 healthy young adults, a single dose of Td-eIPV was shown to be immunogenic, eliciting antibody levels considered protective against disease for each vaccine component in ≥99.6% of the subjects. In 112 healthy older subjects (>40 years of age), two doses of Td-eIPV elicited seroprotective levels of antibodies in 94% of the subjects for diphtheria, and in all subjects for tetanus and poliovirus types 1, 2 and 3. Safety data from all 368 subjects, as well as 31 phase I volunteers and 1,742 subjects included in a safety study, reveal that the vaccine is safe. Most reactions were predictable, temporary and mild. There was no evidence that the vaccine was associated with any clinically serious event or modification of clinical laboratory parameters. The data reviewed here show that Td-eIPV is immunogenic and safe when administered as a booster vaccination in healthy adults of all ages.     

Immune status and booster effects of low doses of diphtheria toxoid in Swedish medical personnel

During a diphtheria outbreak among Swedish alcoholics in 1984-1985, only 60% of 328 medical staff at risk for exposure had diphtheria antitoxin titers greater than or equal to 0.01 IU/ml, which is usually considered to give relative protection. 21% had levels between 0.01-0.09 IU/ml and the remaining 39% had titers greater than or equal to 0.1 IU/ml. Booster doses of 0.5 Lf-12.5 Lf of diphtheria toxoid were given to 450 vaccinees. Of 72 individuals with low pre-immunization titers, who were immunized with less than or equal to 2.5 Lf diphtheria toxoid, 40% failed to reach greater than or equal to 0.1 IU/ml when analyzed 4 weeks after vaccination. Local tenderness and swelling greater than 5 cm at the site of injection or general discomfort was found in 11% of those immunized with low dose diphtheria toxoid (less than or equal to 2.5 Lf). When the dose 0.5 Lf of diphtheria toxoid was combined with tetanus toxoid (3.75 Lf) the frequency of adverse reactions increased to 34% (p less than 0.001). The study shows that vaccination status in medical personnel must also be continuously examined in countries where diphtheria is rare and that low booster doses of diphtheria toxoid may not achieve an adequate immune response.     

Evidence of efficacy of the Lederle/Takeda acellular pertussis component diphtheria and tetanus toxoids and pertussis vaccine but not the Lederle whole-cell component diphtheria and tetanus toxoids and pertussis vaccine against Bordetella parapertussis infection.

A subanalysis of a recent cohort efficacy trial of a pertussis vaccine was performed to determine its efficacy against cough illnesses due to Bordetella parapertussis infections. Infants received four doses of either the Lederle/Takeda acellular pertussis component diphtheria and tetanus toxoids and pertussis (DTaP) vaccine or the Lederle whole-cell component diphtheria and tetanus toxoids and pertussis (DTP) vaccine at 3, 4.5, 6, and 15-18 months of age; controls received three doses of diphtheria and tetanus toxoids (DT) vaccine only. All subjects were prospectively followed for cough illnesses of > or = 7 days' duration; cases of B. parapertussis infection were confirmed by positive culture, household contact, or serology. Seventy-six cough illnesses due to B. parapertussis were identified; 24 occurred in 929 DTaP recipients, 37 in 937 DTP recipients, and 15 in 321 DT recipients, resulting in an efficacy of 50% for DTaP vaccine (95% CI [confidence interval], 5% to 74%) and 21% for DTP vaccine (95% CI, -45% to 56%). The data in the present analysis suggest that the Lederle/Takeda DTaP vaccine but not the Lederle whole-cell component DTP vaccine has efficacy against B. parapertussis infection.     

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

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

Determination of tetanus and diphtheria antitoxin content in dried samples of capillary blood: a convenient method applied to infants

To assess the effect of vaccination of infants against tetanus and diphtheria capillary blood was drawn from 51 randomly selected healthy infants 2 years of age. The blood was applied directly to filter paper. In the laboratory the blood dots were eluted in phosphate buffered saline for 2 h at room temperature yielding 100% recovery of antitoxin activity. Serum volume in the blood dots was determined by calculation of dot area or by measuring albumin content in the eluted samples by means of rocket immunoelectrophoresis. These approaches were found to be equally applicable. Concentration of antitoxin to tetanus and diphtheria was assessed with ELISA and in vitro toxin neutralization assay respectively. Mean diphtheria antitoxin concentration was 0.53 IU/ml, and mean tetanus antitoxin concentration 4.1 IU/ml. Low initial immune response to diphtheria vaccination may be responsible for the risk among school children to have antitoxin concentration below protective level (reported elsewhere). In environments where diphtheria is disappearing a lowered vaccination response may be expected.     

Low seroprotection against diphtheria and tetanus in Lao adolescents

Objectives

There is currently no booster diphtheria or tetanus vaccine for Lao children before adolescence, despite international recommendations. We investigated seroprotection against diphtheria and tetanus among Lao adolescents.

Methods

Seven hundred seventy-nine serum samples were tested for anti-diphtheria and anti-tetanus antibodies.

Results

Overall, 25.8% of the adolescents had antibody titers corresponding to protection against diphtheria and 30.9% to sufficient immunity against tetanus. Female participants >16 years were more likely to be protected against diphtheria (p < 0.001) and tetanus (p < 0.029).

Conclusion

Low protection against diphtheria and tetanus, possibly due to low vaccination coverage or antibody waning, suggests booster doses are warranted before adolescence.     

Tetanus and diphtheria immunity in refugees in Europe in 2015

Background

Current political crises in the Middle East and economic discrepancies led millions of people to leave their home countries and to flee to Western Europe. This development raises unexpected challenges for receiving health care systems. Although pan-European initiatives strive for updated and optimized vaccination strategies, little data on immunity against vaccine-preventable diseases in the current refugee population exist.

Methods

We quantified serum IgG against tetanus and diphtheria (TD) in n = 678 refugees currently seeking shelter in six German refugee centers.

Findings

Reflecting current migration statistics in Europe, the median age within the cohort was 26 years, with only 23.9 % of female subjects. Insufficient IgG levels without long-term protection against tetanus were found in 56.3 % of all refugees. 76.1 % of refugees had no long-term protection against diphtheria. 47.7 % of subjects needed immediate vaccination against tetanus, and 47.7 % against diphtheria. For both diseases, an age-dependent decline in protective immunity occurred.

Interpretation

We observed a considerably low rate of tetanus-protected refugees, and the frequency of diphtheria-immune refugees was far from sufficient to provide herd immunity. These findings strongly support recent intentions to implement and enforce stringent guidelines for refugee vaccination in the current crisis.

     

Effect of month of vaccine administration on antibody responses in The Gambia and Pakistan

OBJECTIVE: To explore the relationship between calendar month of administration and antibody (Ab) response to vaccination in subjects from The Gambia and Pakistan, two countries with distinct patterns of seasonality. METHODS: Three cohorts were investigated: Responses to rabies and pneumococcal vaccine were assessed in 472 children (mean age 8 years, males 53%) from rural Gambia. Responses to tetanus, diphtheria and hepatitis B (HBsAg) were investigated in 138 infants also from The Gambia (birth to 52 weeks of age, males 54%). Responses to rabies and Vi typhoid vaccines were assessed in 257 adults from Lahore, Pakistan (mean age 29.4 years, males 57%). RESULTS: In Gambian children, significant associations were observed between month of vaccination and Ab response for the pneumococcal and rabies vaccines. As no consistent pattern by month was observed between the responses, it is assumed that different immunomodulatory stimuli or mechanisms were involved. In Pakistani adults, a significant pattern by month of vaccination was observed with both rabies and typhoid vaccine. No monthly influences were observed in the infant study to the tetanus, diphtheria or the HbsAg vaccines. CONCLUSIONS: Antibody responses to certain specific vaccines are influenced by month of administration. Further research is required to elucidate the precise mechanisms explaining these observations, but a co-stimulatory effect of seasonally variable environmental antigens is a likely cause. Future studies of Ab response to vaccination in countries with a seasonally dependent environment should consider month of vaccination when interpreting study findings.